CA3221608A1 - Fused heteroaryl compounds useful as anticancer agents - Google Patents

Fused heteroaryl compounds useful as anticancer agents Download PDF

Info

Publication number
CA3221608A1
CA3221608A1 CA3221608A CA3221608A CA3221608A1 CA 3221608 A1 CA3221608 A1 CA 3221608A1 CA 3221608 A CA3221608 A CA 3221608A CA 3221608 A CA3221608 A CA 3221608A CA 3221608 A1 CA3221608 A1 CA 3221608A1
Authority
CA
Canada
Prior art keywords
optionally substituted
compound
pharmaceutically acceptable
solvate
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CA3221608A
Other languages
French (fr)
Inventor
Liansheng Li
Xiuwen Zhu
Pingda Ren
Yi Liu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kumquat Biosciences Inc
Original Assignee
Kumquat Biosciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kumquat Biosciences Inc filed Critical Kumquat Biosciences Inc
Publication of CA3221608A1 publication Critical patent/CA3221608A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts thereof, and methods of using the same. The compounds and methods have a range of utilities as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic proteins.

Description

FUSED HETEROARYL COMPOUNDS USEFUL AS ANTICANCER AGENTS
CROSS-REFERENCE
100011 This application claims priority to U.S. Provisional Application Nos.
63/210,474 filed on June 14, 2021, 63/291,320 filed on December 17, 2021, and 63/313,132 filed on February 23, 2022, each of which is incorporated by reference in its entirety.
BACKGROUND
100021 Cancer (e.g., tumor, neoplasm, metastases) is the second leading cause of death worldwide estimated to be responsible for about 10 million deaths each year. Many types of cancers are marked with mutations in one or more proteins involved in various signaling pathways leading to unregulated growth of cancerous cells. In some cases, about 25 to 30 percent (%) of tumors are known to harbor Rat sarcoma (Ras) mutations. In particular, mutations in the Kirsten Ras oncogene (K-Ras) gene are one of the most frequent Ras mutations detected in human cancers including lung adenocarcinomas (LUADs) and pancreatic ductal adenocarcinoma (PDAC).
100031 Although Kras is known to be an oncogenic driver, there is no clinically approved targeted therapy for Ras mutant cancers thus far. Ras proteins have long been considered to be "undruggable," due to, in part, high affinity to their substrate Guanosine-5'-triphosphate (GTP) and/or their smooth surfaces without any obvious targeting region.
Recently, a specific G12C Ras gene mutation has been identified as a potential druggable target. However, such therapeutic approach is still limiting, as the Gl2C mutation in Ras has a low prevalence rate (e.g., about 3% in PDAC) as compared to other known Ras mutations.
SUMMARY
100041 In view of the foregoing, there remains a considerable need for a new design of therapeutics and diagnostics that can specifically target Ras mutants and/or associated proteins of Ras to reduce Ras pathway signaling. Such compositions and methods can be particularly useful for treating a variety of the diseases including, but not limited to, cancers and neoplasia conditions. The present disclosure addresses these needs, and provides additional advantages applicable for diagnosis, prognosis, and treatment for a wide diversity of diseases.
100051 In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

,µ
X
R2 Formula (I);
wherein W is C(0), S(0), or S(0)2;
V is C(R17) and J is C(R"), or V is C(R17) and J is N, or J is C(R") and V is C(R"), or J is C(R") and V is N;
R" is -L7-117;
s_ I," is a bond, -0-, -N(R")-, -C(0)-, -N(RH)C(0)-, -C(0)N(R14 ), - S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(Ri1)S(0)-, -N(EC)S(0)2-, Ci-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein Ci-C6a1kyl, C2-C6a1kenyl, and C2-C6alkynyl, are optionally substituted with one, two, or three R'a;

R7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroalyl, wherein the 3-12 membered nitrogen containing heterocycloalky71 or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more TV;
wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3.12cycloa1kyl, Ci.iiheterocycloalkyl, C6_12ary1, or Ci.iiheteroaryl, wherein the C342cycloalkyl, Ci_iiheterocycloalkyl, C6.12ary1, or Ci.iiheteroaryl are optionally substituted with one, two, or three R20a;
each R1 is independently selected from hydrogen, Ci_6alkyl, C2.6a1kenyl, C2.6alkynyl, Ci_6ha1oa1ky1, C3_12cycloalkyl, -CH2-C3_12cycloallcyl, Ci_iiheterocycloalkyl, -CH2-Ci_iiheterocycloalkyl, C6_122nyl, -CH2-C6_12aryl, -CH2-C1-itheteroaryl, and Ci_iiheteroatyl, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C1_6haloalkyl, C342cyc10a1ky1, -CH2-C3_12cycloalkyl, Ci_iiheterocycloalkyl, -CH2-C,,iheterocycloalkyl, C6_12aryl, -CH2-C6_12aryl, -CH2-C1-itheteroaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three R2 a;
each R1 is independently selected from hydrogen, halogen, oxo, -CN, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3-ocycloalkyl, C2.6heterocycloalkyl, C.6_10atyl, Ci_91ictcroary1, -01212, -SR12, -N(R12)(R13), -C(0)0R12, -OC(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), (e.g. wherein R4 is optionally an electrophilic moiety capable of forming a covalent bond with a cy-steine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein), wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6cycloalkyl.
C2_9heterocycloalkyl, C6_10aryl, and Ci.9heteroaryl are optionally substituted with one, two, or three R2 a;
R6 is -L2-R5;
each L2 is independently selected from a bond, CI-Coalkyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R11)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(R'4)C(0)0-, and -N(R14)C(0)N(R14)-;
each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from halogen, -CN, Ci_6a11ky1, C2_6a1kenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6_ioaryl, Cl.,heteroaryl, -0R12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R11)C(0)0R15, -N(R11)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R11)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_ 6cycloalkyl, C2.6heterocycloalkvl, C6_ioaryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R2.0c 1117 is -1_,1-11";
1,1 is selected from a bond, Cl-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -000N(R14)-, -N(R14)C(0)0-, N(R1c), C(0)N(R1c), S(0)2N(R1c), S(0)N(R1c), C(R11)(R1)0, C(Rif)(R1)N(R1c), and C(10(R1g);
2 R1e, R1f, and R_1g are independently selected from hydrogen, halogen, -CN, C,6a1ky1, Ci_6ha1oa1ky1, C2_6alkeny1, C2-6alkynyl, C3_6cycloalky1, C2_9heterocycloalkO, C6_10aryl, Ci_9heteroary1, -0R12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -OC(0)R15, -C(0)N(R12)(R13) . _ C(0)C(0)N(R12)(R13), -N(R11)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, , S(=0)(=NH)N(R1.2)(R13µ) CH2C(0)N(R12)(R13), -CH2N(RH)C(0)R", -CH2S(0)2R15, and -CH2S(0)2N(R1-2)(R1-3), wherein Ci-oalkyl, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6-ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20; or Rif and R1g are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R2';
R1` is selected from hydrogen, Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2_9heterocycloa1kyl, C640aryl, and C1.9heteroaryl, wherein Ci_6a1ky1, C2_6a1kenyl, C2_6alkynyl, C3_6cycloa1kyl, C2.9heterocycloalkyl, C6_ioaryl, and C1.9heteroaryl are optionally substituted with one, two, or three R201 R19 is selected from a C3_12cycloalkyl (e.g., monocyclic, bicyclic, or polycyclic), C2.11heterocycloalk¶ (e.g., monocyclic, bicyclic, or polycyclic), C6_12aryl (e.g., monocyclic, bicyclic, or polycyclic), and C2_12heteroaryl (e.g., monocyclic, bicyclic, or polycyclic), wherein the C342cycloallcyl, C2_illieterocycloalkyl, C6_12aryl, and C2_ 12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11;
each R11 is independently selected from halogen, -CN, Cl_6a1ky1, Cl_6haloa1kyl, C2_6a1kenyl, C2_6alkynyl, ocycloalkyl, C2.9heterocycloalkyl, C6_ioaryl, Ci_9heteroaryl, -OR', -SRll, -N(R12)(R13), -C(0)0R12, -0C(0)N(R')(103), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R")S(0)2R15, -C(0)R15, -S(0)R12, -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R')(R'), -N(R')C(0)R15, -S(0)2105, -S(0)2N(R12)(RH)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R11)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C1_6a1ky1, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6-ioaryl, and Ci_9heteromy1 are optionally substituted with one, two, or three R201;
1116 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6a1kenyl, C2.6a1kyny1, C3_6cycloalkyl, C2-9heterocycloalkyl, C64oaryl, Ci_9heteroaryl, -OR", -SR", -N(R12)(R"), -C(0)0R", -0C(0)N(R")(R"), -N(R14)C(0)N(R12)(R13), _N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R", -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6alkyl, C2_6a1keny1, C2_6a1kyny1, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_ ioaryl, and C1_9heteroary1 are optionally substituted with one, two, or three R20g;
112 is -C(0)0R", -0C(0)N(R12)(R"), -N(R")C(0)N(R12)(R"), -N(RN)C(0)0105, -N(R")S(0)2R15. -C(0)105, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(Ri2)(R).3), _S(0)2N(R12)(R13)-S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R13, -CH2S(0)2R15, -CH2S(0)2N(R12)(R13), -(CI-C6alkyl)-R'2', -(C2.6alkeny1)-R12b, -(C2_6alkyny1)-R12b, -0-R12a, -N(R1)R'2", _s_Ri.2b, -(C3_ locycloalkyl)-Rub, -(C2.9heterocycloall1)-R12b, -(C6_10ary1)-R12b, or -(C1.9heter0ary1)-R1211, wherein said Cl_ 6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3_10cycloalkyl, C2_9heterocy-cloalky1, C6.ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three Rmd;
R12a is selected from C1.6alkyl, C2_6a1kenyl, C2.6alkynyl, C340cycloalkyl, -CH2-C3_10cycloalkyl, C2_,heterocycloalkyl, -CH2-C2_9heterocycloa1kyl, C6_i2aryl, -CH2-C6_10aryl, -CH2-Ci_9heteroaryl, and Ci_9heteroary1, wherein Ci_6a1ky1, C2_6a1kenyl, C2_6a1kynyl, C34ocycloalkyl, -CH2-C3_10cycloalkyl, C2_9heterocycloa1kql, -CH2-C2_9heterocycloalk¶,
3 C6_10ary1, -CH2-C6_ioaryl, -CH2-C1_9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20c1;
RI' is selected from hydrogen, Cl_nalkyl, C2_6a1kenyl, C2_6a1kynyl, C3_10cycloa1kyl, -CH2-C3.10cycloalkyl, C2 9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6_ioary1, -CH2-C6_icaryl, -CH2-Ci_9heteroaryl, and Ci_9heteroaryl, wherein Ci_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_10cycloalkyl, -CH2-C3_10cycloalkyl, C2_9heterocycloalkyl, -CH2-C2.9heterocycloalky1, C6_ioaryl, -CH2-C6_10alyl, -CH2-Ci_9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20';
Xis C(R3) or N;
113 is selected from hydrogen, halogen, -CN, C1_6alkyl, C2_6alkenyl, C26alkyny1, C3_6cycloalkyl, C2_9he1erocycloalkyl, C6_10aryl, Ci_9heteroaryl, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6_10aryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R2ob;
each R12 is independently selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6alkyny1, C3_6cycloalkyl, -CH2-C3_ 6cyc1oa11y1, C2.9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6.10aryl, -CH2-C6_10aryl, -CH2-C1_9heteroaryl, and Ci.9heteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3.6cycloalkyl, C2_ 9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, Co_loaryl, -CH2-C6_ioaryl, -CH2-C1_9heteroaryl, and Ci_9hcteroaly1 are optionally substituted with one, two, or three R2";
each R13 is independently selected from hydrogen, C1_6alkyl, and Ci_6haloa1kyl; or 1112 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R2 e;
each R14 is independently selected from hydrogen, Ci_6alkyl, and Ci_6haloa1kyl;
each R15 is independently selected Ci_6a1kyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_10aryl, and Ci.9heteroaryl, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloallcyl, C2_9heterocycloallcyl, C6_10my1, and Ci_,heteroaryl are optionally substituted with one, two, or three Rm.;
each R20a, R2ob, R20c, R2od, R20e, Rag-, R20g, and R2 1 are each independently selected from halogen, oxo, -CN, Ci_ 6a1ky1, C2_6alkenyl, C2_6allcynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6_10aryl, -CH2-C6_10aryl, -CH2-C1_9heteroaryl.
C1_9heteroatyl, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23). -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23). -OCH2C(0)0R22, and -0C(0)R25, wherein Ci_6alkyl, C2_6a1kenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, 9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10aryl, -CH2-C6_ioaryl, -CH2-Ci_9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci.
6a1ky1, Ci_6haloalkyl, Ci_6alkoxy, Ci_6ha1oalkoxy, -N(R22)(R22), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R21), -0C(0)N(R22)(R21), -N(R24)C(0)N(R22)(R21), -N(R22)C(0)0R25, -N(R24)C(0)R23, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R21 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2_ 9heterocycloalkyl, C6_10aryl, and Ci_9heteroaryl;
4
5 each R22 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2_6a1kenyl, C2_6alkynyl, C3_6cycloalkyl, C2_ 9heterocycloalkO, C6.10ary1, and Ci_9heteroaryl;
each R23 is independently selected from H and C1_6alkyl:
each R' is independently selected from H and Ci_6a1k0;
each R25 is independently selected from C1_6a1ky1, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloalkyl, C2_9heterocycloalky1, C6_ ioaryl, and Ci_9heteroaryl; and ¨ indicates a single or double bond such that all valences are satisfied.
[0006] In embodiments, X is C(R3). In embodiments, X is N. In embodiments, J
is C(R16) and V is C(R17). In embodiments, W is C(0).
[0007] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure:
O R1'3 0 R1 R8 R8. I I
\ N
'-'---L.-.1-:'''''-- N 'N" .-'.--1 N
I
R17''''' N R2 R1 R2 R16 Formula (IA1), R16 Formula (IA2), ,, R8 \ N\\s' N

...---\N ..L'''N
R17''''' N -----.--.' R2 R16 Formula (IA3), R17 N N R Formula (IA4), R8 1 I R8 s//
\ N
'''- N \ N ...'-----1 N
I
-'=-=:=,-,,, ___.-., .,-;:"., 2 ==":::::õ,\ ...../ ',..,.. ...-;%\ 2 R17 N N R Formula (IA5), R17 N N R Formula (IA6), R8 R3 R8s,õ ...õ,_ s ,..,..,........)õ...

N ....õ
N -,,,, R 17 NR2 R17----N "-----. R2 Formula (IA?), R16 Formula (IA8), R8 \'s'cR3 0 Rio NN,,-N

R16 Formula (IA9), R17 N N R2 Formula (IA10).

\ss'!,,.,>.,..,,.õ, R3 ,, õ...-S .,,,.,,..-1-,..,,z, R3 \N..--N

R , ' '7 N N ¨ Formula (IA1 1), or R17 N N R Formula (IA12).
[0008] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure:

I I
R3 R8 s NN -----'-''''-i N NN -.'`----1 N
I I

R
R17 Formula (IIA1), R17 Formula (IIA2), o o R10 0 Ri 0 \N
I I I
---,,......z... .....):::-..õ.
R16 N N '-'-' R2 N R2 R17 Formula (IIA3), R17 Formula (IIA4), R, I I 0 0 R1 \N./SN.N

N-..õ,-- r\r-j-...,, R2 N -,:z__--,, N,.....).5.-..,, R2 R17 Formula (11A5), R17 Formula (11A6), I I
R8 ._s s.N ,....1..",,_ R3 R8,NN õ,,.,.,,,, R3 R16....-- N R2 R16 ....---.'...-y---. N R2 R17 Formula (IA?), R17 Formula (IIA8), 0,,x zp R1 0 R1 R8 µ'S.r....s.,...,}.....õ, R3 R8 \N ,,- -, NN R3 I I
N R2 N -...õ..,<õ....... .....)-,----...õ, R17 Formula (IIA9), R17 Formula (IIA10), O R1 0,, ,,10 R1 I I R8 \'s'/ R8 N

..õ,s,õ......___õõ. 3 \N/ -=õ_,,-.õ, -Nõ, N -...._--- N R2 N

R17 Formula (IIA1 1), or R17 Formula (IIA12).
[0009] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure:

\ N -)N-''N

R16 Formula (IA1).
[0010] In embodiments, L7 is a bond.
[0011] In embodiments, 1_,7 is -NH-.
[0012] In embodiments, fe is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R', optionally substituted with one or more 10, and optionally substituted with one or more R6; and wherein two substituents selected from R1, 10, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3_12cyc1oalkyl, C1-iiheterocycloalkyl, C6_12a1yl, or Ci_iiheteroaryl, wherein the C3_12cyc1oalkyl, Ci.iiheterocycloalkyl, C6.12aryl, or Ci.
iiheteroaryl are optionally substituted with one, two, or three R20a.
X2 _.......õ.õ..X2,........., X2 -....'"=-=.õ ------I___-(R4).... r -1 X i Xi P 1 i e......., >--(R4)p ,..., , ,....;;;,1 L., ,-.., (R4) p ..'.,..., ==>0
[0013] In embodiments, R7 is -I- , -I- -I-, , X2 )( (R4) (R4)p ........./ -****,,...., A ...\ p ( ..).....-""---- < ''..*) 1 1 _________________________________________________ R4) p : : __ ( R4) p _L. 1 ... ...
or -; p is an integer from 0 to 12; X1- is selected from CH2, C(R4)(R6), C=N-0R4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), 0, S, S(0), S(=0)(=NR4), S(0)2N(R4), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), OC(0)N(R4), N(R4)C(0)N(R4), S(0)2, CH2C(R4)(R6), CH2C(R*)(R6)CH2, C(R4)(R6)C(R4)(R.6)C(R4)(R6), C(R4)(R6)C=N-0R4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R6)0, C(R4)(R6)0C(R4)(R6), C(R4)(R6)S, C(R4)(R6)SC(R4)(R6), C(R4)(R6)S(0), C(R4)(R6)S(0)C(R4)(R6), C(R4)(R6)S(0)2C(R4)(R6), C(R4)(R6)S(=0)(=NR4), C(R4)(R6)S(0)2N(R4), C(R4)(R6)N(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R4)(R6)S(0)N(R4), C(R4)(R6)0C(0)N(R4), C(R4)(R6)N(R4)C(0)N(R4), C(R1)(R6)S(0)2, C=NN(R4)(R6)C(R4)(R6), C(0)N(R4)C(R4)(R6), S(0)2N(R4)C(R4)(R6), S(0)N(R4)C(R4)(R6), OC(0)N(R4)C(R4)(R6), C(R4)(R4), C=N-0R4, C=NN(R4)(R4), CH2C(R4)(R4), CH2C(R1)(R4)CH2, C(R4)(R4)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C=N-0R4, CH2C=NN(R4)(R4), C(R4)(1V)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0.
C(R4)(R4)0C(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(10), C(R4)(R4)S(0).
C(R4)(R4)S(0)C(10)(10), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(W)S(-0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R1)(R1), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and OC(0)N(R4)C(R4)(R4); X2 is selected from N, C, C(R6), C(R4), CH, N(R1), N(R4), N(R6), 0, S. 5(0), C(H)(R6), C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X' is selected from N, C, C(R6), and C(R4).
H H H H
N,... N,.... N.....õ ,..N.,,, C. -(R4)p Cy j_____(R4)p _____________________________________ .....,"1____(R4)p Il N
1 ri
[0014] In embodiments, R7 is ''''..in' -H H H H H
e. N N
\101,---(R4)P \f0V1-(R4)p il ri N
. N

..AA/V , JUMP I
15 HN\aõ. NEI H
R4 ) HN----p H H
______________________ NH \, ,, N ,_ (Rlp _____.(R4)p C ....,--c-/¨(R4)p r-N-1 .\:s.c"____(R4)p N N N
H
N
4.. !..)----(R4)p e..:; ("P

N N
,or , ; and p is an integer from 0 to 12.
[0015] In embodiments, R16 is independently selected from hydrogen and halogen. In embodiments, R16 is independently selected from hydrogen and fluor .
[0016] In embodiments, R8 is selected from Ci_6alky1, C3_10cyc1oalkyT1, and C2.9heterocyc1oalkyk wherein Ci_6a1ky1, C3_iocyc1oallcyl, and C2_9heterocyc1oalkyl are optionally substituted with one, two, or three R2" independently selected from halogen, Ci_6alky1, C2.6alkeny1, C2_6alkyny1, C3_iocycloalkyl, and C2.9heterocycloalky1. In embodiments, le is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R2' independently selected from fluoro.
methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments, IV is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
[0017] In embodiments, R3 is hydrogen or CN.
[0018] In embodiments, L1 is a bond. In embodiments, L1 is selected from a Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C(0)-, -NHC(0)-, -C(0)NH-, CH20, CH2NH, and CH2.
[0019] In embodiments, R19 is a monocyclic ring. In embodiments, R19 is a bicyclic ring system. In embodiments, R19 is a polycyclic ring system.
¨ ¨ ¨ ¨
x12 x4%.***- x10 x4X11 I II I Rill I 1 __ 1 1 1 r--.1.µ
x5,,... x9 x9 6 9 .:::,_... x10 x9,... 6 Q 1 X5- N
X X ---- '' '' ' Q
[0020] In embodiments, R19 is: X6' , X , X6 , .......... ............

¨Rih Rih 0 N Q3 r I I \l I I _._, I \ Rih "". x11 Q" --)01 Q' --)(8 Q -')(8 Q4 ,N,_-_-Q3 N 1h oy 1h x16 X13_ __________________________ h x14 x15 or C1,5 I h =
Qi, Q3, and Q5 are independently N or Q4 and Q6 are independently 0, S, C(R1a)(R1b), or N(R);
X4, X5, X6, X6, X10, X", X", and X16 are independently selected from C(R1a) or N;
X' and X8 are independently selected from C(R1a), C(Rla)(R1b), N, or N(R16);
X13 is selected from a bond, C(0), C(R1a)(Rth), c(o)c(R1a)(R1b), c(R1a)(R1b)c(Rla)(R1b), c(R1a)(R11))N(R1c), and N(R1c):
X14 and X' are independently selected from a bond, C(0), C(111')(R1"), and N(R");
each Rla, Rib, Rid, Rif, Rig, and Rth are each independently selected from hydrogen, halogen, -CN, C2_6alkyl, Ci-6haloalkyl, C2_6allcenyl, C2_6alkynyl, C340cycloalkyl, C2_9heterocycloalkyl, C6.ioa1yl, Ci_9heteroaryl, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(RH)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R"), -C(0)C(0)N(R12)(R13), -N(RH)C(0)R15, -S(0)2R15, -S(0)2N(R12)(RH)-, S(=0)(=NH)N(R12)(Rn), -CH2C(0)N(R12)(R'), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6alkyl, C2_6alkenyl, C2_6allcynyl, C34cicycloalkyl, C2_ 9heterocycloalkyl, C6_20aryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R201; or Rla and Rib bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3_10eyeloa1kyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3_llicycloa1kyl ring are optionally substituted with one, two, or three R261; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_10aryl ring, a 5-12 membered heteroaryl ring, or a C3_10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C64(oryl ring, 5-12 membered heteroaryl ring, or C3_1(icycloalkyl ring are optionally substituted with one, two, or three R2 1; or Rib and one of Rla, Rib, Ric, and R1" bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_1(aryl ring, a 5-12 membered heteroaryl ring, or a C3_10cycloallql ring, wherein the 3-10 membered heterocycloalkyl ring, a C6_ioaryl ring, a 5-12 membered heteroaly1 ring, and Ciicycloalkyl ring are optionally substituted with one, two, or three R2"': or R"
and Rig are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R"i; and each Ric is independently selected from hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6a1kyny1, C3_10cyc1oalkyl, C2_ ,heterocycloalkyl, C6.10aryl, C1_9heteroary1, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, C2_ 9heterocycloalkyl, C6.20aryl, and Ci_9heteromyl are optionally substituted with one, two, or three R201.

CN
CN
0 N,--NH2 01S/)¨NH2 \ NH2 \JII_ S N S
N
H
[0021] In embodiments, R19 is: F , F , F , F
ON ON
ON S
\ \ NH2 N
S
H H 0 ,--NH2 01 ¨NH2 N CN
, F F H F S
N
, , N
ON
S 0 N,¨
NH2 0 S>¨N H2 / NH2 s N S
\ NH2 F
S CN F , F
F
S F N F S N
F --,NH2 >¨NH2 IP

F F F , F
, , , CN

411 (:)--NH2 \ NH2 0 ,--N H2 0 --NH2 F , F , F N
N N

,¨ NH 0 (:: --N H2 F
,¨NH2 /

\ N
O ON F , F
F
, ---NH2 --'NH2 >¨NH2 s S

F , F
F , H2N CN H2N CN H2N CN H2N CN H2:
DACN
¨
_ S S S S
./ 1 N ... I
F , F
, .

S ..õ, A, S -----r).s. S ----µ,., S
N
F
F , i.,, :r\CN H2N ON H2N CN
ON H2Ns S_,..-- S _....- S ...... 2.....
x....\ s ......... ::r_,1/4 F F
F F
, , ¨

s ,..:., CN H2N H2N
S ON
S.......- % S
.....,...-- ...,,._ N-1, H2N ON H2N CN HO 'V. \.- HO
S SX ./..,- ../..
F
F , , ' HO \:" 4.6.: H2N
)7----N
S
)--=---N X---N HO
V.
CI CI 0 0F F s gill 'V 'V 0 'V
, F, F
, H2N H2N N,.., .-ti: H2N N,,, I L) ..-F I
-., , /N_ N-NH N-N/ N-N/
._ /
F HN' F , 0 HN \ _" 0 cV 0 '''i. 0 Olin F , , , H
.õN 1 N,..... z:
H1\1 H

HIV
0 '2V: 101 '''C

CI
CI , H2N N,._ µa22 H
y H2N N...,,..x.
H2N N,., .722 -- CF3 -1.:5õ,,, 1.), C.,.
CF3 .1..,.,j CF3 1;.C, ' HO cziz-. HO 0 '2,.; HO
4(z.

NO;

OCF3 , Ci Ci Ci CF3 , or F
NH2.
A
N
[0022] In embodiments, R2 is selected from I
, , F
AO
,a Ao N A.06-)\I N isss'0 F
OMe F
c'srs'.0' N
N HC 2F '31Z0---ej H \

-,,/.0-1C

cissNO'L'= 0 ' J 0 0--N/N) . I ., \ N crss,0 ,,,,No_ r N--------c:ss0\---3 F
F
a " 0".--''0 me Ao',' 'T-D.....ocF2H Ao' D<FF 0 "'=
/N
cics-01,.,...... ce-0--",.
10--NF . IF ON r'sss'ON--, "------/ , =

gr- v''',. s:5-r&- "'===
0 D 0 D.....0Me 5 c34:r0 AO "" ' c"" = õ F c:r<OID .õ.2-r-0-1) = = " \

, = , F.,y,_ F
r3.(0")/'=-r-- cl-r0"I'''.r---Ki... j AO N'Th----"------.'' I
KI-...j LO r, /-0-------% Ao-----1\1-----N/
i..--r.N1' S'NO 0'' OH Xo."R AO c.(10 -- N
ii---c) SI
C:rr5s:CY-'''fi D.....CN i:ssT,N,-,.....N,N
F
..= N ----- õAs r'sl-s-n / ,J., 0 ', -40 -1'.1---1 40-1==µ-----3'- F
,,I,..0N

N C F3 p ' N
AO --.=--j rls.0-) "Iss'eCij\i''' iss-s-Cr-C c-5-(0 , R.4) ,õ ---c-0 ,.!õ
.-------"N ---------S'-- rr ' 0 =Y' . ' 1.-."0< F
, `1(0)' Y
?is-0 '",No riss-X0_ ,140,-,.. /- --,,,.õ--Nril N b ,,,...õ
õ 7 , ,N , , , , , F
5-54.0V r14.076¨S
r"' HN -2C NO ' N C N ---I
L------/ , s}5:6Ls--"--/c- 0 /?C NJ ;"-o^2C--NO<FF rFf-o^2C-NO_.F
, O.,,F, r'''ONO ;sss.'0)CN3 r-rss'OcNn I---./
, r1-0-'-'7CN "'-'' ;'5-1.e rijs)CN --'.`i 1 L-../. '0'.'X'' NO

' ;r5.5-02CNI ;15s-OWCN c-js-02c N --- r-sss.0CN , AO--')cCN
, S
c140Z.N1 1.352: "JD ' Ni/D
t / OH, r-sss.--n AO
===.,,,, N ,,,/-- 1 \r-- N .,,,./".. N / cIss 4111 I c'sis'IC-1....
I

sss{bj,'=1----S- F
'. =-....
/N
r3.5N
rrsj:. J F
,..^-i 1.,.. N / ,c15 ' F N ---I N ---N
/ /
,-, , , , \ ______________ \
N N
\-0Me, \-0Me, / /
, F
: CLO
"sy N -,-/-' NO /-0-.A646)Ni 0 , and
[0023] In embodiments, each L2 is independently a bond.
[0024] In embodiments, each R5 is independently selected from:
SP 4.4.) sl.P 9 P'-' x's-r.t.4.:' vsyN,..p.,-i Ne...ei, 1334 41, -N}1.2.,-OH. -N14(.C...f, alky . l), , 3N-.. , k4s5-7i - -a , k=-.0i."7"
0 9.
XX-1.'-4tsifilil kY'r."':1 P*1 -,.L. -02-4 õFs ..:P:., .,-*-i ,.. ..-,9 ow qe" ot-i it_rt ,ON
\ ..-%. , I'L,, " , ' " - , 0 P- .. 3c' '4' . H

9 : Ili 1,44 /HiNH2 -,c,..y m 6 ,-' .
-N -N i -4 ' tr-R ......tso 1.47?---NH:4 , irS4 >c.....,C ,t,3 ,_ 4, _j_ ,N µ4.),44, N
Y
NH H H NH NH NH
HN N cN HNN, --r- CN

H 2NA NH NC,NANH NC"--''NANH
-z. NH2 ' .9^-' , , , , H I , H I
, -CN, *1i ...lir"

ON
17.10, ,44) )1r1-$.4m = if4 AR*
o , v-==N, riNti sz;
Air-C), 0 . N N
Vir "ON
N , 0 6 (141 MI 0 33kdULWIEUAI T331:::!3kt, O. I, 2, Of
[0025] In embodiments, R4 is independently -C(0)105. In embodiments, 114 is independently -C(0)105 and the 105 is independently selected from C2.6alkeny1, C2.6alkynyl, C2_9heterocycloa1kyl, and C1_9heteroaryl, wherein C2_ 6alkenyl, C2_6a1kynyl, C2_9heterocycloalkyl, and Ci_91teteroaryl are optionally substituted with one, two, or three R20.
In embodiments, R4 is independently -C(0)R15 and the R15 is independently C2_6a1kenyl, wherein C2_6a11eny1 is optionally substituted with one, two, or three R20. In embodiments, RI is independently -C(0)R15 and the R13 is independently C2.9heterocycloa1kyl, wherein C2_9heterocycloalkyl is optionally substituted with one, two, or three R20. In embodiments, leis independently -C(0)R1' and the R1' is independently C1_9heteroaly1, wherein CI_ 9heteroaly1 is optionally substituted with one, two, or three R20. In embodiments, R4 is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein.
[0026] In an aspect is provided a compound having the formula A-1_,A13-B
wherein A is a monovalent form of a compound described herein; LAB is a covalent linker bonded to A and B; and B
is a monovalent form of a degradation enhancer.
[0027] In embodiments, the degradation enhancer is capable of binding a protein selected from E3A, miidmn2, APC, EDD1, SOCS/BC-box/eloBC/CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, BERCI, HERC2, HERC3, HERC4, HERS, HERC6, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, P1AS2, P1AS3, P1AS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL
(von-Hippel-Lindau ubiquitin ligasc), WWP1, WWP2, Parkin, MKRN1, CMA (chaperon-mediated autophagc), SCFb-TRCP
(Skip-Cullin-F box (Beta-TRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAP1 (cellular inhibitor of apoptosis protein 1), APC/C (anaphase-promoting complex/cyclosome), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4cR13N) ubiquitin ligase, XIAP, TAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBX04, FBX031, BTRC, FBW7, CDC20, PIV1L, TRIM21, TRIM24, TRTM33, GID4, avadomide, iberdomide, and CC-885.
[0028] The compound of claim 74 wherein the degradation enhancer is capable of binding a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2LI, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.
[0029] In embodiments, LAB s _LAB 1 _LAB 2 _LAB 3 _LAB 4 _LAB _, LAB 1, LAB 2 , L -r AB 3 , LAB4, and LA' are independently a bond, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(Rm)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(10S(0)2-, C1.6alkylene, C2_6alkenylene, C2_6alkynylene, C1-6ha1oa1ky1ene, C342cycloalkylene, Ci_iiheterocycloalkylene, C6_12aiylene, or Ci_iiheteroarylene, wherein C1_ 6alkylene, C2.6alkeny1ene, C2_6alkynylene, C1_6haloalkylene, C3.12cyc1oalky1ene, Ci_iiheterocycloalkylene, C6-12arylene, or C1_1 iheteroalylene,are optionally substituted with one, two, or three R20J; wherein each Cl_nalkyl of (-0-C1.6alkyl)z- and (-Ci_6alky1-0)z- is optionally substituted with one, two, or three R201; z is independently an integer from 0 to 10; each R12 is independently selected from hydrogen, Ci_6alkyl, C2_6a1kenyl, C2_6a1kynyl, C3-6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocycloalkyl, C6_10myl, -CH2-C640aryl, -CH2-Ci_9heteroaryl, and Ci_9heteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, Co_loaryl, -CH2-C6_10aryl, -CH2-C1,9heteroaryl, and Ci_91Kteroaryl are optionally substituted with one, two, or three R2"; each R13 is independently selected from hydrogen, C1.6a1kyl, and Ci_6haloalkyl; or R12 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloa1kyl ring optionally substituted with one, two, or three R2 e; each R14 is independently selected from hydrogen, Ci_6alkyl, and Ci.6haloalkyl; each R15 is independently selected Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_ 9heterocycloalkyl, C6,10aryl, and C1_9heteroary1, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloa11cyl, C2-9heterocycloalkyl, C6.ioaryl, and C1_9heteroaryl are optionally substituted with one, two, or three R201; each R2", R20', R20f, and R20j are each independently selected from halogen, -CN, Ci_6a1lcyl, C2_6alkeny1, C2_6alkyny1, C3_6cycloalkyl, -CH2-C3_6cycloa1kyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10myl, -CH2-C6_10aryl, -CH2-Ci_9heteroaryl, Ci_9heteroaryl, -0R21. _sR21, _N(R22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein Ci_balkyl, C2_6a1kenyl, C2_6a1kyny1, C3_ 6cyc10a11cy1, -CH2-C3_6cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocycloalkyl, C6_10alyl, -CH2-C640aryl, -CH2-Ci_9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci.6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_ yheterocycloalkyl, C6.ioaryl, and C1_91ieteroatyl; each R22 is independently selected from H, Ci_6alkyl, Ci.6haloalkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_10a1yl, and Ci_9heteroaryl; each R23 is independently selected from H and Ci_6alkyl; each R24 is independently selected from H and Ci_6a1kyl; and each R25 is selected from Ci_6alkyl, C2_6alkenyl. C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalll, C6_10aryl, and C1_ yheteroaryl. In embodiments, LAB is -(0-C2alkyl),- and z is an integer from 1 to 10. In embodiments, LAB
is -(C2alky1-0-)z- and z is an integer from 1 to 10. In embodiments, LAB is -(CH2)ziL'2(CF-120)z2-, wherein LAB2 is a bond, a 5 or 6 membered heterocycloalkylene or heteroarylene, phenylene, -(C2-C4)alkynylene, -SO2- or -NH-; and zl and z2 are independently an integer from 0 to 10. In embodiments, LAB is -(CH2)z1(CH20)z2-, wherein zl and z2 are each independently an integer from 0 to 10. In embodiments, LAB is a PEG linker. In embodiments, B is a monovalent form of a compound selected from ce,, . ,r- P14 , , =
,...... , ...H.õI o --- r-9H
g ,,--c 1 %, 0 ii ' e.7"s`t",14 H 0 , ,õ=---,<'''N''Is 11 ...3 ON=
...õ. ,a ,....
14,k.,. ? 11 r) 0 -,...õ....õõJ,..,k,õ,..N.,...õ, _,...t.. ......
..-C:f., - "st. 0 NH, (=:-,:' '''%, e.:s.,: I.1 4 ).., .,,'-, \=-"''µ i S...:$
0 0 0 oH
, n , a , \
rTh 1 ;;=------Of. `. d /Th\--\,...,il.
,. -1r,..-,-õ, if gi 1....,.....}
6õ,,AzZO
tryk...
$
Ø
o Nutlin n n F \ i '''9 gl Ht:-- = .,A., ,21 0 ,P
.4.,......õ.34. ...
A'i?Vt i- =-) - t-Z---e'S'ti"'-'11...\---C1 HO. I\ !=1 a jkõr" ..-...,N
c$ , ',...,=1, .>, :'; ,s, ,....4=`
t =
0 LIµCt idasanutlin ,õ.....f.õ....t., 0..."
OCki ine,&=
C4 .'"--e-N-..-=== ':;. ,..: ?
tsks...... SP 9 0, =- 4 1 L";?<, 1 Hsi, Ai =''.-,, , ,and
[0030] In an aspect is provided a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
[0031] In an aspect is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.
[0032] In an aspect is provided a method of modulating activity of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.
[0033] In embodiments, the method includes administering an additional agent or therapy.
[0034] In an aspect is provided a method of inhibiting cell growth, comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.
[0035] In embodiments, the method includes administering an additional agent to said cell.
100361 In some embodiments, the additional agent comprises (1) an inhibitor of MEK; (2) an inhibitor of epidermal growth factor receptor (EGFR) and/or of mutants thereof; (3) an immunotherapeutie agent; (4) a taxane;
(5) an anti-metabolite; (6) an inhibitor of FGFR1 and/or FGFR2 and/or FGFR3 and/or of mutants thereof; (7) a mitotic kinase inhibitor, (8) an anti-angiogenic drug; (9) a topoisomerase inhibitor; (10) a platinum-containing compound; (12) an inhibitor of c-MET and/or of mutants thereof; (13) an inhibitor of BCR-ABL and/or of mutants thereof; (14) an inhibitor of ErbB2 (1-ler2) and/or of mutants thereof; (15) an inhibitor of AXL and/or of mutants thereof; (16) an inhibitor of NTRK1 and/or of mutants thereof; (17) an inhibitor of RET and/or of mutants thereof;
(18) an inhibitor of A-Raf and/or B-Raf and/or C-Raf and/or of mutants thereof; (19) an inhibitor of ERK and/or of mutants thereof; (20) an MDM2 inhibitor; (21) an inhibitor of mTOR; (23) an inhibitor of IGF1/2 and/or of IGF1-R;
(24) an inhibitor of CDK9; (25) an inhibitor of famesyl transferase; (26) an inhibitor of SHIP pathway; (27) an inhibitor of SRC; (28) an inhibitor of JAK; (29) a PARP inhibitor, (31) a ROS1 inhibitor; (32) an inhibitor of SHP
pathway, or (33) an inhibitor of Src, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl or AKT; (34) an inhibitor of KrasG12C mutant; (35) a SHC inhibitor (e.g., PP2, AID371185); (36) a GAB
inhibitor; (38) a PI-3 kinase inhibitor;
(39) a MARPK inhibitor; (40) a CDK4/6 inhibitor; (41) a MAPK inhibitor; (42) a SHP2 inhibitor; (43) a checkpoint immune blockade agent; (44) a SOS1 inhibitor; or (45) a SOS2 inhibitor. In some embodiments, the additional agent comprises an inhibitor of SHP2 selected from RMC-4630, TN0155, JAB-3068, IACS-13909/BBP-398, SHP099, ERAS-601, and RMC-4550. In some embodiments, the additional agent comprises an inhibitor of SOS selected from RMC-5845, BI-3406, BI-1701963, MRT'X0902, and BAY 293. In some embodiments, the additional agent comprises an inhibitor of EGFR selected from afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, olmutinib, and EGF-816. In some embodiments, the additional agent comprises an inhibitor of MEK
selected from trameti nib, cobimeti nib, binimetinib, selumeti nib, refameti nib, and AZD6244 In some embodiments, the additional agent comprises an inhibitor of ERK selected from ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, and ravoxertinib. In some embodiments, the additional agent comprises an inhibitor of CDK4/6 selected from palbociclib, ribociclib, and abemaciclib. In some embodiments, the additional agent comprises an inhibitor of BRAF selected from sorafenib, vcmurafenib, dabrafenib, cncorafenib, regorafenib, and GDC-879.
[0037] In an aspect is provided a Ras protein bound by a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein activity of said Ras protein is reduced as compared to a Ras protein unbound to said compound.
[0038] In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

R
X
R2 Formula (I);
wherein W is C(0), 5(0), or S(0)2;
V is C(R17) and J is C(R16), or V is C(R17) and J is N, or J is C(R17) and V
is C(R16), or J is C(R17) and V is N;
R1 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R")-, -N(R")S(0)-, -N(R14)S(0)2-, Ci-C6alky1, C2-C6aMnyl, or C2-C6a1kynyl, wherein Ci-C6alkyl, C2-C6alkeny1, and C2-C6a1kynyl, are optionally substituted with one, two, or three R2Da;
R7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteromyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more R1, one or more le, or one or more R6;

wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C342cycloalkyl, C111heterocycloalkyl, C6_12aryl, or Ci_iiheteroaryl, wherein the C3_12cyc1oa1ky1, Ci.liheterocycloalkyl, C6_12a1yl, or CI_Iiheteroaryl are optionally substituted with one, two, or three R2 a;
each R2 is independently selected from hydrogen, C1_6a1kyl, C2_6a1kenyl, C2_6alkynyl, C1_6haloalkyl, C3-12cycloalkyl, -CH2-C342cyc10a1ky1, Ci_iiheterocycloalkyl, -CH2-Ci_iiheterocycloalkyl, C6_12a1y1, -CH2-C6-12ary1, -CH2-C1-iiheteroaryl, and Ci_iiheteroaryl, wherein C1_6alkyl, C2_6alkenyl, C2.6a1kynyl, C3_12cycloalkyl, -C1-12-C342cycloalkyl, Ci_iiheterocycloalkyl, -CH2-Ci_1iheterocycloalkyl, C6_12ary1, -CH2-C6_12a1yl, -CH2-C1_iiheteroaryl, and Ci_iiheteroary I are optionally substituted with one, two, or three R2';
each R4 is independently selected from hydrogen, halogen, oxo, -CN, C1_6alky1, C2_6a1kenyl, C2_6a1kynyl, C3_ 6cyc1oa1ky1, C2_9heterocycloalkyl, C6_10a1yl, Ci_9heteroatyl, -0102, -SR12, _N(R12)(R13), -C(0)OR", -OC(0)N(R22)(R13), -N(R14)C(0)N(R12)(R"), -N(R14)C(0)0R15, -N(R14)S(0)2R25, -C(0)R25, -S(0)R1), -OC(0)R25, -C(0)N(R")(R13), -C(0)C(0)N(R12)(R13), _N(R14)c(0)R15, _s(0)2R15, _S(0)2N(R12)(R13)-, S(=0)(=NH)N(R'2)(R13). -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R 13), wherein C1_6a1lcy1, C2_6alkenyl, C2_6allcynyl, C3_6cyc1oa1ky1, C2_9beterocycloallcyl, C6_ waryl, and C1_9heteroatyl are optionally substituted with one, two, or three R2 a;
R6 is -L2-R5;
each L2. is independently selected from a bond, Cl-C6alkyl, -0-, -N(R24)-, -C(0)-, -N(R'4)C(0)-, -C(0)N(R24)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(RH)-, -S(0)N(R24)-, -N(R24)S(0)-, -N(104)S(0)2-, -000N(R14)-, -N(R24)C(0)0-, and -N(R44)C(0)N(R")-;
each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6a1kyny1, C3_6cycloa1kyl, C2-9heterocycloalkyl, C6_ioaryl, Ci_9heteroary1, -OR", -SR", -N(H)(R"), -C(0)01122, -0C(0)N(R22)(R13), -N(R14)C(0)N(R12)(R'3), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R", -S(0)R15, -0C(0)R15, -C(0)N(R22)(Ri3), -C(0)C(0)N(R12)(R13), _1\T(R14)c(o)R15, _s(o)2R15, _S(0)2N(R12)(R13)-, S(=0)(=NH)N(R22)(R23), -CH2C(0)N(R")(R23), -CH2N(R24)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C1-6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6 -wary], and Ci_9heteroaryl are optionally substituted with one, two, or three R2.0c;
R27 is -L'-R'9:
1_,4 is selected from a bond, Cl-C6allcyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R')-, -C(0)-, -N(RN)C(0)-, -C(0)N(R")-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R")-, -S(0)N(R21)-, -N(R")S(0)-, -N(R")S(0)2-, -OCON(R24)-, -N(R24)C(0)0-, N(R2e), C(0)N(R2c), S(0)2N(R1c), S(0)N (Rh:), C(Rif)(R1)0, C(R1f)(R2)N(R2c), and C(Rif)(R2g);
Ric, Rif, and It'g are independently selected from hydrogen, halogen, -CN, C1_6a1ky1, Ci_6haloalkyl, C2_6a1keny1, C2_6a1kynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_ioaryl, Ci_9hetermu-yl, -OR", -SR", -N(R")(R23), -C(0)0R1 2, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R"), -N(Rm)C(0)0R15, -N(R14)S(0)2R13, -C(0)R' -S (0)R25, -0C(0)R25, -C(0)N(R22)(R"), -C(0)C(0)N(R22)(103), -N(R14)C(0)R15, -S(0)2R", -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R")(R23), -CH2C(0)N(R22)(R22), -CH2N(R14)C(0)R15, -CH2S(0)2R25, and -CH2S(0)2N(R")(R12), wherein Ci_6alky1, C2_6alkenyl, C2_6alkynyl, C3_6cyc1oa1ky1, C2-9heterocycloalkyl. C6-1 oalyl, and C1_,heteroaryl are optionally substituted with one, two, or three R2 1; or Rif and Rig are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R2";
R" is selected from hydrogen, Ci.6a1ky1, C2_6alkenyl, C2_6alkyny1, C3.6cycloallql, C2_9heterocycloa1kyl, C6.
wary', and Ci_9heteromyl, wherein Ci_6a1ky1, C2_6alkeny1, C2_6alkynyl, C3_6eye1oalkyl, C2_9heterocycloalkyl, C610myl, and Ci.9heteroa1y1 are optionally substituted with one, two, or three R2"
R19 is selected from a C3_12cyc10a1kyl, C2-iiheterocycloalkyl, C6_12aryl, and C2_12heteroaryl, wherein the C3.
ucycloalkyl, C2_1(hetcrocycloalkyl, C6_12aryl, and C2-12heteroary1 arc optionally substituted with one, two, three, four, five, six, or seven le;
each is independently selected from halogen, -CN, Ci_6a1ky-1, Ci_6haloalkyk C2_6alkenyl, C2_6alkynyl, C3-6cycloalkyl, C2_9heterocycloa1kyl, C6_10aryl, Ci_9heteroaty1, -0R12, _N(Ru)(Rus), _ C(0)0R12, -OC(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R", -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), _N(R14)c(0)R15, _s(0)2R15, _S(0)2N(R12)(R13)-, S(=0)(=NH)N(R'2)(R13), -CH2C(0)N(RI2)(RI3), -CH2N(RI4)C(0)R13, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C1_6a1lcy1, C2_6a1keny-1, C2_6allcynyk C3_6cyc1oa1ky1, C2_9heterocycloalkyl, Cr waryl, and C1_9heteromyl are optionally substituted with one, two, or three R201;
R1' is selected from hydrogen, halogen, -CN, Ci_6alky1, C2_6alkenyl, C2_6alkynyl, C3_6cyeloa1kyl, C2-9heterocycloalkyl, C6_10alyl, Ci.9heteroaryl, -OR', -SR', -N(R12)(103), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R')S(0)2R1', -C(0)R15, -S(0)R1', -0C(0)R1', -C(0)N(R12)(Rn), -C(0)C(0)N(R')(R'), -N(R')C(0)R15, -S(0)2R15, -S(0)2N(R')(RH)-, S(=0)(=NH)N(R')(R13), -CH2C(0)N(R12)(R13), -CH2N(Rm)C(0)R15, -CH2S(0)2TC, and -CH2S(0)2N(R12)(R13), wherein Ci_6alkyl, C2_6alkeny-1, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6-low-yin and Ci_9heteroaly1 are optionally substituted with one, two, or three R20;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R')S(0)2R15, -C(0)R15, -S(0)R'3. -0C(0)1C, -C(0)N(11")(R"), -C(0)C(0)N(RI2)(R"), -N(RH)C(0)RI5, -S(0)2R", -S(0)2N(R12)(R13)-, S(=0)(=N1-T)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R12)(R13), -(Ci-C6alkyl)-R'2", -R'2", _Rub -(C2_6alkynyl) , _Rub, _o_Ruan -N(R)-R, _ S-R'2', -(C3_10cyc10a1ky1)-R12b, -(C2_9heterocycloalkyl)-R12b, -(C6_10ary1)-R'2', or -(Ci_9heter0ary1)-R12b, wherein said Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_iocycloalkyl, C2_9heterocycloalkyl, C6.10aryl, and Cl_ 9heteroaryl are optionally substituted with one, two, or three R201;
R12a is selected from Ci_6a1kyl, C2.6alkenyl, C2_6alkynyl, C3_10cycloalkyl, -CH2-C3.10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10ar0, -CH2-C640aryl, -CH2-Ci_9heteroary1, and C1-9heteroaryl, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C340cycloalkyl, -CH2-C3_10cy-cloalkyl, C2-9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10aryl, -CH2-C640aryl, -CH2-Ci.9heteroary1, and C1-9heteroaryl are optionally substituted with one, two, or three R20(1;
R12b is selected from hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloa1kyl, -CH2-C3_10cycloalkyl, C2_ 9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10aryl, -CH2-C640aryl, -CH2-Ci_9heteroaryl, and Cl-,heteroaryl, wherein C1_6alky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, -CH2-C3_10cy-eloalkyl, C2-9heterocycloalkyl, -0-12-C2_9heterocycloalkyl, C6_10aryl, -CH2-C6_10ary1, -CH2-C1.9heteroary1, and C1-9heteroaryl are optionally substituted with one, two, or three R20d;
X is C(R3) or N;

R3 is selected from hydrogen, halogen, -CN, C,6a1ky1, C2_6alkenyl, C2_6alkyny1, C3_6cycloalkyl, C2_ 9heterocycloalkO, C6_10myl, Ci.9heteroary1, -0R12, -N(R12)(R13), -C(0)0R12, -0C(0)N(1112)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R")S(0)2R15, -C(0)Ri5, -S(0)R15, -0C(0)R15, -C(0)N(R12)(RH), -C(0)C(0)N(R12)(R13), -N(R')C(0)R', -S(0)2R15, -S(0)2N(1112)(Rn)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(Ri3), wherein Ci-oalkyl, C2_6alkenyl, C2_6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-i0aryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R2 b;
each R12 is independently selected from hydrogen, Ci_oalkyl, C2_6alkenyl, C2_6alkynyl, C3_6cyc1oalkyl, -CH2-C3-6cycloalkyl, C2_91ieterocycloa1kyl, -CH2-C2_9heterocycloalkyl, C6_10airyl, -CH2-C640aryl, -CH2-C1-9heteroaryl, and Ci_9heteroary1, wherein Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3_6cyc1oa1kyl, -CH2-C3-6cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocyc1oalky1, C6_10alyl, -CH2-C6_10aryl, -CH2-Ci-9heteroaryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R20d;
each R13 is independently selected from hydrogen, Ci_6alkyl, and Ci_6haloalkyl; or R12 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R20e;
each RH is independently selected from hydrogen, Ci_6alkyl, and Ci_6ha1oa1ky1;
each R" is independently selected C1.6a1ky1, C2_6alkenyl, C2_6alkynyl, C1.6cycloalkyl, C2_9heterocycloalky1, C6.
ioaryl, and Ci_9heteroaryl, wherein Ci_6a1ky1, C2_6alkenyl, C2.6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_10aryl, and Ci.9heteroary1 are optionally substituted with one, two, or three R20f;
each R20a, R2ob, R200, R2od, R20e, R20r, 20g, ic and R20i are each independently selected from halogen, -CN, 6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cyc1oalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloalky1, -CH2-C2-9heterocycloalkyl, C6_10alyl, -CH2-C64oaryl, -CH2-C1_9heteroaly1, C1.9heterowy1, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein Ci_6alky1, C2_6alkenyl, C2_6alkynyl, C3.6cycloalky-1, -CH2-C3-6cycloallcyl, C2_91ieterocycloalkyl, -CH2-C2_91ieterocycloalkyl, C6_10alyl, -CH2-C6_10atyl, -CH2-Ci-9heteroaryl, and Ci_,heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, Ci_6ha1oa1ky1, Ci_6a1koxy, Ci_6ha1oa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N
(R22)(1223), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R2';
each R21 is independently selected from H, Ci_6a1ky1, Ci_6haloalk0, C2_6alkenyl, C2_6alkyny1, C3_6cycloalkyl, C2_ 9heterocycloalkyl, C6_10alyl, and Ci_9heteroa1y1;
each R22 is independently selected from H, Ci_6a1ky1, Ci_6haloalkyl, C2.6alkenyl, C2.6alkyny1, C3.6cycloalkyl, C2_ 9heterocycloalkyl, C6_10alyl, and Ci_9heteroaryl;
each R23 is independently selected from H and Ck6a1ky1;
each R24 is independently selected from H and Ci_6a1ky1;
each R25 is independently selected from C1_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2.9heterocycloa1l, C6_10alyl, and Ci.9heteroary1; and - indicates a single or double bond such that all valences are satisfied.

[0039] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X
is C(10). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is N.
[0040] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof.
V is C(R16) and J is C(R"). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is N and J is C(R17). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, J is N and V is C(107). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, J is C(R16) and V is C(R17). In further embodiments of the subjcct compound, or a pharmaceutically acceptable salt or solvate thereof, W
is C(0). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0)2.
[0041] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure:
O Rl 0 Ri o N.N S
I
R17-' - N
"`-',,-.,..õ,-"=-,R2 R17-. N-_-:;"-.R2 R16 Formula (1A1), R16 Formula (1A2), õ
R8 %/c,. 0 R10 '-'= N R8 N
R17 'N R2 .---,, õ......-----..., Formula (IA3), R17 N N R2 Formula (IA4), O R1 0 0 Rio li NN

'<N
I
.-----. ..õ..----...õ, ...--.. 2 .---..,õ.N....õ----....,, R17 N N R Formula (IA5), R17 N R2 Formula (IA6), O R 1 o 0 .. R 1 o R8 R A.--1, 8 ...õ.-,.,,,R3 NN NN
......, ,.,.., Ri, ----------------N R2 R17Th.- N"'. R-R18 Formula (IA7), R18 Formula (IA 8), o o R10 R8 S/c R3 0 R10 NN --- \...
R8N )._ , R3 N

R16 Formula (IA9), R17--"%sN-i---R2 Formula (IA10), 0 Ri 0 R10 11 q \ ,p R!
N ,,.. s_______..L__R3 R8 \'s' R3 \N..---N.

R17NI\IR2 Formula (IA1 1), or RilN '-'-l\R2 Formula (IA12).
[0042] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure:

R8 s I I

R17 Formula (IIA1), R17 Formula (IIA2), o 0 R10 0 R10 \N.1 N
s\N,--'----'"----'1 N
I I I
,----.., ,,,,j--,, R17 Formula (IIA3), R17 Formula (IIA4), 0 Ri o o o Rlo R8 I I R8 V_c_, N
\N/
N -'''N N

..;.---..., N

R17 Formula (11A5), R17 Formula (11A6), N R .S

--,_, N \.,,..

R17 Formula (IIA7), R17 Formula (IIA8), 0 0 Rl Ri N ,--N

R16NR2 N ---............õ--..,,,,N
../..,--....õR2 R17 Formula (IIA9), R17 Formula (IIA 10), 0 wo 0 R1 o 8 s 3 ss'N'S'i://R3 NN..õ...,,______,,,õNõ....,:>-...õR2 N =-=N,...:..õ--i-,,,R2 R17 Formula (IIA11), or R17 Formula (IIA12).
[0043] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is a bond. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is -Nil-.
100441 In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R', one or more re, or one or more R6; and wherein two substituents selected from R4, R4, and R'' that are bonded to the same or adjacent atoms are optionally joined to form a C3_12cycloalky1, Ci_uheterocycloalkyl, Co_uaryl, or Ci_iihetcroaryl, wherein the C3_12cycloalkyl, Ci-uheterocycloalkyl, C6_12a1yl, or Ci_iiheteroaryl are optionally substituted with one, two, or three R2.8a.
[0045] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 X2 ,..,......õ X2õ........... X2 4.
I is (R4)p X1 X1 4 ) < >-(R4),, .........::z.....,. ,,...,...' , ..., (R <4).p S.,.

- _..L
.2 .2 ___________________ (R4) p ...2.......,...,õ.......>.: xl (R4)p X1,1 '......')(3'.
,__I_ - , p is an integer from 0 to 12;
X4 is selected from CH2, C(12_4)(12_6), C=N-012_4, C=NN(12_4)(R6), C(0)N(R4), N(R4), N(R6), 0, S, S(0), S(=0)(=NR4). S(0)2N(R4), N(R4)S(0)N(R4), NOVIS(0)2N(R4), S(0)N(V), OC(0)N(fe), N(1e)C(0)N(12,4), S(0)2, CH2C(R4)(R6), CH2C(R4)(R6)CH2, C(R4)(R6)C(124)(126)C(R4)(R6), C(124)(R6)C=N-0R4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(124)(126)N(R4), C(124)(R6)N(R6), C(R4)(R6)0, C(R4)(R6)0C(124)(R6), C(R4)(R6)S, C(R4)(R6)SC(R4)(R6), C(R4)(R6)S(0), C(R4)(R6)S(0)C(R4)(R6), C(R4)(R6)S(0)2C(R4)(R6), C(R4)(R6)S(-0)(-NR4), C(R4)(R6)S(0)2N(R4), C(R4)(R6)N(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R4)(R6)S(0)N(R4), C(R4)(R6)0C(0)N(R4), C(R4)(R6)N(R4)C(0)N(R4), C(R4)(R6)S(0)2, C=NN(R4)(R6)C(R4)(R6).
C(0)N(R4)C(R4)(10, S(0)2N(R4)C(124)(R6), S(0)N(10C(124)(R6), OC(0)N(10C(R4)(R6), C(R4)(124), C=N-0R4, C=NN(R4)(R4), CH2C(R4)(R4), CH2C(R4)(124)CH2, C(124)(124)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C=N-0R4, CH2C=NN(R4)(R4), C(R4)(R4)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0, C(R4)(R4)0C(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(10S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R1S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(124)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and OC(0)N(R4)C(R4)(R4);
X2 is selected from N, C, C(R6), C(R4), CH, N(R1), N(R4), N(R6), 0, S, S(0), C(H)(R6), C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X' is selected from N, C, C(R6), and C(R4).
[0046] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is X2 X2-\ (R4) >AR4)p ( , P
=--- >7-(R4)p (R
x3 //>

, , , , i I i I
, Xi _______________ Xi I
> (R4)p ,...õ.õ.,...> (R4)p I, OT .^^,....=
100471 In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is H H H H H H
r (R \
----(R4)p E)1P yt..-.(R4)p sftL., II li ...,......, H H H H H
HN\N
C........j--(R4)p '\.c:/(R4) -p (0,\X___ 4 (".....>1 4 A( _l___./
R4) p ......õ-T(R ) p > k " P
rl N N li 11 ,,,,,, JVUI.I I I
, , , , , , ____________________________________________________ N H
-1--.(R4)p S'3---(R4)P (R4)p ( .'( R4)p ......1-., ( R4) p > N
ri 11 11 li Il H
N
H
N, C 1- (R4) p \o"Cl H H \ 4 (R4)p N)V 4 \,...0 (R4)p 'N;-C- N
, . or . ; and p is an integer from 0 to 12.
[0048] In sonic embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 127 H H H H H H H H H H
N N N N N N .,,,N N N
y c......õ-: 6:::)./
N N N N N N 'N li is "":('' '"Yv -"1""' '4"" ====="' '4"' -"""' - ''''''' ' ' CN
H H -NH H
H
HNO,....N iiiN ZI_D </pH
NH NC 4, _.,,C, Nj _,...-J.., N
vw pv , H
N

HO) H2Nj A,...,,,,N

, N Y
[0049] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is or \ .
[0050] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R" is independently selected from hydrogen, halogen, -CN, Cl_nalkyl, C2.6alkeny1, C2.6alkynyl, and C,_ 6cyc10a11cy1, wherein Ci.6alkyl, C2.6a1kenyl, C2.6alkynyl, and C3_6cycloalkyl are optionally substituted with one, two, or three R'g. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 106 is independently selected from hydrogen and halogen. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and fluoro.
[0051] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof.
R8 is selected from halogen, -CN, Ci_6a11ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6_10aryl, Ci_9he1eroary1, -0R12; -SR12, _N(H)(Rus), _ C(0)0R12, -0C(0)N(R12)(R13), -NT(Ria)c(o)NT(R12)(R13), _ N(R14)C(0)0R15, -NT(R14)s(0)2Ri5, -C(0)R'5, -S(0)R'5, _oc(o)Ris, _c(0)N(R'2)(R13), _c(o)c(0)N(R12)(R13), _ N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(Ru)(R13), wherein C1.6alkyl, C2.6alkenyl, C2.6alkynyl, C3-6cyc1oa1ky1, C2.9heterocycloalkyl, C6_10aty1, and Ci_9heteroaryl are optionally substituted with one, two, or three R'''.
In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, le is selected from Ci_6a111, C3_10cycloalkyl, and C2_9heterocycloalky1, wherein C1_6alkyl, C3_10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R2 `
independently selected from halogen, Cl_ 6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, and C2_9he1erocycloalkyl.
In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
[0052] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen or CN. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen.
[0053] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, is a bond. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, Ll is selected from a Ci-C6a1kyl, C2-C6alkenyl, C2-C6alkynyl, -C(0)-, -NI-IC(0)-, -C(0)N1-1-, CH20, CH2NFI, and CH2.
[0054] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R'Y is a monocyclic ring. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a bicyclic ring system In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, F09 is a polycyclic ring system. In embodiments of the subject compound, or a x12 x4%."- x10 x4",./ x11 x4 II I I I
I h .x9 -..x1 x5õ
X6 X9 .-X6 Q
pharmaceutically acceptable salt or solvate thereof, R19 is: X6 , (13 X41-%"-`4 X94 ___R1h \=>___R1h h I ________ R18 N X6 Q xi o Q 4 X-' Q
N Q3 1 Q4 O. Q4 03 R1 h r-- .. yN
h I \s\>__ R1 h X 7- X7- 3 y7 '9 Q4 Q %' X9 Q \Q6 cy, \ `2z \ (22 Q --5/ I C14) / R1 h X6, x5-. X4 X6, x5', X4 ,or Q6 Q3 =
Q1. Q3, and Q5 are independently N or C(Rld);
04 and 06 are independently 0, S. C(Ria)(Rth), or N(R1c);
X', X', X6, X9, X', X", and X' are independently selected from C(R1 a) or N;
X7 and X8 are independently selected from C(R1a), C(R1a)(Rth), N, or N(R1c);
each Ria, R. Rid, and Rh are each independently selected from hydrogen, halogen, -CN, C2_6alkenyl, C2_6alkynyl, C3.10cycloalkyl, C2_9heterocycloalkyl, C640aryl, Ci_9heteroaryl, -OR", -SR', -N(R13)(103), -C(0)0R", -0C(0)N(Ru)(1113), -N(R14)C(0)N(R12)(R13), -N(RH)C(0)010-5, -N(RH)S(0)2R15, -C(0)R15, -S(0)R15, -OC(0)R15, -C(0)N(R13)(R"), -C(0)C(0)N(R")(R"), -N(R")C(0)R15, -S(0)2R15, -S(0)2N(R12)(R')-, S(-0)(=N}I)N(R12)(R33), -C112C(0)N(R12)(R33), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R")(R13), wherein Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, C340cycloalkyl, C2_9heterocycloa1kyl, C6_ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R201; or Ria and Rib bonded to the same carbon are joined to form a 3-membered heterocycloalkyl ring or a C340cycloalk0 ring, wherein the 3-10 membered heterocycloalkyl ring or Cl_locycloalkyl ring are optionally substituted with one, two, or three R'l:
or two Ria bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_1oaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C640a1yl ring, 5-12 membered heteroaryl ring, or C340cycloalkyl ring are optionally substituted with one, two, or three R2ci; or Rib and one of Ria, Rib, tc ¨ lc, and Rid bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6.10aryl ring, a 5-12 membered heteromyl ring, or a C340cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6.1oa1yl ring, a 5-12 membered heteroaryl ring, and C3.10cycloallcyl ring are optionally substituted with one, two, or three R2oi; and each Ric is independently selected from hydrogen, Ci_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_iocycloa1kyl, C2-9heterocycloalkyl, Co.loaryl, Ci_9heteroaly1, wherein Ci_6alkyl, C2.6a1kenyl, C2_6alkynyl, C3_10cycloa1kyl, C2-9heterocycloalkyl, C6.ioaryl, and C1_9heteroary1 are optionally substituted with one, two, or three R201.
[0055] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, )=---N )=-N HO 42C > HO \-.: :------N

0 cv 0 0 Rig is: F , F F
. .
. .
HO '2,( / H2N Nõ.. \-: H2N Nõ vz.. H2N Nõ v I F e...
/ I I
/ N
F I
F , N H2 '22Zµ. \-. \-- 5-22.
-./' / F CI

F , HN
,N____ `2,,r H14 H N
0 F , CI
CI
- .
. .
H
H ...,N N '2,- H2N Nõ '?.2-z.
.,,N
yF3 H2 N Nõ C F3 "?..4. H2N 1\1....r)2,-;
C
..,..Al 'Uv ./.

, , , ' =

H HO
,,..N .,õ..N INI , ,22-L
N X
H2N N µ2,- X ,,... ....,,,.-2, HO
CF3 ii CF3 CF3 OCF3 , CI
µ2,2 ' n X F
co. CI

CI CI CF3 , or NH2.
100561 In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R2 is selected from , N
I ,... a, N
, F F OM e crs' 0 F
H
0 16 )--CH2F rcr!-.0 c3.5-ZO& '''f/¨j\\
N
---6--->. 0 N--- \
r-55.40---)N ', /O.-AC
N ---N---,:4 ----- r 0 ., ,, /OA N--- \/N----N
ö
, F
F

0 0....
N,.....,-, I /N ¨I / / , ".'0""' ', '0.....0Me ".--e- -0....0CF2H =-= r-D<F
N
zN F
/ z , 0-1"' OM e 11:1-D--=
N--/
rsss'ON- 5 5 /'C) \ L ,F40n n.F -,--- o 2\1--/ .
. , ANa"---co----, 0 A -N N-.5 -_ I
/0 L.,,0 ....,,,A,... J.. cIss = N 1,,,,õc, I c' 0 NO
, , /

ossf`. X o ,4- NO rSiS'O'''.1D-...0H o ,X0µ, = R lel N
H
0...CN N.,..).N,N rsrs!,N.,.,.N.,.) , N ,,-1-N-N
,.<0--\\,õ)---N-N N
, H H
---' rssc) ,..,0(3.-1 ' , c3s-s'0 , .
, F
rls1.0V
r14N
N r14 W ;A.0K NrD 1\rX NO I NO
, c14 S -'2C NO r/js-2C1\ti-- c140-X-- NO<F vls()C NI.D'IF
F
, C55.1 riss'OlC 0 r4CY-)C Nt3 (31\ii -- ,, NO ;A-0-x--y---, v-A0--)\----No N '' ;r's'(:)-)C NL,,,,, N
1 , N1 ,- ciss, 0 C N s CN
;rcs'O/CN10 j40WCN cljs-OW
ccss'OX
N ----- rIss--S0 iD /

/ '''''\-- 0 H , ;ssri rissi N,_,,,õ,-,,,N---= -,,,,,N.,.õ,-",,N.-' I
, and , , (LO
,,,--, N

[0057] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof;
each R5 is independently selected from:
c1.1) cl, ,c) cl.P
,.....r. pH pi-i li.,s-,,-N.,,,.,1 pH 3. N.t.z, pH
-FL -NI-I2., -01-I, -NI-1(C1_6 alkyl), .õ..----, = . -,,,.......-.-) , X., n _IL.. 0,,,P o 4-N H A N'''' }4 -r'N N-4)14 7"'"---.NIN' 1/ Ns- N- " 4--;r1LN-cH
-OH

4......-.) NI' ,----, OH \
l'H' '=) 4S)õ_./N -m -OH
t:,i (Al *0-= >--r N
' tr< fr-N r-NH
Is----N1H-, ,.,1"-µ,N , ,k. \,N it sN If N ->ss 0 ' 1.,. -.'N
'-11¨G" - 6,-) flr ..,,jr.,,...._ 8 ,..., NH2, 0 , . .
NH H H NH NH NH
HN N cN HNN, ....- ........- CN H2NA NH NN) NH NCN'IL NH
NH2 ' I , ,,,,!,, , H I , H
I
, -CN, OH OH
NHz )--...OH 0.iri,,,...õOH Ar.--',....-14H2 &1( NH "4r-----OH 1 "OH
= 01 , LI) H H N"- \ vtri.õ---=\
/---- N H r---0 õpi, 1,--(--om ;-.7sir---t---/), / N
r,-, - N ,----- NH ,,,,, ......r......cN2.1 tie' ''''SIrk'N ) 4 8::.---1' rIC / F
''''''''' 'i'gs = . 1\1 )ee 41'011 A'''''''''-,r-' NI 'OH
. . , H
N
ØH cial.TrA)4 ) C and 0 :-, and m, when present, is 0, 1, 2, OT
3.
[0058] In an aspect is provided a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
R 1 o N N
I \ 1 \ fl X
I

R17 Formula (II);
wherein W is C(0), S(0), or S(0)2;
V is C(R16) or N;
R" is -1_,7-R7;
1_,7 is a bond, -0-. -N(R")-, -C(0)-, -N(R")C(0)-, -C(0)N(R")-, -S-. -S(0)2-, -S(0)-. -S(0)2N(R")-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-C6alkyl, C2-C6alkenyl, or C2-C6alkyny1, wherein Cl-C6a1kyl, C2-C6alkeny1, and C2-C6alkynyl, are optionally substituted with one, two, or three Rna;
R7 is a 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl, wherein the 3-12 membered hetcrocycloalkyl or 5-12 membered heteroaryl arc optionally substituted with one or more R1, one or more R4, or one or more le;
two substituents selected from R1, 114, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3_12cycloalkyl, Ci_iiheterocycloalkyl, C6_12aryl, or Ci_iiheteromyl, wherein the C3-izeyeloalkyl, Ci_iiheterocycloalkyl, C6_12a1y1, or Ci_iiheteroaryl are optionally substituted with one, two, or three R206;
each R' is independently selected from hydrogen, Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C1_6haloalky1, C3_ 12cycloalkyl, -CH2-C342cycloalkyl, Ci_nlieterocycloalkyl, -CH2-Ci_iiheterocycloalkyl, C6_12a1y1, -CH2-C6_ -CH2-C1_uheteroaryl, and Ci_iiheteroaryl, wherein C1_6a1ky1, C2_6alkenyl, C2_6alkynyl, -C1-12-C3.12eyc1oa1ky1, C1_, heterocycloalkyl, -CH2-C1_1 hetero cycloalkyl, C6-izaryl, -CH2-C6_12aryl, -CH2-Ci_iiheteroaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three R2 6;
each R4 is independently selected from hydrogen, halogen, oxo, -CN, CL.6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.
6cycloalkyl, C2_9heterocycloa1kyl, C6_10aryl, C1_9heteroa1yl, -OR', -SR', -N(R')(R13), -C(0)OR', -0C(0)N(R12)(R13), -N(R11)C(0)N(R")(R13), -N(R11)C(0)0R15, -N(R11)S(0)2R15, -C(0)R15, -S(0)R1', -OC(0)R15, -C(0)N(R12)(R"), -C(0)C(0)N(R12)(R"), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cyc1oa1ky1, C2.9heterocycloalkyl, C6_ ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R206;
R6 is -L2-R5;
each L2 is independently selected from a bond, Cl-C6alkyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -000N(R14)-, -N(R14)C(0)0-, and -N(R14)C(0)N(R14)-;
each R' is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkeny1.
C2_6a1kynyl, C3_6cycloalkyl, C2-9heterocycloalkyl, C6_ioaryl, Ci.9heter0ary1, -0R12, -SR12, -N(1-1)(R12), -C(0)0R12, -0C(0)NR12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R")C(0)R13, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R"), -CH2C(0)N(R")(R"), -CH2N(RH)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R11), wherein Ci_6a1ky1, C2_6alkenyl, C2_6a1kyny1, C3_6cy cloalkyl, C2_9heterocycloalkyl, C6-ioaryl, and C1_9heteroaly1 are optionally substituted with one, two, or three R20c;
R17 is -L1-R19;
1_,1 is selected from a bond, Cl-C6alky1, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(R14)C(0)0-, N(R1e), C(0)N(Ric), S(0)2N(Ric), S(0)N(Ric), C(Rif)(Rig)0, C(Rif)(Rig)N(Ric), and C(Rif)(Rig);
R", Rif, and Rig are independently selected from hydrogen, halogen, -CN, C1_6alky1, C1_6ha1oa1ky1, C2_6alkenyl, C2_6a1kynyl, C3_6cycloa1kO, C2_9heterocycloalkyl, C6_10aryl, Ci.9heteroary1, -OR', -SR", -N(1112)(Ri3), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R", -S(0)R15, -0C(0)R15, -C(0)N(R12)(103), -C(0)C(0)N(R12)(R13), -N(R14)C(0)10-5, -S(0)2R, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R')(R13), wherein Ci_oalkyl, C2_6a1keny1, C2_6a1kyny1, C3.6cycloalky1, C2-9heterocycloalkyl, C6_10aryl, and Ci_9heteroary I are optionally substituted with one, two, or three R20; or Rif and Rig are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
R" is selected from hydrogen, Ci.6a1ky1, C2_6alkeny1, C2_6alkynyl, C3.6cycloalkyl, C2_9heterocycloalkyl, Co_ ioaryl, and Ci_gheteroalyl, wherein Ci_6alkyl, C2_6alkenyl, C2.6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_ioaryl, and Ci_91ieteroary1 are optionally substituted with one, two, or three R201 R19 is selected from a C342cyc10a1ky1, C2_iiheterocycloalkyl, C6_22aryl, and C2_22heteroaryl, wherein the C3_ ,cycloalkyl, C2_, heterocycloalkyl, Co_uaryl, and C2_12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven Ril;
each is independently selected from halogen, -CN, Ci_bhaloalkyl, C2_6alkeny1, C2_6alkynyl, C3-6cycloalkyl, C2_9heterocycloa1kyl, C6_1oaryl, Ci_9heteroalyl, -OR', -SR', -N(R')(R'), -C(0)OR', -0C(0)N(R')(R13), -N(R11)C(0)N(R")(R13), -N(R11)C(0)OR'5, -N(R11)S(0)2R15, -C(0)R15, -S(0)R1', -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R"), wherein C2_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6_ ioaryl, and Ci_9heteromyl are optionally substituted with one, two, or three R201;
1216 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_ ,heterocycloalkyl, C6_bparyl, Ci_,heteroaryl, -OR", -SR", -N(Ri2)(R13), -C(0)0R12, -0c (0)N(R12)(R13), _ N(Rioi)c(0)N(R12)(--1() 13, _ N(R14)C (0)010 5, -N(R14)S(0)2R", -C(0)R", -S(0)R15, -0C(0)R15, -C(0)N(R12)(R"), -C(0)C(0)N(R12)(R13), -N(R '4)C(0)R15, -S(0)2R15, -S(0)2N( R12)(R13)-, S(=0)(=NH)N(R')(R13), -CH2C(0)N(R')(R13), -C1-12N(R14)C(0)R1', -CH2S(0)2R1', and -CH2S(0)2N(R')(R'), wherein C2_6a1ky1, C2_6alkeny-1, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R2 ;
R2 is -C(0)0R12, -0C(0)N(R')(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(103), -C(0)C(0)N(R12)(R13), -N(R14)C(0)10-5, -S(0)2105, -S(0)2N(R')(R13)-, S(=0)(=NH)N(R')(R13), -CH2C(0)N(R12)(R"), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R')(R'), -(Ci-C6alkyl)_Rub, _Rub _Rub, _o_Ri2a, _ -(C2_6alkenyl) , -(C2_6alkynyl) S-R' 2", -(C3-locy cloalkyl)-R1 2h -(C2_9heterocycloalkyl)-Ruh, -(C6_10ary1)-R' 2h or -(Ci_9he1eroary1)-R12h, wherein said C2-6alkyl, C2_6alkenyl, C2_6alkynyl, C3_iocycloa1kyl, C2_,heterocycloalkyl, C6_20aryl, and CI-9heteroaryl are optionally substituted with one, two, or three R2 d;
Rua is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, C340cycloalkyl, -CH2-C34ocycloalkyl, C2-,heterocycloalkyl, -CH2-C2_,heterocycloalkyl, C6_10aryl, -CH2-C6_, -C112-C1.,heteroaryl, and CI_ 9heteroaryl, wherein C1-6alkyl, C2_6alkenyl, C2_6alkynyl, C340cycloalkyl, -CH2-C3_2ocycloalky1, C2-9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10ary1, -CH2-C6_20aryl, -CH2-C2.9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20;
R12b is selected from hydrogen, Ci_6alky1, C2_6alkenyl, C2_6alkynyl, C3_30cycloa1kyl, -CH2-C3_30cycloalkyl, C2_ 9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_30aryl, -CH2-C6_10aryl, -CH2-C3_9heteroaryl, and C1-9heteroaryl, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_30cycloalkyl, -CH2-C3_10cy-cloalky1, C2-9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_30aryl, -CH2-C6_10ary1, -CH2-C3.9heteroaryl, and C1-9heteroaryl arc optionally substituted with one, two, or three R2 d;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyk C2_6a1kynyl, C3_6cycloa1kyl, C2-9heterocycloalkyl, C6_10aryl, Ci.9heteroary1, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(Ru)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(RI3), -CH2C(0)N(RI2)(RI3), -CH2N(RI4)C(0)RI5, -CH2S(0)2RI 5, and -CH2S(0)2N(R12)(R13), wherein C1_6allcyl, C2_6alkeny-1, C2_6allcynyl, C3_6cycloalkyl, C2_911eterocycloallcyl, C6_ waryl, and C1_9heteroaly1 are optionally substituted with one, two, or three R2 b;
each R12 is independently selected from hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6a1kynyl, C1_6cycloalkyl, -CH2-C3-6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_30aryl, -CH2-C6_30aryl, -CH2-Ci-9heteroaryl, and Ci_9heteroary1, wherein C,6a1ky1, C2_6a1kenyl, C2_6alkynyl.
C3_6cycloa1kyl, -CH2-C3-6cycloallcyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocycloalkyl, C6_30alyl, -CH2-C6_30aryl, -CH2-Ci-9heteroaryl, and C3_9heteroary1 are optionally substituted with one, two, or three R20d;
each R13 is independently selected from hydrogen, C3_6a1ky1, and C3_6ha1oa1ky1; or R12 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R2 ';
each kid is independently selected from hydrogen, Ci_6a1ky1, and Ci_6ha1oa1ky1;
each R15 is independently selected Ci.6a1ky1, C2_6alkenyl, C2_6allcynyl, C3.6cycloallcy-1, C2_9heterocycloalkyl, C6.
ioaryl, and Ci_9heteroalyl, wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C36cycloalkyl, C2_9heterocycloalkyl, C6_20alyl, and Ci_9heteroary1 are optionally substituted with one, two, or three R20f;
each R20a, R20b, R2oc, R20ci, R20e, Rag-, 20g, K
and R2 1 are each independently selected from halogen, -CN, C, ,,alkyl, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2.
9heterocycloalkyl, C6_30myl, -CH2-C6_30aryl, -CH2-C3_9heteroaty1, C3.9heteromyl, -0R21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein C3_6alky1, C2_6alkenyl, C2_6alkynyl, C3.6cycloalkyl, -CH2-C3-6cyc1oa11ky1, C2_9heterocycloa1kyl, -CH2-C2_9heterocycloalkyl, C6_30aryl, -CH2-C6_30ary1, -CH2-Ci-9heteroaryl, and Ci_cheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1ky1, C3_6ha1oa1ky 1, C3_6a1koxy, Ci_6ha1oa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;

each R22 is independently selected from H, Ci_6alkyl, Ci_6haloalky1, C2_6a1kenyl, C2_6alkyny1, C3_6cyc1oa1kyl, C2_ 9heterocycloalkyl, C6_1oary1, and Ci_9heteroaryl;
each R22 is independently selected from H. Cl_nalkyl. Cl_nhaloalkyl.
C2.6a1kenyl. C2.6alkynyl. C3.6cycloa1kyl. C2_ 9heterocycloalkyl, C6_ioaryl, and C1_9heteroaryl;
each R23 is independently selected from H and C1_6alkyl;
each R24 is independently selected from H and Ci_6alkyl;
each R25 is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6_10alyl, and Ci_9heteroaryl; and ¨ indicates a single or double bond such that all valences are satisfied.
[0059] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X
is C(R3). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is N.
[0060] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is C(R16). In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is N.
[0061] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is C(0). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof. W is S(0). In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof. W
is S(0)2.
[0062] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the 0 R 1 o 0 Ri o R8 R8.N_ I I
...õ..--.....õ.õ..¨..,_õ

compound has the structure: Formula (IIA1), Formula 0 Rio R 1 o 0õ0 R8 N\s/ R8 NN
I I I

....=,\,.,.õ/"\, (IIA2), R17 Formula (IIA3), R17 Formula (IIA4), 0 Ri o R10 V/
NN/
s R8 ''''---"----1 N NINI '-'"----''''''=-i N

N.",...,-,,,, _.%;=.-. N -......... ,.....2.--' --...õ.

Formula (IIA5), R17 Formula (IIA6), 0 R 1 o 0 Rio R R3 ,..,R3 R8N, .,sR3 R16.-....---: N R2 R16.--...- N -. R2 R17 Formula (IIA7), R17 Formula (IIA8), R8 NN VcR3 R8 ,-- N./"===,,,,,,,R3 I I I
R16 R2 N ---............:::___ ....),-.3-......., _ N R`
R17 Formula (IIA9), R17 Formula (IIA10), õ
N.N

R8 \\S'( R3 /S \/R3 -=,, NN,-- --..
I I I
N*......_.,N,._:,:=-,R2 N --..<,.....õ:õ...õ---,,,,N,..:;:-.õR2 R17 Formula (IIA11), or R17 Formula (IIA12).
[0063] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is a bond. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is -NH-.
[0064] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R', one or more 10, or one or more R6; and wherein two substitue ins selected from R', R1, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3.12cyc10a1ky1, Ci-iiheterocycloalkyl, C6_12a1yl, or Ci_iiheteroaryl, wherein the C3_12cycloalkyl, Ci.iiheterocycloalkyl, C6.12ary1, or C1.
nheteroaryl are optionally substituted with one, two, or three R2.0a.
100651 In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof.

< > X2 . ,,'^`>/(1R4)P
----iRC 1 Xi Xi k JP 1 1 ' >-(R4)p 4', R7 is ..1 , , 1 _1.....
(x2 x2 , X2 7. (R4)p </-*. ----,-,1 (R -,--.
1., 1 ' Xi ' 4p :
) ( R4)p ...I.... .....L. = ,,or, p is an integer from 0 to 12;
X' is selected from CH2, C(R4)(R6), C=N-0R4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), 0, S, S(0), S(=0)(=NR1), S(0)2N(R1), N(R1)S(0)N(R1), N(R1)S(0)2N(R1), S(0)N(R1), OC(0)N(R1), N(R1)C(0)N(R1), S(0)2, CH2C(R1)(R6), CH2C(R1)(R6)CH2, C(R1)(R6)C(R1)(R6)C(R1)(R6), C(R1)(R6)C=N-010, CH2C=NN(R1)(R6), C(10)(R6)C(0)N(R1), C(10)(R6)N(R4), C(R4)(R6)N(R6), C(R1)(R6)0, C(R4)(R6)0C(R1)(R6), C(10)(R6)S, C(10)(R6)SC(R1)(126), C(R1)(R6)S(0), C(R1)(R6)S(0)C(R1)(R6), C(R/)(R6)S(0)2C(R1)(R6), C(R4)(R6)S(=0)(=NR1), C(R4)(R6)S(0)2N(R1), C(R4)(R6)N(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R1)(R6)S(0)N(R4), C(R1)(R6)0C(0)N(R1), C(R1)(R6)N(R1)C(0)N(R1), C(R1)(R6)S(0)2, C=NN(R1)(R6)C(R1)(R6), C(0)N(R1)C(R1)(R6), S(0)2N(R1)C(R1)(R6), S(0)N(R1)C(R1)(R6), OC(0)N(R1)C(R1)(R6), C(R1)(R1), C=N-0R1,
36 C=NN(R4)(R4), CH2C(R4)(R4), CH2C(R4)(R4)CH2, C(R4)(R4)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C=N-0R4, CH2C=NN(R4)(R4), C(R4)(R4)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0.
C(R4)(R4)0C(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(10)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4). C(R4)(R4)0C(0)N(10), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and OC(0)N(R4)C(R4)(R4);
X2 is selected from N, C, C(R6), C(111), CH, N(R1), N(10), N(R6), 0, S. S(0), C(H)(R6), C(1:02, CH2, C(RI)(R6), S(=0)(=NR4), S(0)2, and X3 is selected from N, C, C(R6). and C(R4).
[0066] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 Xi 1 4 II-----(R4)P ->-(R )p ...._ X ) (IRLI)p iS .1. , I._ I L.
, X2 / ->...(R4)p < I
) > ,)(1 1 Xi'l (R4)p ,.,.......,..õ,õ...) (R4)p X3 x3 , ,or 100671 In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, IC
H H H H H H
N õ ...,Nõ ....,..N,.... Nõ.
....y...)-(R
krµ )10 NN
I ri li is n .A.A.N
n n ' H H H A _H HN H
a_N
\o/y---(R4)P /13\A -N1--i-(R4)p -(R4)pj-----(R4)p -?-, H HN----1 c.,Ti 4 -N H
OcNõ
6X(R4)P (R )P ,t--1 (R4)P 4, (R4)p ...1-----, (R4)p ll ri ri ri --...--) H
N
H
N, 1,(CH
0 4.e5(R4)P
\.o. ---(R4)p II
11 ',......) or .
; and p is an , ' =
integer from 0 to 12.
37 [0068] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, H H H H H H H H H H
N N N N N
N N
ri N N N ii-C1) N N
Il 117 is .^. -^1'-''' ' .
CN
H H [NH H
H
HN3,,,N TioN FAI,D </ciNH c=-= \NH

NC
"/""C j ( jv Y Y 11 11 ri N N
N
J=1^' H
N

C
HO N
)L- j H2NNIµN) \(c)NH I)-1 C-NH2 CN
-,...N N II Y
, [0069] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 ,1/2(c5H OH
is or \ .
[0070] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R'6 is independently selected from hydrogen, halogen, -CN, Ci_6alky1, C2_6alkenyl, C2_6alkynyl, and C3_6cycloalkyl, wherein Ci.6a1ky1, C2.6alkenyl, C2.6a1kynyl, and C3_6cycloalkyl are optionally substituted with one, two, or three R22g.
In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, RI' is independently selected from hydrogen and halogen. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R'6 is independently selected from hydrogen and fluoro.
[0071] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6_uaryl, Ci_9heteroary1, -0R12: _SR12, _N(H)(R12 ,), _ C(0)0R12, -0C(0)N(R12)(R13), _N(R14)C(0)N(R12)(R13), -N(R14)C(0)OR', -N(R14)S(0)2R'5, -C(0)R'5, -S(0)R'5, _OC(0)R15, -C(0)N(Ri2)(Ri3), _ C(0)C(0)N(R12)(R13), -N(Rii)c (0)Ri 5, -S(0)2R'5, -S(0)2N(R12)(R13,_ ), S (=0)(=NH)N (R12)(R13 ), -CH2C(0)N(R12)(R13), -CH2N(Ri4)c(o)Ri5, _C,,i_12s(0)2,,D 15, and _C. _,T_I-2,s(0)2NT,,(R12)(R13), wherein C1_6alkyl, k_C2_6a,n_11-enyl, C2_6alkynyl, C3-6cyc1oa1ky1, C29heterocycloalkyl, C6_i0aryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R2".
In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from Ci_6a1ky1, C3_wcycloalkyl, and C2_9heterocycloalkyl, wherein C1_6a11(0, C340cycloalkyl, and C2-yheterocycloalkyl are optionally substituted with one, two, or three R2 `
independently selected from halogen, CI_ 6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, and C2_9heterocycloalkyl.
In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R2" independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 118 is selected from methyl, cyclopropyl, cyclobutyl, oxetanylmethyl, and oxetanyl. In embodiments of the subject compound, or a
38 pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
[0072] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen or CN. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen.
[0073] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is a bond. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L' is selected from a C1-05a111, C2-C6alkenyl, C2-C6a1kynyl. -C(0)-, -NEIC(0)-, -C(0)NI-1-, CH20, CH2NH, and CI-12.
[0074] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic ring. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a bicyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R'9 is a polycyclic ring system. In some embodiments of the subject compound, - -x12 x4-%"'s x10 x4 x11 I II I I I
x5õ X
x9 x5, 0 "-x1 or a pharmaceutically acceptable salt or solvate thereof, R19 is: .... X6' . X8 8 , ............ .......... ....v..... ...v.v.

X4 -'-''----=--__.1 R1 r >__ R
Ns>_.R1h 1 h _ II \,,__R1 h 1 1 i \ 1 h ir-R1 h Y ,1"..".z. X8s. N --- i xi o -,... 4 xi o -,... 3 X7- ..------- 4 .s8.:z.x6 Q1X8' Qx11 Q ''= xi i Q

Q3 N Q4 0 .,.....,..N 04 o=Z',-,-, --- N

1 __________________________ Rill [ __ I Ri h 1 7 I
I ________________________________________________________ 1 h R Q5 I "_.R
i LI
X7- .
.X8 4 .N:_-_-Q3 N -Q4 X6 X4 \
x6, X6-- x4 ,or Q8 ------ Q3 , = , 01, Q3, and Q5 are independently N or C(Rld);
Q4 and Q6 are independently 0, S, C(R1a)(Rib), or N(R1c);
x4, xs, x6, x9, xio, xii, and X12 are independently selected from C(R1a) or N;
X' and X' are independently selected from C(R1a), C(Rla)(R1b), N, or N(R);
each Ria, Rib, Rid, and - K lh are each independently selected from hydrogen, halogen, -CN. CI-fancy', C1_6ha1oalkyl, C2_6alkenyl, C2_6alkynyl, C3.40cycloalkyl, C2_9heterocycloalkyl, C6_40aryl, C4_9heteroaryl, -0R12., -SR12., -N(R12)(R13), -C(0)0R12., -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R11)C(0)0R15, -N(RH)S(0)2R15, -C(0)R15, -S(0)R15, -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci.6alkyl, C2.6alkenyl, C2.6a1kynyl, C340cycloalkyl, C2_9heterocycloa1kyl, C6_10aryl, and Ci_9heteroaryl are optionally substituted with one, two, or three Rm; or Ria and Rib bonded to the same carbon are joined to form a 3-membered heterocycloalkyl ring or a C340cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C340cycloalkyl ring are optionally substituted with one, two, or three R201;
or two Rio bonded to adjacent atoms are
39 joined to form a 3-10 membered heterocycloalkyl ring, a C6_ioary1 ring, a 5-12 membered heteroaryl ring, or a C3-i0cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6_10a1y1 ring, 5-12 membered heteroaryl ring, or C3-locycloalky1 ring are optionally substituted with one, two, or three R
'1; or Rth and one of Rla, Rib, Ric, and Rid bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6.ioaryl ring, a 5-12 membered heteroatyl ring, or a C3_10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6_10aryl ring, a 5-12 membered heteroaryl ring, and C3.10cycloalkyl ring are optionally substituted with one, two, or three R2N; and each Re is independently selected from hydrogen, Ci_oalkyl, C2_6a1kcnyl, C2_6a1kyny1, C3_10cycloalkyl, C2-9helerocycloalkyl, C6.ioaryl, Ci_9heteroaryl, wherein Ci_6alkyl, C2.6a1kenyl, C2_6alkynyl, C3-locycloalkyl, C2_ 9heterocycloalkyl, C6_10aryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20i.
[0075] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is:

H2N )-----7N )- >7---N HO \-. HO
0 'v. --:----N
S 0 S 0 'Lc:- ,-;,-0 '-zar. F
F , F F n F , n n tc:
HO \-: H2N N "0-2? H2N N,., .2.,2 H2N N
-->- I I I,õ F F .-- N

....
F , NH2 , "22c.
C I C F3 F LLlCI
F , F , F , N_ i N___ N.__ N¨NH N¨N /
N/ p HN
HN lel HN io /

µV
/ N-0 _ HN 0 H
H
,.....N R.õ \ H2N N.., V.i.
_ N \
N F3, H2 N N .õ.,_ y HN ..Nl ,ytt-z.
N.\ ,-Uv , H HO
,NN '2,- H
'24.
H2N N ---j,,,..X.2- .,..., N HO
, -Gc-k.....r 3 ..L,.._ .j CF3 CFq OCF3, 01 - , , HO 0 'zizi HO-)2 F
µ,..

Na.,... ., 0\
CI CI C F 3 or NH2 .
. = , [0076] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R2 AO N----/
is selected from . N
, F F
OM e XO F
c:4410"---6:1 N 0 H \
N----Ao'6---) cH2F AcY'e N
---N----, , "s--0---\

, ..,,,01 _......6.--.
Xr,....,..õ Nr.,..,,.-- _,N--- , N----.
c'-'0 N
-----\ 0 F
0 ,,, F
, 0 . ,...
N
o .,..,.,=-, ¨r .21 ----.7 ,0 , .
x--", , 0.....0Me Xe, - 0CF2H -0... 1-D<F
N N F
/ z z ' A 0 Ao''''.
0 N (cy0Me $ ) \ N
= I xN-Th , L0 1\11- õ:0õ,),,, /.0,-..,- N. L,õ,0 . .
, N xo IN 40 '' 0 X0 NID-ass OH irss.o.s=Ce v-0 N
/ 0-- , N I
N
N, / H H , ".&.01\1-' ¨
I , , CiN c-'0 , r3st-0 r34t-0 1--I

Szzo N _..-. .*-=.,.,...0-.
' N
0p j, Xr\O 0 T1-1 0 /N
, ' , F
c:Fc.076-:? ,Iss'O
76\--Si ;goKNif-D rIsIFINO risl.INID
' S ' .7 c - ' - NO r 1 s 5:" ) c - NO 1:64 0 - ) C NO .. F ;5-51.'=
0 . ) c NO ., . .. F
F
c-ssZO2C NO ,,µF ;s4.07C NO ?ss"'OC N3 ;rrs.'0)C1\11 L-- , 0)C NO ;555-.0N ?ss',0c I
L,,, N ,, NO r140-'-'2c , ciss,o2sCN .
r'sr{0.)C N -Th A.OWCN ,5-02c 0 rlsOc , isrs OH / , .,..F
c-ssse siss ;Os ,:rss-Nõ......N. õ.,..õ.N..õ,..õ--N.- 0 1 c-ssf-a,, 0.--=:5?
--, ==....
and .
' Ot,o N

- -5(:)----) [0077] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, each R5 is independently selected from:

(R, P qp ,..,.......3,,,,,., _ pH vs,,,,õ---t1 pH -s---Nz-õ. pH,,, A.
.--N-,,,:= ,OH
õ1õ.. cr.....), NH .,.,.,...0), r41, i -r-NH
--H, --NII-.,., --OH, --NIA(C]..6 alkyl), Q
..Z.
A', N-0H -1--N ' N -0H ''Fr.".-''''''N Th'I-(3H NS ,N,OH
N
, x , ANOH
OH 1?
.-, rn ...,...) N-OH 117'nNi.12 ' [11 NH-, NH:, /
õ,.
r-N .1r---µ, , ,,,,,,,,t ',--NH2 õ. -",J,L, 0 x.. ,0 õ--., 0 , t.., NH H H NH NH NH
CN HNN, .II,, NCõNõA., NH
µ-2'zNH ' Y HN N ------ 1.- CN H2N
NH NC-r' N A NH
H I
2 , I , 1 , H I , , -CN, OH OH
OH
-;0I
-, ..--- -..rt -===,,e _..õ---,õ,_,...N H 2 ^,11,-,-,..õ.õ..01-1 1,,õµõ,,, '''Il kniC oFi Ar-L.,....-NH2 -gir----N1-12 "s-rr----OH I
N
FIJO ?-Thsv H i , ,r-NH 01(.4g , xi.) õ
õ..r.N...õ,õ.."^.-,0H =..,,,,.<õ, , glris-;
v,rcs,=,. ,-.
0 , 6 , 6 , 0 , 0 n-0 0 0 ow-0 b.,- 6-0 . .
,. .
..rt:1 r-----N ,-NH
H H
N.'S-A-)4 '4<-.S.',--1- '')* '''')., "'". N ';r N -OH
YirThr'N'OH
0 i,'"'0 0 0 0 0 a NH o fi , . = , , . , .
- --n-N'OH
ID and 6 -, and m, when pTeSeitt, is 0, 1, 2, or 100781 In an aspect is provided a compound having the formula A-LAB-B wherein A is a monovalent form of a compound of Formula I, IAL IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IAll, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIAll, IIA12, III, IV, V. VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; LAB is a covalent linker bonded to A and B; and B
is a monovalent form of a degradation enhancer.
190791 In an aspect is provided a compound having the formula A-LAB-B wherein A is a monovalent form of a compound of Formula I, IAL IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IAll, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIAll, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, I', IF, I", II", I-1, I-1', 1-1", 1-1'", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX; LAB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.

[0080] In embodiments, the degradation enhancer is capable of binding a protein selected from E3A, mdm2, APC, EDD1 , SOCS/BC-box/e1oBC/CUL5/RING, LNXp80, CBX4, CBLL 1, HACE 1, HECTD 1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HERS, HERC6, HUWEL ITCH.
NEDD4, NEDD4L, PPIL2, PRPF 19, PIAS 1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF
1, SMURF2, STUB 1 , TOPORS, TRIP 12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL
(von-Hippel-Lindau ubiquitin ligase), WWP 1, WWP2, Parkin, MKRNI, CMA (chaperon-mediated autophage), SCFb-TRCP
(Skip-Cullin-F box (Beta- __ IRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAP 1 (cellular inhibitor of apoptosis protein 1), APC/C (anaphase-promoting complex/cyclosomc), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4clun ubiquitin ligase, XIAP, TAP, KEAP 1, DCAF 15, RNF1 14, DCAF 1 6, AhR, SOCS2, KLIIL1 2, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB 1, SPSB2, SPSB4, SOCS6, FBX04, FBX031, BTRC, FBW7, CDC20, PML, TRIM2 1, TRIM24, TR1M3 3, GID4, avadomide, iberdomide, and CC-885.
[0081] In embodiments, the degradation enhancer is capable of binding a protein selected from UBE2A, UBE2B, UBE2C, UBE2D 1, UBE2D2, UBE2D3, UBE2DR, UBE2E 1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L 1, UBE2L2, UBE2L4, UBE2M, UBE2N, URF,20, URE201, URE2Q2, URE2R 1, URF2R 2, URE2S, UR-F.2T, URE2U, iTBEI2V 1, URF2V2, URE2W, UBE2Z, ATG3, BIRC6, and UFC1 .
[0082] In embodiments LAB is -LAw-LAB2-LAB3-LAB4-LAB5_, LAB1, LAB2, LAB3, AB4, 1_, and L'35 are independently a bond, -0-, -N(R")-, -C(0)-, -N(R")C(0)-, -C(0)N(R")-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R")-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci_balkylenc, (-0-C1.6alkyl)z-, (-C1-6alky1-0)z-, C2_6a1kenylene, C2_6alkynylene, C1_6haloalkylene, C3_12cycloa1ky1ene, Ci_nheterocycloalkylene, C6.
122uylene, or Ci_iiheteroarylene, wherein C1_6a1kylene, C2_6alkenylene, C2_6a1kyny1ene, Ci_6haloalkylene, C3-ucycloalkylene, C1.11heterocycloa1kylene, C6_12arylene, or Ci_iiheteroarylene,are optionally substituted with one, two, or three R20-i, wherein each Ci_6alkyl of (-0-C1_6a1kyl)z- and (-C1.6a1ky1-0)z- is optionally substituted with one, two, or three R20-j:
z is independently an integer from 0 to 10:
each R12 is independently selected from hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3.
6cyc1oa1ky1, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10aryl, -CH2-C6_10ary1, -CH2-Ci_9heteroaryl, and C1_ 9heteroaryl, wherein C1-6a1kyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cyc1oalkyl, C2_9heterocycloa1ky1, -CH2-C2_9heterocycloalkyl, C6_maryl, -CH2-C6_10aryl, -CH2-Ci.9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R203:
each R13 is independently selected from hydrogen, C1_6a1kyl, and C1_6haloalkyk or 1112 and R43, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R20e;
each R14 is independently selected from hydrogen, C1_6a1kyl, and C1_6haloalkyl;
each R15 is independently selected C1_6alkvl, C2_6a1kenyl, C2_6alkynyl, C3_6cyc1oa1kyl, C2_9heterocycloa1kyl, C6_10aryl, and C1.9heteroalyl, wherein C1_6alkyl, C2_6allcenyl, C2_6a1kynyl, C3_6cyc1oalkyl, C2.9heterocycloalkyl, C6_10aryl, and C1_9heteroary1 are optionally substituted with one, two, or three R20f;
each R2 d, 2R 0e, rc ,-,20f, and R20-1 are each independently selected from halogen, -CN, C1_6alkyl, C2_6alkeny1, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloal1kyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_1oaryl, -CH2-C6_10aryl, -CH2-C1_9heteroary1, C1_9heteroaryl, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein Ci_6alky1, C2-6alkenyl, C2-6alkynyl, C3_6cyc1oa1ky1, -CH2-C3_6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocyc1oalkyl, C6--CH2-C6.10aryl, -CH2-C1_9heteroaryl, and C1_9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci.6a1k0, Ci_6haloalkO, Ci_6alkoxy, Ci_6haloalkoxy, -sR217 _N(R22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
cach R21 is independently selected from H, C1_6alkyl, C1_6haloalkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cyc1oalkyl, C2_ 9heterocycloalkyl, C6.10aryl, and Ci_9he1eroary1;
each R22 is independently selected from H, Ci_6alkyl, Ci6haloalkyl.
C2_6alkenyl, C2_6a1kynyl, C3_6cyc1oalkyl, C2_ 9heterocycloalkyl, C6.1oaryl, and Ci_9heteroaryl;
each R23 is independently selected from H and Ci_6alkyl;
each R24 is independently selected from H and C1_6alky1; and each R2' is selected from Ci_6a1kyl, C2.6a1kenyl, C2_6alkynyl, C_6cycloalkyl, C2_9heterocycloa1kyl, C6_10aryl, and C1.
9heteroa tyl [0083] In embodiments, LAB is -(0-C2alkyl),- and z is an integer from 1 to 10.
[0084] In embodiments, LAB is -(C2alky1-0-),- and z is an integer from 1 to 10.
[0085] In embodiments, LAB is -(CH2)z1Dth2(CH20)z2-, wherein LA-132 is a bond, a 5 or 6 membered heterocycloalkylene or heteroarylene, phenylene, -(C2-C4)alkynylene, -SO2- or -NH-; and zl and z2 are independently an integer from 0 to 10.
[0086] In embodiments, LAB is -(CH2)zi(C1-120)z2-, wherein zl and z2 are each independently an integer from 0 to 10.
100871 In embodiments, LAB is a PEG linker (e.g., divalent linker of 1 to 10 ethylene glycol subunits).
[0088] In embodiments, B is a monovalent form of a compound selected from PH
QV PH

,=

\
11:1C
0 fi4 0 = =

t4 9 õAs..ç 0 1, A w 0 NH, a irt,41-1 , rTh j =====<
c. fi'Nr =
t4A
õz\i.11 p $ 0 t Nutlin .:(--pgrNya M = 1 X
-4"z idasanutlin -:
a a Nk\. , s'y''-`tas.-^ -Ns '=====r" "
ti .1414.-v"
404 ' and `C) [0089] In an aspect is provided a pharmaceutical composition comprising a compound described herein (e.g., compound of Formula 1, IA1, IA2, IA3, IA4, TA5, TA6, IA7, TAR, IA9, TA 1 0, TA
I I, TA 12, II, TIA 1, IIA2, TIA3, TIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA1 0, IIA1 I, I1Al2, III, IV, V. VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV;
compound of Formula I', II', I", II", I-I, I-1', I-1", I-i", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
[0090] In an aspect is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., compound of Formula T, IA 1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA1, IA1 1, IA12, II, IA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA1 1, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", 11", 1-1, 1-1', 1-1 ", 1-1 ", 1-3, 1-4, 11-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof.
[0091] In an aspect is provided a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA1, IA1 1, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA1 0, HAUL, I1Al2, Ill, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', 1", II", 1-1, 1-1', 1-1 ", 1-1 ' ", 1-3, 1-4,11-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras (e.g., K-Ras) protein [0092] In some embodiments, the subject method comprises administering an additional agent or therapy.
100931 In an aspect is provided a method of inhibiting cell growth, comprising administering an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA1, 1A1 1, 1Al2, 11, 11A1, 11A2, 11A3, 11A4, 11A5, 11A6, 11A7, 11A8, 11A9, 11A10, 11A1 1, I1Al2, 111, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", II", I-1, I-1', 1-1", 1-1" 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras (e.g., K-Ras) protein, thereby inhibiting growth of said cells. In embodiments, the subject method comprises administering an additional agent to said cell.
100941 In an aspect is provided a Ras (e.g., K-Ras) protein bound by a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA1 1, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA1 0, IIA1 I, I1Al2, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV;
compound of Fonnula I', II', I", II", I-1, I-1', I-1", 1-1"', 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein activity of said Ras (e.g., K-Ras) protein is reduced as compared to a Ras (e.g., K-Ras) protein unbound to said compound.

INCORPORATION BY REFERENCE
[0095] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION
[0096] The practice of some embodiments disclosed herein employ, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See for example Sambrook and Green, Molecular Cloning:
A Laboratory Manual, 4th Edition (2012); the series Current Protocols in Molecular Biology (F. M. Ausubel, et al.
eds.); the series Methods In Enzymology (Academic Press, Inc.), PCR 2: A
Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th Edition (R.I. Freshney, ed. (2010)).
[0097] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public di sse m i natio n of such info rmatio n.
[0098] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the tem_ "including" as well as other fonns, such as "include", "includes,"
and "included," is not limiting.
[0099] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
[00100] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg "Advanced Organic Chemistry 41h Ed." Vols. A (2000) and B
(2001), Plenum Press, New York.
Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology.
[00101] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field.
Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.
[00102] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.
[00103] As used herein, C1-Cõ includes C1-C2, C1-C3. . .
Ci-Cx refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).
[00104] An "alkyl" group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. In some embodiments, the "alkyl" group may have 1 to 18, 1 to 12, 1 to 10, 1 to 8, or 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as "1 to 6" refers to each integer in the given range; e.g., "1 to 6 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated).
The alkyl group of the compounds described herein may be designated as "Ci-e6allcyl" or similar designations By way of example only, "Ci-C6allcyl"
indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, and hex0. Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).
[00105] An "alkoxy" refers to a "-0-alkyl" group, where alkyl is as defined herein.
[00106] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond.
Non-limiting examples of an alkenyl group include -CH=CH,, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2 and ¨C(CH3)=CHCH3. In some embodiments, an alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted.
Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).
[00107] The term "alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond.
Non-limiting examples of an alkynyl group include -CCCH3, ¨CCCH2CH3 and ¨C.CCH2CH2CH3. In some embodiments, an alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted.
Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).
[00108] "Amino" refers to a -NH? group.
[00109] The term "alkylamine- or "alkylamino- refers to the -N(alkyl)õHy group, where alkyl is as defined herein and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system.
"Dialkylamino" refers to a -N(alkyl)2 group, where alkyl is as defined herein.
[00110] The tenni "aromatic" refers to a planar ring having a delocalized a-electron system containing 4n+2 a electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The temi -aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
[00111] As used herein, the term "aryl" refers to a monocyclic aromatic ring wherein each of the atoms forming the ring is a carbon atom (e.g., phenyl) or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is carbocyclic and aromatic, 2) a bond to the remainder of the compound is directly bonded to a carbocyclic aromatic ring of the aryl ring system, and 3) the carbocyclic aromatic ring of the aryl ring system of 2) is not directly bonded (e.g., fused) to a heteroaryl ring in the polycyclic ring system. Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the stmcture, an awl group can be a monoradical or a diradical (i.e., an arylene group). As used herein, the aiy1 radical is a monocyclic, bicyclic, or tricyclic ring system. In embodiments, an aryl is a monocyclic ring. In embodiments, an aryl is a fused ring polycyclic system. In embodiments, an aryl is a bridged ring polycyclic system. In some embodiments the aryl is a "fused ring aryl" wherein the aryl ring is fused with a cycloalkyl or a heterocycloalkyl ring.
[00112] "Carboy" refers to -CO2H. In some embodiments, carboy moieties may be replaced with a "carboxylic acid bioisostere", which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group.
Examples of bioisosteres of a carboxylic NV" = N-0 m¨S
is.
=
)1, N _OH AN,CN

, H
acid include, but are not limited to, OH
cr, 0 I \NI IN I
OH OH 0 and the like.
[00113] The term "cycloalkyl" refers to a monocyclic carbocyclic saturated or partially unsaturated non-aromatic ring or a polycyclic carbocyclic (i.e., does not include heteroatom(s)) ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is carbocyclic saturated or partially unsaturated and non-aromatic, 2) a bond to the remainder of the compound is directly bonded to a carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system, and 3) the carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system of 2) is not directly bonded (e.g., fused or spirocyclic) to a heterocycloalkyl ring in the polycyclic ring system. Cycloalkyls may be saturated or partially unsaturated. In some embodiments, a cycloalkyl ring is a spirocyclic cycloalkyl ring. In embodiments, a cycloalkyl is a monocyclic ring. in embodiments, a cycloalkyl is a fused ring polycyclic system. In embodiments, a cycloalkyl is a bridged ring poly-cyclic system. In embodiments, a cycloalkyl is a spirocyclic polycyclic ring system. In some embodiments, cycloalkyl groups include groups having from 3 to 10 ring atoms.
Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (i.e., a cvcloalkylene group).
[00114] The terms "heteroatyl" or, alternatively, "heteroaromatic" refers to an monocyclic aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur; or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is aromatic and includes one or more heteroatoms selected from nitrogen, oxygen and sulfur and 2) a bond to the remainder of the compound is directly bonded to an aromatic ring including one or more heteroatoms selected from nitrogen, oxygen and sulfur or an aromatic ring directly bonded (e.g., fused) to an aromatic ring including one or more heteroatoms selected from nitrogen, oxygen and sulfur, of the atyl ring system. As used herein, the heteroatyl radical may be a monocyclic, bicyclic, or tricyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated (i.e., aromatic) and includes a heteroatom. In embodiments, a heteroaryl is a monocyclic ring. In embodiments, a heteroarvl is a fused ring polycvclic system. In embodiments, a heteroaryl is a bridged ring polycyclic system. In some embodiments is a "fused ring heteroaryl"
wherein the heteroaryl ring is fused with a cycloalkyl, aryl, or heterocycloall0 ring. An N-containing "heteroaromatic- or "heteroaryl. moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group).
[00115] A "heterocycloalkyl- group or "heteroalicyclic- group refers to a cycloalkyl group, wherein at least one skeletal ring atom of a saturated or partially unsaturated non-aromatic ring is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. A heterocycloalkyl refers to a monocyclic saturated or partially unsaturated non-aromatic ring including one or more heteroatoms or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is saturated or partially unsaturated, non-aromatic, and includes one or more heteroatoms and 2) a bond to the remainder of the compound is directly bonded to a ring of the ring system that is a saturated or partially unsaturated and non-aromatic ring that includes one or more heteroatoms or a non-aromatic ring directly bonded (e g , fused) to a saturated or partially unsaturated and non-aromatic ring that includes one or more heteroatoms of the ring system. Heterocycloalkyls may be saturated or partially unsaturated.
The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In some embodiments, a heterocycloalkyl ring is a spirocyclic heterocycloalkyl ring. In embodiments, a heterocycloalkyl is a monocyclic ring. In embodiments, a heterocycloalkyl is a fused ring polycyclic system. In embodiments, a heterocycloalkyl is a bridged ring polycyclic system. In embodiments, a heterocycloalkyl is a spirocyclic polycyclic ring system. Unless otherwise noted, heterocycloalkyls have from 2 to 13 carbons in the ring or ring system. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group).
[00116] The term "halo" or, alternatively, "halogen- means fluoro, chloro, bromo and iodo.
[00117] The abbreviations "Fmoc", "Ac", "Bn", "PMB", "Tr", "Ts", "Boc", and "Cbz" are used in accordance with their well understood common meanings in Chemistry and mean the monovalent chemical substituents fluorenylmethyloxycarbonyl, acetyl. benzyl, p-methoxybenzyl, trityl or triphenylmethyl, tosyl, tert-butyloxycarbonyl, and carbobenzyloxy, respectively.
[00118] The term "haloalkyr refers to an alkyl group that is substituted with one or more halogens. The halogens may the same or they may be different. Non-limiting examples of haloalkyls include -CH2C1, -CF3, -CHF2, -CH2CF3, -CF2CF3, and the like.
[00119] The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyls include -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, and the like. Non-limiting examples of fluoroalkoxy groups, include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -0CF2CF3, -0CF2CF2CF3, -0CF(CH3)2, and the like.
[00120] The term "heteroalkylene linker" refers to a divalent alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. In some embodiments, the heteroatom(s) may be placed at any interior position of the heteroalkyl group. In some embodiments, the heteroatom(s) may be placed at one or both terminal positions of the heteroalkylene linker (i.e., position(s) directly bonded to portion(s) of the molecule other than the heteroalkylene linker). Examples include, but are not limited to, -CH2-0-CH2-, -CH2-CH2-0-CH2-. -CH2-NH-CH2-, -C112-CH2-NH-CH2-, -CH2-N(CH3)-CH2-, -CH2-CH2-N(CH3)-CH2-, -CH2-S-CH2-CH2-, -CH2-CH2-S(0)-CH2-, -CH2-CH2-S(0)2-CH2-, -CH2-NH-O-CH2-, -CH2-0-Si(CH3)2-, -CH2-CH=N-0-CH2-, and -CH=CH-N(CH3)-CH2-.
Examples include, but are not limited to, -CH2-0-, -CH2-CH2-0-, -CH2-NH-, -CH2-CH2-NH-, -CH2-N(CH3)-, -CH2-CH2-N(CH3)-, -CH2-S-, -CH2-CH2-S-, -CH2-CH2-S(0)-, -CH2-CH2-S(0)2-, -CH2-S(0)-, -CH2-S(0)2-, -CH2-CH2-CH2-S(0)-, -CH2-CH2-CH2-S(0)2-, -CH2-CH2-CH2-0-, -CH2-CH2-CH2-0-, -CH2-CH2-CH2-S-, -CH2-CH2-CH2-S-, -CH2-CH2-CH2-NH-, -CH2-CH2-CH2-NH-, -CH2-CH2-CH2-N(CH3)-, -CH2-CH2-CH2-N(CH3)-, -CH2-NH-0-, -0-Si(CH3)2-, -CH2-CH=N-0-, and -CH=CH-N(CH3)-. Examples include, but are not limited to, -0-CH2-, -0-CH2-CH2-, -NH-CH2-, -NH-CH2-CH2-, -N(CH3)-CH2-, -N(CH3)-C112-CH2-, -S-CH2-, -S(0)-CH2-CH2-, -S(0)2-CH2-CH2-, -S(0)-CH2-, -S(0)2-CH2-, -S(0)-CH2-CH2-CH2-, -S(0)2-CH2-CH2-CH2-, -0-CH2-CH2-CH2-, -0-CH2-CH2-CH2-, -S-C112-CH2-CH2-, -S-C112-CH2-042-, -NH-CH2-CH2-CH2-, -NH-CH2-CH2-CH2-, -N(C113)-C112-CH2-CH2-, -N(CH3)-CH2-CH2-CH2-, -0-NH-CH2-, -Si(CH3)2-0-, -0-N=CH-CH2-, and -N(C113)-CH=CH-. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-0- and -0-Si(CH3)2-Examples include, but are not limited to, -P(0)(CH3)-CH2-, -P(0)(CH3)-CH2-CH2-, -P(0)(CH3)-CH2-CH2-CH2-,-CH2-P(0)(CH3)-, -CH2-CH2-P(0)(CH3)-, and -CH2-CH2-CH2-P(0)(CH+. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-0- and -0-SUCH3)2-. Alieteroalkylene linker" may have from 2 to 4 main chain atoms unless specified otherwise.
[00121] The term "heteroalkyl" refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group.
Examples include, but are not limited to, -CH2-0-CH3, -CH2-CH2-0-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-C112-N(CH3)-CH3, -C112-S-C112-CH3. -C112-C112-S(0)-CH3, -C112-CM-S(0)2-CH3. -CH2-NH-0C113, -CI12-0-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3 and -CH2-0-Si(CH3)3. Excluding the number of heteroatoms, a "heteroalkyl- may have from 1 to 6 carbon atoms.
[00122] The term "oxo" refers to the =0 radical.
[00123] The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
[00124] The term "moiety" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
[00125] The suffix "-di-yr will be understood to mean the substituent or linker is a divalent substituent or linker.
[00126] As used herein, the substituent "R" appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.
[00127] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.
[00128] The term "optionally substituted" or "substituted" means, unless otherwise specified, that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1-C6alkylalkyne, halo, acyl, acyloxy, -0O2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g. ¨NH2, -NHR, -N(R)?), and the protected derivatives thereof. By way of example, an optional substituents may be L'Rs, wherein each LS is independently selected from a bond, -0-, -C(=0)-, -S-, -S(=0)-, -S(=0)2-, -NH-, -NHC(0)-, -C(0)NH-, S(=0)2NH-, -NHS(=0)2, -0C(0)NH-, -NHC(0)0-, -(Ci-C6alkyl)-, or -(C2-C6alkeny1)-; and each Rs is independently selected from among H, (Ci-C6alkyl), (C3-C8cycloalkyfl, aryl, heteroaryl, heterocycloalkyl, and C1-Coheteroalkyl. The protecting groups that may form the protective derivatives of the above sub stituents arc found in sources such as Greene and Wuts, above.
[00129] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
[00130] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarbox0c acids, phenyl-substituted alkanoic acids, hydmxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and, aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galarturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
[00131] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, anmionium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines.
piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.
[00132] The terms "polypeptide", "peptide" and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified;
for example, disulfide bond formation, glycosylation, lipidation, acetylation, phospholylation, or any other manipulation, such as conjugation with a labeling component. As used herein the term "amino acid- refers to either natural and/or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.
[00133] The terms "polynucleotide", "nucleotide", "nucleotide sequence", "nucleic acid" and "oligonucleotide"
are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A
polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid (PNA), Morpholino and locked nucleic acid (LNA), glycol nucleic acid (GNA), threose nucleic acid (TNA), 2'-fluoro, 2'-0Me, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.
[00134] As used herein, "expression" refers to the process by which a polynucleotide is transcribed from a DNA
template (such as into and mRNA or other RNA transcript) and/or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. Transcripts and encoded polypeptides may be collectively referred to as "gene product." If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell.
[00135] The terms "subject," "individual," and "patient" are used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.
[00136] The terms "therapeutic agent", "therapeutic capable agent" or "treatment agent" are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject. The beneficial effect includes enablement of diagnostic determinations;
amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.
[00137] As used herein, "treatment" or "treating," or "palliating" or "ameliorating" are used interchangeably.
These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment.
For prophylactic benefit, the compositions may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more of the physiological symptoms of a disease, even though the disease, condition, or symptom may not have yet been manifested. Typically, prophylactic benefit includes reducing the incidence and/or worsening of one or more diseases, conditions, or symptoms under treatment (e.g. as between treated and untreated populations, or between treated and untreated states of a subject).
[00138] The term -effective amount- or "therapeutically effective amount"
refers to the amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manlier of administration and the like, which can readily be determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or in multiple doses. A
component may be described herein as having at least an effective amount, or at least an amount effective, such as that associated with a particular goal or purpose, such as any described herein. The term "effective amount" also applies to a dose that will provide an image for detection by an appropriate imaging method. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.
[00139] The term -in vivo" refers to an event that takes place in a subject's body.
[00140] The term "ex vivo" refers to an event that first takes place outside of the subject's body for a subsequent in vivo application into a subject's body. For example, an ex vivo preparation may involve preparation of cells outside of a subject's body for the purpose of introduction of the prepared cells into the same or a different subject's body.
[00141] The term "in vitro" refers to an event that takes place outside of a subject's body. For example, an in vitro assay encompasses any assay run outside of a subject's body. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.
[00142] The term "Ras" or "RAS" refers to a protein in the Rat sarcoma (Ras) superfamily of small GTPases, such as in the Ras subfamily. The Ras superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK
subfamily, Pit subfamily, Miro subfamily, and Unclassified subfamily. In some embodiments, a Ras protein is selected from the group consisting of KRAS (also used interchangeably herein as K-Ras, K-ras, Kras), HRAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.
[00143] The terms "Mutant Ras" and "Ras mutant," as used interchangeably herein, refer to a Ras protein with one or more amino acid mutations, such as with respect to a common reference sequence such as a wild-type (WT) sequence. In some embodiments, a mutant Ras is selected from a mutant KRAS, mutant HRAS, mutant NRAS, mutant MRAS, mutant ERAS, mutant RRAS2, mutant RALA, mutant RALB, mutant RIT1, and any combination thereof, such as from a mutant KRAS, mutant HRAS, mutant NRAS, mutant RALA, mutant RALB, and any combination thereof. In some embodiments, a mutation can be an introduced mutation, a naturally occurring mutation, or a non-naturally occurring mutation. In some embodiments, a mutation can be a substitution (e.g., a substituted amino acid), insertion (e.g., addition of one or more amino acids), or deletion (e.g., removal of one or more amino acids). In some embodiments, two or more mutations can be consecutive, non-consecutive, or a combination thereof. In some embodiments, a mutation can be present at any position of Ras. In some embodiments, a mutation can be present at position 12, 13, 62, 92, 95, or any combination thereof of Ras relative to SEQ ID No. 1 when optimally aligned. In some embodiments, a mutant Ras may comprise about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50 mutations. In some embodiments, a mutant Ras may comprise up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mutations. In some embodiments, the mutant Ras is about or up to about 500, 400, 300, 250, 240, 233, 230, 220, 219, 210, 208, 206, 204, 200, 195, 190, 189, 188, 187, 186, 185, 180, 175, 174, 173, 172, 171, 170. 169, 168, 167, 166, 165, 160, 155, 150, 125, 100, 90, 80, 70, 60, 50, or fewer than 50 amino acids in length. In some embodiments, an amino acid of a mutation is a proteinogenic, natural, standard, non-standard, non-canonical, essential, non-essential, or non-natural amino acid. In some embodiments, an amino acid of a mutation has a positively charged side chain, a negatively charged side chain, a polar uncharged side chain, a non-polar side chain, a hydrophobic side chain, a hydrophilic side chain, an aliphatic side chain, an aromatic side chain, a cyclic side chain, an acyclic side chain, a basic side chain, or an acidic side chain. In some embodiments, a mutation comprises a reactive moiety. In some embodiments, a substituted amino acid comprises a reactive moiety. In some embodiments, a mutant Ras can be further modified, such as by conjugation with a detectable label In some embodiments, a mutant Ras is a full-length or truncated polypeptide. For example, a mutant Ras can be a truncated polypeptide comprising residues 1-169 or residues 11-183 (e.g., residues 11-183 of a mutant RALA or mutant RALB).
[00144]
indicates the location of attachment (e.g., location of a bond to another atom) of the depicted chemical formula or atom to a substituent, a further component of a molecule, or an atom. - may equivalently be located at the end of a bond or overlapping a bond.
[00145] The term "corresponds" or "corresponding" as used herein to refer to an amino acid or protein residue shall be understood to mean that the selected residue occupies the same essential structural position within the protein as the given residue. The essentially same structural position within the protein may be within the three dimensional conformation of the folded protein or may be the location of the residue in the primary sequence of the protein. For example, a selected residue in a protein corresponds to Cys12 of a human Ras (e.g., human K-Ras) protein when the selected residue occupies the same essential spatial or other structural position as Cys12 in the human Ras (e.g., human K-Ras) protein. In some embodiments, where a selected protein is aligned for maximum homology with the human Ras (e.g., human K-Ras) protein, the position in the aligned selected protein aligning with Cys12 is said to correspond to Cys12. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the human K-Ras protein and the overall structures compared. In this case, an amino acid that occupies the same essential position as Cys12 in the structural model is said to correspond to the Cys12 residue. For example, a selected residue in a protein corresponds to Cys13 of a human Ras (e.g., human K-Rasa) protein when the selected residue occupies the same essential spatial or other structural position as Cvs13 in a human Ras (e.g., human K-Ras) protein, similar to the example of Cys12 above.
[00146] In embodiments, a C3_10cycloalkyl is a 3 membered cycloalkyl. In embodiments, a C3_iocy cloalkyl is a 4 membered cycloalkyl. In embodiments, a C3_10cycloalkyl is a 5 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 6 membered cycloalkyl. In embodiments, a C3_iocycloalkyl is a 7 membered cycloalkyl. In embodiments, a C340cycloalkyl is a 8 membered cycloalkyl. In embodiments, a C3.10cycloallwl is a 9 membered cycloalkyl. In embodiments, a C3-10cycloalkyl is a 10 membered cycloalkyl. In embodiments, a Ci-locycloalkyl is a 3-10 membered cycloalkyl. In embodiments, a C2_9heterocycloalkyl is a 3 membered heterocycloalkyl. In embodiments, a C2_9heterocycloallql is a 4 membered heterocycloalkyl. In embodiments. a C29heterocycloalkyl is a membered heterocycloalkyl. In embodiments, a C2_9heterocycloalkyl is a 6 membered heterocycloalkyl. In embodiments, a C2_9heterocycloalkyl is a 7 membered heterocycloalkyl. In embodiments. a C2_9heterocycloalkyl is a 8 membered heterocycloalkyl. In embodiments, a C2_9heterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, a C2_9heterocycloalkyl is a 10 membered heterocycloalkyl. In embodiments, a C2_9heterocycloalkyl is a 11 membered heterocycloalkyl. In embodiments, a C2_9heterocycloalkyl is a 12 membered heterocycloalkyl. In embodiments, a C2_9heterocycloalkyl is a 3-12 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 3 membered heterocycloalkyl. In embodiments, a C2_iiheterocycloalkyl is a 4 membered heterocycloalkyl. In embodiments, a C24iheterocy-cloalkyl is a 5 membered heterocycloalkyl. In embodiments, a C2-liheterocycloalkyl is a 6 membered heterocycloalkyl. In embodiments, a C2.13heterocycloalkyl is a 7 membered heterocycloalkyl. In embodiments, a C2-liheterocy-cloalkyl is a 8 membered heterocycloalkyl. In embodiments, a C2-liheterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, a C2.13heterocycloalkyT1 is a 10 membered heterocycloalkyl. In embodiments, a C24 iheterocy-cloalkyl is a 11 membered heterocycloalkyl. In embodiments, a Cl_llheterocycloalkyl is a 12 membered heterocycloalkyl. Tn embodiments, a Cl_llfieterocycloalkyl is a 3-12 membered heterocycloalkyl. In embodiments, a Ci_iiheterocycloalkyl is a 3 membered heterocycloalkyl. In embodiments, a C1_, heterocycloalkyl is a 4 membered heterocycloalkyl. In embodiments, a Ci.ilheteroeycloalkyl is a 5 membered heterocycloalkyl. In embodiments, a Ci_pheterocycloalkyl is a 6 membered heterocycloalkyl. In embodiments, a Cr_iiheterocycloalkyl is a 7 membered heterocycloalkyl. In embodiments, a Ci.iiheteroeycloalkyl is a 8 membered heterocycloalkyl. In embodiments, a Ci_iiheterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, a Cr_iiheterocycloalkyl is a 10 membered heterocycloalkyl. In embodiments, a Ci_iiheterocycloalkyl is a 11 membered heterocycloalkyl. In embodiments, a Ci_iiheterocycloalkyl is a 12 membered heterocycloalkyl. In embodiments, a Cr_iiheterocycloalkyl is a 3-12 membered heterocycloalkyl. In embodiments, a C642aryl is a 6 membered aryl. In embodiments, a C6_paryl is a 7 membered aryl. In embodiments, a C6_12aryl is a 8 membered aryl. In embodiments, a C6.12a1y1 is a 9 membered aryl. In embodiments, a C6_12ary-1 is a 10 membered aryl. In embodiments, a C642atyl is a 11 membered aryl. In embodiments, a C642a1y1 is a 12 membered aryl. In embodiments, a C6_12a1yl is a 6-12 membered aryl. In embodiments, a Ci_iiheteroaryl is a 5 membered heterocycloalkyl. In embodiments, a Ci_iiheteroaryl is a 6 membered heterocycloalkyl. In embodiments, a llheteroaryl is a 7 membered heterocycloalk0. In embodiments, a Ci_llheteroaryl is a 8 membered heterocycloalk0.
In embodiments, a C1_, iheteroaryl is a 9 membered heterocycloalkyl. In embodiments. a C14 I heteroaryl is a 10 membered heterocycloalkyl. In embodiments, a Ci_iiheteroaryl is a 11 membered heterocycloalkyl. In embodiments, a Cr_iiheteroaryl is a 12 membered heterocycloalkyl. In embodiments, a Ci_iiheteroaryl is a 5-12 membered heterocycloalkyl. In embodiments, a C3_6cycloalkyl is a 3 membered cycloalkyl. In embodiments, a C3-6cycloalkyl is a 4 membered cycloalkyl. In embodiments, a C3.6cycloalkyl is a 5 membered cycloalkyl. In embodiments, a C3_6cycloalkyl is a 6 membered cycloalkyl. In embodiments. a C6_10ary1 is a 6 membered aryl. In embodiments, a C6_10aryl is a 7 membered aryl. In embodiments, a C6_10aryl is a 8 membered aryl. In embodiments, a C6_10aryl is a 9 membered aryl. In embodiments, a C6_10aryl is a 10 membered aryl. In embodiments, a Cm_ ,heteroaryl is a 5 membered heterocycloalkyl. In embodiments, a Cl.,heteroaryl is a 6 membered heterocycloalkyl.
In embodiments, a Ci_9heteroaryl is a 7 membered heterocycloalkyl. In embodiments, a Ci_9heteroaryl is a 8 membered heterocycloalkyl. In embodiments, a Ci_9heteroaryl is a 9 membered heterocycloalkyl. In embodiments, a C1_9heteroary1 is a 10 membered heterocycloalkyl. In embodiments, a CI.,heteroaryl is a 11 membered heterocycloalkyl. In embodiments, a Ci_9heteroaryl is a 12 membered heterocycloalkyl. In embodiments, a C1_ 9heteroaryl is a 5-12 membered heterocycloalkyl.
Compounds [00147] The compounds of Fommla I, IA1, IA2, IA3, IA4, IA5, JAG, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, hAl 1, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, I', II', I", II", I-1, I-1', I-1", I-1" I-3, I-4, II-1, XVI, XVII, XVIII, or XIX, or a pharmaceutically acceptable salt or solvate thereof, are Ras (e.g., K-Ras, K-Ras WT, or K-Ras (iIl12D) modulators (including Ras inhibitors) and have a wide range of applications in therapeutics, diagnostics, and other biomedical research.
[00148] In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

N
N X

R Formula (I);
wherein W is C(0), S(0), or S(0)2;
V is C(R') and J is C(R"), or V is C(R") and J is N, or J is C(R') and V is C(R'), or J is C(R') and V is N;
R1 is -1_,7-R7;
1_,7 is a bond, -0-, -N(R")-, -C(0)-, -N(R")C(0)-, -C(0)N(RH)-, -S-, -S(0)2-, -S(0)-. -S(0)2N(R14)-, -S(0)N(R")-, -N(R")S(0)-, -N(R14)S(0)2-, Ci-Coalkyl, C2-C6alkenyl, or C2-C6a1kynyl, wherein CI-C6alkyl, C2-C6alkenyl, and C2-C6a1kynyl, are optionally substituted with one, two, or three R2 a;
R7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl, wherein the 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more R1, one or more R4, or one or more R6;
wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C342cycloalkyl, Ci_iiheterocycloalkyl, C6_12a1yl, or Ci_iiheteroaryl, wherein the C3_12cyc1oa1ky1, Citiheterocycloalkyl, C6_12ary1, or Ci_iiheteroaryl are optionally substituted with one, two, or three R2 a;
each R1 is independently selected from hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6haloalkyl, C3_ 12cyc1oa1ky1, -CH2-C3_12cyc1oa1ky1, Ci_iiheterocycloalkyl, -CH2-C1_11heterocycloallcyl, C6_12aryl, 12aryl. -Cf12-Cl_ilheteroaryl, and Ci_iiheteroaryl, wherein Cl_nalkyl, C2.6alkenyl, C2.6alkynyl, C1_6haloalkyl, C342cycloalkyl, -CH2-C3.12cyc1oa1ky1, Ci_iiheterocycloalkyl, -CH2-Ci_nheterocycloalkyl, C6_12a1y1, -CH2-C642a1yl, -CH2-Ci_11heteroa1y1, and Ci_iiheteroaryl are optionally substituted with one, two, or three R26a;
each R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci.6alkyl, C2_6alkenyl, C2_6a1kynyl, C3.
6cycloalkyl, C2_9heterocycloa1kyl, C6_10aryl, C1_9heteroatyl, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -OC(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R1', -N(R14)S(0)2R1', -C(0)R1), -S(0)R15, -OC(0)R15, -C(0)N(R12)(R'), -C(0)C(0)N(R12)(R'), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R')-, S(-0)(=NH)N(R12)(Ri3).
, CH2C(0)N(Ri2)(Ri3s) CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C1_6a1ky1, C2_6a1keny1, C2_6a1kyny1, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6 ,aryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20a;
R is -L2.-R5;
each L2 is independently selected from a bond, Cl-C6alkyl, -0-, -N(Rm)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R13)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(Rm)-, -S(0)N(104)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(R14)C(0)0-, and -N(R14)C(0)N(104)-;
each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cystcine residue at position 12 of a KRAS protein;
fe is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3.6cy cloalkyl, C2_ 9heterocycloalkyl, C6_10alyl, Ci_9heteroa1y1, -0R12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0105, -N(R14)S(0)2R15, -C(0)105, -S(0)105, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(102)(103), -N(104)C(0)105, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=N11)N(R12)(R13), -CH2C(0)N(1212)(-13), CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(102)(R-13), wherein Ci_salkyl, C2.6alkenyl, C2.6alkynyl, C3.6cycloalkyl, C2.9heterocycloalkyl, Cs.
ioaryl, and Ci_9heteroaty1 are optionally substituted with one, two, or three 1:22 c;
R1' is -L1-R19;
1_,1 is selected from a bond, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R')C(0)-, -C(0)N(104)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R")-, -S(0)N(104)-, -N(104)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(104)C(0)0-, N(Rie), C(0)N(109, S(0)2N(f0c), S(0)N (10c), C(Rif)(10g)0, C(R1f)(10g)N(R1), and C(111f)(R1g);
R1e, Rif, and Rls are independently selected from hydrogen, halogen, -CN, C1_6alkyl, Ci_6haloalkyl, C2_6alkenyl, C2.6a1kynyl, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6_10aryl, Ci.9heteroary1, -SR12, -N(R12)(103), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(102)(R13), -N(R14)C(0)01:05, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15. -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)105, -S(0)2R15, -S(0)2N(F02)(RH)-, S(=0)(=NH)N(R12)(RH), -CH2C(0)N(102)(R13), -CH2N(RH)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6alkenyl, C2_6allcynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, Co_loatyl, and Ci_,heteroaryl are optionally substituted with one, two, or three R2 1; or RH.
and R1g are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Ric is selected from hydrogen, Ci.6a1ky1, C2_6alkenyl, C2.6alkynyl, C3.6cycloalkyl, C2_9heterocycloa1kyl, C6.
ioaryl, and Ci_9heteroaryl, wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C610atyl, and Ci.9heteroa1y1 are optionally substituted with one, two, or three R20i 109 is selected from a C342cyc1oa11cv1, C2-liheterocycloalkyl, C6_12aryl, and C2_12heteroaryl, wherein the C3.
12cycloalkyl, C24iheterocycloalkyl, C6_12ary1, and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven Rli;
each Ru is independently selected from halogen, -CN, Ci_6alkyl, C,6ha1oa1ky1, C2_6alkenyl, C2_6alkynyl, C3-6cycloalkyl, C2_,heterocycloalkyl, C6_10aryl, C1_9heteroatyl, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -OC(0)N(R12)(R13), -N(R14)C(0)N(102)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R1', -0C(0)R15, -C(0)N(R2)(R13), -C(0)C(0)N(R12)(R13), -N(104)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(1212)(103), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C2_6a1ky1, C2_6a1keny1, C2_6a1kyny1, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6 ,aryl, and Ci_6heteroaryl are optionally substituted with one, two, or three R21)1;
RI" is selected from hydrogen, halogen, -CN. C,-,alkyl. C2_6a1kenyl.
C2_6alkyny1, C3_6cyc1oalkyl. C2-9heterocycloalkO, C6_10aryl, C1.9heter0ary1, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(RH), -N(R14)C(0)N(R12)(R13), -N(R11)C(0)0R15, -N(RH)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R'4)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -C1-12C(0)N(R12)(R13), -C1-12N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_oalkyl, C2_6alkeny-1, C2_6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, wary!, and Ci_gheteroaryl are optionally substituted with one, two, or three R208;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R11)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2105, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(Ri2.7A ri 13 ), -(Ci-C6alkyl)-R12b, -(C2_6alkeny1)-R12b, -(C2_6alkyny1)-12,12b, -0-R12a, -_ S-R12", -(C3_10cycloalkyl)-R1 2h , -(C2_9heterocycloalkyl)-R12h, -(C6-10ar3,1)-R12h, or -(Ci_9heteroary1)-R12h, wherein said C2_6alkyl, C2_6alkenyl, C2_6allcynyl, C3_10cycloallcyl, C2_61ieterocycloallcyl, C6_20aryl, and C-91-ieteroaryl are optionally substituted with one, two, or three R2 d;
R12a is selected from C1-6a1kyl, C2.6a1kenyl, C2_6alkynyl, C3locycloallryl. -C1-12-C3.mcycloalkyl. C2-9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_0oryl, -C1-12-C6_20aryl, -CH2-C2.9heteroaryl, and C1_ 9heteroaryl, wherein Ci_oalkyl, C2_6alkenyl, C2_6alkynyl, C34ocycloalkyl, -CH2-C34ocycloalkyl, C2-9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_maryl, -C1-12-C6_20awl, -C1-12-C2.9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, C2_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_2ocycloalkyl, -CH2-C2_10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C640alyl, -C1-12-C6_20myl, -0-12-C2.9heteroaryl, and C1-9heteroaryl, wherein C1_6alky1, C2_6alkenyl, C2_6alkynyl, C34ocycloalkyl, -C1-12-C3_20cycloalkyl, C2-9heterocycloalkyl, -C1-12-C2_9heterocycloalkyl, C6_maryl, -CH2-C2.9heteroaryl, and C1-9heteroatyl are optionally substituted with one, two, or three R2 d;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, C,6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2-9heterocycloalkyl, C6_10aryl, C4.9heteroary1, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(Ru)(R13). -N(R11)C(0)0R15. -N(R14)S(0)2R15. -C(0)R15. -S(0)R1'. -0C(0)R1', -C(0)N(Ru)(RH), -C(0)C(0)N(Ru)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -C1-12C(0)N(R12)(R13), -C1-12N(R11)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C2_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6-loaryl, and Ci_9heteromyl are optionally substituted with one, two, or three R20";
each R12 is independently selected from hydrogen, Ci_6a11ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3-6cycloalkyl, C2_91ieterocycloalkyl, -C1-12-C2-9heterocycloalkyl, C6_10aryl, -CI-12-C64oaryl, -C1-12-C,9heteroaryl, and Ci_91ie1eroary1, wherein Ci_6a1ky1, C2_6alkenyl, C2_6alky1yl, C3_6cycloalkyl, -CH2-C3_ 6cycloalkyl, C2_9heteroeycloa1kyl, -C1-12-C2_9heterocycloalkyl, C640atyl, -CE12-C640aryl, 9heteroaryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R2 d;

each Ft.' is independently selected from hydrogen, C1_6a1kyl, and Ci_6haloalkyl; or R12 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R20e;
each R" is independently selected from hydrogen, Ci_6a1kyl, and Ci_6haloalkyl;
each R15 is independently selected C1_6a1ky1, C2_6a1kenyl, C2_6alkyny1, C3_6cyc10a1ky1, C2_9heterocycloalky1, C6-ioaryl, and Ci_9heteroatyl, wherein Ci_6alkyl, C2_6alkenyl, C2.6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C610atyl, and Ci.9heteroaryl are optionally substituted with one, two, or three R20f;
each R20a, R201), R20c, Ram, R20e, R20,tt - 20g, and R2 ' are each independently selected from halogen, -CN, Ci 6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cy cloalkyl, C2_9heterocycloa1kyl, -CH2-C2.
9heterocycloalkyl, C6_10atyl, -CH2-C6_10ary1, -CH2-C1_9heteroatyl, C1_9heteromyl, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25. wherein Ci_6alkyl, C2_6a1kenyl, C2_6alkynyl, C3.6cyc1oa1kyl, -CH2-C3-6cycloalkyl, C2-9heterocycloa1kyl, -CH2-C2-9heterocycloalkyl, C6_10atyl, -CH2-C6_10aryl, -CH2-C1-9heteroaryl, and C1_9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N (R22)(R23), and -0C(0)R25;
each R2' is independently selected from H, C1_6alky1, C1_6haloalkyl, C2.6a1kenyl, C2.6a1kyny1, C3.6cycloalkyl, C2_ 9heterocycloalkyl, C6_10atyl, and Ci_9heteroa1yl;
each R22 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2.6alkenyl, C2.6alkyny1, C3.6cyc1oalkyl, C2_ 9heterocycloalkyl, C6_10atyl, and Ci_9heteroatyl;
each R23 is independently selected from H and Ci_6alkyl:
each R24 is independently selected from H and Ci_6alkyl;
each R25 is selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalky-1, C64Datyl, and Ci_,heteroaryl; and - indicates a single or double bond such that all valences are satisfied.
1001491 In an aspect is provided a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof:

N X
R2 Formula (1');
wherein W is C(0), S(0), or S(0)2;
V is C(R17) and J is C(R16), or V is C(R") and J is N, or J is C(R17) and V is C(R'6), or J is C(R") and V is N;
WI' is -1_2-R7, L7 is a bond, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R')-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-C6alkyl, C2-C6aMnyl, C2-C6alkynyt, or 2 to 4 membered heteroalkylene linker, wherein Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R20a;
R7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalky71, 6-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cy-cloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more re;
wherein two substituents selected from R1, fe, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C342cyc1oa1ky1, Ci_iiheterocycloalkyl, C642a1yl, or Cl_iiheteroaryl, wherein the C3_12cycloalkyk Ci.iiheterocycloalkyl, C6_12aryl, or Ci_iiheteroaryl are optionally substituted with one, two, or three R2 a;
each R1 is independently selected from hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6a1kynyl, C1_6haloalkyl, C3-12cycloalkyl, -CH2-C342cycloalkyl, Ci_iiheterocycloalkyl, -CH2-Ci1iheterocycloalkyk C6_12alyl, -CH2-C6-12ary1, -C112-C1_iiheteroaryl, and Ci_iiheteroatyl, wherein C4_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_61ia1oa1ky1, C3_12cycloalkyk -CH2-C3_12cyc1oa1ky1, Ci_iiheterocycloalkyl, -CH2-Ci_1iheterocycloalkyl, C6_12ary1, -CH2-C6_12alyl, -C1-12-Ci_11heteroary1, and C1_, iheteroaryl are optionally substituted with one, two, or three R2 a;
each R4 is independently selected from hydrogen, halogen, oxo, -CN, C1.6alkyl, C2_6alkenyl, C2_6alkynyl, C3.
6cycloalkyl, C2_9heterocyc1oa1ky1, C6_10aryl, Ci_9heteroaty1, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R')(10, -N(R")C(0)N(R')(R'), -N(R14)C(0)0R15, -N(R')S(0)2R15, -C(0)R', -S(0)R1', -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R11)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6_ ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R2 a;
R' is -L2-R5;
each L2 is independently selected from a bond, Cl-C6allcyl, -0-, -N(RH)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -000N(R14)-, -N(R14)C(0)0-, and -N(R14)C(0)N(R1-4)-;
each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein:
fe is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl.
C2_6a1kynyl, C3_6cycloa1kyl, C2_ 9heterocycloalkyl, C6_ioaryl, Ci_9heteroary1, -0R12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(RH)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6alkeny-1, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, Cs_ ioaryl, and Ci_91ie1eroary1 are optionally substituted with one, two, or three R2ne;
R17 is -L1-R19;
L4 is selected from a bond, C,-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R')C(0)-, -C(0)N(R14) ,-S-, S(0)2-, -S(0)-, -S(0)2N(R')-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(R14)C(0)0-, N(R1e), C(0)N(Ric), S(0)2N(Ric), S(0)N(Ric), C(Rif)(Rig)0, C(Rif)(Rig)N(Ric), and C(Rif)(Rig);
R", Rif, and Rig are independently selected from hydrogen, halogen, -CN, C1_6alky1, C1_6ha1oa1ky1, C2_6alkenyl, C2_6a1kynyl, C3_6cycloa1kO, C2_9heterocycloalkyl, C6_10aryl, Ci.9heteroary1, -OR', -SR", -N(1112)(Ri3), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R", -S(0)R15, -0C(0)R15, -C(0)N(R12)(103), -C(0)C(0)N(R12)(R13), -N(R14)C(0)10-5, -S(0)2R, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R')(R13), wherein Ci_oalkyl, C2_6a1keny1, C2_6a1kyny1, C3_6cycloalky1, C2-9heterocycloalkyl, C6_10aryl, and Ci_9heteroary I are optionally substituted with one, two, or three R20; or Rif and Rig are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
R" is selected from hydrogen, Ci.6a1ky1, C2_6alkeny1, C2_6alkynyl, C3.6cycloalkyl, C2_9heterocycloalkyl, Co_ ioaryl, and Ci_gheteroalyl, wherein Ci_6alkyl, C2_6alkenyl, C2.6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_ioaryl, and Ci_91ieteroary1 are optionally substituted with one, two, or three R201 R19 is selected from a C342cyc10a1ky1, C2_iiheterocycloalkyl, C6_22aryl, and C2_22heteroaryl, wherein the C3_ ,cycloalkyl, C2_, heterocycloalkyl, Co_uaryl, and C2_12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven Ril;
each is independently selected from halogen, -CN, Ci_bhaloalkyl, C2_6alkcny1, C2_6alkynyl, C3-6cycloalkyl, C2_9heterocycloa1kyl, C6_1oaryl, Ci_9heteroalyl, -OR', -SR', -N(R')(R'), -C(0)OR', -0C(0)N(R')(R13), -N(R11)C(0)N(R")(R13), -N(R11)C(0)0105, -N(R11)S(0)2R15, -C(0)R15, -S(0)R1', -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R"), wherein C2_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6_ ioaryl, and Ci_9heteromyl are optionally substituted with one, two, or three R201;
1216 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_ ,heterocycloalkyl, C6_bparyl, Ci_,heteroaryl, -OR", -SR", -N(Ri2)(R13), -C(0)0R12, -0c (0)N(R12)(R13), _ N(Rioi)c(0)N(R12)(--1() 13, _ N(R14)C (0)010 5, -N(R14)S(0)2R", -C(0)R", -S(0)R15, -0C(0)R15, -C(0)N(R12)(R"), -C(0)C(0)N(R12)(R13), -N(R '4)C(0)R15, -S (0)2 R15, -S(0)2N( R12)(R13)-, S(=0)(=NH)N(R')(R13), -CH2C(0)N(R12)(R13), -C1-12N(R14)C(0)R1', -CH2 S(0)2R1', and -CH2S(0)2N(R')(R'), wherein C2_6a1ky1, C2_6alkeny-1, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R2 ;
R2 is -C(0)0R12, -0C(0)N(R')(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(103), -C(0)C(0)N(R12)(R13), -N(R14)C(0)10-5, -S(0)2105, -S(0)2N(R')(R13)-, S(=0)(=NH)N(R')(R13), -CH2C(0)N(R12)(R"), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R')(R'), -(Ci-C6alkyl)_Rub, _Rub _Rub, _o_Ri2a, _ -(C2_6alkenyl) , -(C2_6alkynyl) S-R' 2", -(C3-locy cloalkyl)-R1 2h -(C2_9heterocycloalkyl)-Ruh, -(C6_10ary1)-R' 2h or -(Ci_9he1eroary1)-R12h, wherein said C2-6alkyl, C2_6alkenyl, C2_6alkynyl, C3_iocycloa1kyl, C2_,heterocycloalkyl, C6_20aryl, and CI-9heteroaryl are optionally substituted with one, two, or three R2 d;
Rua is selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3-iocycloalkyl, -C(R12c)2-C340cycloallcyl, C2-,heterocycloalkyl, -C(Ri292-C2.,heterocycloalkyl, C6_10aryl, -C(R1292-C6.10aryl, -C(R1292-Ci_,heteroaryl, and Ci_9heteroary1, wherein Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C340cycloalkyl, -C(R12 )2-C340cycloalkyl, C2_9heterocycloalkyl, -C(R12c)2-C2_9heterocycloalkyl, C6.10a1y1, -C(R12c)2-C6_ioaryl, -C(R12c)2-Ci.9heteroaryl, and Cl_yheteroaryl are optionally substituted with one, two, or three R20;
R12b is selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C340cycloalkyl, -C(R12e)2-C3.10cycloalkyl, C2.
9heterocycloalkyl, -C(R12e)2-C2_9heterocycloalkyl, C6_lioryl, -C(R12c)2-C6_10aryl, -C(R12c)2-Ci_9heteroa1yl, and Ci_9heteroary1, wherein C1-6a11cy1, C2_6alkenyl, C2_6a1kynyl, C340cycloalkyl, -C(R12c)2-C3_10cycloalkyl, C2_9heterocycloalkyl, -C(R12c)2-C2_9heterocycloalkyl, C6.ioaryl, -C(R12e)2-C6_10aryl, -C(R12 )2-C1.9heteroaryl, and C1_9heteroary1 arc optionally substituted with one, two, or three R2";
R'e is independently selected from hydrogen and R';
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2-9heterocycloalkyl, C6_ioaryl, Ci.9heteroary1, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(Ru)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)1115, -C(0)N(R12)(R'3), -C(0)C(0)N(R'2)(R'3), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R'2)(R'3)-, S (-0)(=NT-1)N(R 12)(R 13), -CH2C(0)N(R 12)(R 13), -CH2N(R '4)C(0)R15, -CH2 S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Cl_salkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, Cs_ ioaryl. and Ci_9heteromyl are optionally substituted with one, two, or three R";
each R12 is independently selected from hydrogen, Ci_6a1ky1, C2_6a1kenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3-6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10myl, -CH2-C6_ioaryl, -CH2-C1-9heteroaryl, and Ci_9heteroary1, wherein Ci_6a1ky1, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloa1kyl, -CH2-C3.
6cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocycloalkyl, C6_10myl, -CH2-C6_10aryl, -CH2-Ct-9heteroaryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R20';
each R13 is independently selected from hydrogen, Ci_6a11ky1, and Ci_6ha1oa1ky1; or R12 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R2"';
each R14 is independently selected from hydrogen, Ci_6a1lcy1, and Ci_6ha1oa1lcy1;
each R15 is independently selected Ci_salkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6-ioaryl, and Ci_9heteromyl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkO, C2_9heterocycloalkyl, C6_ioaryl, and Ci.9heteroary1 are optionally substituted with one, two, or three R20f;
each R20a, R2ob, R20c, R2od. woe. Rag-. R20g. R201. and ic -=-= 20k are each independently selected from halogen, oxo, -CN, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloa1kyl, C2_9heterocycloa1kyl, -CH2-C2-9heterocycloalkO, C6_10aryl, -CH2-C6_20aryl, -CH2-Ci_9heteroary1, Ci_9heteroary1, -0R21. -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25. wherein Ci_6alky1, C2_6alkenyl, C2_6alkynyl, C3.6cycloalky1, -CH2-C3-6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10myl, -CH2-C6_10aryl, -CH2-Ct-9heteroaryl, and Ci_91ie1eroary1 are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6ha1oa1ky1, Ci_salkoxy, Ci_6ha1oa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25:

each R22 is independently selected from H, Ci_6alkyl, Ci_6haloalky1, C2_6alkenyl, C2_6alkyny1, C3_6cyc1oa1kyl, C2_ 9heterocycloalkyl, C6_1oary1, and Ci_9heteroaryl;
each R22 is independently selected from H. Cl_nalkyl. Cl_nhaloalkyl.
C2.6alkenyl. C2.6alkynyl. C3.6cycloa1kyl. C2_ 9heterocycloalkO, C6_ioaryl, and C1_9heteroaryl;
each R23 is independently selected from H and C1_6alkyl;
each R24 is independently selected from H and Ci_6alkyl;
each R25 is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C640atyl, and Ci.9heteroaryl; and ¨ indicates a single or double bond such that all valences are satisfied.
[00150] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X
is C(R3). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is N.
[00151] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof.
V is C(R16) and J is C(R17). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is N and J is C(R17) In some embodiments of the subject compound;
or a pharmaceutically acceptable salt or solvate thereof, J is N and V is C(R17). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof. J
is C(R16) and V is C(1117). In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W
is C(0). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0)2.
[00152] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure:
0 Ri o 0 Ri o R8 R8.N
N

Formula (IA1), Formula (IA2), o 0 R10 N. 0 R10 N

Formula (IA3), R2 R Formula (IA4), R8 R8 I 0õ0 \\d/
N \
N N

R17 R Formula (IA5), R17 R Formula (1A6), I I
R8N .,,.,,,,,,R3 R8, s R17N--;------'R2 R17 N R2 Formula (IA?). R16 Formula (IA8), R
(D, ,p R8 `s'c, R3 0 R1 N,...- ,,..õ..

N

Formula (IA9), R17-Ni N%-: p 2 R18 ¨ Formula (IA10), O ni o io I I R8 `ss. R3 R8,,,, _..__,,p3 \N,--N ,,,...,,, ---:::õ_= .,-. õõ..------õ, ,--;;i"---.,õ / 'NZ,,, _.,,, .,:)...
R17 N N R2 Formula (IA11), or R17 N N R2 Formula (TA1 2).
1001531 In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure:

N. R8 I I
s 'N"--------1 N .1 N
I I

R17 Formula (IIA1), R17 Formula (IIA2), o o R10 0 R10 \N
NNõ.=
I I
N

R17 Formula (IIA3), R17 Formula (IIA4), R8... R8 V/
'N'S '"'=--- -<:'-i N \N.-I I I I
N,-...õ, e..õ, R2 Nõ,,---z:_z_____ .....---.õ.õ ...-õ,-----,,.,.

Formula (IIA5), R17 Formula (IIA6), 1\11 R3 N.'N----'---'.-"-----1 I I
R16 N R2 R18 e R2 Formula (IIA7), Formula (IIA8), 0 0 Rlo 0 R8 VcR3 R8 N
j-N N

R17 Formula (IIA9), R17 Formula (IIA10), 0 Rto Rto Rs Rs 0 0 N N

R17 Formula (IIA11), or R17 Formula (IIA12).
[00154] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is a bond. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is -NH-.
[00155] In embodiments, L7 is a bond. In embodiments, L7 is -0-. In embodiments, L7 is -N(R')-. In embodiments, L7 is -C(0)-. In embodiments, L7 is _N(R14)c(0)_.
In embodiments, L7 is -C(0)N(R14)-. In embodiments, L7 is -S-. in embodiments, L' is -S(0)1-. in embodiments, L7 is -S(0)-. in embodiments, L7 is -S(0)2N(R1)-. In embodiments, L2 is -S(0)N(R14)-. In embodiments, L7 is -N(R14)S(0)-. In embodiments, L7 is -N(R14)S(0)2-. In embodiments, L.' is Ci-C6alkyl. In embodiments, 1_,7 is C2-C6alkenyl. In embodiments, Cis C2-C6alkynyl. In embodiments, L7 is 2 to 4 membered heteroalkylene linker. In embodiments, L7 is Ci-C6alkyl optionally substituted with one, two, or three R20a. In embodiments, L7 is C2-C6alkeny1 optionally substituted with one, two, or three R20a. In embodiments, L7 is C2-C6alkynyl optionally substituted with one, two, or three R20a. In embodiments, L7 is 2 to 4 membered heteroalkylene linker optionally substituted with one, two, or three R20a. In embodiments, L7 is -N(H)-. In embodiments, L7 is -N(H)C(0)-. In embodiments, L7 is -C(0)N(H)-. In embodiments, L7 is -S(0)2N(H)-. In embodiments, L7 is -S(0)N(H)-. In embodiments, L7 is -N(H)S(0)-. In embodiments, L7 is -N(H)S(0)2-.
[00156] In some embodiments of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, Fe is a 4-12 membered cycloalLyl, 3-12 membered heterocycloalkyl, 7-12 membered my], or 5-12 membered heteroatyl, wherein the 4-12 membered cycloalkyL 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroatyl are optionally substituted with one or more RI, optionally substituted with one or more R4, and optionally substituted with one or more R6; wherein two substituents selected from R', re, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3_12cy-cloalkyl, Ci_itheterocycloalkyl, C6_12aryl, or C1.1theteroaryl, wherein the C3_12cycloalkyl, Ci_itheterocycloalkyl, C6_12aryl, or Ci_itheteroaryl are optionally substituted with one, two, or three R20a.
[00157] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloallcyl is optionally substituted with one or more 111, one or more R4, or one or more R6; and wherein two substituents selected from Rl, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-12cyc1oalkyl, Ci_nheterocycloalkyl, C642ary1, or Ci_llheteroaryl, wherein the C3_1/cycloa1kyl, Ci-tiheterocycloalkyl, C6_pary1, or Ci_iiheteroaryl are optionally substituted with one, two, or three R20.
[00158] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more optionally substituted with one or more R4, and optionally substituted with one or more R6; and wherein two substituents selected from R', R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3_12cycloalkyl, Ci_i iheterocycloalkyl, C6-ilaryl, or Ci_iiheteroalyl, wherein the C3_12cycloalkyl, Ci.iiheterocycloalkyl, Co.ilaryl, or Cmiheteroaryl are optionally substituted with one, two, or three R20.
[00159] In embodiments, R7 is a 3-12 membered cycloalkyl. In embodiments, R7 is a 5-12 membered cycloalkyl.
In embodiments, R7 is 3-12 membered heterocycloalkyl. In embodiments, R7 is 6-12 membered aryl. In embodiments, R7 is 7-12 membered aryl. In embodiments, R7 is 5-12 membered heteroaryl.
[00160] In embodiments, R7 is a 3-12 membered cycloalkyl comprising one or more ring nitrogen atoms. In embodiments, R7 is a 5-12 membered cycloalkyl comprising one or more ring nitrogen atoms. In embodiments, R7 is 3-12 membered heterocycloalkyl comprising one or more ring nitrogen atoms In embodiments, R7 is 6-12 membered aryl comprising one or more ring nitrogen atoms. In embodiments, R7 is 7-12 membered aryl comprising one or more ring nitrogen atoms. In embodiments, R7 is 5-12 membered heteroaly1 comprising one or more ring nitrogen atoms.
[00161] In embodiments, R7 is a 3-12 membered cycloalkyl comprising one or more ring oxygen atoms. In embodiments, IC is a 5-12 membered cycloalkyl comprising one or more ring oxygen atoms. In embodiments, R7 is 3-12 membered heterocycloalkyl comprising one or more ring oxygen atoms. In embodiments, R7 is 6-12 membered aryl comprising one or more ring oxygen atoms. In embodiments, R7 is 7-12 membered aryl comprising one or more ring oxygen atoms. In embodiments, R7 is 5-12 membered heteroaryl comprising one or more ring oxygen atoms.
[00162] In embodiments, R7 is a 3-12 membered cycloalkyl optionally substituted with one or more le, optionally substituted with one or more R4, and optionally substituted with one or more R6. in embodiments, R7 is a 5-12 membered cycloalkyl optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 3-12 membered heterocycloalkyl optionally substituted with one or more Ftl, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 6-12 membered aryl optionally substituted with one or more 121, optionally substituted with one or more fe, and optionally substituted with one or more fe. In embodiments, R7 is 7-12 membered aryl optionally substituted with one or more Rl, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 5-12 membered heteroaryl optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00163] In embodiments, R7 is a 3-12 membered cycloalkyl comprising one or more ring nitrogen atoms optionally substituted with one or more It', optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, 1=22 is a 5-12 membered cycloalkyl comprising one or more ring nitrogen atoms optionally substituted with one or more optionally substituted with one or more le, and optionally substituted with one or more R6. In embodiments, R7 is 3-12 membered heterocycloalkyl comprising one or more ring nitrogen atoms optionally substituted with one or more Rl, optionally substituted with one or more fe, and optionally substituted with one or more R6. In embodiments, R7 is 6-12 membered aryl comprising one or more ring nitrogen atoms optionally substituted with one or more R4, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, Ie is 7-12 membered arvl comprising one or more ring nitrogen atoms optionally substituted with one or more RI, optionally substituted with one or more R4, and optionally substituted with one or more R. In embodiments, R7 is 5-12 membered heteroaryl comprising one or more ring nitrogen atoms optionally substituted with one or more ft', optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00164] In embodiments, IC is a 3-12 membered cycloalkyl comprising one or more ring oxygen atoms optionally substituted with one or more 10, optionally substituted with one or more fe, and optionally substituted with one or more R6. In embodiments, IC is a 5-12 membered cycloalkyl comprising one or more ring oxygen atoms optionally substituted with one or more 124, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 3-12 membered heterocycloalkyl comprising one or more ring oxygen atoms optionally substituted with one or more Ft', optionally substituted with one or more RI, and optionally substituted with one or more R6. In embodiments, R7 is 6-12 membered aryl comprising one or more ring oxygen atoms optionally substituted with one or more R', optionally substituted with one or more RI, and optionally substituted with one or more R6. In embodiments, R7 is 7-12 membered aryl comprising one or more ring oxygen atoms optionally substituted with one or more R', optionally substituted with one or more RI, and optionally substituted with one or more R6. In embodiments, R7 is 5-12 membered heteromyl comprising one or more ring oxygen atoms optionally substituted with one or more ft', optionally substituted with one or more RI, and optionally substituted with one or more R6.
[00165] In embodiments, IC is a C3cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R1. In embodiments, 12:7 is a C4cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C5cycloalkyl optionally substituted with one R6 and optionally substituted with one or more RI. In embodiments, R7 is a C6cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C7cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C8cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C9cycloalky1 optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Ciocycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C3cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C4cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C5cycloalkyl optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, R7 is a monocyclic C6cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C7cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C8cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R' is a monocyclic C9cycloalkyl optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, R7 is a monocyclic Ciocycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C5cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC is a fused bicyclic C6cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7cycloa1kyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R' is a fused bicyclic C8cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C9cycloalkyl optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, R7 is a fused bicyclic Clocycloalkyl optionally substituted with one le and optionally substituted with one or more R4.
In embodiments, R7 is a bridged bicyclic C5cycloalkyl optionally substituted with one re and optionally substituted with one or more R4. In embodiments, R' is a bridged bicyclic C6cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R' is a bridged bicyclic C7cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 11.7 is a bridged bicyclic C9cycloalkyl optionally substituted with one R6 and optionally substituted with one or more 10.
In embodiments, R7 is a bridged bicyclic Ciocycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C5cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C6cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C7cycloalkyl optionally substituted with one R and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more In embodiments, R7 is a spirocyclic bicyclic C9cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl optionally substituted with one It and optionally substituted with one or more R4.
1001661 In embodiments, It" is a C5cycloalkyl including at least one nitrogen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R7 is a C6cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R1. In embodiments, R7 is a C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C9cycloalkyl including at least one nitrogen atom and optionally substituted with one fe and optionally substituted with one or more R4. In embodiments, R7 is a Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC is a fused bicyclic C5cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 117 is a fused bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC is a fused bicyclic C9cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, RY is a bridged bicyclic C5cycloalkyl including at least one nitrogen atom and optionally substituted with one re and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C6cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more 114. In embodiments, R7 is a bridged bicyclic C9cycloa1kyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R' is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC is a spirocyclic bicyclic C6cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with onc or more R4. In embodiments, R7 is a spirocyclic bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C9cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00167] In embodiments, R7 is a C3cycloa1kyl optionally substituted with one R1 and optionally substituted with one or more R1. In embodiments, re is a Cicycloalkyl optionally substituted with one it' and optionally substituted with one or more R4. In embodiments, R7 is a C5cycloalkyl optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a C6cycloalkyl optionally substituted with one IV and optionally substituted with one or more R4. In embodiments, R7 is a C7cycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl optionally substituted with one ft' and optionally substituted with one or more R. In embodiments, R7 is a C9cycloalkyl optionally substituted with one It' and optionally substituted with one or more R4. In embodiments, R7 is a Ciocycloalkyl optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C3cycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cicycloalkyl optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cocycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C7cycloalkyl optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cscycloalkyl optionally substituted with one 111 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C9cycloalkyl optionally substituted with one IC and optionally substituted with one or more R4. In embodiments, R" is a monocyclic Ciocycloalkyl optionally substituted with one Rl and optionally substituted with one or more 10.
[00168] In embodiments, R7 is a fused bicyclic C5cycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C6cycloalkyl optionally substituted with one 111 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7cycloalkyl optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl optionally substituted with one 124 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C,cycloalkyl optionally substituted with one 121 and optionally substituted with one or more R4. In embodiments, IC is a fused bicyclic Ciocycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4.

[00169] In embodiments, R7 is a bridged bicyclic C5cycloalky1 optionally substituted with one 10 and optionally substituted with one or more R4. In embodiments, le is a bridged bicyclic C6cycloalkyl optionally substituted with one R4 and optionally substituted with one or more R4. In embodiments, 127 is a bridged bicyclic C7cycloalkyl optionally substituted with one RI and optionally substituted with one or more R4. In embodiments, R' is a bridged bicyclic Cscycloalkyl optionally substituted with one R.' and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C9cycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Ciocycloalkyl optionally substituted with one le and optionally substituted with one or more R4. In embodiments, IC is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one le and optionally substituted with one or more R4. In embodiments, IC is a spirocyclic bicyclic C6cycloalkyl optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C7cycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C9cycloalkyl optionally substituted with one R and optionally substituted with one or more R'. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl optionally substituted with one Rl and optionally substituted with one or more R4 [00170] In embodiments, R7 is a C5cycloalkyl including at least one nitrogen atom and optionally substituted with one R and optionally substituted with one or more R4. In embodiments, R7 is a C6cycloalkyl including at least one nitrogen atom and optionally substituted with one RI and optionally substituted with one or more R4. In embodiments, R7 is a C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cacycloalkyl including at least one nitrogen atom and optionally substituted with one Rl and optionally substituted with one or more R1. In embodiments, R7 is a C9cycloalkyl including at least one nitrogen atom and optionally substituted with one re and optionally substituted with one or more 1=0. In embodiments, R7 is a Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C5cycloalkyl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C6cycloalkyl including at least one nitrogen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C9cycloalkyl including at least one nitrogen atom and optionally substituted with one re and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C5cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C6cycloalky1 including at least one nitrogen atom and optionally substituted with one 11' and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one IC and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C9cycloalkyl including at least one nitrogen atom and optionally substituted with one RI and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one re and optionally substituted with one or more R4. In embodiments, le is a spirocyclic bicyclic C5cycloalk0 including at least one nitrogen atom and optionally substituted with one RI and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C6cycloalkyl including at least one nitrogen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R' is a spirocyclic bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one re and optionally substituted with one or more 10. In embodiments, fe is a spirocyclic bicyclic C9cycloalkyl including at least one nitrogen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one re and optionally substituted with one or more R4.
[00171] In embodiments, R7 is a C5cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C6cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C7cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C9cycloalkyl including at least one oxygen atom and optionally substituted with one It and optionally substituted with one or more fe. In embodiments, R7 is a Ciocycloalkyl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, le is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one re and optionally substituted with one or more Fe. In embodiments, R7 is a fused bicyclic C6cycloalkyl including at least one oxygen atom and optionally substituted with one fe and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one Fe and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. in embodiments, R7 is a fused bicyclic C,cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C6cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more R'. In embodiments, fe is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R1. In embodiments, R7 is a bridged bicyclic C9cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C5cycloalll including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C6cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC
is a spirocyclic bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C8cycloalkyl including at least one oxygen atom and optionally substituted with one Re' and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C9cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00172] In embodiments, R7 is a C5cycloalkyl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R7 is a C6cycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a C7cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a C8cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a C9cycloalkyl including at least one oxygen atom and optionally substituted with one 11' and optionally substituted with one or more R4. In embodiments, R7 is a Ciocycloalkyl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, Ie is a fused bicyclic C9cycloalkyl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C6cycloalkyl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more 10. In embodiments, R7 is a fused bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more R1. In embodiments, R7 is a fused bicyclic C8cycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, le is a fused bicyclic C9cycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C6cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, 1:27 is a bridged bicyclic C8cycloalkyl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more RI. In embodiments, R7 is a bridged bicyclic C9cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R' is a spirocyclic bicyclic C5cycloalkyl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C6cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one TO and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C8cycloalkyl including at least one oxygen atom and optionally substituted with one RI and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C9cycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4.
[00173] In embodiments, IC is a 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, R7 is a 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more In embodiments, R7 is a 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 1:27 is a 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R'. In embodiments, R7 is a 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00174] In embodiments, re is a fused bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R and optionally substituted with one or more IV. In embodiments, R7 is a fused bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00175] In embodiments, IC is a bridged bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more In embodiments, R7 is a bridged bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00176] In embodiments, R7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more W. In embodiments, R7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R' is a spirocyclic bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more 1:24 In embodiments, R7 is a spirocyclic bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00177] In embodiments, R7 is a 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one IV and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R1. In embodiments, R7 is a 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one re and optionally substituted with one or more R4. In embodiments, R" is a 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00178] In embodiments, R7 is a fused bicyclic 5 membered cycloallcyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more In embodiments, R7 is a fused bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R" is a fused bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00179] In embodiments, IC is a bridged bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R' is a bridged bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, IC is a bridged bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one 111 and optionally substituted with one or more R4. In embodiments, R" is a bridged bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, le is a bridged bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4 In embodiments, R7 is a bridged bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00180] In embodiments, R7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more 1/1. In embodiments, R' is a spirocyclic bicyclic '7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more 1=0. In embodiments, R7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R' is a spirocyclic bicyclic membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00181] In embodiments, R7 is a 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R: is a 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one fe and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, R7 is a 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00182] In embodiments, IC is a fused bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more RI. In embodiments, R7 is a fused bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more 124 Tn embodiments, R7 is a fused bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00183] In embodiments, R7 is a bridged bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or moreR4. In embodiments, R7 is a bridged bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R1. In embodiments, R7 is a bridged bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more fe. In embodiments, IC is a bridged bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00184] In embodiments, R7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more 114. In embodiments, re is a spirocyclic bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more R4.
[00185] In embodiments, R7 is a 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one 11' and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R. In embodiments, R7 is a 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00186] In embodiments, R7 is a fused bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or moreR4. In embodiments, R7 is a fused bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R1. In embodiments, R7 is a fused bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more Fe. In embodiments, R7 is a fused bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one 111 and optionally substituted with one or more R4.
[00187] In embodiments, R7 is a bridged bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, 1=22 is a bridged bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one IV and optionally substituted with one or more R4. In embodiments, re is a bridged bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one 11' and optionally substituted with one or more R4.
[00188] In embodiments, R7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one IV and optionally substituted with one or more 114. In embodiments, 117 is a spirocyclic bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4 Tn embodiments, R7 is a spirocyclic bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one TV and optionally substituted with one or more 114. In embodiments, R7 is a spirocyclic bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R4 and optionally substituted with one or more 10.
[00189] In embodiments, R7 is a 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more RI. In embodiments, R7 is a 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, R7 is a 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more re. In embodiments, 117 is a 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, R7 is a 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00190] In embodiments, IC is a monocyclic 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, Fe is a monocyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more RI. In embodiments, R7 is a monocyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, 127 is a monocyclic 8 membered heterocycloallwl including at least one nitrogen atom and optionally substituted with one R and optionally substituted with one or more R4. In embodiments, R' is a monocyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC is a monocyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more 10.
[00191] In embodiments, R7 is a fused bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4 In embodiments, R7 is a fused bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC is a fused bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one It and optionally substituted with one or more R4. In embodiments, R' is a fused bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R1. In embodiments, R7 is a fused bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00192] In embodiments, IC is a bridged bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, le is a bridged bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00193] In embodiments, 1=27 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more 1=0. In embodiments, R7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one Re' and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 117 is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00194] In embodiments, R7 is a 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4 In embodiments, R7 is a 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more 114. In embodiments, R7 is a 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more 10. In embodiments, R7 is a 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R and optionally substituted with one or more R`I. In embodiments, 117 is a 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00195] In embodiments, R7 is a monocyclic 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R1. In embodiments, R7 is a monocyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R4 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.

[00196] In embodiments, IC is a fused bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one Fe and optionally substituted with one or more Ie. In embodiments, R7 is a fused bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R1. In embodiments, Fe is a fused bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more 10. In embodiments, R7 is a fused bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one le and optionally substituted with one or more le. In embodiments, le is a fused bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R1. In embodiments, R7 is a fused bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more le.
[00197] In embodiments, 1:27 is a bridged bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one Fe and optionally substituted with one or more R1. In embodiments, le is a bridged bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more le. In embodiments, le is a bridged bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one le and optionally substituted with one or more R1. In embodiments, IC is a bridged bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more Fe. In embodiments, le is a bridged bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R1. In embodiments, R7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R1.
[00198] In embodiments, R7 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one fe and optionally substituted with one or more Ie. In embodiments, re is a spirocyclic bicyclic 6 membered heterocycloallcy-1 including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R1. In embodiments, re is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more le. In embodiments, R7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more le. In embodiments, R7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more le. In embodiments, R7 is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one le and optionally substituted with one or more le. In embodiments, R7 is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00199] In embodiments, R" is a 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R and optionally substituted with one or more R4. In embodiments, R7 is a 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, It7 is a 6 membered hetcrocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 117 is a 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more TO. In embodiments, R' is a 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4 Tn embodiments, IC is a 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one It and optionally substituted with one or more R4.
[00200] In embodiments, IC is a monocyclic 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R1. In embodiments, R7 is a monocyclic 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 117 is a monocyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00201] In embodiments, R7 is a fused bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R" is a fused bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, ft7 is a fused bicyclic 10 membered heterocycloall including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00202] In embodiments, IC is a bridged bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, 117 is a bridged bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, le is a bridged bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4 In embodiments, R7 is a bridged bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one IV and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00203] In embodiments, R7 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more 114. In embodiments, le is a spirocyclic bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 117 is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 117 is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, re is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more R4. 111 embodiments, IC is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00204] In embodiments, IC is a 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one 111 and optionally substituted with one or more R4. In embodiments, le is a 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more re. In embodiments, IC
is a 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more R4. In embodiments, IC is a 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00205] In embodiments, R7 is a monocyclic 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4 Tn embodiments, R7 is a monocyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more 10. In embodiments, R7 is a monocyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one 111 and optionally substituted with one or more R4.
[00206] In embodiments, R7 is a fused bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R. In embodiments, R7 is a fused bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R4 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00207] In embodiments, R7 is a bridged bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, re is a bridged bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R' is a bridged bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one 111 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00208] In embodiments, R7 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R'. In embodiments, R7 is a spirocyclic bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R. In embodiments, R7 is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more R4. In embodiments, lre is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more re. In embodiments, 117 is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4.
[00209] In embodiments, R7 is a C6aryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C7aryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cxaryl optionally substituted with one R6 and optionally substituted with one or more fe. In embodiments, R7 is a C9aiy1 optionally substituted with one le and optionally substituted with one or more In embodiments, R7 is a Cloaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C6aiy1 optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R" is a monocyclic C7aryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R' is a monocyclic Csaryl optionally substituted with one R6 and optionally substituted with one or more Fe. In embodiments, R7 is a monocyclic C9aryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cioaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C-aryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Coaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7aryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl optionally substituted with one R6 and optionally substituted with one or more 114. In embodiments, R7 is a fused bicyclic C9aryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic CI
oaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R' is a bridged bicyclic C6aryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7aryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl optionally substituted with one 116 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C9aryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cioatyl optionally substituted with one R6 and optionally substituted with one or more R4.
[00210] In embodiments, R7 is a C7aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more Fe. In embodiments, R7 is a Csaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C9aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cioaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, re is a fused bicyclic Caryl including at least one nitrogen atom and optionally substituted with one R and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Ctiaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7a1yl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more 124. In embodiments, R7 is a fused bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C9aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cioaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. in embodiments, R' is a bridged bicyclic C5aiy1 including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C6aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C9aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cioarvl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00211] In embodiments, IC is a C6myl optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a C7aryl optionally substituted with one 124 and optionally substituted with one or more R4. In embodiments, R7 is a Caryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a C9aryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cioaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C6aryl optionally substituted with one 124 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C7aryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Gary' optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C9aryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cioaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Coaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, It7 is a fused bicyclic C7aryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, 1=t7 is a fused bicyclic Csaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Coly1 optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cioaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C6aryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7aryl optionally substituted with one R1 and optionally substituted with one or more R4 In embodiments, R7 is a bridged bicyclic Csaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C9aryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cioaryl optionally substituted with one R1 and optionally substituted with one or more R4.
[00212] In embodiments, IC is a C7a1yl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R1. In embodiments, R7 is a Csaiy1 including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a C9myl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cioaryl including at least one nitrogen atom and optionally substituted with one 111 and optionally substituted with one or more R4. In embodiments, re is a fused bicyclic C-aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. in embodiments, R7 is a fused bicyclic C6aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R" is a fused bicyclic C7aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, 127 is a fused bicyclic Caryl including at least one nitrogen atom and optionally substituted with one 111 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C9aiy1 including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cioaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R' is a bridged bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, IC is a bridged bicyclic C6aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, BY is a bridged bicyclic C7aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, le is a bridged bicyclic C9aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cioaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00213] In embodiments, R7 is a C7aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Csaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C9aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cioaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more 170. In embodiments, R7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, R7 is a fused bicyclic C6aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R" is a fused bicyclic C7a1yl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C9a1yl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4 Tit embodiments, R7 is a fused bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C9aryl including at least one oxygen atom and optionally substituted with one R and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C-aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7a1yl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R. In embodiments, R7 is a bridged bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C9aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00214] In embodiments, R7 is a C7aryl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a C8aiy1 including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a C9a1yl including at least one oxygen atom and optionally substituted with one 111 and optionally substituted with one or more R4. In embodiments, re is a Cioaryl including at least one oxygen atom and optionally substituted with one 111 and optionally substituted with one or more 1/4. In embodiments, R7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C6aryl including at least one oxygen atom and optionally substituted with one 111 and optionally substituted with one or more R4. In embodiments, R' is a fused bicyclic C7aryl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Caryl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one RI and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C3aryl including at least one oxygen atom and optionally substituted with one it' and optionally substituted with one or more R4. In embodiments, It7 is a bridged bicyclic C6ary1 including at least one oxygen atom and optionally substituted with one It' and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7aryl including at least one oxygen atom and optionally substituted with one It' and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R' is a bridged bicyclic C9aryl including at least one oxygen atom and optionally substituted with one It' and optionally substituted with one or more ft4. In embodiments, ft7 is a bridged bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more R4.
[00215] In embodiments, R7 is a 7 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4 In embodiments, R7 is a 11 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, it7 is a 12 membered aryl including at least one nitrogen atom and optionally substituted with one It and optionally substituted with one or more R4.
[00216] In embodiments, R7 is a fused bicyclic 7 membered aiy1 including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, It7 is a fused bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more It4. In embodiments, R7 is a fused bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC is a fused bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. in embodiments, R7 is a fused bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00217] In embodiments, R7 is a bridged bicyclic 7 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 117 is a bridged bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one Ft6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00218] In embodiments, R7 is a 7 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered aryl including at least one nitrogen atom and optionally substituted with one It' and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R`I. In embodiments, R7 is a 10 membered aiy1 including at least one nitrogen atom and optionally substituted with one R4 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered myl including at least one nitrogen atom and optionally substituted with one R4 and optionally substituted with one or more R4. In embodiments, R' is a 12 membered aryl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4.
[00219] In embodiments, R7 is a fused bicyclic 7 membered aryl including at least one nitrogen atom and optionally substituted with one 11' and optionally substituted with onc or more 10. In embodiments, R7 is a fused bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one Fe and optionally substituted with one or more R4. In embodiments, 127 is a fused bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one Rl and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one re and optionally substituted with one or more R4.
[00220] In embodiments, R7 is a bridged bicyclic 7 membered aryl including at least one nitrogen atom and optionally substituted with one RI and optionally substituted with one or more IV. In embodiments, IC is a bridged bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one Rl and optionally substituted with one or more R1. In embodiments, R7 is a bridged bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, IC is a bridged bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one Rl and optionally substituted with one or more R4.
[00221] In embodiments, R7 is a 7 membered aly1 including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 127 is a 9 membered aryl including at least one oxygen atom and optionally substituted with one R5 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R. In embodiments, R7 is a 11 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00222] In embodiments, IC is a fused bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. hi embodiments, R7 is a fused bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered aryl including at least one oxygen atom and optionally substituted with one R and optionally substituted with one or more R4.
[00223] In embodiments, R7 is a bridged bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, ft7 is a bridged bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered aryl including at least one oxygen atom and optionally substituted with one EV and optionally substituted with one or more R4.
[00224] In embodiments, R7 is a 7 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R. In embodiments, R7 is a 8 membered aryl including at least one oxygen atom and optionally substituted with one it' and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, IC is a 12 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00225] In embodiments, R7 is a fused bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one re and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00226] In embodiments, R7 is a bridged bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one Wand optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered awl including at least one oxygen atom and optionally substituted with one TV and optionally substituted with one or more R4.
[00227] In embodiments, R7 is a 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R and optionally substituted with one or more 114. In embodiments, R7 is a 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heteroawl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00228] In embodiments, R7 is a monocyclic 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R'. In embodiments, R7 is a monocyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more fe. In embodiments, R7 is a monocyclic 7 membered heteroawl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R1. In embodiments, R7 is a monocyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00229] In embodiments, R7 is a fused bicyclic 6 membered heteromyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, le is a fused bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC is a fused bicyclic 11 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC is a fused bicyclic 12 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00230] In embodiments, R7 is a bridged bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC is a bridged bicyclic 11 membered heteroaryl including at least one nitrogen atom and optionally substituted with one 116 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00231] In embodiments, R7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, R7 is a spirocyclic bicyclic 11 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00232] In embodiments, R7 is a 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one 1=0 and optionally substituted with one or more 114. In embodiments, R7 is a 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R4 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R4 and optionally substituted with one or more R4. in embodiments, R7 is a 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one Wand optionally substituted with one or more R4.
[00233] In embodiments, R7 is a monocyclic 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one 114 and optionally substituted with one or more R4. In embodiments, R7 is a monocycle 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one re and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one IV and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heteroalyl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one ft' and optionally substituted with one or more R4.
[00234] In embodiments, R7 is a fused bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one RI and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one It' and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4.
[00235] In embodiments, R7 is a bridged bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more 10. In embodiments, R7 is a bridged bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one TV and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4 [00236] In embodiments, R7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one IV and optionally substituted with one or more R1. In embodiments, R7 is a spirocyclic bicyclic 9 membered heteromyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, IC is a spirocyclic bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one TV and optionally substituted with one or more R4.
[00237] In embodiments, R7 is a 5 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R' is a 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, IC is a 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more 124. In embodiments, R7 is a 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00238] In embodiments, R7 is a monocyclic 5 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heteromyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, le is a monocyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R and optionally substituted with one or more 10.
[00239] In embodiments, R7 is a fused bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, R7 is a fused bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R'. In embodiments, R7 is a fused bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 12:1 is a fused bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00240] In embodiments, R7 is a bridged bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more fe. In embodiments, IC is a bridged bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more 10. In embodiments, R7 is a bridged bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R1.
[00241] In embodiments, R7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, 117 is a spirocyclic bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is spirocyclic bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00242] In embodiments, IC is a 5 membered heteroaryl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more 10. In embodiments, R7 is a 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one IV and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heteroatyl including at least one oxygen atom and optionally substituted with one IC and optionally substituted with one or more R4. In embodiments, le is a 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one fe and optionally substituted with one or more R4.

[00243] In embodiments, R7 is a monocyclic 5 membered heteroaly1 including at least one oxygen atom and optionally substituted with one and optionally substituted with one or more 10. In embodiments, re is a monocyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one 114 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one ft.' and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heteroatyl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one 10 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R.' and optionally substituted with one or more 10.
[00244] In embodiments, R7 is a fused bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R' is a fused bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4 Tn embodiments, R7 is a fused bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one 1:0 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one It' and optionally substituted with one or more R4.
[00245] In embodiments, IC is a bridged bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R1. In embodiments, R7 is a bridged bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one le and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one Rl and optionally substituted with one or more R4.
[00246] In embodiments, R7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one 11' and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one IV and optionally substituted with one or more 1/4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered heteroaly1 including at least one oxygen atom and optionally substituted with one R' and optionally substituted with one or more R4.
[00247] In embodiments, R4 is independently halogen. In embodiments, 114 is independently R4 is independently oxo. In embodiments, R4 is independently -CN. In embodiments, R4 is independently Ci.6alkyl. In embodiments, R4 is independently C2_6alkenyl. In embodiments, R4 is independently C2_6alkynyl. In embodiments, R4 is independently C1.6haloalkyl. In embodiments. R4 is independently C3_12cycloa1kyl. In embodiments, R4 is independently -CH2-C3_12eye1oa1ky1. In embodiments, R4 is independently Ci_liheterocycloalkyl. In embodiments, R4 is independently -CH2-Ci_i1heteroeyeloalkyl. In embodiments, le is independently C6.paryl. In embodiments, R4 is independently -CH2-C6_12ary1. In embodiments, R4 is independently -CH2-CI_Iiheteroaryl. In embodiments, R4 is independently Ci_iiheteroaryl. In embodiments, R4 is independently -0R12.
In embodiments, R4 is independently -SR12. In embodiments, R4 is independently -N(R12)(R13). In embodiments, 10 is independently -C(0)0R'2. In embodiments, le is independently -0C(0)N(R12)(R13). In embodiments, R4 is independently -N(R14)C(0)N(R12)(R13). In embodiments, R4 is independently -N(R14)C(0)0R15. In embodiments, le is independently -N(RH)S(0)2R15. In embodiments, R4 is independently -C(0)R15. In embodiments, TO is independently -S(0)R19. In embodiments, R4 is independently -0C(0)R19. In embodiments, R4 is independently -C(0)N(R12)(R13) .
In embodiments, R4 is independently -C(0)C(0)N(Ru)(R13). In embodiments, R4 is independently -N(R14)cor 15.
I( In embodiments, R4 is independently -S(0)2R15.
In embodiments, R4 is independently -S(0)2N(R12)(R13)-. In embodiments, R4 is independently S(=0)(=NH)N(R12)(R13). In embodiments, R4 is independently -CH2C(0)N(R12)(Ri3) .
In embodiments, R4 is independently -CH2N(R14)C(0)R15. In embodiments, R4 is independently -CH2S(0)2R15. In embodiments, R4 is independently and -CH2S(0)2N(R12)(R13).
[00248] In embodiments, R4 is independently Ci_6a1lcy1 optionally substituted with one, two, or three R20a Tn embodiments, R4 is independently C2_6alkenyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently C2_6alkynyl optionally substituted with one, two, or three R20. In embodiments. R4 is independently Ci.6ha1oa1ky1 optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C3_12eyeloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -CH2-C3_ 42cyc10a1ky1 optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cl.
iiheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, le is independently -CH2-iiheterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently C6.12aryl optionally substituted with one, two, or three R2". In embodiments, R4 is independently -CH2-C6_12aly1 optionally substituted with one, two, or three R20a. In embodiments, R4 is independently -C112-Ci_nheteroaryl optionally substituted with one, two, or three R2'. In embodiments, R4 is independently Ci_iiheteroaryl optionally substituted with one, two, or three R20a.
[00249] In embodiments, L2 is a bond. In embodiments, L2 is CI-C6alky1. In embodiments, L2 is -0-. In embodiments, L2 is _N(Ri4)_.
In embodiments, L2 is -C(0)-. In embodiments, L2 is _N(R14)c(0)_.
In embodiments, L2 is -C(0)N(Ri4_.
In embodiments, L2 is -S-. In embodiments, L2 is -S(0)2-. In embodiments, L2 is -S(0)-. In embodiments, L2 is -S(0)2N(R14-,)_.
In embodiments, L2 is -S(0)N(R14)_.
In embodiments, L2 is -N(R14)S(0)-. In embodiments, L2 is -N(R14)S(0)2-. In embodiments, L2 is -OCON(R14)-. In embodiments, L2 is -N(R14)C(0)0-. In embodiments, L2 is -N(R")C(0)N(R')-. In embodiments, L2 is -N(H)-. In embodiments, L2 is -N(H)C(0)-. In embodiments, L2 is -C(0)N(H)-. In embodiments, L2 is -S(0)2N(H)-. In embodiments, L2 is -S(0)N(H)-. In embodiments, L2 is -N(H)S(0)-. In embodiments, L2 is -N(H)S(0)2-. In embodiments, L2 is -000N(H)-. In embodiments, L2 is -N(H)C(0)0-. In embodiments, L2 is -N(H)C(0)N(1114)-.
[00250] In embodiments, R4 is independently Cialkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently C2alkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently C3a1kyl optionally substituted with one, two, or three R20U. In embodiments, Te is independently C4alkyl optionally substituted with one, two, or three R2 . In embodiments, R4 is independently C5alkyl optionally substituted with one, two, or three R2C)4. In embodiments, R4 is independently C6alkyl optionally substituted with one, two, or three R2Cia. In embodiments, R4 is independently C2alkenyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C3alkenyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cialkenyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C5alkenyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C6alkenyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently C?alkynyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently C3alkynyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C4alkynyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Csalkynyl optionally substituted with one, two, or three R20a. In embodiments, 114 is independently Coalkynyl optionally substituted with one, two. or three R20a. In embodiments, R4 is independently Ciltaloalkyl. In embodiments, R4 is independently C2haloalkyl. In embodiments, R4 is independently C3haloa1kyl. In embodiments, R4 is independently C4haloalkyl. In embodiments, R4 is independently C5haloalkyl. In embodiments, R4 is independently C6haloalkyl.
[00251] In embodiments, R4 is independently C3cycloalkyl optionally substituted with one, two, or three R2 . In embodiments, R4 is independently C4cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C5cycloalkyl optionally substituted with one, two, or three Rma. In embodiments, R4 is independently C6cycloallcyl optionally substituted with one, two, or three Rma In embodiments, R4 is independently C7cycloalkyl optionally substituted with one, two, or three R2'. In embodiments, R4 is independently Cscycloalkyl optionally substituted with one, two, or three R2". In embodiments, le is independently C9cycloalkyl optionally substituted with one, two, or three R2". In embodiments, R4 is independently Ciocycloalkyl optionally substituted with one, two, or three R20a.
[00252] In embodiments, R4 is independently C2heterocycloalkyl optionally substituted with one, two, or three R20a.
In embodiments, R^ is independently C3heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C4heterocycloalkyl optionally substituted with one, two, or three R2 . In embodiments, R4 is independently C5heterocycloalkyl optionally substituted with one, two, or three R2 . In embodiments, R4 is independently C6heterocycloalkyl optionally substituted with one, two, or three R2C)a. In embodiments, R4 is independently C7heterocycloalkyl optionally substituted with one, two, or three R2". In embodiments, R4 is independently Csheterocycloalkyl optionally substituted with one, two, or three R2 . In embodiments, R4 is independently C,heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C6aryl optionally substituted with one, two, or three R2 . In embodiments, R4 is independently C7aryl optionally substituted with one, two, or three R20a. In embodiments. R4 is independently Caryl optionally substituted with one, two, or three R20a. In embodiments, le is independently C9atyl optionally substituted with one, two, or three R2'. In embodiments, R4 is independently Cloaly1 optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cllaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cuaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C2heteroaryl optionally substituted with one, two, or three R2". In embodiments, R4 is independently C3heteroaryl optionally substituted with one, two, or three R2". In embodiments, R4 is independently C4heteroatyl optionally substituted with one, two, or three R2".
In embodiments, R4 is independently C5heteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently C6heteroaryl optionally substituted with one, two, or three R20U. In embodiments, le is independently C7heteroaryl optionally substituted with one, two, or three R2 . In embodiments, R4 is independently Csheteroaryl optionally substituted with one, two, or three R2 . In embodiments, R4 is independently C9heteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently Cioheteroaryl optionally substituted with one, two, or three R20.
In embodiments, R4 is independently Ciiheteroaryl optionally substituted with one, two, or three R20a.
[00253] In embodiments, R4 is independently 3 membered cycloalkyl optionally substituted with one, two, or three In embodiments, R4 is independently 4 membered cycloalkyl optionally substituted with one, two, or three Rau. In embodiments, R4 is independently 5 membered cycloalkyl optionally substituted with one, two, or three R20.. In embodiments, R4 is independently 6 membered cycloalkyl optionally substituted with one, two, or three In embodiments, R4 is independently 7 membered cycloalkyl optionally substituted with one, two, or three Rau. In embodiments, 114 is independently 8 membered cycloalkyl optionally substituted with one, two, or three R20. In embodiments, le is independently 9 membered cycloalkyl optionally substituted with one, two, or three R20.. In embodiments, R4 is independently 10 membered cycloalkyl optionally substituted with one, two, or three R2oa.
[00254] In embodiments, R4 is independently 3 membered heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently 4 membered heterocycloalkyl optionally substituted with one, two, or three R20'. In embodiments, R4 is independently 5 membered heterocycloalkyl optionally substituted with one, two, or three R20a Tit embodiments, R4 is independently 6 membered heterocycloalkyl optionally substituted with one, two, or three R204. In embodiments, 10 is independently 7 membered heterocycloalkyl optionally substituted with one, two, or three R2'. In embodiments, R4 is independently 8 membered heterocycloalkyl optionally substituted with one, two, or three R2". In embodiments, R4 is independently 9 membered heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently 10 membered heterocycloalkyl optionally substituted with one, two, or three R20'. In embodiments, R4 is independently 6 membered aryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently 7 membered aryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently 8 membered aryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently 9 membered aryl optionally substituted with one, two, or three R20a. In embodiments, 114 is independently 10 membered aryl optionally substituted with one, two, or three R2". In embodiments, 114 is independently 11 membered aryl optionally substituted with one, two, or three R20. in embodiments, R4 is independently 12 membered aryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently 5 membered heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 6 membered heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 7 membered heteroaly1 optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 8 membered heteroaly1 optionally substituted with one, two, or three R20. In embodiments, R4 is independently 9 membered heteroaryl optionally substituted with one, two, or three R20. In embodiments, Rl is independently 10 membered heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 11 membered heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 12 membered heteroaryl optionally substituted with one, two, or three R20.
[00255] In embodiments, R4 is independently -OH. In embodiments, R4 is independently -SH. In embodiments, 10 is independently -NH2. In embodiments, 124 is independently -C(0)0H. In embodiments, R4 is independently -OC(0)NH2. In embodiments, R4 is independently -N(H)C(0)NH2. In embodiments, R4 is independently -N(H)C(0)01-1. In embodiments, R4 is independently -N(H)S(0)2CH3. In embodiments, R4 is independently -C(0)H. In embodiments, R4 is independently -S(0)CH3. In embodiments, R4 is independently -0C(0)CH3. In embodiments, R4 is independently -C(0)Nth. In embodiments, R4 is independently -C(0)C(0)N112. In embodiments, R4 is independently -N(H)C(0)H. In embodiments, R4 is independently -S(0)2CH3. In embodiments, R4 is independently -S(0)2N1H2-. In embodiments, R4 is independently S(=0)(=NH)NH2. In embodiments, 114 is independently -CH2C(0)NH2. In embodiments, R4 is independently -CH2N(H)C(0)CH3. In embodiments, R4 is independently -CH2S(0)2CH3. In embodiments, R4 is independently and -CH2S(0)2NH2. In embodiments, R4 is independently -OCH3. In embodiments, R4 is independently -SCH3. In embodiments, R4 is independently -N(CH3)(H). In embodiments, R4 is independently -C(0)0CH3. In embodiments, R4 is independently -OC(0)N(CH3)(H). In embodiments, R4 is independently -N(H)C(0)N(CH3)(H). In embodiments, R4 is independently -N(H)C(0)0CH3. In embodiments. R4 is independently -N(H)S(0)2CH3. In embodiments, 111 is independently -C(0)CH3. In embodiments, R4 is independently -S(0)CH3. In embodiments, R4 is independently -OC(0)CH3. In embodiments, R4 is independently -C(0)N(CH3)(H). In embodiments, R4 is independently -C(0)C(0)N(CH3)(H). In embodiments, R4 is independently -N(H)C(0)CH3. In embodiments, R4 is independently -S(0)2CH3. In embodiments, R4 is independently -S(0)2N(C113)(H)-. In embodiments, R4 is independently S(=0)(=NH)N(C113)(H). In embodiments, R4 is independently -CH2C(0)N(CH3)(H).
In embodiments, R4 is independently -C112N(H)C(0)CH3. In embodiments, R4 is independently -CH2S(0)2CH3. In embodiments, R4 is independently and -CH2S(0)2N(CH3)(H) Tn embodiments, R4 is independently -0C(0)N(CH3)2 In embodiments, R4 is independently -N(H)C(0)N(CH3)2. In embodiments, re is independently -C(0)(CH3). In embodiments, R4 is independently -C(0)N(CH3)2. In embodiments, R4 is independently -C(0)C(0)N(CH3)2. In embodiments, R4 is independently -N(H)C(0)(CH3). In embodiments, R4 is independently -S(0)2N(CH3)2. In embodiments, R4 is independently S(=0)(=NH)N(CH3)2. In embodiments, R4 is independently -CH2C(0)N(CH3)2. In embodiments, R4 is independently and -CH2S(0)2N(CH3)2. In embodiments, R4 is independently -CH3. In embodiments, R4 is independently -CF3. In embodiments, R4 is independently -CHF2. In embodiments, 10 is independently -CFH2. In embodiments, R4 is independently ethyl. In embodiments, R4 is independently propyl. In embodiments, R4 is independently isopropyl. In embodiments, R4 is independently butyl. In embodiments, R4 is independently tert-butyl.
[00256] In embodiments, leis capable of forming a covalent bond with the 121h amino acid of a G12D KRas mutant. Tn embodiments, R4 is capable of forming a covalent bond with the 121h amino acid of a G12C KRas mutant. In embodiments, R4 is capable of forming a covalent bond with the 124h amino acid of a G12S KRas mutant.
In embodiments, R4 is capable of forming a covalent bond with the 13th amino acid of a G13D KRas mutant. In embodiments, R4 is capable of forming a covalent bond with the 13111 amino acid of a G13C KRas mutant. In embodiments, R4 is capable of forming a covalent bond with the 131h amino acid of a G13 S KRas mutant.
a0 R
=
[00257] In embodiments, R4 is selected from the group consisting of Ra Ra Ra Ra Ra 1-Ra Ra R
R a Ra R.
R Ra a Ra Ra >F, Ra Ra C-(C(Ra)2),-) 0 (C(Ra)2)x Ra , Rb¨N/ 0 Ra-1 E - I 0 0 El N-Rb \ I
/ a Ra¨S-S(C(Ra)2), Ra Rb (C(Ra)2) R 0 y 0-Rb , , (C(RaMx (C(Ra)2)x t / El / Ra N \

Th \ I 0 !\1Th Ra_$_ ------1:(3 \--N, (C(Ra)2)y c0 -- (C(Ra) Ra 2)y n n n j1-(CH2)z 0 jc 0 0 ,...1..¨ Ra .,,.......),. -Lye j2J1CH2,7,1 J1(CH) J1-(CH2) z 12 CH2 1 J1-(CH2)z Ra , 0 Ra RaRa = , , ' CO2J2 Ra 2 y j,_ , 02c CE12,/
J202C CH2 li I
Ra Ra , and Ra Ra ; where each Ra is independently hydrogen, C1, ' alkyl, carboxy, Ci_6carboalkoxy, phenyl, C2_7carboalkyl, Re_(c(Rb)2),._, Re_(¶Rb)2),v_m_(c(Rb)2),._, (Rd-, )1-.( )CH-M-(C(Rb)2)r-, or Het-J3-(C(Rb)2),-; each Rb is independently hydrogen, Ci_6alkyl, C2_6alkeny1, C2_6a1kynyl, C3-6cycloalkyl, C2.7carboalky1, C2_7carboxya1ky1, phenyl, or phenyl optionally substituted with one or more halogen, Ci_ nalkoxy, trifluoromethyl, amino, C1_3alkOamino, C2_6dia1kOamino, nitro, azido, balomethyl, C2_7alkoxymethyl. C2_ 7alkanoyloxymethyl, Ci_6a1kylthio, hydroxy, carboxyl, C2_7carboa1koxy, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, C1_6alkanoylamino, or Ci_6a1kyl; each Re is independently -NRbRb or -ORb; Rd and RC are each, independently, -(C(R1))2)1_NRbRb, or -(C(Rb)2),-0Rb; each J1 is independently hydrogen, chlorine, fluorine, or bromine; J2 is Ci_6alkyl or hydrogen; each M is independently -N(Rb)-, -0-, -NRC(Rb)2)w-NR
bRb:
1 or -NRC(Rb)2)w-ORb]-; each J3 is independently -N(Rb)-, -0-, or a bond; each Het is independently a heterocycle, optionally mono- or di-substituted on carbon or nitrogen with le and optionally mono-substituted on carbon with -CH2ORb; wherein the heterocycle is selected from the group consisting of molpholinc, thiomorpholinc, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran, and tetrahydropyran;
each r is independently 1-4; each w is independently 2-4; x is 0-1; y is 0-4, and each z is independently 1-6:
wherein the sum of x+y is 2-4.

[00258] In embodiments, R4 is independently selected from the group consisting of , 0 00 0 Rb 0\µ0 o Rb -.::,---, czõp 0 ve.),_ N
\,(S -,v1 C1 , and ; where each Rb is independently selected from the group consisting of hydrogen, hydroxyl, Ci-C6 alkoxy, and C1-C6 alkyl, or two Rb are optionally join to form heterocycle having 3-12 ring atoms or C3-C6 cycloalkyl. In embodiments, R4 is independently selected from the group consisting of 14*(j'YN H2, )lyCI
and [00259] In embodiments, R4 is independently -C(0)N(R12)(R13), _Ntic''-'14)C(0)R15, or -C(0)R15. In embodiments, R4 is independently -C(0)N(R12)(R23) .
In embodiments, R1 is independently _N(R14)C(0)R15. In embodiments, R1 is independently -C(0)R15.
Yo Yo OTO OTO oo [00260] In embodiments, R4 is independently selected from N¨N
N_N ,Th0 ci ________________________ 0,(,) 0,1 NC"/
F ..vCN
, -C(0)R15 wherein R15 is C4_6alkyl optionally substituted with one, two, or three R20f, _C(0)R15 wherein R1' is C2_6alkcnyl optionally substituted with one, two, or three R20, -C(0)R'' wherein R is C2_6alkynyl optionally substituted with one, two, or three R2", -C(0)R" wherein R" is C3-6cycloalicy 1 optionally substituted with one, two, or three R20, -C(0)R15 wherein R15 is C2_9heterocycloalky I
optionally substituted with one, two, or three R20, -C(0)105 wherein R15 is C6_40aryl optionally substituted with one, two, or three R20, and -C(0)R15 wherein R15 is C4_9heteroaryl optionally substituted with one, two, or three R20.
[00261] In embodiments, R4 is independently -C(0)NH(R12) and R12 is independently C4_9heteroaryl, wherein Ci_ yheteroatyl is optionally substituted with one, two, or three R20'. In embodiments, R4 is independently -C(0)NH(R12) and R12 is independently Ci_sheteroaryl, wherein C4_5heteroatyl is optionally substituted with one, two, or three R2 d. In embodiments, R1 is independently -C(0)NH(R12) and R12 is independently Ci_5heteroaryl.
[00262] In embodiments, R12 is independently Cialkyl optionally substituted with one, two, or three R20. In embodiments, R12 is independently C2alkyl optionally substituted with one, two, or three R2". In embodiments, R12 is independently C3alkyl optionally substituted with one, two, or three R2".
In embodiments, R12 is independently C4alkyl optionally substituted with one, two, or three R2". In embodiments, R12 is independently Csalkyl optionally substituted with one, two, or three R20. In embodiments, Ru is independently C6alkyl optionally substituted with one, two, or three R2". In embodiments, R12 is independently C2alkenyl optionally substituted with one, two, or three R2". In embodiments, R12 is independently C3alkenyl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently C4alkenyl optionally substituted with one, two, or three R20". In embodiments, R12 is independently Csalkenyl optionally substituted with one, two, or three R20". In embodiments, R12 is independently C6alkenyl optionally substituted with one, two, or three R20. In embodiments, R12 is independently C2alkynyl optionally substituted with one, two, or three R2". In embodiments, R12 is independently C3alkynyl optionally substituted with one, two, or three fe". In embodiments, R12 is independently C4alkynyl optionally substituted with one, two, or three R2". In embodiments, R12 is independently Csalkynyl optionally substituted with one, two, or three R2". In embodiments, R12 is independently C6alky/nvl optionally substituted with one, two, or three R20d. In embodiments, Ril is independently Clhaloalkyl. In embodiments, R12 is independently C2haloalkyl.
In embodiments, IC is independently C3lialoalkyl. In embodiments, R' is independently C4haloalkyl. In embodiments, R12 is independently Cshaloalkyl. In embodiments, R12 is independently C6haloalkyl.
[00263] In embodiments, R12 is independently C3cycloa1kyl optionally substituted with one, two, or three R2 d. Iii embodiments, R12 is independently C4cy-cloalkyl optionally substituted with one, two, or three R2 d. In embodiments, Rll is independently Cscy-cloalkyl optionally substituted with one, two, or three R2 d. In embodiments, Ru is independently C6cycloalkyl optionally substituted with one, two, or three R2'. In embodiments, R'2 is independently C7cy-cloalky1 optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cscy-cloalkyl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently C9cy-cloalky1 optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently Ciocycloalkyl optionally substituted with one, two, or three R20d.
[00264] In embodiments, R12 is independently C2heterocycloalkyl optionally substituted with one, two, or three R2od In embodiments, R12 is independently C3heterocycloallcyl optionally substituted with one, two, or three R2 d.
In embodiments, R12 is independently C4heterocycloalkyl optionally substituted with one, two, or three R2". In embodiments, R12 is independently C9heterocy-cloalkyl optionally substituted with one, two, or three R20. In embodiments, R12 is independently C6heterocycloalkyl optionally substituted with one, two. or three R20. In embodiments, R12 is independently C7heterocy-cloalkyl optionally substituted with one, two, or three R2". In embodiments, R12 is independently Csheterocy-cloalkyl optionally substituted with one, two, or three R2'. In embodiments, R12 is independently C9heterocy-cloalkyl optionally substituted with one, two, or three R2". In embodiments, R12 is independently C6aryl optionally substituted with one, two, or three R20". In embodiments, R12 is independently C7aryl optionally substituted with one, two, or three R20'.
In embodiments, R12 is independently Csaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently C9ary1 optionally substituted with one, two, or three R2". In embodiments, R12 is independently Cioaryl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently Clialy1 optionally substituted with one, two, or three Rad. In embodiments, R12 is independently Cuaryl optionally substituted with one, two, or three R2". In embodiments, R12 is independently C2heteroaryl optionally substituted with one, two, or three R20". In embodiments, R12 is independently C3heteroaryl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently C4heteroaryl optionally substituted with one, two, or three R2 d. In embodiments, RI' is independently Csheteroatyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently C6heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently C7heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Csheteroaryl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently C9heteroaryl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently Cioheteroaryl optionally substituted with one, two, or three R"d. In embodiments, Ru is independently Ciiheteroaryl optionally substituted with one, two, or three R2".
[00265] In embodiments, R12 is independently 3 membered cycloalkyl optionally substituted with one, two, or three Rzod. In embodiments, IC is independently 4 membered cycloalkyl optionally substituted with one, two, or three R2od. In embodiments, R12 is independently 5 membered cycloalkyl optionally substituted with one, two, or three R20ci. In embodiments, Ril is independently 6 membered cycloalkyl optionally substituted with one, two, or three Rau. In embodiments, R12 is independently 7 membered cycloalkyl optionally substituted with one, two, or three Rad. In embodiments, R12 is independently 8 membered cycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 9 membered cycloalkyl optionally substituted with one, two, or three Raid. In embodiments, R12 is independently 10 membered cycloalkyl optionally substituted with one, two, or three Raid.
[00266] In embodiments, R12 is independently 3 membered heterocycloalkyl optionally substituted with one, two, or three R20'. In embodiments, R12 is independently 4 membered heterocycloalkyl optionally substituted with one, two, or three R2". In embodiments, R12 is independently 5 membered heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R12 is independently 6 membered heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 7 membered heterocycloalkyl optionally substituted with one, two, or three R20'. In embodiments, R12 is independently 8 membered heterocycloalkyl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently 9 membered heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R12 is independently 10 membered heterocycloalkyl optionally substituted with one, two, or three R2".
In embodiments, R'' is independently 6 membered aryl optionally substituted with one, two, or three R2 d Tn embodiments, R12 is independently 7 membered aryl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently 8 membered aryl optionally substituted with one, two, or three R2". In embodiments, R12 is independently 9 membered aryl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently 10 membered aryl optionally substituted with one, two, or three R2". In embodiments, R12 is independently 11 membered aryl optionally substituted with one, two, or three R'. In embodiments, R12 is independently 12 membered aryl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently 5 membered heteroatyl optionally substituted with one, two, or three R20". In embodiments, R12 is independently 6 membered heteroaryl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently 7 membered heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 8 membered heteroaryl optionally substituted with one, two, or three R2". In embodiments, RI' is independently 9 membered heteroaryl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently 10 membered heteroaryl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently 11 membered heteroaryl optionally substituted with one, two, or three R2 d. In embodiments, R12 is independently 12 membered heteroaryl optionally substituted with one, two, or three R20d.
[00267] In embodiments, R1' is independently Cialkyl optionally substituted with one, two, or three R20. In embodiments, R1 is independently C?alkyl optionally substituted with one, two, or three R2111. In embodiments, R15 is independently C3alkyl optionally substituted with one, two, or three R20.
In embodiments, R15 is independently C4alkyl optionally substituted with one, two, or three R20. In embodiments, R1' is independently C5alky1 optionally substituted with one, two, or three R20. In embodiments, R15 is independently Coalkyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently Czalkenyl optionally substituted with one, two, or three R201. In embodiments, R1' is independently C3alkenyl optionally substituted with one, two, or three R20. In embodiments, R" is independently Cialkenyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently Csalkenyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently Coalkenyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently Czalkynyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently C3alkynyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently C4alkynyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently Csalkynyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently C6a1kynyl optionally substituted with one, two, or three R201. In embodiments, R" is independently Clhaloalkyl. In embodiments, R" is independently C2haloalkyl.
In embodiments, R" is independently C31taloalkyl. In embodiments, R" is independently C4haloalkyl. In embodiments, R" is independently Cshaloalkyl. In embodiments, R15 is independently C6haloalkyl.
[00268] In embodiments, R15 is independently C3cycloa1kyl optionally substituted with one, two, or three R20. In embodiments, R" is independently C4cy-cloalky1 optionally substituted with one, two, or three R20. In embodiments, R15 is independently Cscy-cloalkyl optionally substituted with one, two, or three R20f. In embodiments, R" is independently C6cycloalkyl optionally substituted with one, two, or three R20. In embodiments, R" is independently C7cy-cloalky1 optionally substituted with one, two, or three R20. In embodiments, R" is independently Cscy-cloalkyl optionally substituted with one, two, or three R20. In embodiments, R" is independently C9cy-cloalky1 optionally substituted with one, two, or three R20. In embodiments, R" is independently Ciocycloalkyl optionally substituted with one, two, or three R20.
[00269] In embodiments, R15 is independently C2heterocycloalkyl optionally substituted with one, two, or three R2" In embodiments, R15 is independently C3heterocycloalkyl optionally substituted with one, two, or three R2' In embodiments, R15 is independently C4heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R" is independently Csheterocy-cloalkyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently C6heterocycloalkyl optionally substituted with one, two. or three R20. In embodiments, R15 is independently C7heterocy-cloalkyl optionally substituted with one, two, or three R2" In embodiments, R" is independently Csheterocy-cloalkyl optionally substituted with one, two, or three R2011 In embodiments, R1' is independently C9heterocy-cloalkyl optionally substituted with one, two, or three R2" In embodiments, R" is independently C6aryl optionally substituted with one, two, or three R201.. In embodiments, R15 is independently C7atyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently Csaryl optionally substituted with one, two, or three R20. In embodiments, R15 is independently C9aryl optionally substituted with one, two, or three R2m. In embodiments, R" is independently Cloaryl optionally substituted with one, two, or three R20. In embodiments, R15 is independently Ci la tyl optionally substituted with one, two, or three R20. In embodiments, R1 is independently Cisaryl optionally substituted with one, two, or three R20. In embodiments, R" is independently C2heteroaryl optionally substituted with one, two, or three R2" In embodiments, R" is independently C3heteroaryl optionally substituted with one, two, or three R20. In embodiments, R15 is independently C4heteroatyl optionally substituted with one, two, or three R20.
In embodiments, R" is independently Csheteromyl optionally substituted with one, two, or three R2'.
In embodiments, R" is independently C6heteroaryl optionally substituted with one, two, or three R20.
In embodiments, R" is independently C7heteroatyl optionally substituted with one, two, or three R20.
In embodiments, R15 is independently Csheteromyl optionally substituted with one, two, or three R201.
In embodiments, R15 is independently C9heteroaryl optionally substituted with one, two, or three R20.
In embodiments, R15 is independently Cioheteroaly1 optionally substituted with one, two, or three R20. In embodiments, R" is independently Ciiheteroatyl optionally substituted with one, two, or three R20.
[00270] In embodiments, R15 is independently 3 membered cycloalkyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently 4 membered cycloalkyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently 5 membered cycloalkyl optionally substituted with one, two, or three R2" In embodiments, R15 is independently 6 membered cycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 7 membered cycloalkyl optionally substituted with one, two, or three R20. In embodiments, It" is independently 8 membered cycloalkyl optionally substituted with one, two, or three R20. In embodiments, R" is independently 9 membered cycloalkyl optionally substituted with one, two, or three 1120. In embodiments, R15 is independently 10 membered cycloalkyl optionally substituted with one, two, or three Rag-.
[00271] In embodiments, 1(15 is independently 3 membered heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently 4 membered heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R" is independently 5 membered heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R" is independently 6 membered heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R" is independently 7 membered heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently 8 membered heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R" is independently 9 membered heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R15 is independently 10 membered heterocycloalkyl optionally substituted with one, two, or three re".
In embodiments, R" is independently 6 membered atyl optionally substituted with one, two, or three R2" in embodiments; R" is independently 7 membered aryl optionally substituted with one, two, or three R20f. In embodiments, R" is independently 8 membered aryl optionally substituted with one, two, or three R20f. In embodiments. R15 is independently 9 membered aryl optionally substituted with one, two, or three R20f. In embodiments. R" is independently 10 membered aryl optionally substituted with one, two, or three R20. In embodiments, R1' is independently 11 membered aryl optionally substituted with one, two, or three R20. In embodiments, R" is independently 12 membered aryl optionally substituted with one, two, or three 1(20. In embodiments, R15 is independently 5 membered heteroatyl optionally substituted with one, two, or three R20f. In embodiments, 1115 is independently 6 membered heteroaryl optionally substituted with one, two, or three R20. In embodiments, 1(15 is independently 7 membered heteroaryl optionally substituted with one, two, or three R20. In embodiments, R" is independently 8 membered heteroaryl optionally substituted with one, two, or three R20. In embodiments, R" is independently 9 membered heteroaryl optionally substituted with one, two, or three R2" in embodiments, R" is independently 10 membered heteroaryl optionally substituted with one, two, or three R20f. In embodiments, R" is independently 11 membered heteroaryl optionally substituted with one, two, or three R20f. In embodiments, R" is independently 12 membered heteroaryl optionally substituted with one, two, or three R2".
[00272] In embodiments, R4 is independently -C(0)R" and R" is independently selected from C2_6a1kenyl, C2-6alkynyl, C?_9heterocycloalkyl, and Ci.9heteroary-1, wherein C2_6alkenyl, C2_6alkynyl, C,_9heterocycloalkyl, and Cl_ 9heteroaryl are optionally substituted with one, two, or three 1:(20. In embodiments, RI is independently -C(0)R15 and R15 is independently Czalkenyl optionally substituted with one, two, or three R20. In embodiments, le is independently -C(0)1(15 and R15 is independently C3alkenyl optionally substituted with one, two, or three R2" In embodiments, It4 is independently -C(0)R15 and R15 is independently Cialkenyl optionally substituted with one, two, or three R"f. In embodiments, 1(4 is independently -C(0)R" and R" is independently Csalkenyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R" and R" is independently C6alkenyl optionally substituted with one, two, or three R2"
[00273] In embodiments, R4 is independently -C(0)R15 and 1(15 is independently Czalkynyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R15 and R15 is independently C3alkynyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R15 and R" is independently Cialkynyl optionally substituted with one, two, or three R20. In embodiments, Ft4 is independently -C(0)R15 and ft" is independently Csalkynyl optionally substituted with one, two, or three R2" In embodiments, 114 is independently -C(0)R" and R" is independently Galkynyl optionally substituted with one, two, or three Rmf.
[00274] In embodiments, It4 is independently -C(0)R" and R" is independently C2heteroeyeloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R" and R15 is independently C3heterocycloalkyl optionally substituted with one, two, or three R201. In embodiments, R4 is independently -C(0)R" and Ft" is independently C4heterocycloalkyl optionally substituted with one, two, or three R201. In embodiments, leis independently -C(0)R" and R" is independently Csheterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R15 and R15 is independently C6heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R15 and R15 is independently C7heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R15 and R15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R15 and R15 is independently C9heterocycloa1kyl optionally substituted with one, two, or three It2".
[00275] In embodiments, R4 is independently -C(0)R15 and R15 is independently Ciheteroaryl optionally substituted with one, two, or three R20. In embodiments, R1 is independently -C(0)R15 and R15 is independently C2heteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R15 and R15 is independently C3heteroaryl optionally substituted with one, two, or three R20.
In embodiments, R4 is independently -C(0)R" and R" is independently C4heteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R15 and R15 is independently Csheteroaryl optionally substituted with one, two, or three R20. In embodiments, 124 is independently -C(0)R15 and R15 is independently C6heteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R15 and 1115 is independently C7heteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -C(0)R15 and R15 is independently Csheteroaryl optionally substituted with one, two, or three R20.
In embodiments, R4 is independently -C(0)R1' and R15 is independently C9heteroaryl optionally substituted with one, two, or three It211.
[00276] In embodiments, R4 is independently -NHC(0)R15 and R15 is independently selected from C2.6alkenyl, C2-6a1kyny1, C2_9heteroeyeloalkyl, and Ci_,heteroaryl, wherein C2_6alkenyl, C2_6alkynyl, C2_9heterocycloalkyl, and Ci_ 9heteroaryl are optionally substituted with one, two, or three R2" In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C2alkenyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R" and R" is independently C3alkenyl optionally substituted with one, two, or three In embodiments, R4 is independently -NHC(0)R" and ft" is independently Cialkenyl optionally substituted with one, two, or three R20. In embodiments, R1 is independently -N}-IC(0)R'5 and R" is independently Csalkenyl optionally substituted with one, two, or three R2" In embodiments, R4 is independently -NHC(0)R15 and R" is independently C6alkenyl optionally substituted with one, two, or three R20.
[00277] In embodiments, It4 is independently -NHC(0)R15 and R15 is independently C2alkynyl optionally substituted with one, two, or three R20. In embodiments, lt1 is independently -NHC(0)R" and It" is independently C3alkynyl optionally substituted with one, two, or three R2" In embodiments, R4 is independently -NHC(0)R" and R15 is independently Cialkynyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C5alkynyl optionally substituted with one, two, or three R20.
In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C6alkynyl optionally substituted with one, two, or three R20.

[00278] In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C2heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NI-IC(0)105 and R15 is independently C3heterocycloa1kyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -N}-IC(0)R'5 and R1' is independently C4heterocycloalk0 optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R" and R" is independently C6heterocycloalkyl optionally substituted with one, two, or three le". In embodiments, R4 is independently -NHC(0)R1' and R1' is independently C7heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R" and R" is independently Csheterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C9heterocycloa1kyl optionally substituted with one, two, or three R20.
[00279] In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Ciheteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C2heteroary1 optionally substituted with one, two, or three R". In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C3heteroaryl optionally substituted with one, two, or three R2" In embodiments, R4 is independently -NHC(0)R" and R15 is independently C4heteroaryl optionally substituted with one, two, or three R20.
In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Csheteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R" and R15 is independently C6heteroaryl optionally substituted with one, two, or three R20. In embodiments, 10 is independently -NHC(0)R15 and ft" is independently C7heteroaly1 optionally substituted with one, two, or three R20.
In embodiments, le is independently -NHC(0)R15 and R15 is independently Csheteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R" and R15 is independently C9heteromyl optionally substituted with one, two, or three R20.
Ra p R _______________________________________________________________________ ) [00280] In embodiments, R4 is selected from the group consisting of Ra Ra (C(Ra)2)x Rb¨N (C(Ra)2)x (C(Ra)2)x Ra 0 _____________ Ra Ra (C(R8)2)y (C(Ra)2)y (C(Ra)2)y , and j1-(CH2)z .11-(CH2 J1- ( C H2 z ) ; where each Ra is independently hydrogen, Cimallcyl, carboxy, Ch6carboalkoxy, phenyl, C2_ 7 carbo Re_(c (R,b)2)z_, Re_(c (Rb)2)w_m_(c (Rb)2),_, (Rd)(Re)cii_m_(c (Rb)2+
)or Het-J3-(C(Rb)2),-; each Rb is independently hydrogen, Ci_6alkyl, C2.6alkenyl, C2_6alkynyl, C3_6cycloa1kyk C2_7carboalkyl, C2_7carboxyalkyl, phenyl, or phenyl optionally substituted with one or more halogen, Ci_Oalkoxy, trifluoromethyl, amino, C1_ 3a1kOamino, C2_6dialkylamino, nitro, azido, halomethyl, C2_7alkoxymethyl, C2_7a1kanoyloxymethyl, CI_Oalkylthio, hydroxy, carboxyl, C2_7carboalkoxy, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, Ci_6alkanoylamino, or C1_6a1kyl; each W is independently -NRbRb or -ORb; Rd and Re are each, independently, -(c(Rb)2), lc_NRb-b, or -(C(Rb),),-ORb; each Id is independently hydrogen, chlorine, fluorine, or bromine; F is C1,6alk0 or hydrogen: each M is independently -N(R b)-, -0-, -N[(C(Rib)2),,_NRb-b,__ K ] or -NRC(Rb)2),,-0Rb1-; each P is independently -N(Rb)-, -0-, or a bond; each Het is independently a heterocycle, optionally mono- or di-substituted on carbon or nitrogen with Rb and optionally mono-substituted on caibon with -CH2ORb; wherein the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tctrahydrofuran, and tetrahydropyran; each r is independently 1-4; each w is independently 2-4; x is 0-1; y is 0-4, and each z is independently 1-6, wherein the sum of x+y is 2-4.
[00281] In embodiments, Rd is capable of forming a covalent bond with a Ras amino acid sidechain. In embodiments, Rd is capable of forming a covalent bond with a KRas amino acid.
In embodiments, Rd is capable of forming a covalent bond with the 12111 amino acid of a human KRas protein. In embodiments, Rd is capable of forming a covalent bond with the 12111 amino acid of a mutant KRas protein selected from KRas G12D, KRas G12C, and KRas G12 S. In embodiments, Rd is capable of forming a covalent bond with the 131h amino acid of a human KRas protein lit embodiments, Rd is capable of forming a covalent bond with the 131l amino acid of a mutant KRas protein selected from KRas G13D, KRas G13C, and KRas G13S.

0 --."-- , , F ,1 ..µ
S-' F '''''&F F N(11 --- NAi \\,T,C1 c=
[00282] In embodiments, Rd is selected from µµ N
I , )\
F , 0 i VIL N H2 .\(--, and .
\
0 ________________________________________ 0 = ) OH R\ 0) N¨
= ) __________ i 7 ¨ _ __________________________________________________________________________ /
[00283] In embodiments, Rd is selected from -N- .
.

0 b 0 0 Ci 0 Ci 0 0 . -6t, -õ,, __________ õ,,,_ =.õõ "1-4, F "-L, -11.( '1,..
F `11-1.- C F3 OH
OM e 0 _________________________________________________________ / I ? __ ' F '.1-t.. ______ \ OH, '1-1.. OM e \
( 0, // __ <F0, __ rcF3 0\ __ ,¨ N 0, , ___ <N H2 / 0 /
0, h e a /
> i/

N¨N
0\ _______________________________________________ 0\ e 0\ e 0, _________ e 0, __ e __________________________________________________ N

( "Lin_ CN
, R\
HN ____________________________ 0 ./K OMe and [00284] In embodiments, R1' is independently C2_6alkeny1 optionally substituted with one, two, or three R20. In embodiments, R15 is independently C2_6alkenyl optionally substituted with one, two, or three halogen. In embodiments, R1' is independently C2_6alkenyl optionally substituted with one, two, or three F. In embodiments, R1' is independently C2.6a1keny1 optionally substituted with -OR'. In embodiments, R1' is independently C2.
6a1keny1 optionally substituted with -N(R22)(R23). In embodiments, R1' is independently C2_6alkenyl optionally substituted with C2_9heterocycloallcyl. In embodiments, R15 is independently C2_6a1ke11y1 optionally substituted with Ci_sheteroaryl optionally substituted with one, two, or three Ci_6alkyl. In embodiments, R15 is independently C2-6a1keny1 optionally substituted with Ci_sheteroaryl optionally substituted with methyl. In embodiments, R15 is independently C2.6a11ceny1 optionally substituted with -CN. In embodiments, R15 is independently C2_6alkenyl optionally substituted with Ci.5heteroaryl optionally substituted with -N(R24)C(0)R23. In embodiments, R15 is independently C2.6a11ceny1 optionally substituted with Ci_5heteroaryl and/or CN. In embodiments, R15 is independently C2.6alkenyl optionally substituted with one, two, or three R20.
In embodiments, R15 is independently C2_6alkenyl optionally substituted with one, two, or three halogen. In embodiments, R15 is independently C2_6alkenyl optionally substituted with one, two, or three F. In embodiments, R15 is independently C2_6alkenyl optionally substituted with -0R21. In embodiments, R15 is independently C2_6a1keny1 optionally substituted with _N(R22)(R23).
In embodiments, R1' is independently C2_6a1keny1 optionally substituted with C2_9hcterocycloalkyl. In embodiments, R15 is independently C2.6a1keny1 optionally substituted with Ci_sheteroaryl optionally substituted with one, two, or three Ci_6alkyl. In embodiments, R1' is independently C2_6alkenyl optionally substituted with Ci_sheteroaryl optionally substituted with methyl. In embodiments, R15 is independently C2.6a1keny1 optionally substituted with -CN. In embodiments, R15 is independently C2_6a1keny1 optionally substituted with Ci.sheteroaryl optionally substituted with -N(R24)C(0)R25. In embodiments, R15 is independently C2_6alkeny1 optionally substituted with -C(0)N(R22)(R23). In embodiments, R is independently C2_6a1keny1 substituted with Cl and optionally substituted with one or two R20. In embodiments, it' is independently C2_6a1kyny1 optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C2_6alkynyl optionally substituted with one, two, or three halogen.
In embodiments, R15 is independently C2_6alkynyl optionally substituted with one, two, or three F. In embodiments, R15 is independently C2.6a1lny1 optionally substituted with -0R21. In embodiments, R15 is independently C2-alkynyl optionally substituted with -N(R22)(R23). In embodiments, R1' is independently C2.6alkynyl optionally substituted with C2_9heteroeycloallcyl. In embodiments, R15 is independently C2_6alkynyl optionally substituted with Ci_sheteroaryl optionally substituted with one, two, or three Ci_6alkyl. In embodiments, R15 is independently C2_ 6a1kyny1 optionally substituted with Ci_5heteroaryl optionally substituted with methyl. In embodiments, R15 is independently C2_6alkynyl optionally substituted with -CN. In embodiments, R15 is independently C2_6alkynyl optionally substituted with C1.5heteroaryl optionally substituted with -N(R24)C(0)R25. In embodiments, R15 is independently C2.6alkynyl optionally substituted with C1_5heteroary-1 and/or CN. In embodiments, R15 is independently C2.6alkynyl optionally substituted with one, two, or three R20.
In embodiments, R1' is independently C2_6alkyny1 optionally substituted with one, two, or three halogen. In embodiments, 1115 is independently C2-6a1kyny1 optionally substituted with one, two, or three F. In embodiments, R15 is independently C2_6alkyny1 optionally substituted with -OR'. In embodiments, 105 is independently C2_6a1kynyl optionally substituted with -N(R22)(R23). In embodiments, 111' is independently C2_6alkynyl optionally substituted with C2.9heterocycloallcyl. In embodiments, R1' is independently C2_6alkynyl optionally substituted with Ci_sheteroaryl optionally substituted with one, two, or three Ci_6alkyl. In embodiments, 12,15 is independently C2_6alkynyl optionally substituted with CI_ 5heteroaryl optionally substituted with methyl. In embodiments, R15 is independently C2_6alkynyl optionally substituted with -CN. In embodiments, R15 is independently C2_6alkynyl optionally substituted with Ci_sheteroaryl optionally substituted with -N(R24)C(0)R25. In embodiments, R45 is independently C2_6alkyny1 optionally substituted with -C(0)N(R22)(R23). In embodiments, R15 is independently C2.6alkyny1 substituted with Cl and optionally substituted with one or two R2" In embodiments, R15 IS
independently C.3_5cycloallcy-1, optionally substituted with one, two, or three R20. In embodiments, R15 is independently C3_5eye1oalkyl, optionally substituted with Cl_6alkyl optionally substituted with one, two, or three halogen. In embodiments, R15 is independently C3.
5cycloalk0, optionally substituted with Ci_6a1ky1 optionally substituted with one, two, or three F. In embodiments.
R1' is independently Ci_sheterocycloalkyl, optionally substituted with one, two, or three R20. In embodiments, R1' is independently Ci_sheterocycloalkyl, optionally substituted with Ci_6a1ky1 optionally substituted with one, two, or three halogen. In embodiments, R15 is independently Ci_sheterocycloalkyl, optionally substituted with Ci_6alkyl optionally substituted with one, two, or three F. In embodiments, R15 is independently Ci.6a1ky1, optionally substituted with one, two, or three R20. In embodiments, R15 is independently Ci.6alkyl, substituted with Cl and optionally substituted with one, two, or three R20. In embodiments, R4 is independently -CN.
[00285] In embodiments, L2 is independently a bond, -C(0)NH-, -NHC(0)-, or -C(0)-; and R5 is independently selected from halogen, -CN, Ci_6alkyl, C2_6alkenyl, C2_6allcynyl, C3_12cycloallcyl, -CH2-C3_12cye1oa1ky1, C1_ iihetero cy cloalkyl, -CH2-Ci_iihetero cy cl o alkyl, C6_12ary 1, -C}12-C6_12ary1, -CH2-C1_1ihetero aryl, Ci_i iheteroatyl, -0R12, _sR12, _N(R12)(R13), _ C(0)0R12, -0C(0)N(R12)(R13), -N(R1-4)C(0)1\1(R12)(R1-3), _N- (_14 )C(0)0R15, -N(R14)S(0)2R15, _C(Or _ 15, K S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), _C(0)C(0)N(R12)(R13), _N(R14)c(0)R15, _ S(0)2R15, -S(0)2N(R12)(R13)_. S(=0)(=NH)N(R12)(R13). _CH2C(0)N(R12)(R'), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R')(1113), wherein the Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_12cycloalkyl, -CH2-C3_12cyc1oa1ky1, C ibetero eyelo alky I, -CI-I2-C,iiheterocycloalkyl, C6_12ary I, -CH2-C6_12ary I, -CH2-C hete ro ary I, C 1_ hete ro ary I
are optionally substituted with one, two, or three R20a.
[00286] In embodiments, L2 is independently -C(0)-; and R5 is independently a Ci_6alkyl, C2_6alkenyl, C2_6alkvnyl, C3_12eyeloalkyl, -CH2-C3_12eyeloalkyl, Ci_iiheterocycloalkyl, -CH2-C1_1iheterocycloalkyk C6_12ary1, -CH2-C6_12aryl, -CH2-C1_u_heteroaryl, or Ci_iiheteroaryl, wherein the Ci_6a1ky1, C2.6alkenyl, C2.6alkynyl, C3_12cyc10a11cy1, -CH2-C3.
12cyc10a1ky1, Ci_iiheterocycloalkyl, -CH2-Ci_iiheterocycloalkyl, C6_12aly1, -CH2-C6_12aryl, -CH2-Ci_iiheteroaryl, and CI_Iiheteroaryl are optionally substituted with one, two, or three R20a.
[00287] In embodiments, L2 is independently -C(0)-; and R5 is independently a C3_12cycloalkyl, Cl_ iiheterocycloalkyl, C6_12ary1, or Ci_iiheteroaryl, wherein the C3_12cyc1oa1ky1, Ci_iiheterocycloalkyl, C6.12aryl, and Cl_ iiheteroaryl are optionally substituted with one, two, or three R20a.

[00288] In embodiments, L2 is independently a bond, -C(0)NH-, -NHC(0)-, or -C(0)-; L2 is independently bonded to a carbon atom of R5; and R5 is independently selected from -CN, C1_6a1ky1, C2_6alkeny1, C2_6alkynyl, C3_ 12cycloalkyl. C6_12aryl, and Ci_i iheteroaryl, wherein Ci_nalkyl, C2_6a1keny1, C2.6alkynyl, C3_12cycloalkyl, C6.12aryl, and Ci_itheteroaryl, are optionally substituted with one, two, or three R"a.
[00289] In embodiments, L2 is independently -C(0)-; L2 is independently bonded to a carbon atom of R5; and R5 is independently selected from C1_6alkyl, C2_6al1cenyl, C2_6a1kynyl, C342cycloa1kyl, C6_12aryl, and Ci_tiheteroaryl, wherein the Ci-6alkyl, C2_6alkenyl, C2_6alkynyl, C342cycloa1kyl, C6_12aryl, and Ci_itheteroaryl, are optionally substituted with one, two, or three R20'.
[00290] In embodiments, L2 is independently -C(0)-; L2 is independently bonded to a carbon atom of R5; and R5 is independently selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_llicycloa1kyl, and 5-6 membered heteroaryl, wherein the C1_6alkyl, C2_6alkenyl, C2_6allnyl, C3_llicycloalkyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20a. In embodiments, L2 is independently -C(0)-; R5 is independently a R5a-R5a 5a heteroaryl having the formula: R
; R5a is independently 0, S, CH, C(R2 0), N, NH, or N(R2 a); R5 comprises 0-3 independent R2aa; and 0-4 R5a are independently N, NH, or N(Rm).
In embodiments, L2 is R5a-R5a cs R5a R5a independently -C(0)-; and R5 is independently a heteroaryl haying the formula:
; fea is independently CH, C(R2 a), N, NH, or N(R2 a); R5 comprises 0-3 independent R2"; and 0-4 R5a are independently N, R5aR5a R5a k ss R5a NH, or N(R2 a). In embodiments, L2 is independently -C(0)-; R5 is independently Rsa; R5a is independently CH, C(R2 a), CH(R2 a), CH2, C(R2 a)2, N, NH, or N(R20'); R5 comprises 0-3 independent R2 a; and 0-4 R5a are independently N, NH, or N(R2").
[00291] In embodiments, L2 is independently -C(0)-; and R5 is independently C3.10cycloalkyl, wherein C3.
iocycloalkyl is independently optionally substituted with one, two, or three R20a. In embodiments, L2 is independently -C(0)-; and le is independently cyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two, or three F. in embodiments, L2 is independently -C(0)-; and R5 is independently cyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two, or three CN. In embodiments, L2 is independently -C(0)-; and R5 is independently cyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two, or three halogen.
[00292] In embodiments, R5 is independently hydrogen. In embodiments, R5 is independently halogen. In embodiments, R5 is independently R5 is independently oxo. In embodiments, R5 is independently -CN. In embodiments, R5 is independently Ci_6alkyl. In embodiments, R5 is independently C2_6alkenyl. In embodiments, R5 is independently C2_6alkynyl. In embodiments, R5 is independently C1_6haloalkyl. In embodiments, R5 is independently C3.12eyeloalkyl. In embodiments, R5 is independently -CH2-C3_12cycloalkyl. In embodiments, R5 is independently C1.1theterocycloalkyl. In embodiments, R' is independently -CH2-C1_ltheterocycloalkyl. In embodiments, R5 is independently C6_12aryl. In embodiments, R5 is independently -CH2-C6_12ary1. In embodiments, R5 is independently -CH2-Ci_iiheteroaryl. In embodiments, R5 is independently Ci_iiheteroaryl. In embodiments, R5 is independently -OR'. In embodiments, R5 is independently -SR12. In embodiments, R5 is independently -N(R12)(R"). In embodiments, R5 is independently -C(0)OR'. In embodiments, R5 is independently -0C(0)N(R12)(1113). In embodiments, R5 is independently -N(R15)C(0)N(R')(R").
In embodiments, R5 is independently -N(R15)C(0)0R15. In embodiments, R5 is independently -N(R15)S(0)2R15. In embodiments, R5 is independently -C(0)R15. In embodiments, R5 is independently -S(0)R15. In embodiments, R5 is independently -OC(0)R15. In embodiments, R5 is independently -C(0)N(R12)(R13). In embodiments, R' is independently -C(0)C(0)N(R12)(R13). In embodiments, R5 is independently -N(R15)C(0)R15. In embodiments, R5 is independently -S(0)2R15. In embodiments, R5 is independently -S(0)2N(R12)(R13)-. In embodiments, R5 is independently S(=0)(=NH)N(R12)(R13) .
In embodiments, R5 is independently -CH2C(0)N(R12)(R13). In embodiments, R5 is independently -CH2N(R15)C(0)R15. In embodiments, R5 is independently -CH2S(0)2R15. In embodiments, R5 is independently and -CH2S(0)2N(R12)(R13). In embodiments, R5 is independently Ci.6a11cy1 optionally substituted with one, two, or three R2". In embodiments, R' is independently C2_6alkenyl optionally substituted with one, two, or three R2" In embodiments, R5 is independently C2_6allcynyl optionally substituted with one, two; or three R2' In embodiments, R5 is independently Ci_6haloalkyl optionally substituted with one, two, or three R20'. In embodiments, R5 is independently C3_12cycloalkyl optionally substituted with one, two, or three R20. In embodiments, R5 is independently -CH2-C3_12cyc1oa1ky1 optionally substituted with one, two, or three R20. In embodiments, R' is independently C14 iheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently -CH2-C t_t theterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C6_12aty1 optionally substituted with one, two, or three R2". In embodiments, R5 is independently -CH2-C6.12atyl optionally substituted with one, two, or three R20. In embodiments, R5 is independently -CH2-Ct_itheteroaryl optionally substituted with one, two, or three R20. In embodiments, R5 is independently Ci_itheteroaryl optionally substituted with one, two, or three R20.
[00293] In additional embodiments of the subject compound, R5 is independently selected from hydrogen, halogen, oxo, -CN, C1.6alkyl, C2_6alkenyl, C2_6alkynyl, -OR12, _1\1(:z.12)(R13), _ C(0)0R12, -0C(0)N(R12)(R13), and _c(0)R12, wherein Ci_6a1ky1, C2_6a1keny1, and C2_6alkynyl, are optionally substituted with one, two, or three R20U. In embodiments of the subject compound, R5 is independently hydrogen. In further embodiments of the subject compound, R5 is independently halogen. In some embodiments of the subject compound, R5 is independently oxo.
In some embodiments of the subject compound, re is independently -CN. In additional embodiments of the subject compound, R5 is independently C1_6allcyl. In embodiments of the subject compound, R5 is independently C2.
6alkenyl. In some embodiments of the subject compound, R" is independently C2_6a1kyny1. In further embodiments of the subject compound, R5 is independently -OR'. In select embodiments of the subject compound, R5 is independently -N(R12)(R13). In additional embodiments of the subject compound, R5 is independently -C(0)OR'.
In embodiments of the subject compound, R5 is independently -0C(0)N(R12)(R").
In some embodiments of the subject compound, R9 is independently -C(0)R'. In select embodiments of the subject compound, R5 is independently -NH2. In further embodiments of the subject compound, its is independently -C(0)0H. In additional embodiments of the subject compound, R5 is independently -0C(0)N}12. In embodiments of the subject compound, R5 is independently -C(0)CH3.
[00294] In embodiments. R5 is independently Cialk0 optionally substituted with one, two, or three R2C)a. In embodiments, R5 is independently C2a1kyl optionally substituted with one, two, or three R2Cia. In embodiments, R5 is independently C3a1kyl optionally substituted with one, two, or three R20. In embodiments, R5 is independently C4a1kyl optionally substituted with one, two, or three R2C)a. In embodiments, R5 is independently C5alkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C6alkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C?alkenyl optional] substituted with one, two, Or three R20. In embodiments, R5 is independently C3alkenyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C4a1kenyl optionally substituted with one, two, or three R20. In embodiments, R5 is independently Csalkenyl optionally substituted with one, two, or three R20.
In embodiments, R5 is independently Coalkenyl optionally substituted with one, two, or three R20. In embodiments, re is independently C2alkynyl optionally substituted with one, two, or three R20. In embodiments, R5 is independently C3alkynyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C4alkynyl optionally substituted with one, two, or three R20. In embodiments, R5 is independently C5alkynyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Coalkynyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cihaloalkyl. In embodiments, R5 is independently C2haloalkyl. In embodiments, R5 is independently C3haloalkyl. In embodiments, R5 is independently C4haloalkyl. In embodiments, Rs is Independently C5haloallcyl Tn embodiments, R5 is independently C6haloallcyl [00295] In embodiments, R5 is independently C3cycloalkyl optionally substituted with one, two, or three WC)a. In embodiments, R5 is independently C4cycloalkyl optionally substituted with one, two, or three R20. In embodiments, R5 is independently C5cycloalkyl optionally substituted with one, two, or three R2". In embodiments, R5 is independently Cocycloalkyl optionally substituted with one, two, or three R20.
In embodiments, R5 is independently C7cycloalkyl optionally substituted with one, two, or three R2'. In embodiments, R9 is independently Cscycloalkyl optionally substituted with one, two, or three R20. In embodiments, R5 is independently C9cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Ciocycloalkyl optionally substituted with one, two, or three R20a.
[00296] In embodiments. R5 is independently C2heterocycloalkyl optionally substituted with one, two, or three R2aa. In embodiments, R5 is independently C3heterocycloalkyl optionally substituted with one, two, or three R2'. In embodiments, R5 is independently Gtheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C5heterocycloalkyl optionally substituted with one, two, or three R2 a. In embodiments, R5 is independently C6heterocycloalkyl optionally substituted with one, two, or three R2 . In embodiments, R5 is independently C7heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Csheterocycloalkyl optionally substituted with one, two, or three R2C)a. In embodiments, R5 is independently C9heterocycloalkyl optionally substituted with one, two, or three R20a.
[00297] In embodiments. R' is independently C6aryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C7aryl optionally substituted with one, two, or three R2 . In embodiments, R5 is independently Csaryl optionally substituted with one, two, or three R2 . In embodiments, R5 is independently C9aryl optionally substituted with one, two, or three R20. In embodiments, R5 is independently CHoryl optionally substituted with one, two, or three R20a. In embodiments, R9 is independently Cliaryl optionally substituted with one, two, or three R20. In embodiments, Rs is independently Cuairyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C2heteroaryl optionally substituted with one, two, or three R20. In embodiments, R5 is independently C3heteroaryl optionally substituted with one, two, or three R2". In embodiments, R5 is independently etheteroaryl optionally substituted with one, two, or three R2Da. In embodiments, R5 is independently C5heteroaly1 optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C6heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C7heteroaryl optionally substituted with one, two, or three R21). In embodiments, R5 is independently Csheteroarvl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C9heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R' is independently Cioheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently CI iheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently -OH. In embodiments, R' is independently -SH. In embodiments, R5 is independently -NH2. In embodiments, R5 is independently -C(0)0H. In embodiments, R5 is independently -OC(0)NH2. In embodiments, R' is independently -N(H)C(0)NH2. In embodiments, R5 is independently -N(H)C(0)0H. In embodiments, R5 is independently -N(H)S(0)2CH3. In embodiments, R5 is independently -C(0)H. In embodiments, R5 is independently -S(0)CH3. In embodiments, R5 is independently -0C(0)CH3. In embodiments, R5 is independently -C(0)NH2. In embodiments, R5 is independently -C(0)C(0)NH2. In embodiments, R5 is independently -N(H)C(0)H. In embodiments, R' is independently -S(0)2CH3. In embodiments, R5 is independently -S(0)2N1H2-. In embodiments, R5 is independently S(=0)(=NH)NH2. In embodiments, R5 is independently -CH2C(0)N112. In embodiments, R5 is independently -CH2N(H)C(0)CH3. In embodiments, R5 is independently -CH2S(0)2CH3 In embodiments, R5 is independently and -CH2S(0)2NH2 [00298] In embodiments, R5 is independently -OCH3. In embodiments, R5 is independently -SCH3. In embodiments, R5 is independently -N(CH1)(H). In embodiments, R5 is independently -C(0)0CH3. In embodiments, R5 is independently -0C(0)N(CH3)(H). In embodiments, R5 is independently -N(H)C(0)N(CH3)(H).
In embodiments, R' is independently -N(H)C(0)0CH3. In embodiments, R5 is independently -N(H)S(0)2CH3. In embodiments, R5 is independently -C(0)CH3. In embodiments, R5 is independently -S(0)CH3. In embodiments, R9 is independently -0C(0)CH3. In embodiments, R5 is independently -C(0)N(CH3)(H). In embodiments, R5 is independently -C(0)C(0)N(CH3)(H). In embodiments, R5 is independently -N(H)C(0)CH3. In embodiments, R5 is independently -S(0)2CH3. In embodiments, R5 is independently -S(0)2N(CH3)(H)-.
In embodiments, R5 is independently S(=0)(=NH)N(CH3)(H). In embodiments, R5 is independently -CH2C(0)N(CH3)(H). In embodiments, R5 is independently -CH2N(H)C(0)CH3. In embodiments, R5 is independently -CH2S(0)2CH3. In embodiments, R5 is independently and -CH2S(0)2N(CH3)(H).
[00299] In embodiments, R5 is independently -0C(0)N(CH3)2. In embodiments, R5 is independently -N(H)C(0)N(CH3)2. In embodiments, ft. is independently -C(0)(CH3). In embodiments, R5 is independently -C(0)N (CH3)2. In embodiments, R5 is independently -C(0)C(0)N (CH3)2. In embodiments, R5 is independently -N(H)C(0)(CH3). In embodiments, R5 is independently -S(0)2N(CH3)2. In embodiments, R5 is independently S(=0)(=NH)N(CH3)2. In embodiments, R5 is independently -CH2C(0)N(CH3)2. In embodiments, 115 is independently and -CH2S(0)2N(CH3)2.
[00300] In embodiments, R5 is independently -CH3. In embodiments, R5 is independently -CF3. In embodiments, R5 is independently -CHF2. In embodiments, R5 is independently -CFH2. In embodiments, R' is independently ethyl. In embodiments, R5 is independently propyl. In embodiments, R5 is independently isopropyl. In embodiments, R5 is independently butyl. In embodiments, R5 is independently tert-butyl.
[00301] In embodiments, le is independently halogen. In embodiments, R6 is independently R6 is independently oxo. In embodiments, R6 is independently -CN. In embodiments, re is independently C1.6alkyl. In embodiments, R6 is independently C2_6alkenyl. In embodiments, R6 is independently C2_6alkynyl. In embodiments, R6 is independently Ci.6haloalkyl. In embodiments. R6 is independently C3_12cycloalkyl. In embodiments, R6 is independently -CH2-C3_12eyeloalkyl. In embodiments, R6 is independently C1_, Iheterocycloalkyl. In embodiments, R6 is independently -CH2-Ci_iiheterocycloalkyl. In embodiments, R6 is independently C6_12ary1. In embodiments, R6 is independently -C1-12-C642aryl. In embodiments, R6 is independently -C1-12-Ci_iiheteroaryl. In embodiments, R6 is independently C1_, iheteroaryl. In embodiments, R6 is independently -0R12.
In embodiments, R6 is independently -SR'. In embodiments, R is independently -N(R12)(R13). In embodiments, R6 is independently -C(0)OR'. In embodiments, R6 is independently -0C(0)N(R12)(R13). In embodiments, R6 is independently -Nr 16%
jC(0)N j (R12)(R13,.
In embodiments, R6 is independently -N(R16)C(0)0R15. In embodiments, R6 is independently -N(R16)S(0)2R15. In embodiments, R6 is independently -C(0)R'. In embodiments, R6 is independently -S(0)R15. In embodiments, R6 is independently -0C(0)R15. In embodiments, R6 is independently -C(0)N(R12)(R13). In embodiments, le is independently -C(0)C(0)N(R12)(R13). In embodiments, R6 is independently -N(R16)C(0)R'5. In embodiments, R6 is independently -S(0)2R15.
In embodiments, R6 is independently -S(0)2N(R12)(R13)-. In embodiments, R6 is independently S(=0)(=NH)N(R12)(R13). In embodiments, R6 is independently -CH2C(0)N(R12)(R13) .
In embodiments, R6 is independently -CH2N(R16)C(0)R15. In embodiments, R6 is independently -CH2S(0)2R15. In embodiments, R6 is independently and -CH2S(0)2N(R12)(R13).
In embodiments, R6 is independently Ci_6a1ky1 optionally substituted with one, two, or three R2". In embodiments, R6 is independently C2_6alkenyl optionally substituted with one, two, or three R20a In embodiments, R6 is independently C2_6alkynyl optionally substituted with one, two, or three Rna.
In embodiments, R6 is independently Cl_6haloalkyl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently 12cycloalkyl optionally substituted with one, two, or three R20. In embodiments, R6 is independently -CH2-C3.
ilcycloalkyl optionally substituted with one, two, or three R20'. In embodiments, ft6 is independently C,.
iiheterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R6 is independently -CH2-Ci-iiheterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R6 is independently C6_12aryl optionally substituted with one, two, or three R20. In embodiments, R6 is independently -CH2-C6_12aryl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently -CH2-Ci_iiheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently Ci_iiheteroaryl optionally substituted with one, two, or three Rna.
[00302] In additional embodiments of the subject compound, R1 is independently hydrogen. In select embodiments of the compound, R1 is independently C1_6alkyl optionally substituted with one, two, or three Rna. In embodiments of the compound, R1 is independently methyl optionally substituted with one or two R20. In further embodiments of the compound, R1 is independently methyl. In some embodiments of the compound, R1 is independently ethyl optionally substituted with one, two, or three R20'. In embodiments of the compound, R1 is independently ethyl. In some embodiments of the compound, re is independently propyl optionally substituted with one, two, or three Rna.
In embodiments of the compound, R1 is independently propyl. In some embodiments, R1 is independently -CH2-C2_ 9heterocycloalkyl optionally substituted with one, two, or three Rna. In some embodiments. R1 is independently -CH2-(monocyclie C2_8heterocycloalkyl) optionally substituted with one, two, or three R20. In some embodiments, 111 is independently -CH2-(monocyclie C3_5heterocycloalkyl) optionally substituted with one, two, or three Rna. In some embodiments, 111 is independently -CH2-(spirocyclie C2_oheterocycloalky-1) optionally substituted with one, two, or three R20. In some embodiments, R' is independently -CH2-(spirocy clic C34 iheterocycloalkyl) optionally substituted with one, two, or three Rna. In some embodiments, 111 is independently -CH2-(fused C2-iiheterocycloalkyl) optionally substituted with one, two, or three R2". In some embodiments, R1 is independently -CH2-(spiroeyclic C6_8heter0cyc10a1ky1) optionally substituted with one, two, or three R20. In embodiments, R' is independently C1.6a11y1. In embodiments, R1 is independently C2_6alkenyl. In embodiments, R1 is independently C2.

6a1kyny1. In embodiments, R1 is independently C3_iocycloalkyl. In embodiments, R1 is independently -CH2-C3_ loeyeloalkyl. In embodiments, R1 is independently C2_9heterocycloa1k)71. In embodiments, R1 is independently -CH2-C2_9heteroeycloalkyl. In embodiments, R1 is independently C6_, Daryl. In embodiments, 111 is independently -0-12-C6_40aryl. In embodiments, R1 is independently -0-12-Ci_9heteroaryl. In embodiments, R1 is independently C1_ 9heter0a1y1. In embodiments, R1 is independently Ci_6alky1 optionally substituted with one, two, or three R2 a. In embodiments, R1 is independently C2_6alkenyl optionally substituted with one, two, or three R20. In embodiments, R1 is independently C2_6alkynyl optionally substituted with one, two, or three R20. In embodiments, R1 is independently C3.10eyeloa1kyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C3_llicycloalkyl optionally substituted with one, two, or three R20. In embodiments, RI- is independently C2_9heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three R2". In embodiments, R1 is independently C6.10aryl optionally substituted with one, two, or three R20a.
In embodiments, R1 is independently -CH2-C6_40aryl optionally substituted with one, two, or three R2Ca. In embodiments, R1 is independently -CH2-C1-9heteroaryl optionally substituted with one, two, or three R2". In embodiments, R' is independently Ci_gheteroaly1 optionally substituted with one, two, or three R2"
[00303] In embodiments, R1 is independently C1_6alkyl. In embodiments, R1 is independently C2_6alkenyl. In embodiments, R1 is independently C2_6alkynyl. In embodiments, R1 is independently C1_6haloalkyl. In embodiments, R1 is independently C3_12eycloalkyl. In embodiments, R1 is independently -CH2-C3.12eyeloalkyl. In embodiments, R1 is independently C14 iheterocycloalkyl. In embodiments, R1 is independently -CH2-C1.
itheterocycloalkyl. In embodiments, RI- is independently C6_12a1yl. In embodiments, R1 is independently -CH2-C6.
42aryl. In embodiments, R1 is independently -CH2-Ci_iiheteromyl. In embodiments, R1 is independently C1_ itheteroaryl.
[00304] In embodiments, R1 is independently C1_6alkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C2_6alkenyl optionally substituted with one, two, or three R20. In embodiments, R' is independently C2_6alkynyl optionally substituted with one, two, or three R2'. In embodiments, R is independently Ci.6haloalkyl optionally substituted with one, two, or three R20a. in embodiments, R1 is independently C3_12cycloa1kyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C3_ 42cyc1oa1ky1 optionally substituted with one, two, or three R20. In embodiments, R1 is independently C1_ iiheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C1.
ilheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C6.12a1yl optionally substituted with one, two, or three R20. In embodiments, R1 is independently -CFL-C6_19myl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-Ci_iiheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Ci_iiheteroaryl optionally substituted with one, two, or three R20.
[00305] In embodiments, R1 is independently Clancy' optionally substituted with one, two, or three R20. In embodiments, R1 is independently C2a1kyl optionally substituted with one, two, or three 1120a. In embodiments, R1 is independently C3alkyl optionally substituted with one, two, or three R20. In embodiments, R' is independently C4alkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C5alkyl optionally substituted with one, two, or three R2 . In embodiments, R1 is independently C6alkyl optionally substituted with one, two, or three R2C)a. In embodiments, R1 is independently C2alkenyl optionally substituted with one, two, or three RIO. In embodiments, R1 is independently C3alkenyl optionally substituted with one, two, or three R2 . In embodiments, R1 is independently Cialkenyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C5alkenyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C6alkenyl optionally substituted with one, two, or three R20. In embodiments, R1 is independently C2alkynyl optionally substituted with one, two, or three R20. In embodiments, R1 is independently C3a1kynyl optionally substituted with one, two, or three R2 . In embodiments, R1 is independently C4alkyny1 optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Csalkynyl optionally substituted with one, two, or three few.. In embodiments, R1 is independently C6alkyny1 optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cihaloalkyl. In embodiments, R1 is independently C2haloalkyl. In embodiments, 111 is independently C3haloalkyl. In embodiments, R1 is independently C4haloalkyl. In embodiments, R1 is independently C5haloalkyl. In embodiments, R1 is independently C6haloalkyl.
[00306] In embodiments, R1 is independently C3cycloalkyl optionally substituted with one, two, or three R2 . In embodiments, R1 is independently C4cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C5cycloallcyl optionally substituted with one, two, or three R2 . In embodiments, R1 is independently C6cycloalkyl optionally substituted with one, two, or three R2".
In embodiments, R' is independently C7cycloalkyl optionally substituted with one, two, or three R20a In embodiments; R1 is independently Cgcycloalkyl optionally substituted with one, two, or three R2'. In embodiments, R1 is independently C9cycloalkyl optionally substituted with one, two, or three R2 . In embodiments, R1 is independently Clocycloalkyl optionally substituted with one, two, or three R20.
[00307] In embodiments, R1 is independently CAteterocycloalkyl optionally substituted with one, two, or three R20.
In embodiments, R' is independently C3heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C4heterocycloalkyl optionally substituted with one, two, or three R2 . In embodiments, R1 is independently C5heterocycloalkyl optionally substituted with one, two, or three R2'. In embodiments, R1 is independently C6heterocycloalkyl optionally substituted with one, two, or three R2C)a. In embodiments, R1 is independently C7heterocycloalkyl optionally substituted with one, two, or three R2C)a. In embodiments, R' is independently Cgheterocycloalkyl optionally substituted with one, two, or three R2'. In embodiments, R1 is independently C9heterocycloalkyl optionally substituted with one, two, or three R20.
[00308] In embodiments, R1 is independently C6aryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C7aryl optionally substituted with one; two, or three R2 . In embodiments, R1 is independently Cgaryl optionally substituted with one, two, or three R2C)a. In embodiments. R1 is independently C9aryl optionally substituted with one, two, or three R2 a. In embodiments, R1 is independently Cloaryl optionally substituted with one, two, or three R2'. In embodiments, RI- is independently Clialy1 optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cuaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C2heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C3heteroaryl optionally substituted with one, two, or three R20. In embodiments, R1 is independently Ciheteroaryl optionally substituted with one, two, or three R2". In embodiments, R1 is independently C5heteroatyl optionally substituted with one, two, or three R2'.
In embodiments, 10 is independently C6heteroaryl optionally substituted with one, two, or three R20. In embodiments, R' is independently C7heteroaryl optionally substituted with one, two, or three R20U. In embodiments, R1 is independently C8heteroaryl optionally substituted with one, two, or three R2 . In embodiments, R1 is independently C9heteroaryl optionally substituted with one, two, or three R2 . In embodiments, R1 is independently Cloheteroaryl optionally substituted with one, two, or three R20. In embodiments, R1 is independently Cllheteroaryl optionally substituted with one, two, or three R20a.
[00309] In embodiments, R1 is independently -CH2-C3cycloalkyl optionally substituted with one, two, or three R20.
In embodiments, R1 is independently -C1-1/-C4cycloalkyl optionally substituted with one, two, or three R20. In embodiments, R1 is independently -CH2-05cycloalkyl optionally substituted with one, two, or three R20. In embodiments, R1 is independently -CH2-C6cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, 10 is independently -CH2-C7cycloalkyl optionally substituted with one, two, or three Rma. In embodiments, R1 is independently -CH2-C8cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, RI- is independently -CH2-C9cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, 10 is independently -CH2-Clocycloalkyl optionally substituted with one, two, or three R20a.
[00310] In embodiments, R1 is independently -CH2-C2heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C3heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R1 is independently -CH2-C4heterocycloalk0 optionally substituted with one, two, or three R20. In embodiments, R1 is independently -CH2-C9heterocycloalkyl optionally substituted with one, two, or three R20a Tn embodiments, R1 is independently -CH2-C6heterocycloallcyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C7heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C8heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C9heterocycloalkyl optionally substituted with one, two, or three R20a.
[00311] In embodiments, R1 is independently -CH2-C6a1y1 optionally substituted with one, two, or three R20. In embodiments, R1 is independently -CH2-C7aryl optionally substituted with one, two, or three R20. In embodiments, R1 is independently -CH2-Csaryl optionally substituted with one, two, or three R20. In embodiments, R1 is independently -CH2-C9aryl optionally substituted with one, two, or three R20.
In embodiments, R1 is independently -C112-Cioaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-Cliaryl optionally substituted with one, two, or three R2". In embodiments, R1 is independently -CH2-C42aryl optionally substituted with one, two, or three R20a. in embodiments, R1 is independently -CH2-C2heteroaly1 optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C3heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C4heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -0-12-05heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C6heteroaryl optionally substituted with one, two, or three feja. In embodiments, RI- is independently -CH2-C7heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-Csheteroaryl optionally substituted with one, two, or three R20. In embodiments, R1 is independently -CH2-C9heteroaryl optionally substituted with one, two, or three R20. In embodiments, R1 is independently -CH2-Cioheteroaryl optionally substituted with one, two, or three R20. In embodiments, R1 is independently -CH2-Cmiheteroaryl optionally substituted with one, two, or three R20a.
[00312] hi embodiments, R1 is independently -CH3. In embodiments, R1 is independently -CF3. In embodiments, R1 is independently -CHF2. In embodiments, R1 is independently -CFH2. In embodiments, R1 is independently ethyl. In embodiments, R1 is independently propyl. In embodiments, R1 is independently isopropyl. In embodiments, R1 is independently butyl. In embodiments, R1 is independently tert-butyl.

[00313] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 X1_(R4)p x3 x3 -x3 x3 is < _L.
P <x 121 X2 (R4) 4 xl _____________ xl __ > (R4)p (R4)p x3 or -p is an integer from 0 to 12;
XI is selected from CH2, C(R4)(R6), C=N-0R4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), 0, S, S(0), S(=0)(=NR4), S(0)2N(R ), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), OC(0)N(R4), N(R4)C(0)N(R4). S(0)2, CH2C(R4)(R6), CH2C(R4)(R6)CH2, C(R4)(R6)C(R4)(R6)C(R4)(R6), C(R4)(R6)C=N-0R4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R6)0, C(R4)(R6)0C(R4)(R6), C(R4)(R6)S, C(R4)(R6)SC(R4)(R6), C(R4)(R6)S(0), C(R4)(R6)S(0)C(R4)(R6), C(R4)(R6)S(0)2C(R4)(R6), C(R4)(R6)S(=0)(=NR4), C(R4)(R6)S(0)2N(R4), C(10(R6)N(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R4)(126)S(0)N(R4), C(10(R6)0C(0)N(R4), C(124)(R6)N(R4)C(0)N(R4), C(R4)(126)S(0)2, C=NN(R4)(R6)C(R4)(R6).
C(0)N(R4)C(R4)(R6), S(0)2N(R4)C(R4)(R6), S(0)N(IV)C(R4)(R6), OC(0)N(R4)C(R4)(R6), C(R4)(R4), C=N-0R4, C=NN(R4)(R4), CH2C(R4)(R4), CH2C(R4)(R4)CH2, C(R4)(R4)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C=N-0R4, CH2C=NN(R4)(R4), C(R4)(R4)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0, C(R4)(R4)0C(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(W)S(0)2C(R4)(R4), C(R')(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and OC(0)N(124)C(R4)(R4);
X2 is selected from N, C, C(R6), C(R4), CH, N(R1), N(R4), N(R6), 0, S. S(0), C(H)(126), C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X' is selected from N, C, C(R6), and C(R4).

[00314] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is , X2 ..,,, X2,,,,_ X2 / ...........--' \,_,... X2 S.N.

X1 --- (124)p X.11 I

( R4) p I , ,I
X2,, X2 (...7....õ...... ( R4) X3) I XI I
( R4) p ( R4) p , ,or - .
_______X2,......õ..., ; 1 c..\.. ------1--( R4) p < X >_____(R4)p Xi , I
..."\s' [00315] In some embodiments R7 is 1 1 , , , x2 X2,,......_ X2 X2 r ( ,...<(R4) (R4 I I
I I
t.
____________________________ ( R4)p 4s, .;2 .....L i I .../.... , Of , , , 1 :
, (R4)p ---,=,.... , p is an integer from 0 to 12;
X' is selected from CH2, C(R4)(R6), C=N-0R4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), 0, S, S(0), S(=0)(=NR4), S(0)2N(W), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), OC(0)N(R4), N(R4)C(0)N(R4). S(0)2, CH2C(R4)(R6), CH2C(R4)(R1CH2, C(R4)(R6)C(R4)(R1C(R4)(R6), C(R4)(R6)C=N-0R4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R6)0, C(124)(R6)0C(R4)(R6), C(R4)(R6)S, C(R4)(R6)SC(R4)(R6), C(R4)(R6)S(0), C(R4)(R6)S(0)C(R4)(R6), C(R4)(R6)S(0)2C(R4)(R6), C(R4)(R6)S(=0)(=NR4), C(R4)(R6)S(0)2N(R4), C(R4)(R6)N(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R4)(R6)S(0)N(R4), C(R4)(R6)0C(0)N(R4), C(R4)(R6)N(R4)C(0)N(R4), C(R4)(R6)S(0)2, C=NN(R4)(R6)C(R4)(R6), C(0)N(R4)C(R4)(R6), S(0)2N(R4)C(R4)(R6), S(0)N(R4)C(R4)(R6), OC(0)N(R4)C(R4)(R6), C(R4)(R4), C=N-0R4, C=NN(R4)(10, CH2C(R4)(R4), CH2C(R4)(R4)CH2, C(R4)(R4)C(R4)(R6)C(124)(R4), C(124)(124)C(R4)(10C(R4)(R4), C(R4)(R4)C=N-0R4, CH2C=NN(124)(124), C(124)(124)C(0)N(R4), C(124)(124)N(124), C(124)(124)N(R6), C(R4)(R4)0, C(122)(124)0C(R4)(R4), C(124)(124)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(124)S(=0)(=NR4), C(124)(12_4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(124)(124)N(124)C(0)N(R4), C(R4)(124)S(0)2, C=NN(124)(10C(R4)(124), C(0)N(R4)C(R4)(124), S(0)2N(R4)C(R4)(124), S(0)N(R4)C(R4)(R4), and OC(0)N(R4)C(R4)(R4);
X2 is selected from N, C, C(R6), C(R4), CH, N(R1), N(R4), N(R6), 0, S, S(0), C(H)(R6), C(124)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and [00316] X is selected from N, C, C(R6), and C(R4).
___________________________________ X2 ../
X 4 ("
X11-------P C ,.....) (R4)p <1 ->-(R )p õ,.. j [00317] In embodiments R7 is -1.- . . ....1.....
.
x2 x2, , .,,, X2 x.2 4 (-\ _(R4)p < ---, < ._,..õ,...(R )p ( R4 )p .. 2 X1\ , (R4)p Xi X3 X3 X3 1 , , i I
, ____ _ (-NH
NH

cpH -NH
NJ ___NH_ El ).
N Q \N

[00318] In some embodiments, R7 is -1-- NJ

or c91H H
H N H H H
0....CINH N ) ciiiS, NFFIj\IH \pH 0 2) cN) H H H H
F N
OH A
F(-NHH H ,.."--NH 7----NH
, m - -., ______________________________ 1 NC, r N
NC N.) Lm) N--) nn" =AA, ,Y.,, , H H
N
r)kl N N N
---:=:..... -1-... H H HN ,..- HN
ril , , =
H H
N N ¨
N ri N N
+", H ,or H .
cO(- - -NH 4) NH -NH (RP
¨(R4) roo ) pe4\
N2 P rl 2 µ" P N_I t ---I, . s ip X1003191 In some embodiments, re is ¨1-- , NH
ri--(R4)p NIH
H
/., ,\_____,¨(R )p n I\ ----, (R4) 0 NH
N., N
p CN2----(R4 P
N --...7-(R4)p X rl ----..I.,..
' ,or H
N H H H
11 ,p--H (R4) ,... .õAN
.7, (R4)p xj_,---(R4)p P 1::-11-,---(R4) ().-----(R4) NI P N P N"
, = =
H
F cN.../-1 ,N
H ,7"-NH
ID
F(-NH-NH(R4)p h--\----(R4)p NC/4" LI
r ..., (R4)p NC, c N3 (R4)p N--7-(R4) N LN) N

, "./^
, H H H

s...,--I-(R4)p N
4 ¨(R4)p N-7-(R )P X--7--(R4)P \cõ...OH ("p cCi_.(R4)p N
N , H
N
1.(R4)p Vi......(R4)p (1 (R4)p ....'.......(R4)p r......... (R4)p .,'.4 , .....ZL N
-I- N
¨L¨ v N,) N ( R4) 4-4,(R4)p n_(R4)p B_____(R4)p p N N N
¨L.. . or ---L- . and p is independently an integer from , 0 to 12.

,R6 cp (--;

;,--(R4)p N---/4¨("P
N

X[00320] In some embodiments 117 is -L.

N
ri¨(R4)p R6 r N) 4 I., (R4)p 4, --------(R4) r-0-cN--XN-....,¨(R4)p II ,...LN....---I P LNp 0-771¨(R4)P
or -----(R4)p (R4)p (R4)p n (R4)p ) (R
1p N /
i N
F--.A,"---N ---3)--(R4)P NC/4"C __1 N ) ) 1 (R4)r) NC, c NJ (R,4,)p (7..... j_____(R4)p N
N N N N

R6 R6 / I i N NN
1\I (R4)p oN.,=,,___(R4)p Ai ,... R4 kN
ci ll =^1^' I/. )p N
. r,i___-õ,--(R4)pSeD1---(R4)p , oin..
, ' N
,,,, R6 4 4)p .N
(R4)p g_(,) ,p ' (R4)p ¨(R)0 p N
N

(.1----(R4)p ....''...'+'7(6R4)p (26(R4)p (---S Ct>
(R4)p 4-(R4)p N -N1-- Ne.N.....9 NeN/--(R4)p Nr- N
-I- , or n_(R4)0 N
-1,..... and p is independently an integer from 0 to 12.

R6 (-IV\
N=R6 cp-R6 ___________________________________________ N- ) __ I
..,, ...
\ NI iN*---/ CN\
xN---./
N
' [00321] In some embodiments R7 is R6 (91-R6 /

N
(0 CiN r,N) ..N[Fliq \pi]
L N
II N
5.,,NrO
, or '1.- , , ' , ' i I I I F R6 Ni ,.."¨N
N
N , N
CJFN' ts > H NC/4' NC,(1\1 j ...1) -J N ri N N N N-j N N
JYu'";"^,c I

N N N N N N
N N
="';''' 'i-t. ,,J,, .A, , I, 14- ---;¨..,.' . ¨1.,,.. -.4,..
, _ 0., R6 R6 (7_,R6 ui . 6 N __________________________________________ N N N
\cõ r!,1 1 ---1-- ---1-- ,or ¨1¨= .
, . µ
H H
N N
CN) Y HHH
H H
N N N
' CI) NC
10 H N Y ,211/4."ONH FF)C NY
NNNNNN
N
[00322] In some embodiments, R7 is =^Aluv= , "" , "" , .AAJW , "Ai. , ."" , "ft' , NY C H
NC) FF)C NHN N N
unolisn asn.lvsn , or ...I., .
, Ra Ra i 1 c: r Fr 114 I I I
N N N
C j CJ N 6 N N
Cy , R4 NNNNN NNNHN
[00323] In some embodiments. R7 is ...4^... .^4.", . .^4,,,,. , -^^ivus . "r"
, .^^", ."^--R4 Ra 91 ...,N....,_ rj _ .I. /
0 F")CN) C 5 NC I i /,., N,, Ey¨ N) F I, ) rk, . i ....1. .1. .F..or ...J. .
' . .
[00324] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is H H H H H H

( YI¨, (R4 )p ........ I-- (R4) \ /I¨ 4 ....... -L---(R4)p ,, /' P \N (R )P Km H H H H
.
@-----(o5 s R4 ') P v. \..;_____(R4)p ___(R4)p AC )---(R4)p H H
HN\N ,..1 HN----1 Kci H
_________________________________________________________________________ NH
,-.)--(R4)p N¨, ( R4)p 6,-)¨(R4 )P
N N N
¨NH H
0..j...'(R4)p '''....'1------(R4)p...,(Cjici \ NIcl \ N.) ,.(R4)p N ..-, H
N
^..5 (R4) m /) 1?) N Y
, or , ; and p is an integer from 0 to 12.
[00325] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 H H H H H E kl kl H
H
N ..., N ,.._ N N N
C D 'N> __ ; --.CII.; (LN¨L.... ----<====\1.>
AC N ) is --y.H

S
HN\N NH FAID c)H r-1H -NH
CN
= =

C
HO)Y) H2NA-CN) \c"c511-1 <I's) , or .
[00326] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is or [00327] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R' is independently selected from hydrogen, halogen, -CN, Cl_nalkyl, C2_6alkenyl, C2_6alkynyl, and C3_6cycloalkyl; wherein Ci.6a1kyl, C2_6alkenyl, C2_6alkynyl, and C3.6cycloalkyl are optionally substituted with one, two, or three R24. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and halogen. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, It' is independently selected from hydrogen and fluoro. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is hydrogen. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is fluoro.
[00328] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, and C2_9heterocycloalkyl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C340cycloalkyl, and C2_9heterocycloalkyl are optionally substituted with one, two, or three R20e. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, Ci.6alkyl, C340cycloalkyl, and C2_9heterocycloalkyl, wherein Ci_6a1ky1, C3_10cycloalkyl, and C2_9heterocycloalkyl are optionally substituted with one, two, or three R2 c independently selected from halogen, Ci_6alkyl, C2_6alkenyl, C2-0alkynyl, C3_10cycloalkyl, and C2_9hcterocycloalkyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R2 c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, re is selected from hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments, Fe is selected from halogen, -CN, C1_6a1k0, C2_6alkenyl, C2_6alkynyl, C1_6cycloalkyl, C2_ 9heterocycloalkyl, C6_10myl, Ci.cheteroaryl, -OR", -SRI', -N(H)(IC), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -1\I(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)1215, -S(0)1215, -0C(0)R15, -C(0)N(Ru)(R13), -C(0)C(0)N(R12)(R13), -N(R'4)C(0)R', -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6-ioaryl, and Ci_9heteroaly1 are optionally substituted with one, two, or three R2 c. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from Ci_6a1ky1, Cl-locycloalkyl, and C2_9heterocycloa1kyl, wherein Cl_nalkyl, C3-10cycloa1kyl, and C2_9heterocyc1oa1kyl are optionally substituted with one, two, or three R2 ` independently selected from halogen, C1.6alkyl, C2_6a1kynyl, C340cycloalkyl, and C2_9heterocycloalkyl. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R'e independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
[00329] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen or CN. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is CN.
[00330] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 1,1 is a bond. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C(0)-, -NHC(0)-, -C(0)NH-, CH20, CH2NH, and CH2.
[00331] In embodiments, L1 is a bond. In embodiments, L1 is Ci-Coalkyl. In embodiments, Ll is C2-C6alkenyl. In embodiments, L1 is C2-C6alkynyl. In embodiments, L1 is -0-. In embodiments, L1 is -N(Rm)-. In embodiments, L1 is -C(0)-. In embodiments, L1 is -N(RH)C(0)-. In embodiments, L1 is -C(0)N(R11)-. In embodiments, L1 is -S-. In embodiments, L1 is -S(0)2-. In embodiments, is -S(0)-. In embodiments, L1 is -S(0)2N(R 4,_.
1 )In embodiments, L ,_.
1 is -S(0)N(R14)In embodiments, L1 is -N(R14)S(0)-. In embodiments, L1 is _1,4-(Ri4)s(0 2_.
) In embodiments, L1 is -000N(R14)-. In embodiments, L1 is -N(R14)C(0)0-. In embodiments, L1 is N(R1e). In embodiments, L1 is C(0)N(R1c).
In embodiments, LI is S(0)2N(R1c). Tn embodiments, Lm is S(0)N(R1c). in embodiments, Lm is C(R1f)(R1g)0. in embodiments, Ll is cosi(Rig)N(R) ic-,.
In embodiments, Ll is C(Rlf)(R1g). In embodiments, 1_,1 is -N(H)-. In embodiments, L1 is -N(H)C(0)-. In embodiments, L1 is -C(0)N(H)-. In embodiments, L1 is -S(0)2N(H)-. In embodiments, L1 is -S(0)N(H)-. In embodiments, L1 is -N(H)S(0)-. In embodiments, L1 is -N(H)S(0)2-.
In embodiments, L1 is -000N(H)-. In embodiments, L1 is -N(H)C(0)0-. In embodiments. L1 is -N(H)-.
In embodiments, LI- is -C(0)N(H)-. In embodiments, L1 is -S(0)2N(H)-. In embodiments, L1 is -S(0)N(H)-. In embodiments, L1 is -CH20-. In embodiments, L1 is -CH2N(H)-. In embodiments, L1 is -CH2-.
[00332] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic ring. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a bicyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a polycy clic ring system. In embodiments of the x4 o II

subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is: X6' x12 ni ni 42-x11 x4 *7"..***-N---=.\ i X4 ''.<-------''' X9 CCI3 I 1 I 1 ,L \--IR=== i ;>__Rih II
'._.R.01 )( 5... _,.... ...., xi o x5z.z. ----X6 Q , 1 x N
- 1 Xi ...
X6 X9 -- 6' Q =-x11 Q4 -N----...---- (-0 0 N 4 ,-/\\
II /)--R1 h I
I \2 __ R1 h Y N
....T9\,)__3 R1h r X 10 -3,......... 3 X7- ...---- 4 X7- ..."------ 4 X7- ....---,--'= x11 Q 3-^- Q -'-X8 Q -X8 1\1.-z-_-Q3 N-Q4 0,7- Q q Q-.....,,,,N 4 3 Rh Q
,Nr......\.........õ....õ......4 Q ,222c.

n X7-e õ.-"---- 3 Q \Q6 Q4 x6, X5-- x4 x6, X5-- x4 , or . . .
T............., Q4 Q', Q3, and Q' are independently N or Q4 and Q6 are independently 0, S, C(R1a)(R1b), or X4, xs, x.6, x9, ,x1c), xii, and X12 are independently selected from C(Rh) or N;
X7 and X8 are independently selected from C(Ria), C(Ria)(Rib), N, or N(R);
each Ria, Rth, R. and tc_ -1h are each independently selected from hydrogen, halogen, -CN, Ch6a1kyl, Ch 6haloalkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, C2_9heterocycloalkyl, C64oaryl, Ci_9heteroaryl, -0R12, -SR12, -N(R12)(RI3), -C(0)0Ru, -0C(0)N(Ru)(Ri3), _N(Rj4)c(o)N(Ri2)(Ri3), _ Ni,ic14, C(0 i )0R15, -N(RH)S(0)2R" 1V 1V , -C(0)R15, -S(0), -0C(0), -C(0)N(R12)(R"). --C(0)C(0)N(102)(Ri3), _N(Ri4)c(0)R15, _s(0)2R15, _s(0)2N(Ri2)(Ri3)_, - ,_ i 0)(=NH)N(R12)(Ri3), -CH2C(0)N(R12)(R"), -CH2N(12_14)C(0)R15, -CH2S(0)2R", and -CH2S(0)2N(R12)(R"), wherein Ci_ 6a1ky1, C2_6alkenyl, C2_6alkynyl, C;_iocycloalkyl, C2_9heterocycloalkyl, Co_ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R261, or Ria and Rib bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C340cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3_tocycloalkyl ring are optionally substituted with one, two, or three R20i; or two Ria bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a Co_ioaryl ring, a 5-12 membered heteroaryl ring, or a C3_tocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6_10aryl ring, 5-12 membered heteroaryl ring, or C3_10cycloa1kyl ring are optionally substituted with one, two, or three R20i; or Rill and one of RI', Rib, I( -lc, and Rid bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_10aryl ring, a 5-12 membered heteroaryl ring, or a Ci_locycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a Co_ioaryl ring, a 5-12 membered heteroaryl ring, and C34ocycloalkyl ring are optionally substituted with one, two, or three R20i; and each Ric is independently selected from hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C310cyc1oa1ky1, C2_ 9heterocycloalkyl, C6-toaryl, C1-9heteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3-iocycloalkyl, C2_9heterocyc1oalkyl, C6_10aryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20'.
[00333] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, )----=N )----=N )------N HO V. V
S S

R19 is: 51( 101 F F F , F, , , HO 'V H2N N..., \.- H2N N.., 'µ H2N
N.., I I I
.--' õ--' F ---- N
F I
.., LL
F , , ''.2c. t:

CI
Lk F , F , F , , , ' / N.__ ,õ
N.__ N.__ N¨N H IN ¨N
/ N¨N
H IV' zia.. H Ni H14V /10Czx H
N.__ i H ..,N N 5.,-_,. H2N
N,... vz.
H N illi v. NiN:Tc( y H2N N,.. .22-2-_ y c3 cF, Lcv ci H
H2N Nõ.. =22-2. ,õõ:2,- H
H2 N 1\1,....,.A. 1 " -2.= ,,N1 N.
LI_ I,,,..c.-2-..., CF3 %.....r3 1.õ....1, HO '2?-2- . HO tiwc. HO-HO 0 \-.
NCO.

./
OCF3 , CI CI CI

, or F
CI
NH2 .
[00334] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, FC is I"--- N
-( AO N
. ---/ crsr.s'O N
selected from F

N N
0 \) F
OM e F
AO c"-0/'" N Ae6----)--cH2F
N N
H \

/, ,,.=6),,,,z0---\-K r=sss, ,,.%6---,,µ,/0--\( r.sis__067\i-y/0--\c , /-O------'v3 Nr- ------c ------\ N,.., , 0 0....F xo.,,,..f.. jass. .,,µ,. F
,, o Nrj-.....F o /6 0 0.....0Me ¨i , 0 csif, --,-N
O<F c:05..Ø..,,..,.,....No 0 F
S-0-/'"0--.0Me N--.7 o.S
o5 A.C:
I
. , . ' I X N
--/
. .ceN
r:cr,co ==_. IN rss3-:0 4111 1:rss-'00H 0.(00 rcr--'10 N
rN --,,,,, ...N__.
O'''= IN \\
Nri----.CN ,,,-Nr.õ..õ),..z..N,N /-...õ.,N,,,,) H
A )-- ,I\1 0,.,.- ,N
'lc.' N
---"- N ^-...-- --- 01 --.''C F 3 c:ss..ON 1 I , --..õ...N ..,, %:,s5-0-^--...----1 AO
, , I
õ,-----....N.-- p ,o, -----N
Oz.-0 ''ss''O AO X0 4:r(S'Ziji ..-, , , I (fµNP.,,., 0 ;s40Y,.0 r:rs Y=
....----õ....õ...0,, rssr 'N----/ -/
F
0"." ;rcs-0/''' fl:ZOW 04- OW
Iri / N---/ N ci4 7,0NID

s-551.HN -')C NO cls't:NI -.7c.- 0 riss-S -'1C- NO r-s5sC NO
, c14-e')CNOKF jsrl.e)c 0...F r-54.0 F
t/s10)C1\11,3 r140)CNI_ rcsl's )CNO
I
N ;i4 f-sjs' 0')CN
r14e)CN3 ____________________________________________________ I LO
, r,6CN
00 C N ,'Iss.-0.-.> jc..r0 (.'N ---1 cisF,0,..-CN

I
i:css, CI
i:ris-- cssr S'''0 g''''''/D = ..._ N '---=-=-.--'. 0 / -OH I , , , _ y i"---0 ;Os.
1 I c-sss 1 --, --, , and , (3µ,0 ,'S' 0 .-"5-j5s0 [00335] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, each R5 is independently selected from:

qõp q,:j, q=P
vs ilo PH 4ze-,-04 pH +.4...+8.x:: pH 3,.. N.........4 pH
NH '''.= 1 ¨NH l= 1 alqii -11, --NE12, --0i1, --N11(C14, alkyl), Q
-14A%-f.., PH 9 .2---c, --- u.3 Q 9 Sk4) .2 n -,.NH AANN,01-1 ---h-.N.A.NrOH
v1A...N.-OH N.S0H A.,r1L. -OH
H
.
, ..... õ.0H
9 r N
: , 1-4) 3., .- )1.1 NE - OH `i,..{-"i'v- ( / . m N (j L,,,-)1 m N-OH 4)-LIN-NH-NH. NH, /
NH_ H ; 1 H
NH H H NH NH
NH
µ3,)-L HN,., N ,..c N HN,__. N, 1.- CN A
H 2N NH NC,N,kNH
...11, NC"-N NH
--e. NH ' I , ,,,,Ls, , H I , H I
, -CN, i N H _R 01-1 .i yir--õ.H2 -;.-s,,,r,r---õo sell, -YOh =ikey...L.Al-#2 HIS =--H \ r-NH i-`0 ti ?-`/ 744fr2) ?"ir'--P) /ir ,, -4.1),, ...,,....-..... .õ..... ...õ
0# A / ,r0 - :,-,-0 ft 17-0 µ.
0 0 < ', .
, I
r p I
,e CN rN,H
oe-, ., eN 1 Ael H
ost =yers .. ...-.." ,,44,-1A-,-.k.,..) ,.7.--,....ri N ,..0H =;.,..e.r.õIr.A.,OH
W''.0 '*1-=0 '-0 g s'fr\--. .
H
f-r0 yNLOH N
0 and. af ; and m, when prescrit, ig 0, 1, 2, or 3.
[00336] In an aspect is provided a compound of Formula (n), or a pharmaceutically acceptable salt or solvate thereof:
R 1 o N. ....-N

R17 Formula (TT);
wherein W is C(0), S(0), or S(0)2;
V is C(R'6) or N;
RN is -L7-R7;

L7 is a bond, -0-, -N(R14)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-; -S(0)2N(R14)-, -S(0)N(R")-, -N(R14)S(0)-, -N(R14)S(0)2-, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkyny1, wherein Cl-C6alky1, C2-C6alkeny1, and C2-C6alkynyl, are optionally substituted with one, two, or three R2 a:
IC is a 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl are optionally substituted with one or more one or more R4, or one or more R6;
Iwo substituents selected from 10, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3_12cycloalkyl, Ci_iiheterocycloalkyl, C6_12ary1, or Ci_iiheteroatyl, wherein the C3-ucycloalkyl, Ci_itheterocycloalkyl, C6_12a1y1, or Ci_iiheteroaryl are optionally substituted with one, two, or three R2 a;
each R1 is independently selected from hydrogen, Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, Ci_6haloalkyl, C3-12CYC1Oa1kO, -CH2-C342cyc1oa1ky1, Ci_nheterocycloalkyl, -CH2-Ci_iiheterocycloalkyl, C6_12aty1, -CH2-C6-12aryl, -CH2-C1_iiheteroaryl, and Ci_iiheteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2.6alkynyl, C3_12cycloalkyl, -C112-C342cyc10a1ky1, Ci_iiheterocycloalkyl, -CH2-Ci_1,heterocycloalkyl, C6_12aryl, -CH2-C-6-12atyl, -CT-12-Ci41heteroaty1, and Ci_iiheteroatyl are optionally substituted with one, two, or three R2 a;
each re is independently selected from hydrogen, halogen, oxo, -CN, Ci6alkyl, C2_6alkenyl, C2_6a1kynyl, C3_ 6cycloalkyl, C2_9heterocycloalkyl, C6_10a1yl, C1_9heteroatyl, -0R12, -SR12, _N(R12)(-- 13) _ C(0)0R12, -0C(0)N(102)(Ri3), -N(R14)C(0)N(R12)(R'), -N(R")C(0)0R15, -N(R")S(0)2R15, -C(0)R1', -S(0)R15, -0C(0)R15, -C(0)N(R11)(R13), -C(0)C(0)N(102)(R13), -N(R14)C(0)105, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R'), -CH2C(0)N(R12)(R'), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6a1ky1, C2_6alkeny-1, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6-tow-yin and Ci_9heteroatyl are optionally substituted with one, two, or three R2 a;
R6 is -L2-R5;
each L2 is independently selected from a bond, Cl-C6alkyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(Rm)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R'4)S(0)2-, -OCON(R14)-, -N(R14)C(0)0-, and -N(R14)C(0)N(R1-4)-;
each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, C,6a1ky1, C2_6alkenyl.
C2_6alkyny1, C3_6cycloalkyl, C2-9heterocycloalkyl, C6_10atyl, C1.9heteroaryl, -0R12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(Ru)(R13), -N(RI4)C(0)N(R12)(R13), -N(R")C(0)0105, -N(R")S(0)2R15, -C(0)10', -S(0)R", -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R")C(0)R1", -S(0)2R1', -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R3), wherein Ci-6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, C6 -wary', and Ci_9heteroaryl are optionally substituted with one, two, or three R20c;
1:07 is -1)-R1-9;
1_,1 is selected from a bond, Cl-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R")-, -C(0)-, -N(R")C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R')S(0)-, -N(R14)S(0)2-, -000N(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(R1c), S(0)2N(R1c), S(0)N(R1c), C(R1f)(Rig)0, C(R1f)(10)N(Ric), and C(R1f)(Rig);

Ric, Rif, and Rig are independently selected from hydrogen, halogen, -CN, Ci_6a1ky1, C3_6haloalkyl, C2_6alkeny1, C2_6a1kyTny1, C3_6cyc1oa1ky1, C2_9heterocycloalkyl, C6_Nary1, C3.9heteroary1, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R1), -S(0)R15, -0C(0)R15. -C(0)N(R12)(RH), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R1), -S(0)2N(R12)(R13)-, s(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R")C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C3_6a1ky1, C2_6a1kenyl, C2_6a1kynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6_30aryl, and C3_9heter0a1y1 are optionally substituted with one, two, or three R20; or Rlf and R1g arc joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Ric is selected from hydrogen, C3.6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.6cyc1oa1ky1, C2_9heterocycloalkyl, C6.
ioaryl, and C1-9heteromyl, wherein C1-6alkyl, C2_6alkenyl, C2.6alkynyl, C3_6cyc1oa1ky1, C2_9heterocycloalkyl, C6_ioaryl, and C1.9heteroary1 are optionally substituted with one, two, or three R2 1 R" is selected from a C342cyc10a11cyl, C2_11heterocycloalkyk C6_32a1yl, and C2_32heteroaryl, wherein the C3-12cyc1oa1lcy1, C2_13heterocycloallcyl, C6_32atyl, and C2_32heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11;
each R11 is independently selected from halogen, -CN, Cl_6a1kyl, C2_6a1kenyl, C2_6alkynyl, 6cycloalkyl, C2_9heterocycloalkyl, C6_1(ar0, C3_9heteroaryl, -OR', -SR".
_N(R12)(-13), _ C(0)0R12, -OC(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R")S(0)2R1), -C(0)R1', -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R')C(0)R15, -S(0)2R1% -S(0)2N(102)(R13)-, S(=0)(=NH)N(R")(R13), -CH2C(0)N(R12)(R13), -CH2N(R11)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C3_6a1ky1, C2_6alkeny-1, C2_6alkynyl, C3_6cycloalkyl, C2.9heteroeyeloalkyl, C6-loalyl, and C3_9heteroaryl are optionally substituted with one, two, or three R20;
R" is selected from hydrogen, halogen, -CN, C3_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cyc1oa1ky1, C2-9heterocycloalkyl, C6_10myl, C1.9heteroary1, -OR", -SR", -N(R12)(R"), -C(0)0R", -0C(0)N(R")(R"), -, N(R14)C(0)N(R12)(R13,) N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), _N(Ri4)c(0)R15, _s(0)2-15, _ S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C3_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cyc1oa1ky1, C2.9heterocycloalkyl, C6_ ,aryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R24;
R2 is -C(0)0R12, -0C(0)N(R12)(R"), -N(RH)C(0)N(R")(R"), -N(R")C(0)0R", -N(R14)S(0)2R15, -C(0)R", -S(0)R15, -0C(0)R15. -C(0)N(R11)(R13), -C(0)C(0)N(R12)(R13), -N(RH)C(0)R15, -S(0)2R1', -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R12A1C µ,,,13 ), -(Ci-C6alkyl)-R12b, -(C2_6alkeny1)-R12b, -(C2_6alkyny1)-R121, -0-R12a, _ -(C3-10cycloalkyl)-R12b, -(C2_9heterocycloa1kyl)-Rilb, -(C640ary1)-102b, or -(C3_9heteroary1)-R12b, wherein said C1-6alkyl, C2_6a1keny1, C2_6alkynyl, C3_10cycloa1kyk C2_9heterocyc1oa11y1, C6.30aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R2nd;
Ri2a is selected from Ci-6alkyl, C2.6alkenyl, C2_6alkynyl, C3_10cycloalkyl, -CH2-C3.1ocycloalkyl, C2-9heterocycloalkyl, -C1T12-C2_9heterocycloalkyl, C6_30aryl, -CH2-C6_10alyl, -CH2-C3.9heteroary1, and C1-9heteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_30cycloalkyl, -CH2-C340cyc1oa11cy1, C2-9heterocycloalkyl, -C1T12-C2_9heterocycloalkyl, C6_ioaryl, -CH2-C6_10alyl, -CH2-C1_9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R2 d;
Ri2b is selected from hydrogen, C, alkyl, C2_6alkenyl, C2_6alkynyl, Cmcycloa1kyl. -CH2-Ci_locycloalkyl, 9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_ioaryl, -CH2-C6_10aryl, -CH2-C1.9heteroaryl, and C1-9heteroaryl, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, -CH2-C3_10cycloalky1, C2 9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10aryl, -CH2-C6_10awl, -CH2-Ci.9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20';
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3_6cycloa1kyl, C2_ 9heterocycloalkyl, C6_10aryl, Ci_9heteroary1, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(RI4)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(Ru)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=N11)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R'3), wherein C1_6alkyl, C2_6alkeny-1, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, Cs_ wary], and Ci_91teteroary1 are optionally substituted with one, two, or three R2 b;
each R12 is independently selected from hydrogen, Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, -CH2-C3_ 6cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocycloalkyl, C6_1 oatyl, -CH2-C6,0aryl, -CH2-C1-9heteroaryl, and Ci_9heteroary1, wherein Ci_6a1ky1, C2_6alkenyl, C2_6a1kyny1.
C3_6cycloalkyT1, -CH2-C3-6cycloalkyl, C2_9hctcrocycloa1kyl, -CH2-C2_9hctcrocycloalkyl, C640alyl, -CH2-C6_ioaryl, -CH2-Ci-9heteroaryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R2';
each R13 is independently selected from hydrogen, Ci_6a1ky1, and Ci_6ha1oa1ky1; or R12 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R2 e;
each R14 is independently selected from hydrogen, Ci_6a1ky1, and Ci_6ha1oa1ky1;
each R'5 is independently selected Ci.6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.6cycloalky-1, C2_9heterocycloalky1, C6.
loalyl, and Ci_91ieteroalyl, wherein Ci_6a1ky1, C2_6alkenyl, C2.6alkynyl, C3_6cycloalkyl, C2_91ieterocycloallcyl, C6_10atyl, and Ci_9heteroary1 are optionally substituted with one, two, or three R20f;
each R20a, R2ob, R20c, Raki, woe, R20f, R20g, and R2 1 are each independently selected from halogen, -CN, Cl_ 6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10alyl, -CH2-C6_10aryl, -CH2-Cl_9heteroaryl, C1.9heteroaly1. -OR". -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein Ci_6alky1, C2_6a1keny1, C2_6alkynyl, C3.6cycloalky-1, -CH2-C3-6cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocycloalkyl, C6_10atyl, -CH2-C6_10aryl, -CH2-Ci-9heteroaryl, and Ci_9heteroary1 are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, Ci_6ha1oa11ky1, Ci_6a1k0xy, Ci_6ha10a1koxy, -OR", -SR", -N(R22)(R21), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R21), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R2' is independently selected from H, Ci_6a1ky1, Ci_6haloalkyl, C2.6a1kenyl, C2.6alkyny1, C3.6cycloalkyl, C2_ 9heterocycloalkyl, C6-loalyl, and C1_,heteroaryl;

each R22 is independently selected from H, Ci_6alkyl, Ci_6haloalky1, C2_6a1kenyl, C2_6a1kyny1, C3_6cyc1oa1kyl, C2_ 9heterocycloalkyl, C6_10ary1, and Ci_9heteroaryl;
each R23 is independently selected from H and Cl_nalkyl;
each R' is independently selected from H and Ci_6alkyl;
each R25 is selected from C1_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloalkyl, C2_9heterocyc1oa1kyl, C640aryl, and Ci_9heteroaryl; and - indicates a single or double bond such that all valences are satisfied.
[00337] In an aspect is provided a compound of Formula or a pharmaceutically acceptable salt or solvate thereof:

x X
R-R17 Formula (IF);
wherein W is C(0), S(0), or S(0)2;
V is C(R16) or N;
Rio is -L7-R7;
LT is a bond, -0-, -N(R14)-, -C(0)-, -N(R")C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R")-, -N(R14)S(0)-, -N(R")S(0)2-, C2-C6alkenyl, C2-C6alkynyk or 2 to 4 membered heteroalkylene linker, wherein Ci-C6alkyl, C2-C6alkeny1, C2-C6alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R2 a;
R7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cy-cloalkyl, 3-12 membered heterocycloalkvl, 6-12 membered aryl, or 5-12 membered heteroaly1 are optionally substituted with one or more R1, optionally substituted with one or more R1, and optionally substituted with one or more R6;
two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3_12cycloalkyl, Ci_iiheterocycloalkyl, C6_12aryl, or Ci_iiheteromyl, wherein the C3-ucycloalkyl, Ci_iiheterocycloalkyl, C6_12aryl, or Ci_iiheteromyl arc optionally substituted with one, two, or three R2 a;
each R1 is independently selected from hydrogen, Ci_6alkyl, C2_6a1keny1, C2_6alkynyl, Ci_6haloalkyl, C3_ 12eyeloalkyl, -CH2-C342eyeloalkyl, Ci_iiheteroeyeloalkyl, -CH2-Ci_iiheterocycloalky1, C6_12ary1, -CH2-C6-12ary1, -CH2-Ci-iiheteroaryl, and Ci_iiheteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2.6alkynyk Ci_6haloalkyl, C3_12cyc1oa1ky1, -CH2-C3_12cyc1oa1ky1, Ci_iiheterocycloalkyl, -CH2-C1_iiheterocycloallcyl, C6_12aryl, -CH2-C6_12a1yl, -0-12-Ci_11heteroary1, and CI_Iiheteroaryl are optionally substituted with one, two, or three R2 a;
each R4 is independently selected from hydrogen, halogen, oxo, -CN, C1.6alkyl, C2_6alkenyl, C2_6alkynyl, C,.
6cycloalkyl, C2_9heterocycloa1kyl, C6_1oa1yl, Ci_9heteroalyl, -0R12, -SR12, -1\T(R12)(R13), _C(0)0R12, -OC(0)N(R12)(R13), -N(R14)C(0)N(R12)(R"), -N(R14)C(0)0R15, -N(R14)S(0)2105, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(Ru)(103), -C(0)C(0)N(R12)(R13), _ N(F04)C(0)R15, -S(0)2105, -S(0)2N(R12)(103)-, S(=0)(=NH)N(1112)(R13), -CH2C(0)N(R12)(103). -CH2N(R")C(0)105, -CH2S(0)2105, and -CH2S(0)2N(102)(103), wherein Ci_6a1ky1, C2_6a1kenyl, C2_6a1kyny1, C3_6cycloa1kyl, C2.9heterocycloalkyl, C6 -wary', and Ci_9heteroatyl are optionally substituted with one, two, or three R2 a;
R6 is -L2-R5;
each L2 is independently selected from a bond, C1-C6alky1, -0-, -N(Rm)-, -C(0)-, -N(R")C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R11)-, -S(0)N(RH)-, -N(RH)S(0)-, -N(R1')S(0)2-, -000N(R")-, -N(R")C(0)0-, and -N(R")C(0)N(R4)-;
each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2-9heterocycloalkyl, C6_ioaryl, Ci.9heteroary1, -0R12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(103), -N(R'4)C(0)N(R12)(1013), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R5, -S(0)R15, -0C(0)R1', -c(o)N(R12)c-= 13+) _, K C(0)C(0)N(R12)(R 13), _N(R14)c(0+,-, 15 _ , ) K S (0)2R 15, -5(0)2N(R
12)(R 13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R")C(0)R15, -CH2 S(0)2105, and -CH2S(0)2N(Ru)(R13), wherein Cl_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocycloalkyl, G_ ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20c;
R17 is -L'-R'9;
L' is selected from a bond, Cl-C6allcyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(f04)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R1')-, -S-, -S(0)2-, -S(0)-, -S(0)2N(Rm)-, -S(0)N(R11)-, -N(R11)S(0)-, -N(R11)S(0)2-, -000N(R14)-, -N(R14)C(0)0-, N(Ric), C(0)N(R1e), S(0)2N(R1e), S(0)N(Rle), C(R1f)(R18)0, C(R1f)(R1g)N(R1c), and C(Rif)(R1g);
R1e, Rif, and Rlg are independently selected from hydrogen, halogen, -CN, C1_6alkyl, Ci_6haloalkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6_10aryl, Ci_9heteroary1, -OR", -S102, -N(R12)(R'3), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0105, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(103), -C(0)C(0)N(R12)(R13), -N(R14)C(0)105, -S(0)2R15, -s(0)2N(R12)(R13)_, s(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-I oaryl, and C1_9heteroary1 are optionally substituted with one, two, or three R2'; or Rif and R'g are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R20;
Rle is selected from hydrogen, Ci.6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.6cycloalkyl, C2_9heterocycloalkyl, C6_ ioaryl, and Ci_9heteroaryl, wherein Ci_6alkyl, C2_6alkeny1, C2.6alkynyl, C3_6cyc1oalkvl, C2_9heterocycloalkyl, C640atyl, and Ci.9heteroaryl are optionally substituted with one, two, or three R2"
R" is selected from a C342cyc1oa1ky1, C2_iiheterocycloalkyl, C6_12aryl, and C2_12heteroaryl, wherein the C3-12CYC1Oa1ky1n C2_11heteroeyeloalkyl, C6_12aryl, and C242heteroaryl are optionally substituted with one, two, three, four, five, six, or seven Rh;
each Rli is independently selected from halogen, -CN, Ci_oalkyl, Ci_6haloalkyl, C2_6alkenyl, C2_6alkynyl, C3-6cycloalkyl, C2_9heterocycloa1kyl, C6-maryl, C1_9heteroary1, -sR12, _N(R12)(-- 13) _ C(0)0R12, -OC(0)N(R")(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(Ru)(R13), -C(0)C(0)N(R12)(R13), _N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(1112)(R'), -CH2C(0)N(R12)(R14). -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(103), wherein Ci_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloa1kyl, C2.9heterocycloalkyl, C6 -wary', and Ci_9heteroaly1 are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci_6alkyl, C2_6a1kenyl, C2_6alkynyl, C3_6cyc1oalkyl, C2-9heterocycloalkyl, C6_10alyl, Ci.9heteroary1, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R11)C(0)N(Ru)(R13), -N(R11)C(0)0R15, -N(RH)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(Ru)(R13), -C(0)C(0)N(Ru)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(RH)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(103), wherein C1-6a1kyl, C2_6a1keny-1, C2_6a1kynyl, C3-6cycloa1kyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci_9heteroaly1 are optionally substituted with one, two, or three R2 ;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R"), -N(1244)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R 12)(R 13), -C,H2N(R14)C,(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R11,,R13 A ), -(C1-C6alkyl)-R12b, -(C2_6alkeny1)-R12b, -(C2_6alkyny1)-R12b, -0-R12a, - Ri()_Ri2b, _ S-R'2'. -(C3_10cycloalkyl)-R12b, -(C2_9heterocycloalkyl)-R12b, -(C6_10ary1)-R12b, or -(Ci_9heteroary1)-R12b, wherein said C1-6alkyl, C2_6alkeny1, C2_6alkyny1, C3_1ocycloalkyl, C2_9heterocycloalkyl, C6.10ary1, and C1-9heteroaryl arc optionally substituted with one, two, or three R20(1;
R12a is selected from Ci-6a1ky1, C2.6alkenyl, C2_6alkynyl, C3_10cycloalkyl, -C(R126)2-C3.upcycloallcyl, C2-9heterocycloalkyl, -C(R126)2-C2_9heterocycloalkyl, C6_10atyl, -C(R126)2-C6_10aryl, -C(R126)2-Ci_9heteroaryl, and Ci_9heteroary1, wherein C1-6a1ky1, C2_6alkenyl, C2_6a1kynyl, C340cycloalkyl, -C(R126)2-C340cycloalkyl, C2_9heterocycloalkyl, -C(R12`)2-C2_9heterocycloalkyl, C6.10aryl, -C(R126)2-C6_10aryl, -C(R126)2-C1.9heter0ary1, and Ci_9heteroarv1 are optionally substituted with one, two, or three R20d;
R'm is selected from hydrogen, C1_6alky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, -C(R13')2-C3.10cycloa1kyl, C2-9heterocycloalkyl, -C(R1292-C2.9heterocycloalkyl, C6_10atyl, -C(R1292-C6.10alyl, -C(R1292-Ci_91ieteroatyl, and Ci_9heteroary1, wherein Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3_10cycloalkyl, -C(R126)2-C340cycloalkyl, C2_9heterocycloalkyl, -C(R1292-C2_9heterocycloalkyl, C6_10aryl, -C(R1292-C6_ioaryl, -C(R12)2-Ci_9heteroaryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R20d;
R12c is independently selected from hydrogen and R201;
X is C(R3) or INT;
R3 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2-9heterocycloalkyl, C6_10alyl, Ci.9heteroary1, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(Ru)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(103), -CH2C(0)N(R12)(R'), -CH2N(RH)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(1242)(R14), wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C5-iaaryl, and C1_9heteroaly1 are optionally substituted with one, two, or three R20b;
each R12 is independently selected from hydrogen, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3-6cyc1oa1ky1, C2_9heterocycloa1kyl, -CH2-C2_9heterocyeloalkyl, C6_10aryl, -CH2-C6_10aryl, -CH2-C1-9heteroaryl, and C1heteroaryl, wherein C1_6a1ky1, C2_6a1kenyl, C2_6alkynyl, C3_6cycloa1kyl, -CH2-C3.

6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocyc1oalky1, C6_10atyl, -CH2-C6_10aryl, -CH2-C1-9heteroaryl, and C1_9heteroary1 are optionally substituted with one, two, or three R20d;
each R13 is independently selected from hydrogen. Cl_nalkyl, and C1_6haloa1kyl; or R12 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyT1 ring optionally substituted with one, two, or three R2 e;
each R14 is independently selected from hydrogen, C1_6alkyl, and Ci_6haloa1kyl;
each R15 is independently selected Ci.6alkyl, C2_6alkenyl, C2_6alkynyl, C3.6cycloalkyl, C2_9heterocycloalky1, C6-toaryl, and Ci_9hetcroatyl, wherein Ci_oalkyl, C2_6alkenyl, C2.6alkynyl, C36cycloalkyl, C2_9heterocycloalkyl, C610a1yl, and Ci.9heteroaryl are optionally substituted with one, two, or three R20%
each R20a, R2ob, R2oc, Raki, woe, R20f, R20g, R201, and 20k -1-c are each independently selected from halogen,oxo, -CN, Ci_6alkyl, C2_6alkenyl, C2.6a1kynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2-9heterocycloalkyl, C6_ioary1, -CH2-C6_10ary1, -CH2-Ci_9heteroalyl, Ci.9heteromy1, -0R21. -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R2.4)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25. wherein Ci_6allcyl, C2_6alkenyl, C26alkynyl, C3_6cycloallcyl, -CH2-C3_ cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocycloalkyl, C6_10atyl, -CH2-C6_10aryl, -CH2-C1_ 9heteroaryl, and C1_9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R21 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2.6a1kenyl, C2_6a1kyny1, C3_6cycloa1kyl, C2_ 9heterocycloalkyl, C6_iletyl, and Ci_9heteroatyl;
each R22 is independently selected from H, Ci_6alky1, Ci_6haloalkyl, C2.6alkenyl, C2_6alkyny1, C3_6cycloa1kyl, C2_ 9heterocycloalkyl, C6_1oa1y1, and Ci_9heteroaryl;
each R23 is independently selected from H and Ci-6a1kyl;
each R24 is independently selected from H and Ci_6alkyl;
each R25 is selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C640aryl, and Ci_9heteroaryl; and - indicates a single or double bond such that all valences are satisfied.
[00338] In some embodiments of Fonnula (II'), or a pharmaceutically acceptable salt or solvate thereof, 11.7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroatyl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more RI-, optionally substituted with one or more R', and optionally substituted with one or more R6; wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3_12cy-c1oalkyl, CI_Iiheterocycloalkyl, C6.12aryl, or Ci.nheteroaryl, wherein the C342cycloalkyl, Ci_iiheterocycloalkyl, C6_12aryl, or Ci_iiheteroaryl are optionally substituted with one, two, or three R2oa.

1003391 In an aspect is provided a compound of Formula (I"), or a pharmaceutically acceptable salt or solvate thereof:

N X
R2 Formula (1");
wherein W is C(0), S(0), or S(0)2;
V is C(R") and J is C(R"), or V is C(R17) and J is N, or J is C(R") and V is C(R"), or J is C(R") and V is N;
Rli) is L7 is a bond, -0-, -N(R14)-, -C(0)-, -N(Ru)C(0)-, -C(0)N(Rm)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cbalkyl, C2-Cbalkenyl, C2-Cbalkynyl, and 2 to 4 membered heteroalkylene linker are unsubstituted or optionally substituted:
R7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl. wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are unsubstituted or optionally substituted;
R8 is selected from hydrogen, halogen, -CN, Ci_oalkyl, C2_6a1kenyl.
C2_6alkynyl, C3_bcycloalkyl, C2-9heterocycloalkyl, C6_10aryl, C1.9heteroaryl, -01e 2, -SR', -N(H)(R12), -C(0)0107, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(Ru)S(0)2R15, -C(0)R13, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(10)C(0)R15, -S(0)2R15, -S(0)2N(Ru)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_balkyl, C2_6alkenyl, C2_6alkynyl, C3_6cyc1oalky1, C2.9heterocycloalkyl, ioaryl, and Ci_9heteroatyl are unsubstituted or optionally substituted;
R17 is -L1-R19;
L1 is selected from a bond, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R11)-, -C(0)-, -N(R11)C(0)-, -C(0)N(RH)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -000N(R14)-, -N(R14)C(0)0-, N(R1e), C(0)N(R1c), S(0)2N(R1c), S(0)N (R1c), C(R1f)(R1g)0, C(R1f)(R15)N(R1c), and C(R1f)(R1g):
Rle, Rif, and R1g are independently selected from hydrogen. halogen. -CN, Ci_6alkyl, C1_6haloa1kyl, C2_6a1keny1, C2_6alkynyl, C36cycloa1kyl, C2_9heterocycloalkyl, C6_30aryl, C3_9heteroaryl, -OR'2, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(Ru)(R13), -CH2C(0)N(R')(R13), -CH2N(RH)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(10, wherein C1_6alkyl, C2_6alkenyl, C2_6alkyny1, C3.6cycloalkyl, C2-9heterocyeloalkyl, C6_30atyl, and C3_91teteroaly1 are unsubstituted or optionally substituted; or R' and R1g are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are unsubstituted or optionally substituted;
R" is selected from hydrogen, C1.6a1ky1, C2_6alkeny1, C2_6alkynyl, C3.6cycloalky1, C2_9heterocycloalkyl, C6.
ioaryl, and Ci_9heteroaryl, wherein Ci_6a1ky1, C2_6a1kenyl, C2.6a1kynyl, C3_6cycloalky1, C2_9heterocycloalkO, C6_10ar341, and Ci_9heter0a1y1 are unsubstituted or optionally substituted;
R19 is selected from a C342cyc10a11cy1, C2, ,heterocycloalkyl, C6_12a1yl, and C2_12heteroaryl, wherein the C3-12cycloalkyl, C24iheterocycloalkyl, C6_12aryl, and C242heteroaryl are unsubstituted or optionally substituted;
R16 is selected from hydrogen, halogen, -CN, C,6a1ky1, C2_6a1kenyl, C2_6alkyny1, C3_6cyc1oalkyl, C2-9heterocycloalkyl, C6_10aryl, Ci.9heteroaryl, -OR', -SR', -N(R')(R"), -C(0)0R42, -0C(0)N(R')(R'), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R44)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C1_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloa1kyl, C2.9heterocycloalk341, C6_ ioaryl, and Ci_gheteroaly1 are unsubstituted or optionally substituted;
R2 is -C(0)0R12, -0C(0)N(R 12)(R 13), -N(R 44)C(0)N(R 12)(R 13), -N(R14)C(0)OR
15, -N(R 14)S(0)2R 15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(Ru)(R13), -CH2C(0)N(R12)(R'), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R')(R"), -(Ci-C6alky1)-Rub, -(C2_6alkeny1)-102b, -(C2_6alkyny1)-R121, -0-R12a, -N(R14)-R12b, _ S-R'2', -(C3_10cycloalkyl)-R12b, -(C2_9heterocycloa1kyl)-Rilb, -(C6_10aiy1)-R'2', or -(Ci_9heter0ary1)-R12b, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyk C3_11)cycloalkyl, C2_9heterocycloalkyl, C6.10aryl, and Ci-9heteroaryl are unsubstituted or optionally substituted;
R12a is selected from Ci-6a1ky1, C2_6a1kenyl, C2_6alkynyl, C2_10cycloalky1, -C(R12e)2-C3_1(pcycloall(yl, C2-9heterocycloalkyl, -C(R12`)2-C2.9heterocycloalkyl, C6_1()alyl, -C(R12e)2-C6_101y1, -C(R12e)2-Ci_9heterowyl, and Ci_9heteroary1, wherein C1-6a11ky1, C2_6alkenyl, C2_6a1kvnyl, C340cycloalkyl. -C(R12)2-C340cycloalkyl, C2_9heterocycloa1kyl, -C(W2c)2-C2_9heterocycloalkyl, C6_mary1. -C(W2c)2-C6_10aryl, -C(111292-C1.9heteroaryl, and Ci_91ieteroa ryl are unsubstituted or optionally substituted;
R12b is selected from hydrogen, C1_6alky1, C2_6alkenyl, C2_6alkynyl, C3_19cycloalkyl, -C(R1292-C340cycloalkyl, C2-9heterocycloalkyl, -C(R1292-C2_9heterocycloalkyl, C64coryl, -C(R12)2-C6_ilaryl, -C(R12)2-Ci_9heteroaryl, and Ci_9heteroary1, wherein Ci_6a1ky1, C2_6alkenyt C2_6a1kvnyl, C340cycloalkyl. -C(R12)2-C340cycloalky1, C2_9heterocycloa1kyl, -C(R12c)2-C2_9heterocycloalkyl, C6-1()aryl, -C(R12c)2-C6_1()aryl. -C(R12c)2-C,.9heteroaryl, and Ci_9heteroary1 are unsubstituted or optionally substituted;
R12c is selected from hydrogen, halogen, oxo, -CN, Ci_6a1ky1, C2_6alkenyl, C26a1kynyl, C3_6cycloalkyl, -CH2-C3-6cycloallcyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocyc1oalky1, C6_10myl, -CH2-C6_10aryl, -CH2-Ci-9heteroaryl, Ci_9heter0ary1, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein Ci-6alky 1, C2_6alkeny 1, C26alkyiiyl. C3_6cy cloalky 1, -CH2-C3_6ey cloalky 1, C2_9heteroey cloalky 1, -CH2 -C2_ ,heterocycloalkyl, C6_10aryl, -CH2-C6_2caryl, -CH2-C1_9heteroaly1, and C1.9heteroary1 are unsubstituted or optionally substituted;
each R21 is independently selected from H, Ci_6a1ky1, Ci_6haloalkyl, C2.6a1kenyl, C2_6alkynyl, C3_6cycloalkyl, C2_ 9heterocycloalkyl, C6-ioaryl, and C1_,heteroaryl;

each R22 is independently selected from H, Ci_6a1ky1, Ci_6ha1oa1ky1, C2_6a1kenyl, C2_6alkyny1, C3_6cyc1oa1kyl, C2_ 9heterocycloalkO, C6_10aryl, and Ci_9heteroary1;
each R23 is independently selected from H and Cl_nalkyl:
each R' is independently selected from H and Ck6a1ky1:
each R25 is selected from Ci_6a1ky1, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloalkyl, C2_9heterocyc1oa1kyl, C640aryl, and Ci_9heter0ary1;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, C,6a1ky1, C2_6alkenyl.
C2_6alkynyl, C3_6cycloalkyl, C2-9heterocycloalkyl, C6_ioaryl, C1.9heteroaryl, -OR', -SR', -N(R')(R13), -C(0)0R12, -0C(0)N(R')(R'), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R")C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C2_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloalkyl, C2.9heterocycloallwl, C6_ ioaryl, and Ci_glieteroawl are unsubstituted or optionally substituted;
each R12 is independently selected from hydrogen, C4_6a1lcy1, C2_6a1kenyl, C2_6allcynyl, C3_6eycloallcyl, -CH2-C3_ ,cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocyc1oalky1, C640awl, -CH2-C640aryl, -CH2-9heteroaryl, and Cl_9heteroaryl, wherein Cl_6a1ky1, C2_6a1kenyl, C2_6a1kynyl.
C3_6cycloalkyl, -CH2-C3-6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocyc1oalky1, C64oaryl, -CH2-C640aryl, -CH2-Ci-9heteroaryl, and Ci_9heteroary1 are unsubstituted or optionally substituted;
each R13 is independently selected from hydrogen, Ci_6a1ky1, and Ci_6ha1oa1ky1; or R12 and RH, together with the nitrogen to which they are attached, form an unsubstituted or optionally substituted C2_9heterocycloalkyl ring;
each R14 is independently selected from hydrogen, Ci_6a1ky1, and Ci_6ha1oa1ky1;
each R15 is independently selected C1.6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.6cycloalkyl, C2_9heterocycloalkyl, C6-ioaryl, and Ci_9heteroaryl, wherein Ci_6a1ky1, C2_6alkenyl, C2.6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6- loa tyl, and C1.91ieteroaty1 are unsubstituted or optionally substituted;
- indicates a single or double bond such that all valences are satisfied.
[00340] In some embodiments of Formula (I"), or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered awl, or 5-12 membered heteroaryl.
wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted or unsubstituted.
[00341] In an aspect is provided a compound of Formula (II"), or a pharmaceutically acceptable salt or solvate thereof:

N \
N - X

R17 Formula (11");
wherein W is C(0), S(0), or S(0)2;
V is C(R16) or N;
R1 is -L7-R7;
is a bond, -0-. -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-. -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R')-, -N(R14)S(0)-, -N(R')S(0)2-, C2-C6alkenyl, C2-C6alkyny1, or 2 to 4 membered heteroalkylene linker, wherein Cl-C6alkyl, C2-C6alkeny1, C2-C6alkyTnyl, and 2 to 4 membered heteroalkylene linker are unsubstituted or optionally substituted;
R7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered beteroaly1 each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are unsubstituted or optionally substituted;
R8 is selected from hydrogen, halogen, -CN, C,oa1ky1, C2_6a1kenyl.
C2_6alkynyl, C3_bcycloalkyl, C2_ 9heterocycloalkyl, C6_10aly1, C1.9heteroary1, -0R12, -SR12, -N(H)(R12), -C(0)01112, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2105, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R11)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_balkyl, C2_6alkenyl, C2_6alkyny1, C3_6cyc1oalky1, C2.9heterocycloalkyl, C6-ioary1, and Ci_9heteroaryl are unsubstituted or optionally substituted;
R'' is -L'-RI9;
L' is selected from a bond, CA-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(Ru)-, -N(R14)C(0)0-, N(Rle), C(0)N(R1c), S(0)2N(R1c), S(0)N(R1c), C(R1f)(R1,)0, C(R1f)(R1g)N(R1c), and C(R1f)(R1g);
R1e, R1f, and Rig are independently selected from hydrogen, halogen, -CN, Cia1ky1, Cl_bhaloalkyl, C2_6alkeny1, C2_6a1kynyl, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6_10aryl, C1.9heter0ary1, -0R12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R121)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6alky1, C2_6a1keny1, C2_6a1kyny1, C3_6cycloalky1, C2-9heterocycloalkyl, Cb_maiyl, and Ci_cheteroaryl are unsubstituted or optionally substituted; or Rif and R1g are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are unsubstituted or optionally substituted;
R" is selected from hydrogen, C1.6a1ky1, C2_6alkeny1, C2_6alkynyl, C3.6cycloalky1, C2_9heterocycloalkyl, C6.
ioaryl, and Ci_9heteroaryl, wherein Ci_6a1ky1, C2_6a1kenyl, C2.6a1kynyl, C3_6cycloalky1, C2_9heterocycloalkO, C6_10ar341, and Ci_9heter0a1y1 are unsubstituted or optionally substituted;
R19 is selected from a C342cyc10a11cy1, C2, ,heterocycloalkyl, C6_12a1yl, and C2_12heteroaryl, wherein the C3-12cycloalkyl, C24iheterocycloalkyl, C6_12aryl, and C242heteroaryl are unsubstituted or optionally substituted;
R16 is selected from hydrogen, halogen, -CN, C,6a1ky1, C2_6a1kenyl, C2_6alkyny1, C3_6cyc1oalkyl, C2-9heterocycloalkyl, C6_10aryl, Ci.9heteroaryl, -OR', -SR', -N(R')(R"), -C(0)0R42, -0C(0)N(R')(R'), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R44)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C1_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloa1kyl, C2.9heterocycloalk341, C6_ ioaryl, and Ci_gheteroaly1 are unsubstituted or optionally substituted;
R2 is -C(0)0R12, -0C(0)N(R 12)(R 13), -N(R 44)C(0)N(R 12)(R 13), -N(R14)C(0)OR
15, -N(R 14)S(0)2R 15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(Ru)(R13), -CH2C(0)N(R12)(R'), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R')(R"), -(Ci-C6alky1)-Rub, -(C2_6alkeny1)-102b, -(C2_6alkyny1)-R121, -0-R12a, -N(R14)-R12b, _ S-R'2', -(C3_10cycloalkyl)-R12b, -(C2_9heterocycloa1kyl)-Rilb, -(C6_10aiy1)-R'2', or -(Ci_9heter0ary1)-R12b, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyk C3_11)cycloalkyl, C2_9heterocycloalkyl, C6.10aryl, and Ci-9heteroaryl are unsubstituted or optionally substituted;
R12a is selected from Ci-6a1ky1, C2_6a1kenyl, C2_6alkynyl, C2_10cycloalky1, -C(R12e)2-C3_1(pcycloall(yl, C2-9heterocycloalkyl, -C(R12`)2-C2.9heterocycloalkyl, C6_1()alyl, -C(R12e)2-C6_101y1, -C(R12e)2-Ci_9heterowyl, and Ci_9heteroary1, wherein C1-6a11ky1, C2_6alkenyl, C2_6a1kvnyl, C340cycloalkyl. -C(R12)2-C340cycloalkyl, C2_9heterocycloa1kyl, -C(W2c)2-C2_9heterocycloalkyl, C6_mary1. -C(W2c)2-C6_10aryl, -C(111292-C1.9heteroaryl, and Ci_91ieteroa ryl are unsubstituted or optionally substituted;
R12b is selected from hydrogen, C1_6alky1, C2_6alkenyl, C2_6alkynyl, C3_19cycloalkyl, -C(R1292-C340cycloalkyl, C2-9heterocycloalkyl, -C(R1292-C2_9heterocycloalkyl, C64coryl, -C(R12)2-C6_ilaryl, -C(R12)2-Ci_9heteroaryl, and Ci_9heteroary1, wherein Ci_6a1ky1, C2_6alkenyt C2_6a1kvnyl, C340cycloalkyl. -C(R12)2-C340cycloalky1, C2_9heterocycloa1kyl, -C(R12c)2-C2_9heterocycloalkyl, C6-1()aryl, -C(R12c)2-C6_1()aryl. -C(R12c)2-C,.9heteroaryl, and Ci_9heteroary1 are unsubstituted or optionally substituted;
R12c is selected from hydrogen, halogen, oxo, -CN, Ci_6a1ky1, C2_6alkenyl, C26a1kynyl, C3_6cycloalkyl, -CH2-C3-6cycloallcyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocyc1oalky1, C6_10myl, -CH2-C6_10aryl, -CH2-Ci-9heteroaryl, Ci_9heter0ary1, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein Ci-6alky 1, C2_6alkeny 1, C26alkyiiyl. C3_6cy cloalky 1, -CH2-C3_6ey cloalky 1, C2_9heteroey cloalky 1, -CH2 -C2_ ,heterocycloalkyl, C6_10aryl, -CH2-C6_2caryl, -CH2-C1_9heteroaly1, and C1.9heteroary1 are unsubstituted or optionally substituted;
each R21 is independently selected from H, Ci_6a1ky1, Ci_6haloalkyl, C2.6a1kenyl, C2_6alkynyl, C3_6cycloalkyl, C2_ 9heterocycloalkyl, C6-ioaryl, and C1_,heteroaryl;

each R22 is independently selected from H, Ci_6a1ky1, Ci_6ha1oa1ky1, C2_6a1kenyl, C2_6alkyny1, C3_6cyc1oa1kyl, C2_ 9heterocycloalkO, C6_10aryl, and Ci_9heteroary1;
each R23 is independently selected from H and Cl_nalkyl:
each R' is independently selected from H and Ck6a1ky1:
each R25 is selected from Ci_6a1ky1, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloalkyl, C2_9heterocyc1oa1kyl, C640aryl, and Ci_9heter0ary1;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, C,6a1ky1, C2_6alkenyl.
C2_6alkynyl, C3_bcycloalkyl, C2-9heterocycloalkyl, C6_10aryl, C1.9heteroaryl, -OR', -SR', -N(R')(R13), -C(0)0R12, -0C(0)N(R')(R'), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R")C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_balkyl, C2_6a1kenyl, C2_6a1kynyl, C3_6cycloalkyl, C2.9heterocycloalkO, C6_ maryl, and Ci_glieteroatyl are unsubstituted or optionally substituted;
each R12 is independently selected from hydrogen, C4_6a1lcy1, C2_6a1kenyl, C2_6alk-ynyl, C3_6eycloallcyl, -CH2-C3_ ,cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocyc1oalky1, C640alyl, -CH2-C64oaryl, -CH2-9heteroaryl, and Cl_9heteroaryl, wherein Cl_6a1ky1, C2_6a1kenyl, C2_6a1kynyl.
C3_6cycloalkyl, -CH2-C3-6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocyc1oalky1, C64oaryl, -CH2-C640aryl, -CH2-Ci-9heteroaryl, and Ci_9heteroary1 are unsubstituted or optionally substituted;
each R13 is independently selected from hydrogen, Ci_6a1ky1, and Ci_6ha1oa1ky1; or R12 and RH, together with the nitrogen to which they are attached, form an unsubstituted or optionally substituted C2_9heterocycloalkyl ring;
each R14 is independently selected from hydrogen, Ci_6a1ky1, and Ci_6ha1oa1ky1;
each R15 is independently selected Ci.6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.6cycloalkyl, C2_9heterocycloalkyl, C6-maryl, and Ci_9heteroaryl, wherein Ci_6a1ky1, C2_6alkenyl, C2.6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6- loa tyl, and C1.91ieteroaty1 are unsubstituted or optionally substituted;
- indicates a single or double bond such that all valences are satisfied.
[00342] In some embodiments of Formula (II"), or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted or unsubstituted.
[00343] In an aspect is provided a compound of Formula (I-1), or a pharmaceutically acceptable salt or solvate thereof:
R 1 o NN
X
R2 Formula (I-1);
wherein W is C(0), S(0), or S(0)2;
V is C(R17) and J is C(R16), or V is C(R17) and J is N, or J is C(R17) and V
is C(R16), or J is C(R17) and V is N;
R" is -1_,7-R7;
1_,7 is a bond, -0-, -N(R")-, -C(0)-, -N(R")C(0)-, -C(0)N(R")-, -S-, -S(0)2-, -S(0)-. -S(0)2N(R")-, -S(0)N(R14)-, -N(R")S(0)-, -N(R14)S(0)2-, Ci-C6alky1, C2-C6alkenyl, C2-C6alkyny1, or 2 to 4 membered heteroalkylene linker, wherein Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R2';
R7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteromyl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6;
wherein two substituents selected from R1, 10, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one, two, or three R2";
each R1 is independently selected from hydrogen, Ci_oalkyl, C2_6alkenyl, C2_6a1kynyl, Ci_ohaloalkyl, ucycloalkyl, -CH2-C3_12cycloalkyl, C2_itheterocycloalkyl, -CH2-C2_11heterocycloalkyl, C6_12a1yl, -CH2-C6-122nyl, -CH2-Ci_iiheteroaryl, and Ci_tiheteroalyl, wherein C1_6alkyl, C2_6alkenyl, C2_6a1kynyl, C1_6haloalkyl, C2_12cycloalkyl, -CH2-C3.12cycloalkyl, C24theterocycloalkyl, -CH2-C2_1theterocycloalkyl, C6_12aryl, -CH2-C612aiyl, -CH2-Ct_itheteroalyl, and Ci1theteroaly1 are optionally substituted with one, two, or three R2 a;
each R4 is independently selected from hydrogen, halogen, oxo, -CN, C1.6alkyl, C2_6a1kenyl, C2_6a1kynyl, C3.
iocycloalkyl, C2_9heterocycloa1kyl, C6_12a1yl, Ci_iiheteroaryl, -N(R12)(R13), -C(0)0R12, -OC(0)N(R12)(R13), , -N(R14)C(0)N(Ri2)(Ri3s) N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)-1212, -S(0)R15, -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R12, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), , -CH2C(0)N(R12)(R13,) CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C2_6a1ky1, C2_6a1keny1, C2_6a1kyny1, C3_20cycloalkyl, C2_9heterocycloalkyl, C6.
12aryl, and CI_Iiheteroaryl are optionally substituted with one, two, or three R20;
R6 is -L2-R5;
each L2 is independently selected from a bond, Ci-C6alkyl, -0-, -N(R")-, -C(0)-, -N(R11)C(0)-, -C(0)N(R11)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R")S(0)-, -N(R")S(0)2-, -000N(R14)-, -N(R14)C(0)0-, and -N(R14)C(0)N(R14)-;
each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R5 is selected from halogen, -CN, C2_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_10cycloalkyl, C2_9heterocycloalkyl, C6-i2aryl, Ci_22heteroaryl, -0R12, -SR12. -N(H)(R12). -C(0)0R12. -0C(0)N(R12) (R13). -N(R14)C(0)N(R12)(R13).
-N(R14)C(0)0R15. -N(R14)S(0)2R15. -C(0)R15. -S (0)R15. -0C(0)R15. -C(0)N(R12)(R13). -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -C112C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH25(0)2R15, and -C112S(0)2N(R12)(R13), wherein C1_6a1kyl, C2_6a1keny1, C2_6alkynyl, C340cycloalkyl, C2_9heterocycloalkyl, C6_12ary1, and Ci_iiheteroaryl are optionally substituted with one, two, or three R2.0c R" is -1_,1-R19;
I,' is selected from a bond, Cl-C6allcyl, C2-C6alkenyl, C2-C6alkyny1, -0-, -N(R")-, -C(0)-, -N(R")C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R")S(0)2-, -000N(R14)-, -N(R")C(0)0-, N(Rle), C(0)N(R"), S(0)2N(R"), S(0)N(R1c), C(Rif)(R1g)0, C(R1f)(R19N(R1c), and C(R1f)(10);
R", Rif, and Ws arc independently selected from hydrogen, halogen, -CN, Ci_oalkyl, C,6haloalkyl. C2_6a1kcny1, C2_6a1kynyl, C3_iocy eloalkyl, C2_911eteroeyeloalkyl, C6_12ary1, Ci_liheteroaryl, -OR', -SR". -N(R12)(R"), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R1', -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R")C(0)R15, -CH2S(0)2R15, and -C1-12S(0)2N(R12)(R13), wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3.10cycloalkyl, C2-9heterocycloalkyl, C6_12aiyl, and Ci_iiheteroaryl are optionally substituted with one, two, or three R201: or Rif and R1g are joined to form a 4-7 membered heterocycloallcyl ring or a 4-7 membered cycloallcyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
R" is selected from hydrogen, Ci.6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.10cycloalkyl, C2.9heterocycloalkyl, C6_ 12ary1, Ci_iiheteroaryl, wherein Ci_oalkyl, C2_6a1keny1, C2_6a1kyny1, C3_iocycloalkyl, C2_9hetcrocyc1oa1ky1, Co-izaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three 1120i;
R19 is selected from a C3_12cyc10a11cy1, C2-liheterocycloalkyl, C6_22aryl, and C2_22heteroaryl, wherein the C3-12CYCl0a110, C2-11heter0CyClOalkyl, C6_12aryl, and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven RH, each Rli is independently selected from halogen, oxo, -CN, Ci.6alky1, Ci_6haloalkyl, C2_6alkenyl, C2-6alkynyl, C3-mcycloalkyl, C2_9heterocycloalkyl, C6_12aryl, Ci-iiheteroaryl, -N(R12)(Rb), -C(0)0R12, -OC(0)N(R12)(R13), , -N(R14)C(0)N(R)2)(Ri3s) N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R1', -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(Ru)(iti3), 4,,j(R14)c(o)R", -S(0)2R", _S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(Ru)(R13), wherein C4_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_iocycloalkyl, C2_9heterocycloalkyl, C6.
12ary1, and CI_Iiheteroaryl are optionally substituted with one, two, or three R201:
R" is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C340cycloalkyl, C2_ 9heterocycloalkyl, C6_12aiyl, Ci_iiheteroaryl, -0R12, _sR12, _N(R12)c,13µ, -C(0)OR", -0C(0)N(Ru)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(104)S(0)2R15, -C(0)R1', -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R"), wherein C2_6a1ky1, C2_6alkeny-1, C2_6alkynyl, C3_10cycloalky-1, C2_9heterocycloalkyl, C6.
12ary1, and Ci_iiheteroaryl are optionally substituted with one, two, or three R2ng;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(1113), -N(R")C(0)0R15, -N(R14)S(0)2R15, -C(0)1115, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R12)(103), -(C, -C6alkyl)-Rub, _(C2_6alkeny1)-R12b, _(C2_6alkyny1)-R12b, -0-RI2a, -N(R14)-R121), S-R12b, -(C3_10cycloalkyl)-Rub, -(C2_9heterocycloalkyl)-102b, -(C6_10ary1)-R121', or -(Ci_9heter0ary1)-R12b, wherein said C1_6a1kyl, C2_6alkenyl, C2_6alkynyl, C3_iocycloalkyl, C2_9heterocycloalkyl, C6.1oary1, and C1-9heteroaryl are optionally substituted with one, two, or three R20;
R12a is selected from Ci_6a1kyl, C2.6a1kenyl, C2_6alkynyl, C3_10cycloalkyl, -C(R12`)2-C3.10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2.9heterocycloalkyl, C6_10aryl, -C(R1292-C6.11aryl, -C(R12c)2-Ci_9heteroaryl, and Ci_9heteroary1, wherein C1-6a11cy1, C2_6alkenyl, C2_6a1kynyl, C340cycloalkyl, -C(R12c)2-C3_10cycloalkyl, C2_9heterocycloalkyl, -C(R12c)2-C2_9heterocycloalkyl, C6.ioaryl, -C(R12c)2-C6_10aryl, -C(R12)2-C1.9heteroaryl, and C1_9heteroary1 arc optionally substituted with one, two, or three R2";
Rim is selected from hydrogen, C1_6a11ky1, C2_6alkenyl, C2_6alkynyl, C340cycloalkyl, -C(R')2-C3.10cycloa1kyl, C2.
9heterocycloalkyl, -C(R12c)2-C2.9heterocycloalkyl, C6_10aryl, -C(R12e)2-C6.10aryl, -C(R12e)2-Ci_9heteroaryl, and Ci_9heteroary1, wherein Ci-6a1ky1, C2_6alkenyl, C2_6a1kynyl, C340cycloalkyl, -C(R1292-C340cycloalkyl, C2_9heterocycloalkyl, -C(R12)2-C2_9heterocycloalkyl, C6.ioaryl, -C(R12)2-C6_10aryl, -C(R12)2-C1.9heteroaryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R20;
R12C is independently selected from hydrogen and re"k;
Xis C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C34ocycloalkyl, C2-9heterocycloalkyl, C6_12a1yl, Cl., iheteroaryl, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(Ru)(R13), -N(R14)C(0)N(R12)(R13), -N(R")C(0)0R15, -N(R")S(0)2R15, -C(0)R", -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R'), -CH2C(0)N(R12)(R'), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(Ri3), wherein C1_6alkyl, C2_6alkeny-1, C2_6alkynyl, C3_iocycloalkyl, C2_9heterocycloalkyl, C6-i2aryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three R2 b;
each R12 is independently selected from hydrogen, Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3_10cycloalkyl, -CH2-C3-tocycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloa1kvl, C6_12ary1, -CH2-C6-12aryl, -C112-C1-iiheteroaryl, and Ci_iiheteroalyl, wherein Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3_iocycloalkyl, C2_9heterocycloallcyl, -CH2-C2_91teterocycloallcyl, C6_12atyl, -CH2-C6_12atyl, iiheteroaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three R20;
each R13 is independently selected from hydrogen, Ci_6a1ky1, and Ci_6ha1oa1ky1; or R12 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloallql ring optionally substituted with one, two, or three R2 e;
each RIA is independently selected from hydrogen, Ci_6a11ky1, and Ci_6haloalkyl;
each R1' is independently selected Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, C2_9heterocycloalkyl, C6_ 12ary1, and Ci_llheteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloalky-1, C2-9heterocycloalkyl, C6_12a1y1, and Ci_iiheteroaryl are optionally substituted with one, two, or three R20;
each R2 , R20b, R2oc, Rao, woe, Rag., wog, Ran, and rc - 20k are each independently selected from halogen, oxo, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalky-1, -CH2-C3_10cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_12ary 1, -CH2-C6_12ary1, -CH2-Ct_itheteroaryt Ci_itheteroaryl, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein Ci_6a1ky1, C2_6a1kenyl, C2_6a1kyny1, C3-locycloalkyl, -CH2-Cs_locycloalkyl, C2_9heterocycloalkyl, -CH2-C2_,heterocycloalkyl, C6_12ary1, -CH2-C6.

12ary1, -CH2-C1_iiheteroaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci_6haloalkvl, C1_6a1koxy, C1_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R21 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2.6a1kenyl, C2.6a1kyny1, C34ocycloa1kyl, C2.
9heteroeyeloalkyl, C6_12ary1, and Ci_iiheteroaryl;
each R22 is independently selected from H, Ci_oalkyl, Ci_ohaloalkyl, C2.6a1kenyl, C2.6a1kyny1, C3.10cycloa1kyl, C2.
9heterocycloalkyl, C6_12ary1, and Ci_iiheteroaryl;
each R23 is independently selected from H and Ci_6alkyl;
each R24 is independently selected from H and Ci_6alkyl;
each R25 is independently selected from Ci_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_iocycloalkyl, C2-9heterocycloalkyl, C6_12ary1, and Ci_iiheteroaryl; and - indicates a single or double bond such that all valences are satisfied.
[00344] In an aspect is provided a compound of Formula (TT-1), or a pharmaceutically acceptable salt or solvate thereof:

N
X

R17 Formula (II-1);
wherein W is C(0), S(0), or S(0)2;
V is C(R16) or N;
Rio is -1_,7-R7 1_,7 is a bond, -0-, -N(R")-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-. -S(0)2N(R11)-, -S(0)N(R')-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-C6alkyl, C2-C6alkeny1, C2-C6alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R2'41;
IC is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteromyl are optionally substituted with one or more R1, optionally substituted with one or more fe, and optionally substituted with one or more R6;
Iwo substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroatyl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one, two, or three R2.6a;

each R1 is independently selected from hydrogen, Ci_6alkyl, C2_6a1keny1, C2_6alkyny1, Ci_6haloalkyl, C3-12cycloalkyl, -CH2-C342cycloalkyl, C241heterocycloalkyl, -CH2-C2_i1heterocycloalkyl, C6_12aryl, -CH2-C6_ 12aryl. -C1-12-Cl_ilheteroary1, and Ci_iiheteroaryl, wherein Ci_nalkyl, C2.6a1keny1, C2.6alkynyl, C1_6haloalkyl, C342cyc1oalky1, -CH2-C3.12eycloalkyl, C2_iiheterocycloalk),1, -CH2-C2_nheterocycloallcy1, C6_12ary1, -CH2-C6_12awl, -CH2-C1_iiheteroaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three R2 a;
each R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci.6alky1, C2_6alkenyl, C2_6alkynyl, C3.
iocycloalkyl, C2_9heterocycloalkyl, C6_12a1y1, Ci_iiheteroaryl, -N(R12)(R13), -C(0)0R12, -0C(0)N(1112)(R13), -N(RH)C(0)N(R12)(R13), -N(R11)C(0)0R15, -N(R")S(0)2R15, -C(0)R12, -S(0)R15, -0C(0)R15, -C(0)N(R")(R"), -C(0)C(0)N(R12)(R"), -N(R14)C(0)R12, -S(0)2R", -S(0)2N(R")(R")-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R")C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C1_6a1kyl, C2_6a1keny-1, C2_6a1kynyl, C3_iocycloalkyl, C2_9heterocycloalkyl, C6-i2ary1, and Ci_iiheteroaryl are optionally substituted with one, two, or three R2 a;
R6 is -L2-R5;
each L2 is independently selected from a bond, Cl-C6alkyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)_, _s(0)1,4(R 14)_, _N-(R IA) s (0)_, 4K
14+
)S(0)2-. -000N(R 14)-, -N(R14)C(0)0-, and -N(R14)C(0)N(R14)-;
each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
IV is selected from halogen, -CN, C,allcy1, C2_6alkenyl, C2_oalkynyl, C3_10cycloalkyl, C2_9heterocycloalkyl, Co.
12ary1, Ci_iiheteroaryl, -SR", -N(H)(R"), -C(0)0R", -0C(0)N(R")(R"), -N(R14)C(0)N(R")(R"), -N(101)C(0)0R15, -N(RH)S(0)2R15, -C(0)R15, -S(0)1115, -0C(0)1115, -C(0)N(R")(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R13, -S(0)2N(R12)(103)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1kyl, C2_6a1kenyl, C2-6alkynyl, C34ocycloalkyl, C2_9heterocycloa1kyl, C6_12ary1, and Ci_iiheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -L1-1219;
1_,4 is selected from a bond, Cl-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R")-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R")-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(R14)C(0)0-, N(R1e), C(0)N(R1c), S(0)2N(R1c), S(0)N(R1c), C(R1f)(R1g)0, C(R1f)(R1g)N(R1c), and C(R1f)(121g);
R1e, R11, and R'g are independently selected from hydrogen, halogen, -CN, C1_6alkyl, Ci_6haloalkyl, C2_6a1keny1, C2_6a1kynyl, C3_10cycloalkyl, C2_9heterocycloalkyl, C6_12ary1, Ci_iiheteroaryl, -OR', -SR', -N(R")(R"), -C(0)0R12, -0C(0)N(R12)(103), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R1), -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R")(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R"), -CH2N(RH)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R")(R"), wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.10cycloalkyl, C2-9heteroeyeloalkyl, C6_12aryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three R20, or Rif and Rig are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;

Rlc is selected from hydrogen, Ci_6a1ky1, C2_6alkenyl, C2_6alkyny1, C340cycloalkyl, C2_9heterocyclealkyl, C6_ 12aryl, Ci_iiheteroaryl, wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkyny1, C3_10cycloalkyl, C2_9heterocycloalkyl, C6-12arY1. and CI_Iiheteroaryl are optionally substituted with one, two, or three R2 1;
R19 is selected from a C3_12cycloalkyl, C24 iheterocycloalkyl, C6_12ary1, and C2_12heteroaryl, wherein the C3.
12cycloalkyl, C2_11heterocycloalkyl, C6_12aryl, and C242heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i;
each R1i is independently selected from halogen, oxo, -CN, Ci.6alkyl, Ci_6haloalkyl, C2_6alkenyl, C2_6alkynyl, C3.
tocycloalkyl, C2_9heterocycloalkyl, C6_12aryl, Ci-iiheteroaryl, -01112, -N(R12)(R13), -C(0)0R12, -0C(0)N(1112)(R13), -N(Rm)C(0)N(R12)(R'), -N(RH)C(0)0R15, -N(R14)S(0)2R16, -C(0)R15, -S(0)R1', -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), _CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_iocycloalkyl, C2_9heterocycloalkyl, C6-12aryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three R2(11;
R'6 is selected from hydrogen, halogen, -CN, C1_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, C2-9heterocycloalkyl, C6_12aiy1, Ci_iiheteroaryl, -0R12, -SR 12, -N(R12)(R13), -C(0)OR 12, -0C(0)N(R12)(R13), -N(R11)C(0)N(R12)(R13), -N(Ri1)C(0)0R15, -N(Ri1)S(0)2R15, -C(0)R'5, -S(0)R15, -0C(0)R15, -C(0)NR12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R'), -CH2C(0)N(R12)(R'), -CH2N(RN)C(0)R15, -CH2S(0)2R", and -CH2S(0)2N(R12)(R13), wherein Ci_oalkyl, C2_6alkeny-1, C2_6alkynyl, C3_iocycloalkyl, C2_9heterocycloalkyl, Co.
12ary1, and Ci_itheteroaryl are optionally substituted with one, two, or three R20g;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R11)C(0)N(R12)(R13), -N(RH)C(0)0R15, -N(R11)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R"), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R12)(R13), -(Ci-C6aikyo-R12b, _(C2_6alkeny1)-R12b, _(C2_6alkyny1)-R1211, _o_R12a, _N(R14)_R12b, _ S-R12", -(C3_10cycloalkyl)-1112", -(C2_9heterocycloalkyl)-Ru", -(C6_10ary1)-R12", or -(Ci_9heteroary1)-Ri2h, wherein said C1-6alky1, C2_6alkenyl, C2_6alkynyl, C3_iocycloalkyl, C2_9heterocycloalkyl, C6.10alyl, and Ct-,heteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from C1-6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, -C(R12)2-C3_10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2.9heterocycloalkyl, C6_10aryl, -C(R12c)2-C6.ioaryl, -C(R12c)2-Ci_9heteroaryl, and C1_9heteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl. -C(R12c)2-C3_10cycloalkyl, C2_9heterocycloalkyl, -C(Ruc)2-C2_9heterocycloalkyl, C6.10aryl, -C(R12c)2-C6_10aryl, -C(1112e)2-Ci.9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20d, R12" is selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C340cycloalkyl, -C(R12c)2-C340cycloa1kyl, C2-9heterocycloalkyl, -C(R12c)2-C2.9heterocycloalkyl, C6_10aryl, -C(R12)2-C6.10aryl, -C(R12c)2-Ci_9heteroaryl, and Ci_9heteroaryl, wherein C1-6a11/1, C2_6alkenyl, C2_6alkyny1, C340cycloalkyl. -C(R12e)2-C3_10cyc1oalkyl, C2_9heterocycloalkyl, -C(R12e)2-C2_9heterocycloalkyl, C6.10aryl. -C(R12e)2.-C6_10aryl, -C(R12c)2-C1.9heteroaryl, and Ci4he1eroary I are optionally substituted with one, two, or three it'd, R12c is independently selected from hydrogen and R201;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl.
C2_6alkynyl, C3_10cycloalkyl, C2-9heterocycloalkyl, C6_12my1, CI.Ilheteroaryl, -0R12, _SR12, _N(R12)(R13) , _ C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(Ru)(R13), -C(0)C(0)N(Ru)(R13), -N(R')C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1k0, C2_6a1kenyl, C2_6a1kyny1, C3_10cycloalkyl, C2_9heterocyeloalkyl, C6.
12aryl, and Ci_itheteroaryl are optionally substituted with one, two, or three R2ab each R12 is independently selected from hydrogen, C1_6alky1, C2_6alkenyl, C2_6a1kyny1, C3_10cycloalkyl, -CH2-C3-tocycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_12aryl, -CH2-C6_12aryl, -CH2-C1-itheteroaryl, and Ci_ithetcroaryl, wherein Ci_oalkyl, C2_6alkenyl, C2_6a1kyny1, C3_tocyc1oalkyl, -CH2-C3_ tocycloalkyl, C2_9he1erocycloalkyl, -CH2-C2_9heterocycloa1kyl, C6_12aryl, -CH2-C6_12a1yl, -CH2-C1-itheteroaryl, and Ci_itheteroaly1 are optionally substituted with one, two, or three R2 d;
each R13 is independently selected from hydrogen, C1_6alkyl, and Ci_6haloa1kyl; or R12 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R201;
each R14 is independently selected from hydrogen, Ci_6alkyl, and Ci_6haloa1kyl;
each R15 is independently selected Ci_6allcyl, C2_6alkenyl, C2_6allcynyl, C3_10cycloallcyl, C2_9heterocycloalkyl, C6_ 12aryl, and Ci_itheteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_iocycloalkyl, C2_ 9heterocycloalkyl, C6_12aty1, and C1_11heteroaryl are optionally substituted with one, two, or three R20;
each R20a, R2ob, Rah:, R20d, R20e, R2or, R20g, R20i, and R20' is independently selected from halogen, oxo, -CN, Ci_ ,alkyl, C2_6alkcnyl, C2_6alkynyl, C3_tocycloalkyl, -CH2-C3_1ocycloalkyl, C2_9hcterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6_12a1yl, -CH2-C642ary1, -CH2-Ci_tiheteroaryl, Ci_iiheteroatyl, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein Ci_oalkyl, C2_6a1kenyl, C2_6alkynyl, C3-iocycloalkyl, -CH2-C340cycloalkyl, C2_9heterocycloalkyl, -C112-C2_9heterocycloalkyl, C6_12ary1, -CH2-C6-12ary1, -CH2-C1_itheteroaryl, and Ci_i iheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1lcy1, Ci_6ha1oa1lcy1, Ci_6a1koxy, Ci_ohaloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R21 is independently selected from H, C1_6alkyl, C1_6ha1oalkyl, C2.6a1kenyl, C2.6alkynyl, C3.1 ocycloalkyl. C2.
9heterocycloalkyl, C6_12myl, and Ci_iiheteromyt each R22 is independently selected from H, Ci_6a1ky1, Ci_6haloalk0, C2_6a1kenyl, C2_6alkynyl, C3_tocycloalkyl, C2_ 9heterocycloalkyl, C6_12ary1, and Ci_iiheteroaryl;
each R23 is independently selected from H and Ci_6a1ky1;
each R24 is independently selected from H and Ci_6alkyl:
each R25 is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, C2-9heterocy cloalkyl, C6_12aryl, and Cl_iiheteroaryl; and - indicates a single or double bond such that all valences are satisfied.
1003451 In embodiments of Formula I-1, one R4 is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein;

[00346] In embodiments of Formula II-1, one R4 is an electrophilic moiety capable of forming a covalent bond with a cysteine, senile, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein;
[00347] In an aspect is provided a compound of Formula (I-1'), or a pharmaceutically acceptable salt or solvate thereof:

N
X
R2 Formula (1-1');
wherein W is C(0); V is C(IC) and J is C(R16);
R1 is -L7-R7;
L7 is a bond, -0-, or R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more R4, and optionally substituted with one or more R6;
each R4 is independently selected from halogen, oxo, -CN, C2_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_20cycloalkyl, C2_9heterocycloalkyl, C6_12aryl, Ci_iiheteroaryl, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(RN)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(RH)S(0)2R15, -C(0)R12, -S(0)R15, -0C(0)R", -C(0)N(Ru)(R13), -C(0)C(0)N(Ru)(R13), -N(R')C(0)R12, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(1142)(R'), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R", and -CH2S(0)2N(R12)(R13), wherein C2_6a1kyl, C2_6a1keny-1, C2_6a1kynyl, C3_20cycloalky-1, C2_9heterocycloalkyl, C6.
12aryl, and C2_22heteroaryl are optionally substituted with one, two, or three R2 a;
one R4 is optionally independently an electropliilic moiety capable of forming a covalent bond with a cysteine, senile, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein;
R6 is -L2-R5;
each L7 is independently selected from a bond and -C(0)-;
each R5 is independently hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
each R5 is independently selected from hydrogen, halogen, oxo, -CN, Ci.6alkyl, C2_6alkenyl, C2_6alkynyl, C3.
tocycloallql, C2_9heterocycloalkyl, C6_12ary1, Ci_itheteroaryl, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -OC(0)N(R')(R13), -N(104)C(0)N(R12)(R13), -N(R')C(0)0R", -N(R14)S(0)2R15, -C(0)R12, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R')C(0)R12, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C2_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_20cycloalkyl, C2_9heterocycloalkyl, Co-izaryl, and C2_22heteroaryl are optionally substituted with one, two, or three R2 a;
R8 is selected from -CN, C2_6alkcnyl, C2_6alkynyl, C340cycloalkyl, C2.9licterocycloalkyl, and -C(0)R12, wherein Ci_6a1ky1, C2_6a1kenyl, C2_6a1kynyl, C3_20cycloalkyl, and C2_9heterocycloalkyl are optionally substituted with one, two, or three R2 e;
R17 is -L1-R19;

Ll is a bond;
R19 is selected from a C6_12aryl and C2_12heteroaryl, wherein the C6.12aryl and C2_12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11;
each R1' is independently selected from halogen, oxo, -CN, Ci.6a1ky1, C2_6a1kenyl, C2_6a1kynyl, C3.
6cyc10a11kyl, C2_5heterocycloalkyl, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -C(0)R12, -C(0)N(Ru)(R13), and -N(R14)C(0)R12, wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, and C2_5heterocycloa1kyl, are optionally substituted with one, two, or three R20';
R16 is selected from hydrogen and halogen;
R2 is -0-R12a;
R12. is _c(R12.)2_ C2_9heterocycloalkyl, wherein -C(R12c)2-C2_9heterocycloalkyl is optionally substituted with one, two, or three R2 d;
Rue is independently selected from hydrogen and C1_3alkyl;
X is C(R3) or N;
R3 is selected from hydrogen and -CN;
each R12 is independently selected from hydrogen, Ci_6a1lcy1, C2_6alkenyl, C2_6allcynyl, C340cycloalkyl, -CH2-C3_ iocycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloa1kyl, C6_12aryl, -CH2-C6_12a1yl, -CH2-C,_ heteroaryl, and C1_, iheteroatyl, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_locycloalkyl, -CH2-C3_ iocycloalkyl, C2_9heterocycloalkO, -CH2-C2_9heterocycloalkvl, C6_12ary1, -CH2-C6-12aryl, -CH2-Ci-iiheteroaryl, and CL_Iihetcroatyl are optionally substituted with one, two, or three Rml;
each R13 is independently selected from hydrogen, Ci_6a1ky1, and Ci_6ha1oa1ky1;
each RH is independently selected from hydrogen, Ci_6alkyl, and Ci_6ha1oa1ky1;
each R15 is independently selected Ci.6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.10cycloalkyl, C2_9heterocycloalkyl, C6_ 12aly1, and Cl_llheteroatyl, wherein C1_6alkyl, C2_6alkeny-1, C2_6alkynyl, C3_10cycloalky-1, C2-9heterocycloalkyl, C6_12ary1, and Ci_iiheteroaryl are optionally substituted with one, two, or three R20;
each R20a, R2`)c, R2d, R20e, R2', and R2' is independently selected from halogen, oxo, -CN, Ci_6a1ky1, C2-6a1keny1, C2_6allcynyl, C3_10cycloalkyl, -CH2-C3_10cycloalkyl, C2_91ieterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6_12ary1, -CH2-C6,12aryl, -CH2-Ci_1iheteroaryl, C1i1heteroaryl,-0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, wcycloalkyl, -CH2-C3_10cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_12a1yl, -CH2-C6.
12ary1, -CH2-C1_uheteroaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6ha1oa1ky1, Ci_6a1k0xy, Ci_6ha1oa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R2' is independently selected from H, Ci_6a1ky1, C,s1ia1oa1ky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, C2_ ,heterocycloalkyl, C6_12ary1, and Ci_iiheteroaryl;
each R22 is independently selected from H, Ci_6a1ky1, Ci_6ha1oa1ky1, C2.6alkenyl, C2_6alkynyl, C340cycloalkyl, C2_ 9heterocycloalkyl, C6_12ary1, and Ci_iiheteroaryl;
each R23 is independently selected from H and C1_6a1ky1;

each R24 is independently selected from H and Ci_6a1ky1;
each R25 is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3_iocycloalkyl, 9heterocycloalkyl, C6_12atyl, and Ci_iiheteroaryl: and ¨ indicates a single or double bond such that all valences are satisfied.
[00348] In an aspect is provided a compound of Formula (I-1¨), or a pharmaceutically acceptable salt or solvate thereof:

N
X
/
R2 Formula (I-1");
wherein W is C(0); V is C(R17) and J is C(R16);
R10 is -L7-R7;
LT is a bond, -0-, or R7 is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each optionally substituted with one or more 1:0;
R1 are independently selected from halogen, oxo, -CN, -C(0)R12, C1.6alkyl, C2_6alkenyl, C2_6alkynyl, C3-iocycloalkyl, C2_9heterocycloalkyl, and -0R12, wherein Ci_6a1ky1, C2_6a1kenyl, C2_6a1kynyl, C3_10cycloalkyl, and C2_9heterocycloa1kyl are optionally substituted with one, two, or three R2 a;
R8 is selected from Ci_6a1ky1, C3_10cycloalkyl, and C2_9heterocycloalkyl, wherein Ci.6a11cy1, C3.10cycloalkyl, and C2_9heterocycloalkyl are optionally substituted with one, two, or three R20c;
R17 is -L1-R19;
L1 is a bond;
R19 is selected from a C6_paryl and 9-10 membered heteroaryl, wherein the C6_paryl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i;
each R1' is independently selected from halogen, -CN, Clalkyl, Chaloalkyl.
C2_6alkenyl, C2_6alkynyl, -OH, -NH?, wherein Ci_6a1ky1, C2.6alkenyl, and C2_6alkynyl are optionally substituted with one, two, or three R20';
R1' is selected from hydrogen and halogen;
R2 is -0-R12a;
R12. is _c(R12,2-) (5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three It'd;
R12e is independently selected from hydrogen and methyl;
X is N;

each R12 is independently selected from hydrogen, C1_6a1kyl, C2_6alkenyl, C2_6a1kynyl, C3_10cycloalkyl, -CH2-C3_ iocycloalkyl, C2_9heterocvcloalky1, -CH2-C2_9heterocycloalkyl, C6_12aryl, -CH2-C6_12aryl, -C112-C1-11heteroaryl, and C1_, iheteroatyl, wherein Cl_nalkyl, C2_6alkenyl, C2_6alkyny1, C3_10cyc1oalkyl, iocycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloa1kvl, C6_12aryl, -CH2-C6_12aryl, -CH2-C1_ iheteroaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three R20;
each R13 is independently selected from hydrogen, C1_6a1kyl, and Ci_6haloa1kyl;
each RN is independently selected from hydrogen, C1_6alkyl, and Ci_6haloalkyl;
each R1' is independently selected Ci.oalkyl, C2_6alkenyl, C2_6alkynyl, C3.10cycloalkyl, C2_9heterocyc1oalkyl, C6_ 12aryl, and Ci_iiheteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_iocy cloalky 1, C2-9heterocycloalkyl, C6_12aryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three R20;
each R20a, woe, Raw, R2oe, Rag., and R2o1 is independently selected from halogen, oxo, -CN, Ci.6alky1, C2-6a1keny1, C2_6alkynyl, C3_10cycloalkyl, -CH2-C3_10cycloalkyl, C2_9heterocyc1oalkyl, -CH2-C2-9heterocycloalkyl, C6_12ary1, -CH2-C6_12aryl, -CH2-C1_i1heteroaryl, Ci_iiheteroaryl, -0R21, -SR24, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein C1_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3-10cycloalkyl, -CH2-C3_10cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_12aryl, -CH2-C6.
12ary1, -CH2-Ci_iiheteroaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_balkyl, C1_6ha1oa1kyl, C1_6alkoxy, Ci_ohaloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R21 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2.6alkenyl, C2.6alkyny1, C340cycloalkyl, C2-9heterocycloalkyl, C6_12my1, and Ci_iiheteroaryl;
each R" is independently selected from H, C1_6alkyl, Ci_6haloalkyl, C2.6a1kenyl, C2.6alkyny1, C3.10cycloalkyl, C2-9heterocycloalkyl, C6_12aiyl, and Ci_iiheteroaly1;
each R23 is independently selected from H and Ci_6a1kyl;
each R24 is independently selected from H and Ci_6a1kyl;
each R25 is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, C2_ 9heterocycloalkyl, C6_12myl, and CI_Iiheteroaryl; and - indicates a single or double bond such that all valences are satisfied.
[00349] In an aspect is provided a compound of Formula (I-1 or a pharmaceutically acceptable salt or solvate thereof:

N
N X
R2 Formula (1-1");
wherein W is C(0); V is C(R17) and J is C(R16);
Rl is -L7-R7;

LT is a bond, -0-, or -N(R14)-;
R7 is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl arc each substituted with one or more le;
R4 are independently selected from halogen, oxo, -CN, -C(0)R12, Ci_6alky1, C2_6alkenyl, C2_6alkynyl, C3-iocycloalkyl, C2_9heterocycloalkyl, and -0R12, wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_iocycloa1kyl, and C2_9heterocycloalkyl are optionally substituted with one, two, or three R2 a;
R8 is selected from Ci_6a1ky1, C3_10cycloallql, and C2_9heterocycloallq1, wherein Ci.6a11cy1, C3.1ocycloalkyl, and C2_9heterocycloalkyl are optionally substituted with one, two, or three R2" ;
R17 is 4,1-R19;
1_,4 is a bond;
R19 is selected from a C6_12aryl and 9-10 membered heteroaryl, wherein the C6_12aryl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R";
each is independently selected from halogen, -CN, C2_6alkenyl, C2_6alkynyl, -OH, -NH2, wherein Ci_6alkyl, C2.6a1keny1, and C2_6alkynyl are optionally substituted with one, two, or three R2";
R16 is selected from hydrogen and halogen;
R2 is -0-R12a;
R12a is -C(R12c)2-(5-8 membered heterocycloalkyl), wherein -C(R12e)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d;
re2c is independently selected from hydrogen and methyl;
X is NT, each R12 is independently selected from hydrogen, Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C34ocycloalkyl, -CH2-C3-10cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloa1kyl, C6_12aryl, -CH2-C6_22aryl, -CH2-C1-iiheteroaryl, and Ci_iiheteroaryl, wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_iocycloalkyl, locycloalkyl, C2_9heterocycloalky1, -CH2-C2-9heterocycloa1kyl, C6-12a1yl, -CH2-C6_12aryl, iheteroatyl, and Ci_iiheteroaly1 are optionally substituted with one, two, or three R20d;
each R13 is independently selected from hydrogen, Ci_6a1ky1, and Ci_6ha1oa1ky1;
each R14 is independently selected from hydrogen, Ci_6a1ky1, and Ci_6ha10a1ky1;
each R15 is independently selected Ci.6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.10cycloalkyl, C2_9heterocycloalkyl, C6_ 12ary1, and Ci_llheteroaryl, wherein C2_6allql, C2_6alkenyl, C2_6a11,Tnyl, C3_i0cyc1oa1ky1, C2-9heterocycloalkyl, C6_12a1y1, and Ci_iiheteroatyl are optionally substituted with one, two, or three R20f;
each R20, R" , R"d, R"e, R20, and R2' is independently selected from halogen, oxo, -CN, Ci_6a1ky1, C2-balkenyl, C2_6a1kynyl, C34ocycloalkyl, -CH2-C3_10cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2-9heterocycloalkyl, C6_12aryl, -CH2-C6_22aryl, -CH2-Ci_11heteroary1, Ci_ilheteromyl, -0R21, -SR21, -N(R22)(R22) _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)c(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)s(0)2R25, _c (0)R25, _s(0)2R25, _ S(0)2N(R22)(R23), _OCH2C(0)0R22, and -0C(0)R25, wherein Ci_6alkyl, C2_6alkenyl, C2_6a1kynyl, locycloalkyl, -CH2-C34ocyc1oalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_12ary1, -CH2-C6-12aryl, -Cf12-CI_Ilheteroaryl, and C1_1 iheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R21 is independently selected from H, Ci6alkyl, Ci6haloalkyl, C2.6a1kenyl, C2.6alkyny1, C3.tocycloa1kyl, C2.
9heterocycloalkyl, C6_12ary1, and Ct_iiheteroaryl;
each R22 is independently selected from H, C1_6alkyl, Ci_6haloalkyl, C2_6alkenyl, C2_6alkyny1, C3_40cycloa1kyl, C2_ 9heterocycloalkyl, C6_12ary1, and Ci_iiheteroaryl;
each R23 is independently selected from H and Ci_6alkyl;
each R24 is independently selected from H and Ci_6alkyl:
each R25 is independently selected from Ci_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3_iocycloa1kyl, C2-9heterocycloallcyl, C6_12aty1, and Ci_iiheteroatyl; and - indicates a single or double bond such that all valences are satisfied.
[00350] In embodiments, R4 is independently -C(0)N(R12)(R13), _N(R14)0(0)R12.
or -C(0)R'2.
In embodiments, R4 is independently -C(0)N(R')(103). In embodiments, R4 is independently -N(R14)C(0)R'. In embodiments, R4 is independently -C(0)R11.
[00351] In embodiments, R4 is independently -C(0)NH(R12) and R12 is independently C4_9heteroary1, wherein C1_ 9heteroaryl is optionally substituted with one, two, or three R2 d. In embodiments, R1 is independently -C(0)NH(R12) and R12 is independently Ci.sheteroaryl, wherein Ci_sheteroaryl is optionally substituted with one, two, or three R2 d. In embodiments, R4 is independently -C(0)NH(R12) and R12 is independently Ci_sheteroaryl.
[00352] In embodiments, R4 is independently -C(0)R12 and R12 is independently selected from C2_6alkeny1, C2-6alkynyl, C2_9heterocycloalkyl, and Ci.9heteroary-1, wherein C2_6a1kenyl, C2_6alkynyl, C2_9heterocycloalkyl, and C1_ 9heteroatyl are optionally substituted with one, two, or three R2 d. Tn embodiments, R4 is independently -C(0)R12 and R12 is C2a1kenyl optionally substituted with one, two, or three R2". In embodiments, R4 is independently -C(0)R12 and R12 is C3alkenyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is Cialkenyl optionally substituted with one, two, or three R2 d. In embodiments, R4 is -C(0)R12 and R12 is Csalkenyl optionally substituted with one, two, or three R2 d. In embodiments, R4 is independently -C(0)R1-2 and RI' is C6alkenyl optionally substituted with one, two, or three R2".
[00353] In embodiments, R4 is independently -C(0)R12 and R12 is independently C2alkynyl optionally substituted with one, two, or three R2w. In embodiments, R1 is independently -C(0)R' and R12 is independently C3alkynyl optionally substituted with one, two, or three R2 d. In embodiments, le is independently -C(0)R' and R12 is independently C4alkynyl optionally substituted with one, two, or three R2 d.
In embodiments, R4 is independently -C(0)R12 and R12 is independently Csalkynyl optionally substituted with one, two, or three R'd. In embodiments, R1 is independently -C(0)R" and R12 is independently C6alkynyl optionally substituted with one, two, or three R2".
1003541 In embodiments, R4 is independently -C(0)R12 and R12 is independently C2heterocycloalkyl optionally substituted with one, two, or three R20'. In embodiments, R4 is independently -C(0)R12 and R12 is independently C3heterocycloalkyl optionally substituted with one, two, or three R2 d. In embodiments, 114 is independently -C(0)R12 and R12 is independently C4heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently C5heterocycloa1kyl optionally substituted with one, two, or three R2". In embodiments, le is independently -C(0)R12 and R12 is independently C6heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently C7heterocycloa1k0 optionally substituted with one, two, or three R2". In embodiments, R4 is independently -C(0)R12 and R12 is independently Csheterocycloalkyl optionally substituted with one, two, or three In embodiments, R4 is independently -C(0)102 and R12 is independently C9heterocycloalkyl optionally substituted with one, two, or three R20.
[00355] In embodiments, leis independently -C(0)1('-'12 and R12 is independently Ciheteromyl optionally substituted with one, two, or three R2". In embodiments, fe is independently -C(0)102 and 102 is independently C2heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently C3heteromyl optionally substituted with one, two, or three R2 d.
In embodiments, R4 is independently -C(0)R12 and R12 is independently C4heteroaryl optionally substituted with one, two, or three R2 d. In embodiments, R4 is independently -C(0)R12 and R12 is independently C5heteroaryl optionally substituted with one, two, or three R2"d. In embodiments, R4 is independently -C(0)R12 and R12 is independently C6heteroaryl optionally substituted with one, two, or three R2 d In embodiments, R4 is independently -C(0)R12 and R12 is independently C7heteroatyl optionally substituted with one, two, or three R2'. In embodiments, leis independently -C(:3)Ru. and R12 is independently C8heteromyl optionally substituted with one, two, or three R2'.
In embodiments, R4 is independently -C(0)R12 and R12 is independently C9heteroaryl optionally substituted with one, two, or three R2 d.
[00356] In embodiments, R4 is independently -NHC(0)102 and 102 is independently selected from C2.6alkenyl, C2-6alkynyl, C2_9heterocycloalkyl, and C1.9heteroa1y-1, wherein C2_6alkenyl, C2_6alkynyl, C2_9heterocycloalkyl, and C1_ 9heteroaryl are optionally substituted with one, two, or three R2 d. In embodiments, R1 is independently -NHC(0)R12 and R12 is independently C2alkenyl optionally substituted with one, two, or three R2 d. In embodiments, leis independently -NHC(0)R12 and R12 is independently C3alkenyl optionally substituted with one, two, or three Raid. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C4alkenyl optionally substituted with one, two, or three R2". In embodiments, leis independently -NHC(0)R12 and R12 is independently C5alkenyl optionally substituted with one, two, or three R2 d. in embodiments, R4 is independently -NHC(0)R12 and R12 is independently C6alkenyl optionally substituted with one, two, or three R20.
[00357] In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C2alkynyl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C3alkynyl optionally substituted with one, two, or three R2". In embodiments, leis independently -NHC(0)R12 and R12 is independently C4alkynyl optionally substituted with one, two, or three R2'. In embodiments, leis independently -NHC(0)R12 and R12 is independently Csalkynyl optionally substituted with one, two, or three R2 d.
In embodiments, fe is independently -NHC(0)R12 and R12 is independently C6alkynyl optionally substituted with one, two, or three R2 d.
[00358] In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C2heterocycloalkyl optionally substituted with one, two, or three R20C1. In embodiments, R1 is independently -NHC(0)R12 and R12 is independently C3heterocycloalky I optionally substituted with one, two, or three R2'. In embodiments, leis independently -NHC(0)R12 and 102 is independently C4heterocycloalkyl optionally substituted with one, two, or three R2". In embodiments, 10 is independently -NHC(0)R12 and 102 is independently C5heterocycloalkyl optionally substituted with one, two, or three R2 d. In embodiments, R4 is independently -NHC(0)Ru and R12 is independently C6heterocycloalkyl optionally substituted with one, two, or three R2". In embodiments, R4 is independently -NHC(0)R12 and 102 is independently C7heterocycloalkyl optionally substituted with one, two, or three R2". In embodiments, leis independently -NHC(0)R12 and R12 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)1112 and 1112 is independently C9heterocycloalkyl optionally substituted with one, two, or three R2 d.
[00359] In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Ciheteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C2heteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R12 and Rll is independently C3heteroaryl optionally substituted with one, two, or three R2 d. In embodiments, 114 is independently -NHC(0)R12 and 102 is independently Ctheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Csheteroaryl optionally substituted with one, two, or three R2". In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C6heteroaryl optionally substituted with one, two, or three R20. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C7heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R" and R" is independently Csheteroaryl optionally substituted with one, two, or three R2Od In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C9heteroaryl optionally substituted with one, two, or three R2".
[00360] In an aspect is provided a compound of Formula (I-1" '), or a pharmaceutically acceptable salt or solvate thereof:

X

Fonnula (I-1¨);
wherein W is C(0); V is C(R17) and J is C(R16);
RD) is -L7-R7;
L7 is a bond;
R7 is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloallcyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each optionally substituted with one or more le;
is independently selected from halogen; Ci_6alkyl, wherein Ci_6alkyl is optionally substituted with one, two, or three R20a; and -C(0)R15, wherein said R15 is independently selected from Ci_6alkyl, C2_6alkenyl, C2-balkynyl, C3_7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein C1_6alkyl, C2.6alkenyl, C2.6alkynyl, C3_7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f;

R8 is selected from Ci_ialkyl and C3_1cycloalkyl, wherein Ci_ialkyl and C3Acycloalkyl are optionally substituted with one, two, or three R20c;
R" is -L1-R19:
L1 is a bond;
R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven Rli:
each R11 is independently selected from halogen, -CN, C1_3alky-1, Ci_3haloalkyl, C2_3alkenyl, C2_3alkynyl, -OH, -NH2, wherein Ci_3a1kyl, Ci.3haloalkyl, C2_3alkenyl, and C2.3alkynyl are optionally substituted with one, two, or three R20';
R16 is selected from hydrogen and F;
R2 is -0-R12a;
Ri2a is _c(R12) ,,2-(5-8 membered heterocycloalkyl), wherein -C(R12)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d;
R12 is independently selected from hydrogen and methyl;
X is N; and each R20a, R2oc, R20d, R20e, R20f, and K-201 is independently selected from halogen, oxo, -CN, Ci_6a1kyl, C2-6alkenyl, C2_6a1kynyl, Ci ocyeloalkyl, -CH2-C3_1ocycloalkyl, C2_9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6_12aryl, -CH2-C6_12aryl, -CH2-Ci_iiheteroaryl, Ci_iiheteroaryl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci_balkyl, C2.6alkenyl, C2-6alkynyl, C3_10cycloalkyl, -CH2-C3_10cycloalkyl, C2_9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6_12ary1, -CH2-C6_12aryl, -CH2-Ci_iiheteroalyl, and Ci_iiheteroaly1 are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloa1kyl, C1_6a1koxy, C1-6haloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00361] In an aspect is provided a compound of Formula (1-1"), or a pharmaceutically acceptable salt or solvate thereof:

X
R2 Formula (I-1-);
wherein W is C(0); V is C(R12) and J is C(R16);
R1 is -L2-1217:
L7 is a bond;
IC is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocy clic bicyclic hctcrocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic helerocycloalkyl, 7-12 membered fused bicyclic helerocy cloalkyl, 7-12 membered spirocy clic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each substituted with one or more fe;
R4 is independently selected from halogen; Cl_nalkyl, wherein C1_6alkyl is optionally substituted with one, two, or three R'a; and -C(0)R", wherein said R" is independently selected from Ci_6alkyl, C2_6alkenyl, C2_ 6a1kyny1, C3_7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteromyl are optionally substituted with one, two, or three R20;
R8 is selected from Ci_4alkyl and C3_4cycloalkO, wherein C1_4alkyl and C3_4cycloalkyl are optionally substituted with one, two, or three R2';
R17 is -L1-R19;
L1 is a bond;
R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven Rhi;
each R" is independently selected from halogen, -CN, C1_3alky-1, Ci_3haloalkyl, C2_3alkenyl, C2_3alkynyl, -OH, -NH2, wherein Ci3alkyl, C1_3haloallcyl, C2_3alkenyl, and C1_3alkynyl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen and F;
R2 is -0-Ri2a;
Rua is -C(102c)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R2';
102c is independently selected from hydrogen and methyl;
X is N; and each R20a, R20c, R20(1, R20e, R20f, and R20i is independently selected from halogen, oxo, -CN, C1_6a1kyl, C2-6a1keny1, C2_6alkynyl, C3tocycloalkyl, -CH2-C3_10cycloalkyl, C2_9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6_12a1yl, -CH2-C6_12ary1, -CH2-Ci_iiheteroaryl, Ci_iiheteromyl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci_6alkyl, C2.6alkenyl, C2-6a1kyny1, C340cycloalkyl, -CH2-C3_iocycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_12aryl, -CH2-C6_12aryl, -C1-12-Ci_1iheteroaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, C1-6haloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00362] In an aspect is provided a compound of Formula (I-3), or a pharmaceutically acceptable salt or solvate thereof:

N N

Formula (I-3);
wherein IC is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each substituted with one or more Ft^;
R4 is independently selected from halogen; Ci_6a1kyl, wherein Ci_6a1kyl is optionally substituted with one, two, or three R'a; and -C(0)R15, wherein said 12.15 is independently selected from Ci_6a1kyl, C2_6a1kenyl, C2-6alkynyl, C3_7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f;
R8 is selected from cyclopropyl, fluoro-substituted cyclopropyl, methyl, ethyl, n-propyl, -CH2CH2CN, and -CH2CH2CH2CN;
CN
HO
\ NH2 R19 is selected from F and F ;

IC is selected from and ; and each -1:220a and 1=20f are independently selected front halogen, oxo, -CN, C3_6alkyl, C2_6alkenyl, C2_6allcynyl, C3-10CYClOalkyl, -CH2-C340cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloa1kyl, C6_32aryl, -CF12-C6-32ary1, -CH2-C1_iiheteroaryl, Ci_iiheteroaryl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein C2_6alkyl, C2.6alkenyl, C2.6alkynyl, C3.2oeyeloa1kyl, -CH2-C3_ tocycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloa1kyl, C6_12a1y1, -CH2-C6_12ary1, -CH2-C1-iiheteroaryl, and Ci_iiheteroaly1 are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00363] In an aspect is provided a compound of Formula (I-4), or a pharmaceutically acceptable salt or solvate thereof:

Formula (I-4);

wherein R7 is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl arc each optionally substituted with one or more le;
R4 is independently selected from -C(0)12.15, wherein said 12_15 is independently selected from C2_6a1kyl, C2-6alkenyl, C2_6a1kynyl, C3_7cycloa1kyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein C2_6alkyl, C2_6a1kenyl, C2_6alkynyl, C3_7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; halogen; and C2_6a1kyl, wherein C2_6alkyl is optionally substituted with one, two, or three lea;
R8 is selected from cyclopropyl, fluoro-substituted cyclopropyl, methyl, ethyl, n-propyl, -CH2CT-12CN, and -CH2CH2CH2CNI:
CN
HO
\ NH2 R19 is selected from F and F =
c;s5-.0-1)=,0 R2 is selected from and ; and each R20a and R20 are independently selected from halogen, oxo, -CN, C2_6alkyl, C2_6alkenyl, C2_6alkyny1, C3_ rocycloalkyl, -CH2-C3_10cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_22aryl, -C112-C6-22aryl, -CH2-C2_22heteroaryl, C2_22heteroaryl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein C2_6a1kyl, C2_6a1keny1, C2_6alkynyl, C3_20cyc1oalkyl, -CH2-C3_20cycloalkyl, C2_9heterocycloak-1, -CH2-C2_9heterocycloalkyl, C6_22aryl, -CH2-C6_22aryl, -CH2-C2_22heteroaryl, and C2_22heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen; oxo, C2_6alkyl, C2_6haloalkyl, C2_6alkoxy, C2_6haloa1koxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00364] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X
is C(R3). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is N.
[00365] In an aspect is provided a compound of Formula (T-1" '), or a pharmaceutically acceptable salt or solvate thereof:

\ /...."-.õ.,.. N ,....---....,_ ..,. ,..-.,:--..,_ R
J 2 Formula (I-1' ");
wherein W is C(0); V is C(R17) and J is C(R16); R1 is -L7-R7; L7 is a bond;
R7 is a 5-7 membered monocyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 5-7 membered monocyclic heterocycloalkyl is optionally substituted with one or more R4;
R1 is independently selected from 1) -C(0)R15, wherein said R15 is independently selected from Ci_6alkyl, C2-oalkenyl, C2_6a1kynyl, C3_2cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein C1.6alkyl, C2_6a1kenyl, C2_6alkynyl, C3.2cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteromyl arc optionally substituted with one, two, or three R20; 2) halogen;
and 3) Ci_6alky-1 optionally substituted with one, two, or three R2 a;
R8 is selected from Ci_4alkyl and cyclopropyl, wherein Ci-talkyl and cyclopropyl are optionally substituted with one, two, or three R2 e;
CN
S
R17 is F or F ;
R16 is selected from hydrogen and F;
F H \
N---- N ¨_ crcssOi"' AO 6---1\-1 = ''I/D-AK .,.r_s*
.,.,...6),,,,/01) R2 is , A .,,,zo--\P /' -1.õ'"O= .11, N 0..._.

µ
c:rNs'O'0 ..-----..õ------.N.-----/

.F
risf-0-2C 0 ,:sif.cr",\..."-- N ----1 and , .
X is N; and each R2 , R20c, and R2' is independently selected from halogen, oxo, -CN, C1_6alkyl, C2_6alkeny1, C2_6alkynyl, C2_20cycloalkyl, -CH2-C3_20cycloalkyl, C2_cheterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_12a1yl, -CH2-C6-12ary1, -CH2-C1_llheteroaryl, Ci_llheteroaryl, -OH, -OCH3, -N(CH3)2, -C(0)0H, -C(0)N112, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein C1_6a1kyl, C2.6a1kenyl, C2.6alkynyl, C34ocycloalkyl, -CH2-C3_ locycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloa1kyl, C6- izaryl, -CH2-C6_12aryl, -CH2-C1-iiheteroaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1,6a1kyl, C4_6ha1oalkyl, C4_6a1koxy, Ci_6haloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00366] In an aspect is provided a compound of Formula (I-1" '), or a pharmaceutically acceptable salt or solvate thereof:
R 1 o X
R2 Formula (I-1' ");
wherein W is C(0); V is C(R17) and J is C(R16); R1 is -L7-R7; L7 is a bond;
R7 is a 7-12 membered fused bicyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 7-12 membered fused bicyclic heterocycloalkyl is optionally substituted with one or more 10;
R4 is independently selected from 1) -C(0)R', wherein said R'5 is independently selected from Ci_6alkyl, C2-6alkenyl, C2_6a1kynyl, C3_7cycloa1kyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci.6alkyl, C2_6alkenyl, C2_6alkynyl, C3.7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteromyl are optionally substituted with one, two, or three R20; 2) halogen;
and 3) Ci_6alkyl optionally substituted with one, two, or three R2 a;
R8 is selected from C14a1lcyl and cyclopropyl, wherein Ci_aallcyl and cyclopropyl are optionally substituted with one, two, or three R20e;
CN
HO
\ NH2 R'7 is F or F ;
TO' is selected from hydrogen and F;
N----453:- r R2 is 0..11\
0 10_0 0 , riss.
A N 1.5.1 r-str`O cy)c-N rsfstl and X is N; and each R20a, R2 c, and R20f is independently selected from halogen, oxo, -CN, C3_6alkyl, C2_6alkeny-1, C2_6alkynyl, C3_10cycloalkyl, -CH2-C3.3ocycloa1kyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C642aryl, -CH2-C6-12ary1. -CH2-C1_l1heteroaryl, Cl_i iheteroaryl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci_6a1ky1, C2.6a1kcnyl, C2.6alkynyl, C3.(ocycloa1kyl, -CH2-C3-tocycloalkyl, C2_9heterocvcloalkyl, -CH2-C2_9heterocycloalkyl, C6_12aryl, -CH2-C6_32ary1, -CH2-C1-itheteroaryl, and Ci_itheteroatyl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1kyl, C3_6haloalkyl, C3_6a1koxy, C34haloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00367] In an aspect is provided a compound of Formula (I-1" '), or a pharmaceutically acceptable salt or solvate thereof:

x X

R Formula (I-1' ");
wherein W is C(0); V is C(R17) and J is C(R16); RH) is -L7-R7; L7 is a bond;
127 is a 7-10 membered spirocyclic bicyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 7-10 membered spirocvclic bicyclic heterocycloalkyl is optionally substituted with one or more R'';
R4 is independently selected from 1) -C(0)R', wherein said R15 is independently selected from C3_6a1ky1, C2-6alkenyl, C2_6alkynyl, C3_7cycloa1kyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered hcteroaryl, wherein Ci.balkyl, C2_6a1kcnyl, C2_6alkynyl, C3.7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroalyl are optionally substituted with one, two, or three R2'll; 2) halogen;
and 3) C1_6alkyl optionally substituted with one, two, or three R2 a;
R8 is selected from C3_4a1kyl and cyclopropyl, wherein C3_4a1kyT1 and cyclopropyl are optionally substituted with one, two, or three R2 e;
CN
HO
\ NH2 R17 is F or F ;
R16 is selected from hydrogen and F;

N--- N

0 r 0 N
R2 is C) A0-1,0 =.,,, 00 N
c-O N

A N
F
-,s r3-0---)C cic=0-,^7C-, and X is N; and each R20a, R20c, and R214 is independently selected from halogen, oxo, -CN, C3_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3_20cycloalkyl, -CH2-C3.3ocycloalkyl, C2_9heterocycloalW, -CH2-C2_9heterocycloallwl, C6_32ary1, -CH2-C6-12aryl, -CH2-Ci_iiheteroaryl, Ci_iiheteroaryl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NFIC(0)H, -C(0)H, and -C(0)CH3, wherein C3_6alkyl, C2.6alkenyl, C2.6alkynyl, C3.30cy-cloalkyl, -CH2-C3-iocycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloa1kyl, C6_12aryl, -CH2-C6_32aryl, -CH2-C1-ihetemaryl, and Ci_iiheteromyl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6alky-1, C3_6haloalkyl, C3_6alkoxy, Ci_6haloalkoxy, -OH, -OCH3, -NH2, -N(C113)2, -C(0)0H, -C(0)N112, -NHC(0)H, -C(0)H, and -C(0)C113.
[00368] In an aspect is provided a compound of Formula (I-1" '), or a pharmaceutically acceptable salt or solvate thereof:
R 1 o X
\
R2 Formula (I-1' ");
wherein W is C(0); V is C(R17) and J is C(Rth); R'" is -L7-R7; L7 is a bond;
R7 is a 7-10 membered bridged bicyclic heterocycloallcyl, comprising one or more ring nitrogen atoms and wherein the 7-10 membered bridged bicyclic heterocycloalkyl is optionally substituted with one or more R4;
R4 is independently selected from 1) -C(0)R15, wherein said R'' is independently selected from C2_6alky1, C2-6alkenyl, C2_6alkynyl, C3_7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl. wherein C3.6alkyl, C2_6a1kenyl, C2_6alkynyl, C3.7cycloalk-yl, 3-7 membered heterocycloalky-1, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20; 2) halogen;
and 3) Ci_6a1kyl optionally substituted with one, two, or three R2 a:
R8 is selected from CI _4alkyl and cyclopropyl, wherein C1_4a1ky1 and cyclopropyl are optionally substituted with one, two, or three R2";
CN
HO
\ NH2 R17 is F or F ;
Rm is selected from hydrogen and F;
N N

R2 is /0 0..-N/N) õsr, ---\co N
s0-µ 0-0 61-40 N. F
.zsF
, and X is 1\1; and each R20a, R2', and R2' is independently selected from halogen, oxo, -CN, C1_6a1kyl, C2_6alkeny-1, C2_6alkynyl, C3_10cycloalkyl, -CH2-C3,10cycloa1kyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C642a1yl, -CH2-C6-12ary1, -C1-12-CI_Iiheteroaryl, Ci_nheteroaryl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci_6a1kyl, C2.6a1kenyl, C2.6alkynyl, C3.10cy-cloa1kyl, -CH2-C3_ iocycloalkyl, C2_9heterocycloalky1, -CH2-C2_9heterocycloallcvl, C6_12aryl, -CH2-C6-12aryl, -CH2-C1-iiheteroaryl, and Ci_liheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalky I, Ci_6alkoxy, Ci_6haloalkoxy, -OH, -OCH3, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00369] In an aspect is provided a compound of Formula (I-1" '), or a pharmaceutically acceptable salt or solvate thereof:

R 1 o X
R2 Formula (I-1-);
wherein W is C(0); V is C(R17) and J is C(R16); R1 is -L7-R7; L7 is a bond;
R7 is a 5-8 membered monocyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl is optionally substituted with one or more R1;
R1 is independently selected from 1) -C(0)R15, wherein said R15 is independently selected from Ci_6alkyl, C2-oalkenyl, C2_6a1kynyl, C3_7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein C1.6alkyl, C2_6a1kenyl, C2_6alkynyl, C3.7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteromyl arc optionally substituted with one, two, or three R20; 2) halogen;
and 3) Ci_6alky-1 optionally substituted with one, two, or three R2 a;
R8 is selected from Ci_4alkyl and cyclopropyl, wherein Ci-talkyl and cyclopropyl are optionally substituted with one, two, or three R29c;
R'7 is -L'-R19; L' is a bond;
R19 is selected from a naphthyl and 9-10 membered heteromyl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11;
each Rh is independently selected from halogen, -CN, Ci_3alkyl, Ci_3haloalkyl, C2_3alkenyl, C2_3alkynyl, -OH, -NH2, wherein Ci_3a1kyl, Ci.3haloalkyl, C2_3alkenyl, and C2.3alkynyl are optionally substituted with one, two, or three R201:
R1' is selected from hydrogen and F;
R2 is _o_Ri2a, Rua is -C(R12c)245-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R2"; R12c is independently selected from hydrogen and methyl;
X is N; and each R20a, R20c, -20d, R20e, R2', and R201 is independently selected from halogen, oxo, -CN, C1_6a1kyl, C2-6a1keny1, C2_6alkynyl, C34 ocy cloalky 1, -CH2-C3_10cy cloalky 1, C2_9heterocy cloalkyl, -CH2-C2-9heterocycloalkyl, C6_12myl, -CH2-C642ary1, -CH2-Ci_iiheteroaryl, Ci_iiheteroaryl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NTC(0)H, -C(0)H, and -C(0)CH3, wherein Ci_6alkyl, C2.6alkenyl, C2-6alkynyl, C3_10cycloalkO, -CH2-C3_10cycloalkyl, C2_9heterocycloalkyl, -CH2-C2.9heterocyeloalkyl, C6_12ary1, -CH2-C6.12aryl, -CH2-Cl_l1heteroaryl, and CI_Iiheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci6alkyl, Ci_6haloa1kyk Ci_6a1koxy, Ci.
6haloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00370] In an aspect is provided a compound of Formula (I-I"), or a pharmaceutically acceptable salt or solvate thereof:

R 1 o X
R2 Formula (I-1-);
wherein W is C(0); V is C(R17) and J is C(R16); R1 is -L7-R.7; L7 is a bond;
R7 is a 7-12 membered fused bicyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 7-12 membered fused bicyclic heterocycloalkyl is optionally substituted with one or more R4;
R1 is independently selected from 1) -C(0)R15, wherein said R15 is independently selected from Ci_6alkyl, C2-oalkenyl, C2_6a1kynyl, C3_7cycloa1kyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein C1.6alkyl, C2_6a1kenyl, C2_6alkynyl, C3.7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered hetcroaryl arc optionally substituted with one, two, or three R20; 2) halogen;
and 3) Ci_6alky-1 optionally substituted with one, two, or three R2 a;
R8 is selected from Ci4alkyl and cyclopropyl, wherein Ci_4a1kyl and cyclopropyl are optionally substituted with one, two, or three R2 e;
R'7 is -L'-R19; L' is a bond;
R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11;
each Rh is independently selected from halogen, -CN, Ci_3a1kyl, Ci_3haloalkyl, C2_3alkenyl, C2_3alkynyl, -OH, -NH2, wherein Ci_3a1kyl, Ci.3haloalkyl, C2_3alkenyl, and C2.3alkynyl are optionally substituted with one, two, or three R201:
R1' is selected from hydrogen and F;
R2 is -0-R12a; Rya is _c(R1202_ ) (5-8 membered heterocycloalkyl), wherein -C(R12 )2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R'"d; Ruc is independently selected from hydrogen and methyl;
X is N; and each R20a, R20c, R2od, R20e, R20r, and K-201 is independently selected from halogen, oxo, -CN, Ci6a1kyl, C2-6alkenYl, C2_6a1kynyl, C3_1ocycloalkyl, -CH2-C3_iocycloalkyl, C2_9heterocycloalkyl, -CH2-C2-91ie te to cy clo alkyl, C6_12aryl, -CH2-C6_12ary1, -CH2-Ci_ he te ro aryl, Ci_ ri he te ary 1, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein C1_6alkyl, C2.6alkenyl, C2-6alkynyl, C3_10cycloalkyl, -C1-12-C3_10cycloalkyl, C2_9hacrocycloalkyl, -C112-C2,9heterocycloalkyl, C6_12aryl, -CH2-C642aryl, -CH2-C1_1iheteroaryl, and Ci_iiheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6a1koxy, CI-6ha1oa1koxy, -OH, -OCH3, -NT-12, -N(CH3)2, -C(0)0H, -C(0)NT-12, -NT-1C(0)H, -C(0)H, and -C(0)CH3.
[00371] In an aspect is provided a compound of Formula (T-1- '), or a pharmaceutically acceptable salt or solvate thereof:

R 1 o X
R2 Formula (I-1-);
wherein W is C(0); V is C(F07) and J is C(F06); 10 is -L7-10; 1_,7 is a bond;
IC is a 7-10 membered spirocyclic bicyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 7-10 membered spirocyclic bicyclic heterocycloalkyl is optionally substituted with one or more R1;
IV is independently selected from 1) -C(0)105, wherein said R'5 is independently selected from C2_6a1ky1, C2-6alkenyl, C2_6a1kynyl, C3_7cycloa1kyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroalyl, wherein C3_6alkyl, C2_6a1kenyl, C2_6alkynyl, C3_7cyeloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; 2) halogen;
and 3) Ci_6alky-1 optionally substituted with one, two, or three R2 a;
R8 is selected from C14a1kyl and cyclopropyl, wherein C1_4alkvl and cyclopropyl are optionally substituted with one, two, or three 100c;
R17 is -L1-R19; Ll is a bond;
R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven Rh;
each Rh is independently selected from halogen, -CN, C3_3alkyl, C3_3haloalkyl, C2_3alkeny1, C2_3alkyny1, -OH, -NH2, wherein Ci_3a1kyl, Ci3ha1oallcyl, C2_3alkenyl, and C2.3alkynyl are optionally substituted with one, two, or three 100i;
R16 is selected from hydrogen and F;
R2 is _o_Ri2.; R12. is _c(Rt2c)245-8 membered heterocycloalkyl), wherein -C(RL2`)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R2"; Ruc is independently selected from hydrogen and methyl;
X is N; and each fen', fe", R2fie, 112', and R2`" is independently selected from halogen, oxo, -CN, C3.6a1kyl, C2-6a1keny 1, C2_6alky nyl, C3-10Cy cloalkyl, -CH2-C34 ocy cloalkyl, C2_9heterocy cloalkyl, -CH2-C2-9heterocycloalkyl, C6_32a1yl, -CH2-C6_22ary1, -CH2-Ci_iiheteroaryl, Ci_iiheteroalyl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein C3_6alkyl, C2.6alkenyl, C2-6alkynyl, C340cycloalkO, -CH2-C3_10cycloalkO, C2_9heterocycloalkO, -CH2-C2.9heteroeyeloalkyl, C642ary1, -C1-12-C6.12ary1, -C1-12-Cl_liheteroaryl, and CI_Iiheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci6haloalkyl, C1_6alkoxy, Ci 6haloalkoxy, -OH, -OCH3, -NT-I2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00372] In an aspect is provided a compound of Formula (1-1"), or a pharmaceutically acceptable salt or solvate thereof:

R 1 o X
R2 Formula (I-1-);
wherein W is C(0); V is C(F07) and J is C(F06); 10 is -L7-10; 1_,7 is a bond;
IC is a 7-10 membered bridged bicyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 7-10 membered bridged bicyclic heterocycloalkyl is optionally substituted with one or more R1;
IV is independently selected from 1) -C(0)105, wherein said R'5 is independently selected from Ci_6a1ky1, C2-6alkenyl, C2_6a1kynyl, C3_7cycloa1kyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteromyl, wherein C3_6alkyl, C2_6a1kenyl, C2_6alkynyl, C3_7cyeloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; 2) halogen;
and 3) Ci_6alky-1 optionally substituted with one, two, or three R2 a;
R8 is selected from C14a1kyl and cyclopropyl, wherein C1_4alkvl and cyclopropyl are optionally substituted with one, two, or three 100c;
R17 is -L1-R19; Ll is a bond;
R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven Rh;
each Rh is independently selected from halogen, -CN, C3_3a1kyl, C3_3haloalkyl, C2_3alkenyl, C2_3alkyny1, -OH, -NH2, wherein Ci_3a1kyl, Ci3ha1oallcyl, C2_3alkenyl, and C2.3alkynyl are optionally substituted with one, two, or three 100i;
R16 is selected from hydrogen and F;
R2 is _o_Ri2.; Rua is _c(Rt2c)245 -8 membered heterocycloalkyl), wherein -C(RL2`)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R2"; Ruc is independently selected from hydrogen and methyl;
X is N; and each fe"a, fe", R2fie, 112', and R2`" is independently selected from halogen, oxo, -CN, C3.6alkyl, C2-6a1keny 1, C2_6alky nyl, C3-10Cy cloalkyl, -CH2-C34 ocy cloalkyl, C2_9heterocy cloalkyl, -CH2-C2-9heterocycloalkyl, C6_32a1yl, -CH2-C6_12ary1, -CH2-Ci_iiheteroaryl, Ci_iiheteroatyl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein C3_6alkyl, C2.6alkenyl, C2-6alkynyl, C340cycloalkO, -CH2-C3_10cycloalkO, C2_9heterocycloalkO, -CH2-C2.9heterocycloalkyl, C642ary1, -C1-12-C6.12ary1, -C1-12-Cl_liheteroaryl, and CI_Iiheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci6haloalkyl, C1_6alkoxy, Ci 6haloalkoxy, -OH, -OCH3, -NT-I2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00373] In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

X
R2 Formula (I);
wherein W is C(0);
V is C(R17) and J is C(1116);
R1 is -L7-117, L7 is a bond, -0-, -N(R14)-, -C(0)-, -N(1114)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(Rii)st-s_n _ N(R14)S(0)2-, Ci-Coalkyl, C2-Coalkenyl, or C2-Coalkynyl, wherein Ci-Coalkyl, C2-COalkenyl, and C2-C6a1kynyl, are optionally substituted with one, two, or three R2 a;
R7 is a 6-10 membered nitrogen containing heterocycloalkyl, wherein the 6-10 membered nitrogen containing heterocycloalkyl is substituted with one or more R4;
each R4 is independently selected from CN, Ci_6alkyl, C2_6alkenyl, C2_9heterocyc1oalky1, -C(0)0R12, and -C(0)R15, wherein Ci_6a1kyl, C2_6a1kenyl, and C2_9heterocycloa1kyl, are optionally substituted with one, two, or three R2 a;
118 is selected from C1_6alkyl and C3.6cycloalkyl, wherein Cl_6alkyl and C1_6cycloalkyl are optionally substituted with one, two, or three 112';
R17 is -L1-R19;
L1 is a bond;
R19 is a fused bicyclic 9-10 membered heterocycloalkyl substituted with one, two, three, four, five, six, or seven 111i;
each R1i is independently selected from halogen, -CN, and -N(R12)(R13);
R16 is halogen;
R2 is selected from -(CI-C6allcy1)-R'2h, -0-12122, and -(C2_9heterocycloa1kyl)-1112h, wherein said C1_6alkyl and C2-9beterocycloalkyl are optionally substituted with one, two, or three R2 d;
R12a is selected from -CH2-C3_10cycloa1kyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, and Co_ioaryl, wherein -CH2-C3_iocycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocycloa1kyl, and C6_10aryl are optionally substituted with one, two, or three R2 d;
R12b is independently selected from hydrogen and C2_,heterocycloalkyk wherein C2_,heterocycloalkyl is optionally substituted with one, two, or three R2";
X is N;
each R12 is independently selected from hydrogen, C3_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, -CH2-C3-6cyc1oa11cy1, C2.9heterocycloa1kyl, -CH2-C2_9heterocycloalky1, C6.3oaryl, -CH2-C6_ioaryl, -CH2-Ci_9heteroaryl, and C1.9heteroaryl, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_ 9heterocycloallcyl, -CH2-C2_9heterocycloalkyl, C6_30aryl, -CH2-C6_36aryl, -CH2-C3_9heteroaryl, and Ck9heteroaryl are optionally substituted with one, two, or three R2";
each R13 is independently selected from hydrogen, C3_6alkyl, and C3_6haloa1kyl; or R12 and 10-3, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R20e;
each R14 is independently selected from hydrogen, Ci_oalkyl, and Ci_ohaloalkyl;

each R15 is independently selected Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_10aryl, and C1.9heteroaryl, wherein C1_6allcyl, C2_6alkenyl, C2_6a1kyny1, C3_6cycloalkyl, C2_9heterocycloa1kyl, C6_10aryl, and C1.9heteroaryl are optionally substituted with one, two, or three R20f;
each R20a, R20c, R20d, R.20e, and R20f are each independently selected from halogen, oxo, -CN, Ci_6alky1, C2_6a1keny1, C2_6a1kynyl, C3_6cycloa1kyl, -CH2-C3_6cycloa1kyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_1oa1yl, -CH2-C6_ioaryl, -CH2-Ci_9heteroaryl, Ci_9heteromyl, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein C2.6a1ke11y1, C2.6a1kyny1, C3_6cyc1oa1ky1, -CH2-C3_6cycloalkyl, C2.9heterocycloalkyl, -CH2-C2_911eterocycloalky1, C6_10aryl, -CH2-C6_10aryl, -CH2-Ci_9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1.6a1ky1, Ci.6haloalkyl, Ci_6alkoxy, Ci-6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25. -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R2.3), and -0C(0)R25;
each R21 is independently selected from H, C4_6alkyl, Ci6haloalkyl.
C2_6alkenyl, C2_6allcynyl, C.3_6cycloallcyl, C2_ 9heterocycloalkyl, C64oaryl, and Ci_9heteroaryl;
each R22 is independently selected from H, Cl_6a1ky1, Cl_nhaloalkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_ 9heterocycloalkyl, C6.10aryl, and Ci_9heteroaryl;
each R23 is independently selected from H and Ci_6allcyl;
each R24 is independently selected from H and Ci_6a1ky1;
each R25 is independently selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_ ioaryl, and Ci_9heteroaryt and - indicates a single or double bond such that all valences are satisfied.
[00374] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is C(R''). In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is N.
[00375] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is C(0). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0). In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W
is S(0)2.
[00376] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the 0 Rio 0 W

N NN/S
N

compound has the structure: Formula (IIA1), 0 Rl Rl \N/ ''''- R8 'N -j''''''LN

...,,,.õ...:õ.õ....-....., N,....._;.-...., Formula (IIA2), R17 Formula (IIA3), R17 Formula 0 Rio NN N
N.'N I ---- *-..-'''''''N I I
N--..,..õ....õ: õ.....2.-----...., N.õ1-,........---...
.....--;õ

(IIA4), R17 Formula (IIA5), R17 Formula (IIA6), 0 Rio 0 Rl R8N ,.,I...,_,R3 R8 1 1 \ N,--=SIR3 R17 Formula (IIA7), R17 Formula (IIA8), R10 0 R i o \N
R8 V'R3 R8 ).
.,,L. R3 ,-- \N
--,, --R2 --...._ .....:;:-..õ

R17 Formula (IIA9), R17 Formula (IIA10), 0 Ric) o o R1 R8 ii R8 \\// R3 R3 N N

N---,....,.....õNR2 N

Fomiula (IIA11), or Fomiula (IIA12).
[00377] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is a bond. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof. L7 is -NH-.
[00378] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered bete rocycloallcyl is optionally substituted with one or more Rl, one or more R1, or one or more R6; and wherein two substituents selected from R', 1:0, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C34 ,cycloalkyl, Ci_ i iheterocycloalkyl, C6_12aryl, or Ci_liheteroaryl, wherein the C3_12cycloalky1, Ci.liheterocycloalkyl, C6.12arvl, or G.
iiheteroaryl arc optionally substituted with one, two, or three R2Ua.

[00379] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof.

R4) p R4)p ,sX1..>j ____________________________________________________________ ( R4)p R' is x2 X2 (R4) P

> _______________________________________ (R4)õ _________ (R4)p x3 x3 or - =
p is an integer from 0 to 12;
X' is selected from CH2, C(R4)(R6), C=N-0R4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), 0, S, S(0), S(=0)(=NR4), S(0)2N(R4), N(10S(0)N(R4), N(W)S(0)2N(R4), S(0)N(R4), OC(0)N(R4), N(R4)C(0)N(R4), S(0)2, CH2C(R4)(R6), CH2C(R4)(R6)CH2, C(R4)(R6)C(R4)(R6)C(R4)(R6), C(R4)(R6)C=N-0R4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R10, C(R4)(100C(R4)(R6), C(R4)(R6)S, C(124)(W)SC(R4)(R6), C(R4)(R1S(0), C(R4)(126)S(0)C(R4)(R6), C(R4)(R6)S(0)2C(R4)(R6), C(R4)(R6)S(=0)(=NR4), C(R4)(W)S(0)2N(R4), C(R4)(126)N(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R4)(R6)S(0)N(R4), C(R4)(R6)0C(0)N(R4). C(R4)(R6)N(R4)C(0)N(R4).
C(R4)(R6)S(0)2, C=NN(R4)(R6)C(R4)(R6), C(0)N(W)C(R4)(R6), S(0)2N(R4)C(R4)(R6), S(0)N(R)C(R4)(R6), 0C(0)N(R4)C(R')(R6), C(R4)(R4), C=N-0R4, C=NN(1e)(R4), CH2C(R4)(R4), CH2C(R4)(R4)CH2, C(R4)(R4)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C=N-0R4, CH2C=NN(R4)(R4), C(R4)(124)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(124)0, C(R4)(R4)0C(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(124)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(124), and 0C(0)N(R4)C(R4)(R4);
X' is selected from N, C, C(R6), C(R4), CH, N(R1), N(R4), N(R6), 0, S, S(0), C(H)(R6), C(12')2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2, and X' is selected from N, C, C(R6), and C(R4).

[00380] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 X2,.,, ...õ X2,,,,,,-- , X2 / ) X2 '''-. -'1 024) \ (R4)P
X1 I X1 P .' tre4x __________________________________________________________ (R4)p < 2 is I , , , i , x2 x2 x2-, (R)( P < ./' I
x37- I XI I
X '',............j_ ( R4)p _ (R4)p X3' I1 9 ,or -- .
[00381] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 H H H H H
H
N .,õ, c -L¨, (R41 '-- i____ 4 __ N /1_ 4 (p4) 1 im4 \
'P < __ 5---v.. 'P /1--(R4)p C-)1---lrx Jp is,.."
Y T N

is ---1- , , /
H H H H
---k' s / p 4 \ (*'(-\'') IP V(R4)p :'''''..1.7____(R4)p ' I
JVNAI .."-r-' n 9 9 , H H HN----, HN\...N
____________________________________________________________________________ NH
N ..,... <,(7.:)¨(R4)p </c1H (R 4 )p (R4) ¨(R) C j(R4)p k...
li 11 11 ri l'i ¨NH H
4, 1-SN'N'(R4)p 0(R4)P CN.., -'i---(R4)p NH I\1-1 N -V
N \.Cõ22___(R4)p ' 'µ
H
N
</N5 (R4)p , or . ; and p is an integer from 0 to 12.
[00382] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, H H H H H H H H H
H
N ,N,<N
A _N
C ) N N N N N N N
N
R7 is s's^r" "s".Y" -^1.", 4^" -^^", -,,,,,,, -,1", , , HN
CN
H
H N -NH
N
NC/'CN) 1µ.4 I-10)y) H2NN) C

\>
or .
[00383] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 Ni(c51H
is or [00384] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 106 is independently selected from hydrogen, halogen, -CN, Cl_malkyl, C2.6alkenyl, C2.6alkyny1, and C3_6cycloa1kyl.
wherein Ci_malkyl, C2.6alkenyl, C2.ma1kynyl, and C3_6cycloalkyl are optionally substituted with one, two, or three R2 g.
In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and halogen. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and fluoro.
[00385] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 118 is selected from hydrogen, C3_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_30cycloalkyl, and C2_9heterocycloalkyl, wherein Cl_malkyl, C2_6a1kenyl, C2_6a1kynyl, C3_10cycloalkyl, and C2_9heterocycloalkyl are optionally substituted with one, two, or three R2". In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, Ci_malkyl, C3_30cycloalkyl, and C2_9heterocycloalkyl, wherein Ci_malkyl, C3-iocycloalkyl, and C2_9heterocycloalkyl are optionally substituted with one, two, or three R2" independently selected from halogen, Ci_malkyl, C2_6a1kenyl, C2_6alkynyl, C340cycloalkyl, and C2_9heterocycloalky-1. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R2" independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments, R8 is selected from halogen, -CN, C3_6a1kyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, Cm_loaryl, Ci-,heteroaryl, -0R12, _sR12, _N(H)(R12), _ C(0)0R12, -0C(0)N(R12)(R13), _N(R11)c(o)N(R12)(R13), )C(0)0R15, _N(R14)s(0)2R15, _c(o)R15, _sor _15, K OC(0)R15, -C(0)N(R12)(R13), _C(0)C(0)N(R12)(R13), -N(Rii)c(o)Ris, S(0)2R15, -S(0)2N(R12)(R13)_, S(=0)(=NH)N(R12)(R13), CH2C(0)N(R12)(R1), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Cl_malkyl, C2_6alkenyl, C2_malkynvl, C3_6cycloalkyl, C2_9heterocycloalkyl, Cm_ naryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R21'. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from Ci_mallcyl, C3_30cycloalkyl, and C2_9heterocycloalkyl, wherein C3_6alkyl, C340cycloalkyl, and C2_9heterocycloalkyl are optionally substituted with one, two, or three R2.0c independently selected from halogen, Ci_malkyl, C2_6alkenyl, C2_6alkynyl, C3_30cycloalkyl, and C2_9heterocycloalkyl. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, le is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R2cc independently selected from fluoro.
methyl, cyclopropyl, cyclobutyl, and oxetanyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, IV is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is methyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, le is cyclopropyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, fe is cyclobutyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is oxetanyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is fluoro-substituted cyclopropyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is fluoro-substituted methyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is fluoro-substituted ethyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is CN-substituted cyclopropyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is CN-substituted methyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, le is CN-substituted ethyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof. R8 is CN-substituted n-propyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is CN-substituted n-butyl.
4>-1-F P.+ 1;11-FF
[00386] In embodiments, R8 is independently selected from NC F F
,0 =
>11- Me0¨ Q\_5 NC¨\\_5 CN F
NC¨\s" >_i_ , Me, Et, n-Pr, n-Bu, t-Bu, iPR, HO
\\_1_ , and H Discr [00387] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen or CN. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, le is hydrogen.
[00388] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L' is a bond. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, Ll is selected from a Ci-C6a1kyl, C2-C6alkenyl, C2-C6alkynyl, -C(0)-, -NHC(0)-, -C(0)NH-, CH20, CH2NI-1, and CH2.
[00389] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 109 is a monocyclic ring. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a bicyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R'9 is a polycy-clic ring system. In some embodiments of the subject compound, or ........... ..........
x12 J\ ni x4%....-- x10 x4 =-='''7.....",..../. .:::.`x11 x4 .."' N-----.
I ii I i I I
: .... '.>__.R1h x5.z...... .X9 X 9X1 ..., 6 X9 x10 )(5,_ 1 -..... 1 ):6 Q
a pharmaceutically acceptable salt or solvate thereof, R19 is:
X6 , X , - - -ro N 3 R1 h r ,...___ ________________________________________________________ \)-_R111 1 1 -IR'lh 1 I i __ R1h I I
X5,.X6 Q N -- i xi o _ Q" .;,...õ..._ , xi o -__Q' , ' --xii x=ii 7 7 7 ..........
Q3 o-N N cyi N =-..., ,-- Q3 I R1 h ,--- , )__ 1 h I / R 1 1 RI h casi I
".:µ\> Ri h X7- ,w7 ,,s -- ...."--..... 3 ,r7 " -. ...."----... 3 '8 Q4 s' X6 Q '' X8 Q \t-%6 -s'` , iN_-:-_-Q3 iN - 04 ceNr.....V....T."c, QgNi.........Liõcõ.
....,, --., I I /

R1 h n n or =
, Q1, Q3, and Q5 are independently N or Q4 and Q' are independently 0, S. C(R1a)(R'"), or N(R1c);
X4, x-5, )(6, x-9, )(10, A x,11, and X12 are independently selected from C(Ria) or N;
X' and X' are independently selected from C(R1a), C(Rla)(R1b), N, or N(R1c);
each Rla, R1b, lc -,-,1d, and Rlh are each independently selected from hydrogen, halogen, -CN, Ci_6a1kyl, Ci-611a1oalkyl. C2_6a1kenyl, C2_6a1kynyl, C3_10cycloalkyl. C2_9heterocycloa1kyl, C6_ioaryl, Ci.9heteroary1, -0R12, -SR12, -N(R12)(R13), -C(0)0102, -0C(0)N(R12)(103), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)105, -S(0)105, -0C(0)R15, -C(0)N(R12)(1243), -C(0)C(0)N(102)(R13), -N(R11)C(0)R15, -S(0)2105, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(10-3), -CH2N(R14)C(0)Rls, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1kyl, C2_6alkeny1, C2_6alkyny-1, C3_10cycloalkyk C2.9heterocycloa1kyl, Cs_ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R2.01: or Ria and Rib bonded to the same carbon arc joined to form a 3-10 membered heterocycloalkyl ring or a C3.10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3.
iocycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_10aryl ring, a 5-12 membered heteroaryl ring, or a C340cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C640aryl ring, 5-12 membered heteroaryl ring, or C3_10cycloalkyl ring are optionally substituted with one, two, or three R2m; or RI' and one of Ria, Rib, RI', and RI' bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6.10atyl ring, a 5-12 membered heteromyl ring, or a C3_10cycloa1kyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6_10aryl ring, a 5-12 membered heteroaryl ring, and C3_ iocycloalkyl ring are optionally substituted with one, two, or three R20i; and each Ric is independently selected from hydrogen, Ci_6alkyl, C2_6a1kenyl, C2_6alkynyl, C3_10cycloalkyl, C2_ ,heterocycloalkyl, C6_10aryl, C1.9heteroaryl, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, C2-9heterocycloalkyl, C6_10myl, and Ci_9heteroa1yl are optionally substituted with one, two, or three R2'.

[00390] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R'9 is:

HO
)-----=N )--:-----N )--------N HO \-:

F
0 µ1?-i. S 0 .22L, S 0 ..v ./...,.., F F F , F , LEr , HO \-: H2N N.. '22,::- H2N 1\1. '2,-;.
H2N N., I I
..-- / F ./ N
F I
--..
F , , 2. µ422-:
..--,..--C I, 1IIIX.ACF3 F lLLCI
F , F, F , , , -N /
N._ N._ N._ N-NH N-N/ IN
HN/ iwzi., HIV' µ HIV
V 0 '2z( 0 l'z (*V
F, CI, H
N._ N 1\1_,, µ-,..4: H2N
N,,, µ222 H
H1\11 I.
µ222.... .1 ,..... N ...c.N,,,..,T,,,.v.2(z.
Tx..1 H2N N .-4--y I ,,,. C F3 -GQ, .F3 H
H2N N =-e,-,,,N,.,..).24. H 1. H2N N -L 2,-I,5"---, N N \-1_ CF3 ,,,,, CF3 1_,..j ,....,r3 CF3 , ' HO 'ye. HO 401 `-a.õ2 H 0 HO 0 \
co.
.F3 ...
OC F3 , CI CI CI
CF3 , or F
CI 0 µ2i2i NH2 .
[00391] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, le n N
6:554.
N---J
I c 0`---D N --- a is selected from N, F

sZo r:fs:r-o---6? N '35.0 N N

F
OM e F

N
H \

''-' ,rr ,...4.6),,0--\c '0 N

, "3.-.0"--------3 \ N,..,,,.- , ' /-0ID_PF F
-4 ,,.
Xo'").--- ir's-o'"-Nrj-...F o - 0......0Me <F liss,0NO csi.-r-ON-F
z z , S-o'''' o = =0--.0Me N --I
o.S

I
. ' ,--/
, 0 OH rcss..00=C_µ>
N
,-.,.., t'ss"0CN N
c/ N-Nc),N
z H , H 'Li, ''=---- -N 'II, '''''''- -N

, I
p ..- ,---.... , ,..-..N,---....,,,.N ..
N.---S_-_-0 Xea"s'0) A0') XS
, , , 0..43 -N --'(:)-rIss'0 rYin /
/
, , , F
;cs.10''-'1\iii r140""' /il N----/
, c-s4ril -/C NO csss-1.T---)cNo ,:gs--)cNo ci5s--9\-----NI
L----/ .
5/40-c Nt...D<F fil0-)c NILD,, F csf-O 0 .
,µ F c:crs NO
F
ciss'CY)CNI..3 c'fsf'01C NO' "c4 ----)C NO rIss'()-CN-'-'1N
I f-rss'OcN--Th ;'-50-)C ND 1:PrZcy N csrs.02c- N ----, ?s=I'OWC N 0 N --- 2r-1 riss.:0,---..CN
0,---x.CN

rrrr'S-0--,,/N) ,3-rr / OH, N
I
.,._,----,N---/
, ;ACilsr N ..,.........N.... 1100 I I cIssa; c:rss..-CY-'416-1?
and ()%,0 Cljq scs'0 [00392] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, each re is independently selected from:

C14:1' CZ.49 cl..9 9 pH L ay..s,õ() pi vsyr.4.r,õ1 pi )- PH
PH ..............t.;k1 .41,iii i¨N NH 1*-.,--" 1 +NH
..,---' it -Niii-2, -OH, -M-11(C14, alkyl), , , .
NL-C- j PH 3.,4L-er- PH Lot.1 2 1. cz,..,P , z à 1-2. NH : i ....:..m, 73 ..41 L,..,....#1 :--: '-'4,- -,1,r011 :,:,..,,e^4.N
NI .,CH NS =,..,,OH
...." ii-1 ...1 ,01-1 4 0 j 011 =N

;ItQH 'M 1.õ.,.........7 t H :./ t.. ill .N-ON 4.-r-N. Arje . it; ril -0 =
Ni-12 N1-12 i 11 ri4 NH H H NH NH NH
'1)1. HN N CN
.)....- ......- HN =,.õ.,N,CN H2N J.L
NH NC,N)1,NH NCNANH
--e_ NH2 ' jr- , , H I , H I
¨
, -CN, OH OH
-of -=-.......,,OH
Vii...^.,....õ.. N H 2 ;:y=eir---",,,0 H Zfirk.,......., 0 H `,5Vs......., NH2 ..-r--..õ------10.1,) zõ,..<(---.0H =3 li N
....,:vm. , ) ...- ) OH +
74t)'-'33/ A.(-3-* + ) õ -,*-N,- rt , rF--<, --3"---.. csgc,"
cs.... , --- .;_õ, , .#11 ".11.--- . 11 .. ' ' '.1-"1.0 i N N
fr N tr-N,1-1 ::::- --..) GN esi ...-X.... 1'4 ols--Lji qr.x. iN K:-. . . ..... s ,...

0 and 0 ; and tit, when present, is 0, 1, 2..
or 3.
[00393] In sonic embodiments of the subject compound, L7 is a bond in embodiments of the subject compound, L7 is -N(R14)-. In further embodiments of the subject compound, L7 is Ci-C6a1kyl. In additional embodiments of the subject compound, L7 is methylene. In some embodiments of the subject compound, L7 is ethylene.
1003941 In embodiments of the subject compound, R7 is a 3-12 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R1, one or more 10, or one or more R6.
In some embodiments of the subject compound, R7 is a 3-12 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R1.
In additional embodiments of the subject compound, R7 is a 3-12 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R4. In further embodiments of the subject compound, R7 is a 3-12 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R6.
[00395] In some embodiments of the subject compound, R7 is a 6-9 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R1, one or more R4, or one or more R6. In embodiments of the subject compound, R7 is a 6-9 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R'. In some embodiments of the subject compound, R7 is a 6-9 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R4. In additional embodiments of the subject compound, R7 is a 6-9 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R6. In some embodiments of the subject compound, R7 is an unsubstituted 6-9 membered nitrogen containing heterocycloalkyl.
[00396] In further embodiments of the subject compound, R' is a 5-12 membered nitrogen containing heteroaryl optionally substituted with one or more R', one or more R4, or one or more R6.
In embodiments of the subject compound, R7 is a 5-12 membered nitrogen containing heteroaryl optionally substituted with one or more R1. In some embodiments of the subject compound, R7 is a 5-12 membered nitrogen containing heteroaryl optionally substituted with one or more R4. In additional embodiments of the subject compound, R7 is a 5-12 membered nitrogen containing heteroaryl optionally substituted with one or more R6. In embodiments of the subject compound, R7 is an unsubstituted 5-12 membered nitrogen containing heteroaryl.
[00397] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R', one or more R4, or one or more le. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more 10. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R4. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more W. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-9 membered heterocycloalkyl, wherein the 4-9 membered heterocycloalkyl is optionally substituted with one or more R1, one or more R4, or one or more R6. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-9 membered heterocycloalkyl, wherein the 4-9 membered heterocycloalkyl is optionally substituted with one or more R'. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-9 membered heterocycloalkyl, wherein the 4-9 membered heterocycloalkyl is optionally substituted with one or more R4. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-9 membered heterocycloalkyl, wherein the 4-9 membered heterocycloalkyl is optionally substituted with one or more R6. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, fe is an unsubstituted 3-12 membered heterocycloalkyl. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, IC is an unsubstituted 4-9 membered heterocycloalkyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a monocyclic Ci_sheterocycloalkyl optionally substituted with one or more R', one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a monocyclic Ci_5heteroaryl optionally substituted with one or more TO, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a spirocy clic Cz_iiheterocycloalkyl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a fused C,_iiheterocycloalkyl optionally substituted with one or more Rl, one or more R4, or one or more le. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a fused 6 to 12 membered aryl optionally substituted with one or more Rl, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a fused 5 to 12 membered heteroaryl optionally substituted with one or more RI, one or more R4, or one or more R6.
1003981 In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R' is a monocyclic nitrogen containing Ci_sheterocycloalkyl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a monocyclic nitrogen containing Ci_sheteroaryl optionally substituted with one or more 10, one or more 10, or one or more 116. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a spirocyclic nitrogen containing C2_iiheterocycloalkyl optionally substituted with one or more one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a fused nitrogen containing C2.4iheterocycloa1kyl optionally substituted with one or more one or more R4, or one or more R6.
In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a fused nitrogen containing C6_42a1yl, optionally substituted with one or more R', one or more R4, or one or more Re'. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 1:27 is a fused nitrogen containing 5 to 12 membered heteroaryl optionally substituted with one or more one or more 114, or one or more R6.
1003991 In additional embodiments of the subject compound, two substituents selected from Ri, R4. and R6 that are bonded to the same atom are joined to form a C3_12cycloalkyl or Ci_iiheterocycloalkyl. wherein the C3-ucycloalkyl and Ci_iiheterocycloalkyl are optionally substituted with one, two, or three R2 . In some embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are optionally joined to form a C3_12cycloalkyl, Ci_iiheterocycloalkyl, C6_12aryl, or C44 iheteroaryl, wherein the C3_ 42cycloalkyl, Ci_iiheterocycloalkyl, C6_12aryl, or Ci_iiheteroaryl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a C3_5cycloalkyl, wherein the C3_5cycloalkyl is optionally substituted with one, two, or three R2 . In embodiments of the subject compound, two TO substitutents bonded to the same atom are joined to form a C3_ 5cycloalkyl. In further embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a C34cycloalkyl, wherein the C34cycloalkyl is optionally substituted with one, two, or three Rna. In some embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a C3_ 4cycloalkyl. In embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a 4 to 5 membered heterocycloalkyl, wherein the 4 to 5 membered heterocycloalkyl is optionally substituted with one, two, or three R2tIa. In additional embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a 4 to 5 membered heterocycloalkyl. In further embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a 4 membered heterocycloalkyl, wherein the 4 membered heterocycloalkyl is optionally substituted with one, two, or three Rna. In some embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a 4 membered heterocycloalkyl. In some embodiments of the subject compound, two substituents selected from R' and R4 that are bonded to the same atom are joined to form a C3_42cycloalkyl or Ci_liheterocycloalkyl, wherein the C3_ 42cyc1oa1ky1 and C1.41heterocycloalkyl are optionally substituted with one, two, or three R2 . In some embodiments of the subject compound, two substituents selected from R4 that are bonded to the same atom are joined to form a C3_12cyc1oalkyl or Ci_ilheterocycloalkyl, wherein the C3_12cycloa1kyl and Ci_liheterocycloalkyl are optionally substituted with one, two, or three R2Cia. In some embodiments of the subject compound, two substituents selected from R4 and R6 that are bonded to the same atom are joined to form a C342cycloalkyl or Ci_iiheterocycloalkyl, wherein the C342cycloalkyl and C1_11heterocycloalk0 are optionally substituted with one, two, or three R2 . In some embodiments of the subject compound, two substituents selected from 124 and R that are bonded to the same atom are joined to form a C3_pcycloalkyl or Cl_iiheterocycloalkyl, wherein the C3_12cyc1oa1ky1 and C1_ iiheterocycloalkyl are optionally substituted with one, two, or three R26a. In some embodiments of the subject compound, two substituents selected from R4 and R4 that are bonded to adjacent atoms are joined to form a C3-12cycloalkyl, Ci_iiheterocycloalkyl, Co_ilaryl, or Ci_iiheteroaryl, wherein the C3.12cycloalkyl, Ci_iiheterocycloalkyl, Co_izaryl, or Ci_iiheteroaryl arc optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two substituents selected from RI- and R4 that are bonded to adjacent atoms are joined to form a C342cycloalkyl, Ci_iiheterocycloalkyl, C6_12ary1, or Ci_iiheteroaryl. In some embodiments of the subject compound, two R4 substituents that are bonded to adjacent atoms are joined to form a C342cycloalkyl, Ci_iiheterocycloalkyl, C6-12ary1, or Ci_iiheteroatyl, wherein the C342cycloalkyl, Ci.iiheterocycloalkyl, C6.12aryl, or Ci.iiheteroaryl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two R4 substituents that are bonded to adjacent atoms are joined to form a C3_12cycloalkyl, Ci_iiheterocycloalkyl, C6.12aryl, or Ci_iiheteroatyl In some embodiments of the subject compound, two substihients selected from R4 and R6 that are bonded to adjacent atoms are joined to form a C3_12cycloalkyl, Ci_iiheterocycloalkyl, C6_12myl, or Ci_iiheteroatyl, wherein the C1_12cycloalkyl. Ci_liheterocycloalkyl, C6_12aryl, or C1_, heteroaryl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two substituents selected from R4 and R that are bonded to adjacent atoms are joined to form a C3_12cyc1oa1ky1, Ci_iiheterocycloalkyl, Co_izawl, or Ci_iihetcromyl. In some embodiments of the subject compound, two substituents selected from R4 and R6 that are bonded to adjacent atoms are joined to form a C3_12cycloa1kyl, Ci_iiheterocycloalkyl, C6_12atyl, or Ci_iiheteroaryl, wherein the C3_ izcycloalkyl, Ci_iiheterocycloalkyl, C6_12atyl, or Ci_iiheteroaryl are optionally substituted with one, two, or three In some embodiments of the subject compound, two substituents selected from R4 and R6 that are bonded to adjacent atoms are joined to form a C3_12cycloalkyl, Ci_iiheterocycloalkyl, C6.12aryl, or Ci_itheteroaryl.
1004001 In additional embodiments of the subject compound, two substituents selected from R1, 1:0, and R6 that are bonded to the same atom are joined to form a C3_pcycloallcyl or Ci_iiheterocycloalkyl, wherein the C3_ 12cyc1oa1ky1 and Ci_iiheterocycloalkyl are optionally substituted with one, two, or three R2 . In additional embodiments of the subject compound, two substituents selected from Rl, R4, and R6 that are bonded to the same atom are joined to form a C3_i2cycloalkyl or Ci_itheterocycloalkyl. In additional embodiments of the subject compound, two substituents selected from ftl, R4, and R6 that are bonded to adjacent atoms are joined to form a C.
ticycloalkyl, Ci_iiheterocycloalkyl, C6_ratyl, or Ci_iiheteroaryl, wherein the C3.12cyc10a11cy1, Ci_iiheterocycloalkyl, C6_12aryl, or Ci_i iheteroaryl are optionally substituted with one, two, or three R2 . In additional embodiments of the subject compound, two substituents selected from 10, and R6 that are bonded to adjacent atoms are joined to form a C3_i2cycloalkyl, Ci_iiheterocycloalkyl, C6_12a1y1, or Ci_iiheteroatyl.
In some embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a C3-ucycloalkyl, wherein the C3_12cycloalkyl is optionally substituted with one, two, or three R"a. In additional embodiments of the subject compound, two substituents selected from R4, R4, and R6 that are bonded to adjacent atoms are joined to form a C3.12cycloalkyl. In further embodiments of the subject compound, two substituents selected from fe, and R6 that are bonded to adjacent atoms are joined to form a Ci_iiheterocycloalkyl, wherein the Ci_iiheterocycloalk0 is optionally substituted with one, two, or three R2C)a. In some embodiments of the subject compound, two substituents selected from RI. R4, and R6 that are bonded to adjacent atoms are joined to form a CI_ iiheterocycloalkyl. In additional embodiments of the subject compound, two substituents selected from RI, R4, and R6 that are bonded to adjacent atoms are joined to form a C6_paryl, wherein the C6_pary1 is optionally substituted with one, two, or three R20a. In embodiments of the subject compound, two substituents selected from 10,10, and Re' that are bonded to adjacent atoms are joined to form a C6_12aiy1. In additional embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a Ci_ iiheteroaryl, wherein the Ci_iiheteroaryl is optionally substituted with one, two, or three R20a. In additional embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms arc joined to form a Ci.iiheteroaryl.
[00401] In some embodiments of the subject compound, R' is hydrogen.
[00402] In additional embodiments of the subject compound, R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, -0R12, _N(R12)(R13), _ C(C)OR12, -0C(0)N(R12)(R13), and -C(0)R15, wherein Ci_6alkyl, C2_6alkenyl, and C2_6alkynyl, are optionally substituted with one, two, or three R20a. In embodiments of the subject compound, R4 is independently hydrogen. In further embodiments of the subject compound, R4 is independently halogen. In some embodiments of the subject compound, R4 is independently oxo.
In sonic embodiments of the subject compound, 1:24 is independently -CN Tn additional embodiments of the subject compound, R4 is independently Ci_6alkyl. In embodiments of the subject compound, R4 is independently C2-6a1keny1. In some embodiments of the subject compound. R4 is independently C2.6alkynyl. In further embodiments of the subject compound, RI is independently -0102. In select embodiments of the subject compound, R4 is independently -N(R12)(Ri3-,) .
In additional embodiments of the subject compound, R4 is independently -C(0)OR'.
In embodiments of the subject compound, R4 is independently -0C(0)N(R')(R13).
In some embodiments of the subject compound, R^ is independently -C(0)R15. In select embodiments of the subject compound, 124 is independently -NI-12. In further embodiments of the subject compound. R4 is independently -C(0)0H. In additional embodiments of the subject compound, R4 is independently -0C(0)N}12. In embodiments of the subject compound, R4 is independently -C(0)CH3.
[00403] In some embodiments of the subject compound, R6 is hydrogen.
[00404] In select embodiments of the subject compound, L2 is a bond. In additional embodiments of the subject compound, L2 is Cl-C6a1kyl.
1004051 In further embodiments of the subject compound, R5 is independently hydrogen.
[00406] In embodiments of the subject compound, R8 is hydrogen. In some embodiments of the subject compound, R8 is C1_6alkyl optionally substituted with one, two, or three R2'.
In select embodiments of the subject compound, Fe is C2_6alkenyl optionally substituted with one, two, or three R2'. In additional embodiments of the subject compound, R8 is C2_6alkynyl optionally substituted with one, two, or three R20'. In some embodiments of the subject compound, R8 is C3_6cycloalkyl optionally substituted with one, two, or three R20'. In embodiments of the subject compound, R8 is C2_9heterocycloalkyl optionally substituted with one, two, or three R20. In further embodiments of the subject compound, R8 is Ci_6a1ky1. In select embodiments of the subject compound, R8 is C2-6alkeny-1. In additional embodiments of the subject compound, R8 is C2_6a11cy11y1. In some embodiments of the subject compound, R8 is C3_6cycloalkyl. In embodiments of the subject compound, R8 is C2_9heterocycloalky I.
[00407] In select embodiments of the subject compound, Ll is a bond. In further embodiments of the subject compound, 1_.1 is Cl-C6alkyl. In additional embodiments of the subject compound, Ll is -C(0)-. In some embodiments of the subject compound, Ll is C(R1)(Rig)0. In embodiments of the subject compound. L2 is CH20.

[00408] In select embodiments of the subject compound, R19 is a C3_12cycloalkyl optionally substituted with one, two, three, four, five, six, or seven Rh. In additional embodiments of the subject compound, R19 is a C,_ iheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In further embodiments of the subject compound, R19 is a C6_12aryl optionally substituted with one, two, three, four, five, six, or seven R11.
In some embodiments of the subject compound, R" is a C2_12heteromyl optionally substituted with one, two, three, four, five, six, or seven R". In embodiments of the subject compound, R19 is a C3_12cycloalkyl. In select embodiments of the subject compound, R19 is a C2_iiheterocycloalkyl. In additional embodiments of the subject compound, R19 is a C6_12a1y1. In some embodiments of the subject compound, R19 is a C2_12hcteroaryl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic C3_9cycloalkyl optionally substituted with one, two, three, four, five, six, or seven Rli. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic Ci_sheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R". In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic phenyl optionally substituted with one, two, three, four, or five R". In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic Ci_sheteroaryl optionally substituted with one, two, three, four, or five 1111. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a spirocyclic C5_12cyc10a1ky1 optionally substituted with one, two, three, four, five, six, or seven R". In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R"
is a spirocyclic C?_iiheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused C4_12cycloa1kyl optionally substituted with one, two, three, four, five, six, or seven R1i. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused C2-iiheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R1i. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused C6_12aryl, optionally substituted with one, two, three, four, five, six, or seven RI'. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused 5 to 12 membered heteroaryl optionally substituted with one, two, three, four, five, six, or seven Rh.
[00409] In further embodiments of the subject compound, R16 is hydrogen. In embodiments of the subject compound, R16 is halogen. In select embodiments of the subject compound, R16 is Ci.6alkyl. In some embodiments of the subject compound, R16 is -0R12.
[00410] In additional embodiments of the subject compound, R2 is [00411] In select embodiments of the subject compound, R1' is Ci_6alkyl optionally substituted with one, two, or three R2od. In embodiments of the subject compound, R12a is methylene optionally substituted with one or two R2 d.
In further embodiments of the subject compound, R12a is methylene. In some embodiments of the subject compound, Rua is ethylene optionally substituted with one, two, or three R2".
In embodiments of the subject compound, Rua is ethylene. In some embodiments of the subject compound, R12a is propylene optionally substituted with one, two, or three R2". In embodiments of the subject compound, R12a is propylene. In some embodiments, R12a is -CH2-C2.9heterocycloa1kyl optionally substituted with one, two, or three R2 d. In some embodiments, Rua is -CH2-(monocyclic C2_8heterocycloalkyl) optionally substituted with one, two, or three R2". In some embodiments, R12a is -CH2-(monocyclic C3_5heterocycloalkyl) optionally substituted with one, two, or three R2". In some embodiments, Rua is -CH2-(spirocyclic C2_,Iheterocycloalkyl) optionally substituted with one, two, or three R20". In some embodiments, Rua is -CH2-(spirocyclic C3_iiheterocycloalky1) optionally substituted with one, two, or three R2od. In some embodiments, R12a is -CH,-(fused C,_iiheterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, Rila is -CH2-(spirocyclic C6_8heterocycloa1kyl) optionally substituted with one, two, or three R2".
[00412] In select embodiments of the compound. Rua is C1_6alky1 optionally substituted with one, two, or three R20,1. In embodiments of the compound, Rua is methylene optionally substituted with one or two R20C1. In further embodiments of the compound, Rua is methylene. In some embodiments of the compound, R1' is ethylene optionally substituted with one, two, or three R2'. In embodiments of the compound. Rua is ethylene. In some embodiments of the compound, Rua is propylene optionally substituted with one, two, or three R2". In embodiments of the compound, Rua is propylene. In some embodiments, R12a is -CH2-C2_9heterocycloa1kyl optionally substituted with one, two, or three R2 d. In some embodiments, Rua is -CH2-(monocyclic C2-sheterocycloalkyl) optionally substituted with one, two, or three R2 d. In some embodiments, Rua is -CH2-(monocyclic C3_5heterocycloa1kyl) optionally substituted with one, two, or three R20d. In some embodiments, Rua is -C112-(spirocyclic C24 iheterocycloalkyl) optionally substituted with one, two, or three lUnd. In some embodiments, R12a is -CH2-(spirocyclic C34ilieterocycloallcyl) optionally substituted with one; two, or three R'd In sonic embodiments, R12a is -CH2-(fused C241heterocycloalkyl) optionally substituted with one, two, or three R2 d. In some embodiments, R12a is -CH2-(spirocyclic C6_8heterocycloalkyl) optionally substituted with one, two, or three R2".
[00413] In embodiments, Rua is C1_6alkyl. In embodiments, Rila is C2_6alkenyl.
In embodiments, Rua is C2-6alkynyl. In embodiments, Rua is C3_10cycloalkyl. In embodiments, R12a is -CH2-C3_10cycloalkyl. In embodiments, 12a is C2_9heterocycloalkyl. In embodiments, Rua is -CH2-C2_9heterocycloalkyl. In embodiments, R12a is C6_10aryl.
In embodiments, Rua is -CH2-C640aryl. In embodiments, R12a is -CH2-Ci_9heteroaryl. In embodiments, Rua is Ci_ 9heteroaryl.
[00414] In embodiments, Rua is Ci_6alkyl optionally substituted with one, two, or three R2 d. In embodiments, Rua is C2.6alkenyl optionally substituted with one, two, or three R20d. In embodiments, R1' is C7_6alkynyl optionally substituted with one, two, or three R2". In embodiments, R12a is C340cycloalkyl optionally substituted with one, two, or three R2 d. In embodiments, Rua is -CH2-C3_10cycloallcyl optionally substituted with one, two, or three R2 d.
In embodiments, Rua is C2_9heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, Rua is -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three R2 d. In embodiments, Rua is C6_ nary] optionally substituted with one, two, or three R2 d. In embodiments, Rua is -CH2-C6_10aryl optionally substituted with one, two, or three R20. In embodiments, Rila is -CH2-C1_9heteroaryl optionally substituted with one, two, or three R20d. In embodiments, Rua is C1_9heteroaryl optionally substituted with one, two, or three Rmd.
[00415] In additional embodiments of the subject compound, Rub is hydrogen. In select embodiments of the compound, R121' is Ci.6alkyl optionally substituted with one, two, or three R2 d. In embodiments of the compound, Rub is methylene optionally substituted with one or two R20d. In further embodiments of the compound, R12b is methylene. In some embodiments of the compound, R12b is ethylene optionally substituted with one, two, or three R2od. In embodiments of the compound, Rub is ethylene. In some embodiments of the compound, Rub is propylene optionally substituted with one, two, or three R2'. In embodiments of the compound, R12" is propylene. In some embodiments, R12b is -CH2-C2_9heterocycloallcyl optionally substituted with one, two, or three R2 d. In some embodiments, R12b is -CH2-(monocyclic C2_8heterocycloalkyl) optionally substituted with one, two, or three R2 d. In some embodiments, R12b is -CH2-(monocyclic C3_5heterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, Rub is -CH2-(spirocyclic C,Ilheterocycloalkyl) optionally substituted with one, two, or three R2". In some embodiments, Rub is -C1-12-(spirocyclic C3_llheterocycloa1kyl) optionally substituted with one, two, or three R2". In some embodiments, 102b is -CI-1,-(fused C2_llheterocyc1oalkyl) optionally substituted with one, two, or three R20". In some embodiments, Rub is -0-12-(spirocyclic C6_sheterocycloalkyl) optionally substituted with one, two, or three R2".
[00416] In embodiments, R12) is Ci_6a1ky1. In embodiments, R"b is C2_6a1keny1.
In embodiments, R12b is C2-6alkynyl. In embodiments, R12b is C3_iocycloalkyl. In embodiments, R12b is -CH2-C3_10cyc10a1ky1. In embodiments, =-= 12b I( is C2_9heterocycloa1kyl. In embodiments, R121' is -0-12-C2_9heterocycloalkyl. In embodiments, R12b is C6_10aryl.
In embodiments, Ri2b is -CH,-C6_10aryl. In embodiments, R12b is -CH,-C1_9heteroaryl. In embodiments, R12b is C1_ 9heteroaryl.
[00417] In embodiments, Rub is Ci_6a1ky1 optionally substituted with one, two, or three R2 d. In embodiments, R12b is C2_6a1kenyl optionally substituted with one, two, or three R2 d. In embodiments, R12b is C2_6allnyl optionally substituted with one, two, or three R2". In embodiments, R12b is C34ocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12b is -CH2-C3_10cyc1oa1ky1 optionally substituted with one, two, or three R2 d.
In embodiments, R'24) is C2_9heterocycloalkyl optionally substituted with one, two, or three Rued. In embodiments, R12b is -CT-12-C2_9heterocycloallcyl optionally substituted with one, two, or three R2" In embodiments, Rim is C6_ ioaryl optionally substituted with one, two, or three R2 d. In embodiments, R12b is -CH2-C6_10aryl optionally substituted with one, two, or three R20. In embodiments, R12b is -C1-12.-Cl_9heteroaryl optionally substituted with one, two, or three R'd. In embodiments, Rub is Ci_9heteroaryl optionally substituted with one, two, or three R20d.
[00418] In further embodiments of the subject compound, X is C(R3). In select embodiments of the subject compound, X is N.
[00419] In some embodiments of the subject compound, R4 is hydrogen. In embodiments of the subject compound, Fe is -CN. In embodiments of the subject compound, le is Ci_6a1kyl.
In additional embodiments of the subject compound, re is methyl. In embodiments, lre is C1_6alkyl optionally substituted with one, two, or three R2 b.
In embodiments, IV is C2_6alkenyl optionally substituted with one, two, or three R'. In embodiments, R3 is C2-6alkynyl optionally substituted with one, two, or three R2'. In embodiments, le is C3_10cycloalkyl optionally substituted with one, two, or three R". In embodiments, R3 is C291ieterocycloalkyl optionally substituted with one, two, or three R2 b. In embodiments, R3 is C6_ioary1 optionally substituted with one, two, or three R' b. In embodiments, R3 is Ci_9heteromyl optionally substituted with one, two, or three R". In embodiments, R3 is -OR".
In embodiments, R3 is -C(0)0R42. In embodiments, R3 is -0C(0)N(R12)(R13). In embodiments, R3 is -C(0)R15. In embodiments, R3 is halogen. In embodiments, R3 is -N(R12)(R13). In embodiments, R3 is -NHL
[00420] In further embodiments of the subject compound, each R12 is independently selected from hydrogen, C1_ 6a1ky1, and C3_6cyc1oa1ky1. In some embodiments of the subject compound, each R12 is independently selected from hydrogen or Ci.6alkyl. In embodiments of the subject compound, R12 is independently hydrogen. In select embodiments of the subject compound, each R13 is independently selected from hydrogen and C14alkyl. In some embodiments of the subject compound, each R14 is independently selected from hydrogen and C14alkyl. In additional embodiments of the subject compound, each R15 is independently C1.4a1ky1.

[00421] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or 0 Rio N

solvate thereof, the compound has the structure R
Formula (IA1) wherein R', R8, R10, R16 and it ¨17 arc as dcscribcd herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA2) wherein R2, R8, Rio, Ri6 and tt ¨17 arc as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the R
0 0 io R8 s!

R16 Rlo, ¨16 compound has the structure Formula (IA3) wherein R2, R8, lc and R" are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or 0 Rio N
solvate thereof, the compound has the structure R17 N N
R2 Formula (IA4) wherein R2, R8, Rl , and R17 are as described herein. In select embodiments of the subject compound, or a pharmaceutically 0 Rio .NN
acceptable salt or solvate thereof, the compound has the structure R17 N
N R` Formula (IA5) wherein R2, R8, R10, and R17 are as described herein In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure õ
R3 \\s/c N
R17 N N R2 Formula (IA6) wherein R2, R8, R10, and R" are as described herein. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the R17=%\ R2 compound has the structure R Formula (IA7) wherein R2, R3, fe, Rio, Ri6 and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or 0 R o NN/

solvate thereof, the compound has the structure R Formula (IA8) wherein R2, R3, R8, Rio, R16 and lc ¨ 17 are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure R o N
R16 R8, Rio, ¨16 Formula (IA9) wherein R2, R2, and R" are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the 0 Rio compound has the structure R17 R2 Formula (IA10) wherein R2, R3, R8, le', and R17 are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or 0 Rio solvate thereof, the compound has the structure R " '` Formula (IA1 1) wherein R2, R3, R8, R3 , and R" are as described herein. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Rio R8 oe N
Rl7NNR2 Formula (IA12) wherein R2, R3, R8, Rio, Ri6 and R'7 are as described herein.

[00422] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the 0 Ri o N

compound has the structure R Formula (IIA1) wherein R2, R8, ¨10, R" and R" are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or 0 Rio R, N

solvate thereof, the compound has the structure R Formula (IIA2) wherein R2, R8, R10, R16 and K-17 are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure NN-w6 R2 R17 R8, R10, "-= 16 Formula (ITA3) wherein R2, rc and RI7 are as described herein. in additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 0 Rio N
N

the compound has the structure R17 Formula (IIA4) wherein R2, R8, R1 , and R17 are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or 0 Rio N
N

solvate thereof, the compound has the structure R Formula (11A5) wherein R2, R8, R1 , and R17 are as described herein. In select embodiments of the subject compound, or a pharmaceutically R
0 0 io R8 s//
N

acceptable salt or solvate thereof, the compound has the structure R Formula (11A6) wherein R2, R8, R1 , and R" are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure 0 R o R17 Formula (IA?) wherein R2, fe, Rs, Rio, ¨16 K and R17 arc as described herein. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 0 R o the compound has the structure R17 Formula (IIA8) wherein R2, R3, R8, R10, R16 and R17 are as described herein. In some embodiments of the subject compound, or a pharmaceutically R8 Vc>R3 R16"N R2 acceptable salt or solvate thereof, the compound has the structure R17 Formula (IIA9) wherein R2, R3, R8, R10, R16 and R17 are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure 0 Ri o N

R17 Formula (HAM wherein R2, R3, R8, 10, and IC are as described herein. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 0 Ri 0 RN, the compound has the structure R17 Formula (IIA11) wherein R2, R3, R8, R10, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or 0õ0 R8 N's'c,7, R3 \
N

solvate thereof, the compound has the structure or R1' Formula (IIA12) wherein R2, R3, R8, RE), and R" are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or I N
N 0 "
Formula (III) wherein R1(' is as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the N
N N
I
R17 N 0 ' structure or Formula (IV) wherein R8, W, R16, and R" are as described herein.
In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the /
N
I
R16 N 0 ' compound has the structure or Formula (V) wherein R8, W, R16, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or R8õW
N irLN
' R17 N N 0 ' solvate thereof, the compound has the structure or Formula (VI) wherein R8, W, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically ,N
R8õWR3 R17 N 0 ' acceptable salt or solvate thereof, the compound has the structure or Formula (VII) wherein R8, W, R3, R16, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or H
N., ( __________________ /
N
R8NõWf., R3 F
I -.'-...1.....õ
R161' N 0,õ N ' Formula (VIII) wherein R8, W, R3. R", and R" are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the H
N....._ __________________________________________ /
N
'N 1 '-,_1.k R17 N N 0 ' N
compound has the structure or Formula (IX) wherein R8, W, R3, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or H
N
( _________________________________________________________ >
0 sN-F

N 0 ' N

solvate thereof, the compound has the structure or Formula (X) wherein R" and R" are as described herein. In embodiments of the subject compound, or a pharmaceutically H
N., ( ______________________________________________________________________ /

/\NLli N F
-..,, Ris_,iI N 0 ' N

acceptable salt or solvate thereof, the compound has the structure or Formula (XI) wherein R" and R" are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or N
N

Formula (XII) wherein R17 is as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the N

N):R
õõ.=õ_ R17 N 0 ' structure or Formula (XIII) wherein R3, R16, and R'7 are as described herein.
In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the N

Ri6 N 0 ' compound has the structure or Formula (XIV) wherein R3, R16, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or I
Ri7 N N 0 solvate thereof, the compound has the structure or Formula (XV) wherein R3 and R17 are as described herein.
[00423] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the H2N Cf\AN
N
N 0 ' Ri6 compound has the structure or F
Formula (XVI) wherein 106 and 10 are as described herein. In embodiments of Formula (XVI), R16 is F and R1 is a 10 membered spirocyclic bicyclic heterocycloalkyl substituted with one R6 and optionally substituted with one, two, or three R4. In embodiments of Formula (XVI), R16 is F and R1 is a 10 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three fe. In embodiments of Formula (XVI), R16 is F and R1 is a 11 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R1. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or Rio 0 ' Ris Formula (XVII) wherein R16 and R1 are as described herein. In embodiments of Formula (XVII), R16 is F and R1 is a 10 membered spirocyclic bicyclic heterocycloalkyl substituted with one R6 and optionally substituted with one, two, or three R4.
In embodiments of Formula (XVII), R16 is F and R" is a 10 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R1.
In embodiments of Formula (XVII), R16 is F and R1 is a 11 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4. In embodiments of the subject compound, or a pharmaceutically acceptable H 2N C IfAN N
I
Rie /N
salt or solvate thereof, the compound has the structure or F Formula (XVIII) wherein R16 and R" arc as described herein. In embodiments of Formula (XVIII), R16 is F and R1 is a 10 membered spirocyclic bicyclic heterocycloalkyl substituted with one R6 and optionally substituted with one, two, or three R1. In embodiments of Formula (XVIII), R16 is F and R1 is a 10 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4. In embodiments of Formula (XVIII), R16 is F and R1 is a 11 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or HO
N
I
, \

Ris N
Formula (XIX) wherein R16 and R1 are as described herein. In embodiments of Formula (XIX), R16 is F and R1 is a 10 membered spirocyclic bicyclic heterocycloalkyl substituted with one R6 and optionally substituted with one, two, or three R4. In embodiments of Formula (XIX), R16 is F and R1 is a 10 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three 10. In embodiments of Formula (XIX), R16 is F and R" is a 11 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4.

[00424] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 11.7 is _L._ wherein X', X', Xl, le, and p are as described herein. In further embodiments of the X2, X1 ''R4 subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is ¨1.¨ wherein X4, X2, V, R4, and p are as described herein. In select embodiments of the subject compound, or a pharmaceutically X2,_ ,....--!"...--.õ
r" --1 . .
i.... :õ...., (R4)p x3 acceptable salt or solvate thereof, R7 is I wherein X2, V, R4, and p are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, Fe is (R4)p <

wherein X', X4, le, and p are as described herein. In embodiments of the subject compound, X,2% \......!..r./(R4)P
i ( or a pharmaceutically acceptable salt or solvate thereof, IC is I wherein X', X4, R1, and p are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate X1>¨(R4)p thereof, R7 is wherein X', X4, X4, R4, and p are as described herein. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is Xl ___________________ (R4)p wherein X', X', fe, and p are as described herein.
[00425] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is < ip wherein Xl, X2, X3, R4, and p are as described herein. In further embodiments of the subject <X1 -(R4)1) compound, or a pharmaceutically acceptable salt or solvate thereof. R.' is wherein X', X2, X3, R4, and p are as described herein. In some embodiments of the subject compound, or a pharmaceutically _____________________________________________ (1714)p acceptable salt or solvate thereof, R7 is wherein X2, X3, R4, and p are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R' is <X X3 wherein X2, X', R4, and p are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R.' is wherein X2, X3, R4, and p are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt NX.1>I (R4) p or solvate thereof, IC is wherein X1, X2, X3, R4, and p are as described herein. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof. R7 is X1 ¨(R4)p wherein X1, X2, fe, and p are as described herein.
[00426] In further embodiments of the subject compound, p is an integer from 0 to 4. In embodiments of the subject compound, p is 0. In select embodiments of the subject compound, p is 1. In some embodiments of the subject compound, p is 2. In embodiments of the subject compound, p is 3. In additional embodiments of the subject compound, p is 4.
[00427] In embodiments of the subject compound, X1 is selected from CH2, C(R1)(R6), CH2C(R1)(R6), CH2C(R4)(R6)CH2, C(R4)(R6)c(R4)(R6),c(R4)(R6), c(R4)(R6)N(R4), c(R4)(R6)N(R6), c(R4)(R6)0, c(R4)(R6)oc(R4)(R6), c(Ri)(Ra)s, c(R4)(R6)sc(R4)(R6), c(R4)tR4,, CH2C(R4)(R4), CH2C(R4)(R4)CH2, c(z4)(R4)c(R4)(R6)c(R4)(R4), c(:0)(R4)c(R4)(R4)c(R4)(R4), c(R4)(R4)c(0)/c(R4), c(z4)(R4)NR4), C(R4)(R4)N(10, ca4xR4)0, c(R4)(R4)0c(R4)(R4), c(Ri, )(1-( ) S, and C(R4)(R4)SC(R4)(R4).
[00428] In further embodiments of the subject compound, is CH2. In some embodiments of the subject compound, X1 is C(R4)(R6). In select embodiments of the subject compound, X1 is CH2C(R4)(R6). In additional embodiments of the subject compound, X1 is CH2C(R4)(R6)CH2. In embodiments of the subject compound, X4 is C(R4)(10C(R4)(R6)C(R4)(R6). In select embodiments of the subject compound, X1 is C(R4)(R6)N(R4). In further embodiments of the subject compound, V is C(R4)(10N(Re). In some embodiments of the subject compound, X1 is C(R4)(R6)0. In select embodiments of the subject compound, X1 is C(10)(R6)0C(R4)(R6). In embodiments of the subject compound, X' is C(R4)(R6)S. In additional embodiments of the subject compound, X' is c(R4)(R6)sc(R4)(-, ) In embodiments of the subject compound, X1 is C(R4)(R4). In further embodiments of the subject compound, X1 is CH2C(R4)(-4,.
In select embodiments of the subject compound, X1 is CH2C(R4)(R4)CH2.
) In embodiments of the subject compound, Xi is c(R4)(R4)c(R4)(R6)c(R4)(R4) .
In some embodiments of the subject compound, X1 is c(R4)(R4)c(R4)(R4)c(R4)(R4) .
In embodiments of the subject compound, X' is ) c(R4)(R4)c(o)Ni(K -4, in additional embodiments of the subject compound, X1 is C(R4)(R4)N(R4) In further embodiments of the subject compound, X1 is c(R4)(R4)N(1(-, ) In embodiments of the subject compound, X1 is C(R4)(R4)0. In some embodiments of the subject compound, X1 is c(R4)(R4)0c(R4)(--) In select embodiments of the subject compound, X1 is C(R4)(R4)S. In some embodiments of the subject compound. X4 is C(R4)(R4)SC(R4)(R4).
[00429] In select embodiments of the subject compound, X2 is N. In embodiments of the subject compound, X2 is C. In further embodiments of the subject compound, X2 is C(R6). In additional embodiments of the subject compound, X2 is C(R4). In some embodiments of the subject compound, X2 is CH.
In select embodiments of the subject compound, X2 is N(R1). In embodiments of the subject compound, X2 is N(R4). In select embodiments of the subject compound, X2 is N(10. In further embodiments of the subject compound, X2 is 0. In additional embodiments of the subject compound, X' is S. In some embodiments of the subject compound, X2 is S(0). In embodiments of the subject compound, X2 is C(H)(10. In embodiments of the subject compound, X2 is C(R4)7. In embodiments of the subject compound, X2 is CH?. In select embodiments of the subject compound, X' is C(10)(10.
In further embodiments of the subject compound, X' is S(=0)(=NR4). In embodiments of the subject compound, X' is S(0)2.
1004301 In additional embodiments of the subject compound, X3 is N. In some embodiments of the subject compound, X3 is C. In select embodiments of the subject compound, X3 is C(10.
In select embodiments of the subject compound, X is C(10).
1004311 In embodiments of the subject compound, le is wherein R4 and p are as described herein.
R4 p In further embodiments of the subject compound, R7 is -'"in" wherein R4 and p are as described herein.
N
f \
rx4 In some embodiments of the subject compound. R7 is wherein R4 and p are as described herein. In additional embodiments of the subject compound, R7 is =Arw wherein 10 and p are as described herein.
<
¨(R4 )p In select embodiments of the subject compound, le is ="
wherein R4 and p are as described herein. In embodiments of the subject compound, R7 is 4"' wherein R4 and p are as described herein. In some embodiments of the subject compound, R7 is -^^-", wherein R4 and p are as described herein. In further embodiments of the subject compound, R7 is 'sr' wherein Fe and p are as described herein. In some ¨(R4 ) P
embodiments of the subject compound, fe is wherein le and p are as described herein. In select embodiments of the subject compound, R7 is wherein 10 and p are as described herein. In AC ,:j1--(R4)p embodiments of the subject compound, Fe is wherein TO and p are as described herein. In (R4)p additional embodiments of the subject compound, It7 is wherein 10 and p are as described OcN,I
-J¨(R4)p herein. In some embodiments of the subject compound, R7 is wherein R4 and p are as described H
herein. In further embodiments of the subject compound, fe is "µ"1"
wherein R1 and p are as described ________________________________________________________ (R )p herein. In some embodiments of the subject compound, R7 is 'Jr wherein R4 and p are as described NH
herein. In embodiments of the subject compound, R7 is -""in' wherein R4 and p are as described herein.
______________________________________________ 11H
In select embodiments of the subject compound, IC is "in' wherein Fe and p are as described herein. In D 4 \
some embodiments of the subject compound, R7 is "Y"
wherein 124 and p are as described herein. In N
C R4)p N
additional embodiments of the subject compound, R7 is wherein le and p are as described herein.

Irefs2H
In further embodiments of the subject compound, R7 is wherein le and p are as described herein.
r-NH
In embodiments of the subject compound, R.7 is wherein R4 and p are as described herein. In 23---( R4) p some embodiments of the subject compound, R7 is wherein R4 and p are as described herein. In e5 (R4)P
select embodiments of the subject compound, R7 is wherein R4 and p are as described herein. In some ____________________________________________ (R4)p embodiments of the subject compound, R7 is "Y" wherein R4 and p are as described herein.
(N) [00432] In some embodiments of the subject compound, R7 is ¨7" . In embodiments of the subject compound, N) R7 is 'yr' . In further embodiments of the subject compound, R7 is -^"^' . In additional embodiments of the (m>
subject compound, R7 is 'A T
n"' . In select embodiments of the subject compound, R7 is -^^^' . In some embodiments of the subject compound, R7 is ''s-r"' . In embodiments of the subject compound, R7 is . In embodiments of the subject compound, R7 is "ry In further embodiments of the subject compound, R7 is /C0\
. In select embodiments of the subject compound, EC is -"-^=^' . In additional embodiments of the subject HN
compound, R7 is --""f" . In some embodiments of the subject compound, R7 is . In embodiments FII\ õDJ
OcN) of the subject compound, R7 is "yr . In some embodiments of the subject compound, R7 is -"'"in` . In <91H
further embodiments of the subject compound, le is '""r' . In select embodiments of the subject compound, NH
NH
R7 is . In some embodiments of the subject compound, R7 is . In additional embodiments of the CN
NC 'CN

subject compound, R7 is ""r" . In embodiments of the subject compound, R7 is '"Y' . In some N
embodiments of the subject compound, R7 is "Y" . In further embodiments of the subject compound, re is H

N.) In select embodiments of the subject compound, R7 is ""ff To some embodiments of the subject compound, R7 is . In embodiments of the subject compound, R7 is = \
. In NS
embodiments of the subject compound, R7 is s'n"
. In additional embodiments of the subject compound, R7 is N
K/C
. In fluffier embodiments of the subject compound, R7 is .

C.3L---(R4)p 1004331 In select embodiments of the subject compound, 10 is '"nY"
wherein le and p are as described ____________________________________________________ (R4)p herein. In embodiments of the subject compound, R11) is wherein R4 and p arc as described herein.
( R4 ) In some embodiments of the subject compound, RR' is wherein R4 and p are as described herein. In R4) p <

some embodiments of the subject compound, Rl is -^r-^' wherein R1 and p are as described herein. in ¨(R4) select embodiments of the subject compound, R1-1) is 'µ"
wherein R4 and p are as described herein. In N
further embodiments of the subject compound, 101' is wherein R4 and p are as described herein. In J¨(R4)p embodiments of the subject compound, RI is ¨ wherein R4 and p are as described herein. In R4) additional embodiments of the subject compound, R11) is wherein R4 and p are as described herein.
cCO
R4) In some embodiments of the subject compound, RI is wherein R4 and p are as described herein. In embodiments of the subject compound, Etl is "1^-^, wherein Wand p are as described herein. In select (R4)p embodiments of the subject compound, R4 is wherein le and p are as described herein. In embodiments of the subject compound, R4 is wherein R4 and p are as described herein. In (R4)1, further embodiments of the subject compound, R4 is wherein R4 and p are as described herein.
H
In some embodiments of the subject compound, le is --r" wherein R4 and p are as described herein.

In additional embodiments of the subject compound, R4 is '''ev wherein R4 and p are as described (R4)p herein. In some embodiments of the subject compound, is .""nr.' wherein R4 and p are as described ¨NH

herein. In embodiments of the subject compound, Rl is '0" wherein R4 and p are as described herein.
___________________________________________________ (R4) P
In select embodiments of the subject compound, Rl is "Y"
wherein R4 and p are as described herein. In 2Lrj_---j_(R4)p further embodiments of the subject compound, 10 is ¨":"
wherein R4 and p are as described herein. In ,Nce.c2H
some embodiments of the subject compound, R4 is wherein R4 and p are as described herein. In C H
,D4\
some embodiments of the subject compound, Itl wherein R4 and p are as described herein. In (R4) N., embodiments of the subject compound, Rl is "'se' wherein R4 and p are as described herein. In z\sõ(R4)p additional embodiments of the subject compound. Itl is '-`nr' wherein 111 and p are as described herein. In select embodiments of the subject compound, 10 is wherein R4 and p are as described herein.
r\ID
[00434] In further embodiments of the subject compound, It' is '-µnin' . In some embodiments of the subject N
compound, R1 is . In embodiments of the subject compound. Rm is -^^^' . In embodiments of the subject (N
compound, Rl is ."r-"-t . In select embodiments of the subject compound, Rl is ¨ . In additional embodiments of the subject compound, Ftl is 'nf'^' . In further embodiments of the subject compound, Rl is . In embodiments of the subject compound, Itl is '"ury . In some embodiments of the subject compound, @D\.
Rio is -µ,-;^, in some embodiments of the subject compound, Rl is -"In,"
. in select embodiments of the subject N j H
compound, ftl is ."Y" . In some embodiments of the subject compound, itl is ""Y' . In N j embodiments of the subject compound, RI is '"+ . In further embodiments of the subject compound, RI is . In additional embodiments of the subject compound, Itl is 'yr' . In some embodiments of the [N;
______________________________ \NH
subject compound, RK) is "-"Y" . In select embodiments of the subject compound, 12.1 is '""r' . In NC
N
'C
embodiments of the subject compound, R'' is . In some embodiments of the subject compound, 1:0 CN
r N
is '''Yv . In further embodiments of the subject compound. Rl is . In embodiments of the subject HOLN
2 ) N

) compound, Rim is . In additional embodiments of the subject compound, FO is "Tv . In \pec5\11-1 embodiments of the subject compound, FO is . In select embodiments of the subject compound, R1 is . in some embodiments of the subject compound, 10 is s'n'y . in further embodiments of the CN
<1\>
subject compound, R'' is . In some embodiments of the subject compound, R1 is .
0.01H
H N
[00435] In embodiments of the subject compound, 10 is -L.
. In select embodiments of the subject cF>1 HN"µ
compound, Rl is Oy-l-----Oy---0.õ0 1 oyo 0,y-0 N N
\IC6 N N N

[00436] In embodiments, Rl is independently selected from .^^^' %NW i /
1101 9) N N¨N
N - N s)0 0 1 ,-, CI
ay-0 0y0 i`,D.,..-1.-- 0,15.--. 0y1-, F
y- k....y",..õ F
r.,,,N,,:.) N N N N N
/ _____________________________________________ / N > >
N N N N N N N N
0,,,-I

0.1...õ.---õF N
N'( N
,(N j S-/
NC F CN 4,,..õN---C----N.,.1 NT______C-N,,.õ, N-j----.., j N li 11 Y N N

, and N)11-N
[00437] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, 106 is hydrogen. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is halogen. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is fluoro.
[00438] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is hydrogen. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is methyl. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cyclopropyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cyclobutyl. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is oxetanyl.
[00439] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is methyl optionally substituted with one, two, or three R2 c. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cyclopropyl optionally substituted with one, two, or three Rafe. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cyclobutyl optionally substituted with one, two, or three R20e. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is oxetanyl optionally substituted with one, two, or three R2".
In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is -CN.
In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof. R8 is In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is -CH2CH2CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is -CH2CH2CH2CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is -CH2CH2CH2CH2CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is -(CI-Cbalkyl)-CN.
In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cylopropyl optionally substituted with one, two, or three R2'. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cylopropyl substituted with CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cylopropyl substituted with -(C1-Coalkyl)-CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is Cl-C6haloalkyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is Cl-C,haloallcyl In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is Cl-C6alkyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof. R8 is-(Ci-C6ak-1)-C(0)NH2. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is-(Ci-C6alkyl)-(C3-C6cycloallw1). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is-(CI-C2a1ky1)-(C3-C4cycloalkyl). In embodiments, R8 is hydrogen. In embodiments, R8 is halogen.
In embodiments, R8 is -CN. In embodiments, R8 is Ci_6a110. In embodiments, R8 is C2_6alkenyl. In embodiments, R8 is C2_6alkynyl. Ill embodiments, le is C3_6cycloalkyl. In embodiments, re is C2_9heterocycloalkyl.
In embodiments, re is C6_1auyl. In embodiments, le is Ci_9heteroalyl. In embodiments, R8 is -0R12. In embodiments, R8 is -SR'. In embodiments, R8 is -N(H)(R12) In embodiments, R8 is -C(0)01C. In embodiments, R8 is -0C(0)N(R12)(R13) . In embodiments, R8 is -N(R")C(0)N(R'2)(R3) . In embodiments, le is -N(R")C(0)0R13. In embodiments, le is -N(R4)S(0)2R15. In embodiments, R8 is -C(0)R15. In embodiments, R8 is -S(0)R15. In embodiments, R8 is -0C(0)R15. In embodiments, R8 is -C(0)N(R12)(R13) In embodiments, R8 is -C(0)C(0)N(102)(R13) . In embodiments, R8 is -N(Rii)c (0)Ris. In embodiments, R8 is -S(0)2R15. In embodiments, R8 is -S(0)2N(R12)(R13)- . In embodiments, R8 is S(=0)(=NH)N(R12)(R13, ) In embodiments, R8 is -CH2C(0)N(R12)(R13-, ) In embodiments, R8 is -CH2N(Ri4)c(o)Rp. In embodiments, R8 is -CH2S(0)2R15. In embodiments, fe is -CH2S(0)2N(R12)(Rn). In embodiments, R8 is Ci_6alkyl optionally substituted with one, two, or three R2'. In embodiments, R8 is C2.6a1keny1 optionally substituted with one, two, or three R2". In embodiments, R8 is C2_6alkynyl optionally substituted with one, two, or three R20. In embodiments, R8 is C3_6cycloalkyl optionally substituted with one, two, or three R20. In embodiments, R8 is C2_9heterocycloalkyl optionally substituted with one, two, or three R20. In embodiments, R8 is C6_10ary1 optionally substituted with one, two, or three R2". In embodiments, R8 is Ci_9heteroaryl optionally substituted with one, two, or three R20C.
[00440] In some embodiments, I.,' is a bond. In some embodiments, L' is Cm-C6alkyl. In some embodiments, L' is C2-C6alkenyl. In some embodiments, LI is C2-C6alkynyl. In some embodiments, Ll is -0-. In some embodiments, Li is _N(Rit-,)_.
In some embodiments, Ll is -C(0)-. In some embodiments. Ll is -N(R14)C(0)-. In some embodiments, Ll is -C(0)N(R14)-. In some embodiments, L1 is -S-. In some embodiments, Ll is -S(0)2-. In some embodiments. LI is -S(0)-. In some embodiments. LI is -S(0)2N(R14)-. In some embodiments. Li is -S(0)N(R11)-.

In some embodiments, L1 is -N(R14)S(0)- . In some embodiments, L1 is -N(R14)S(0)2-. In some embodiments, L1 is -000N(R14)-. In some embodiments, is -N(R")C(0)0-. In some embodiments, Li is N(R1e) . In some embodiments, L' is C(0)N(111c). In some embodiments, L1 is S(0)2N(R"). In some embodiments, L1 is S(0)N(R) . In some embodiments, L1 is C(R1f)(R1g)0. In some embodiments, is C(R1f)(RIg)N(RIc). In some embodiments, L1 is C(R1f)(114). In some embodiments, L1 is -NH-. In some embodiments, L1 is -NHC(0)-. In some embodiments, L1 is -C(0)NH-. In some embodiments, L1 is -S(0)2NH-. In some embodiments, L1 is -S(0)NH-. In some embodiments, Li is -NHS(0)- . In some embodiments, L1 is -NHS(0)2-. In some embodiments, L1 is -000NH-. In some embodiments. L1 is -NHC(0)0-. In some embodiments, Li is CH20.
In some embodiments, L1 is CH2NH. In some embodiments, L1 is CH2. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is selected from a Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C(0)-, -NHC(0)-, -C(0)NH-, CH20, CH2NH, and CH2.
1004411 In embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is:
xi 2 x4%..'"x10 X4X11 X4 X9C13 1 11 1 1 1 1 R1 hI II h X X x6 X9 x5 X9.õ..õ. x1 0 x5,, )(6 6la( X19, xi X6 Q
"

1 r N __ h r N I / h x10 11 Q 3 x 8 h Q5/7KQ3 X7- 3 X6, x5-, X4 X6, x5-- X4 Q \Q6 Q4 X16 (13 X13-' __________________________ R1 h x14 Q5Q6 Q I R1h =

\3 or Q-1. Q3, and Q5 are independently N or C(R1c1);
Q4 and Q6 are independently 0, S, C(R1a)(R1b), or N(R");
X4, X5, X6, X9, X10, X", X12, and X16 are independently selected from C(R1a) or N;
X' and X8 are independently selected from C(R1a), C(Rla)(R1b), N, or N(R16);
X" is selected from a bond, C(0), C(R1a)(Rib), c(o)c(Rla)(R1b), c(Rla)(R1b)c(Rla)(R1b), catiaxRiii)N(R), and N(R1c);
X14 and X are independently selected from a bond, C(0), C(R1')(106), and N(R");
each FP, Rib, Rid, Rif, ic - ig, and Rill are each independently selected from hydrogen, halogen, -CN, Ci_6alkyl, Ci-6haloalkyl, C2_6alkenyl, C2_6alkynyl, C3_iocycloalkyl, C2_9heterocycloalkyl, C640aryl, Ci_9heteroaryli -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(102)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R", -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R12), -C(0)C(0)N(R12)(R12), -N(R")C(0)R15, -S(0)2R15, -S(0)2N(R12)(R")-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(103), -CH2N(R14)C(0)R15, -CH2S(0)21115, and -CH2S(0)2N(R12)(1213), wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C340cycloalkyk C2-9heterocycloalkyl, C6_10aryl, and Ci_9heteroa1yl are optionally substituted with one, two, or three R2 1; or it" and Rib bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3_10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3_10cycloalkyl ring are optionally substituted with one, two, or three R'l: or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_ioary1 ring, a 5-12 membered heteroaryl ring, or a C3_iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C64oary1 ring, 5-12 membered heteroaryl ring, or C3_iocycloalkyl ring are -,-. fb, optionally substituted with one, two, or three R20; or Rib and one of R tcia, Ric, and Rid bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_10ary1 ring, a 5-12 membered heteroaryl ring, or a C3_10cycloa1kyl ring, wherein the 3-10 membered heterocycloalkyl ring, a Co_loaryl ring, a 5-12 membered heteroaryl ring, and C3_10cycloalkyl ring are optionally substituted with one, two, or three R20; or Rif and Rig are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201; and each Ric is independently selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6a1kyny1, C3_tocyc1oalkyl, C2-gheterocycloalkyl, C6_20a1yl, Ci_9heteroary1, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, C2-9heterocycloalkyl, C6_20ary1, and Ci_61teteroatyl are optionally substituted with one, two, or three R201 1004421 In embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is:
- - - - -x12 tN1 x4'7.'" x10 x4. .-*"....:-. -::-... x11 X.1.--------=-µ X5---$:13 I II I I I I ....... \\,>_.R1h I />--R1 h II
x5..., 6 , x9 x5.õ._ õ.. x1 0 x5._ )(6),. --...... Q 1 XX6 5-. N --Q
. 1 Xl x i 1------'5( ' = , , 7 7 'T
N oco N
Q3 N .Q3 4 X9 Cl \.4- r..... -........_,Q>_.
II //R1 h r I __ R1 h I \)_.R1h X1.1x1;'...---Q3 X 7..z.,X7.z.,...x8 X8-_Q3, X' 7 .._ NI-_-_-Q3 N-Q4 dayl..)trz, cy.,,r)õ
Rla Q3 \ X13 R 1 h _____________________________________ R . .. Q5n"----- N I 1 I 4X15 I R1 h x1 õ.2......., 4 )(a Q \Q6- ------Q4.'>
,õ.. Q or "Q6 ------Q3 .
Q1, Qi, and Q5 are independently N or C(R1d), Q4 and Q6 are independently 0, S, C(Ria)(R1b), or N(R);
Xi, X5, X6, X9, Xi , Xii, and Xi2 are independently selected from C(Ria) or N;
X' and X8 are independently selected from C(Ria), C(Ria)(Rib), N, or Xi' is selected from a bond, C(0), C(Ria)(Rtb), c(o)c(Rla)(R1b), c(Rla)(R1b)c(Rla)(R1b), c(Rla)(R11))N(R)1c,, and N(R1c);
X" and X are independently selected from a bond, C(0). C(R1')(Rth), and N(R10);
each Rla, Rib, Rid, Rif, Rig, and Rill are each independently selected from hydrogen, halogen, -CN, C2_6alkyl, Ci-6haloalkyl, C2_6alkenyl, C2_6alkynyl, C3_tocycloalkyl, C2_9heterocycloalkyl, C6_10aryl, Ci_9heteroaryl, -0R12, -SR12, -N(R12)(Rii), -C(0)0R12, -0C(0)N(R12)(103), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)105, -C(0)N(R12)(Ri3), -C(0)C(0)N(R12)(R13), -N(R")C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(Ru)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R", and -CH2S(0)2N(R12)(1213), wherein C2_6alkyl, C2_6alkeny1, C2_6a1kynyl, C310cycloalkyl, C2-9heterocycloalkyl, C6.20ary1, and C2_9heteroaryl are optionally substituted with one, two, or three R2'; or Ria and Rib bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-10cycloa1kyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3_20cycloalkyl ring are optionally substituted with one, two, or three R2"; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_20aryl ring, a 5-12 membered heteroaryl ring, or a C3_20cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6_20aryl ring, 5-12 membered heteroaryl ring, or C3_20cycloalkyl ring are optionally substituted with one, two, or three R2"; or 111b and one of Rh, lb, Ric, and Rid bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_ioaryl ring, a 5-12 membered heteroaryl ring, or a C3_10cycloa1kyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6_ioa1yl ring, a 5-12 membered heteromyl ring, and C3_20cycloalkyl ring are optionally substituted with one, two, or three R2 1; or Rif and Rig are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered eycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalk0 ring are optionally substituted with one, two, or three R201; and each Ric is independently selected from hydrogen, C2_6alkyl, C2_6alkenyl, C2_6allcynyl, C3_20cycloallcy-1, C2_ 9heterocycloalkyl, C6_2oaryl, C2_9heteroary1, wherein C2_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_20cycloalkyl, 9heterocycloalkyl, C6.10aryl, and Cl_9heteroaryl are optionally substituted with one, two, or three R201.
[00443] In embodiments, Rib is selected from hydrogen. C2_6alkvl, C2_6halloalkyl, C2_6alkeny1, C2_6alkynyl, -N(102)(103), -C(0)0102, -0C(0)N(102)(103), -N(104)C(0)N(102)(103), -N(R14)C(0)0R1', -C(0)R", -0C(0)10', -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R'), -N(RH)C(0)R15, -CH2C(0)N(R12)(R13), and -CH2N(R14)C(0)R15, wherein C2_6a1kyl, C2_6a1kenyl, and C2_6a1kynyl are optionally substituted with one, two, or three R20.
[00444] In embodiments, Rth is selected from hydrogen and -N(102)(R13). In embodiments, Rib is hydrogen. In embodiments, Rlh is -N(R12)(Ri3).
In embodiments, Rib is -NH2.
[00445] In embodiments, Rid is independently selected from hydrogen, halogen, -CN, C2,6alkyl, C2_6haloalkyl, C2-6a1keny1, C2_6a1kyny1, C3_20cycloalkyl, C2_9heterocycloalkyl, C6_20aryl, C2_9heteroaryl, -N(R12)(R1'), -C(0)0R12, -0C(0)N(R12)(R13), -/.4(R14)c(o)N(R12)(R13), N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)105, -OC(0)R15, -C(0)N(R12)(R13), _C(0)C(0)N(R12)(103), -N(104)C(0)R15, -S(0)2R15, -S(0)2N(R12)(1:03)-, S(=0)(=NH)N(R12)(1:03), -CH2C(0)N(R12)(R13), _CH2N(R14)C(0)R15, -CH2S(0)21C, and -CH2S(0)2N(R12)(R13), wherein C2.6a1ky1, C2.6a1keny1, C2.6alkynyl, C3_20cycloalkO, C2_9heterocycloalkyl, C6_20aryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R2 a. In embodiments, Rid is independently selected from hydrogen, halogen, -CN, C2,6a1ky1, C2_611aloalkyl, C2_6a1kenyl, C2_6a1kyny1, C3.6cyc10a1ky1, C2_9heterocycloalkyl, C6.ioaryl, Ci-9heteroaryl, -0R12, -N(R12)(103), -C(0)0102, -0C(0)N(R12)(R13), -N(10')C(0)N(Ru)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)105, -C(0)N(R12)(103), -C(0)C(0)N(R')(103), -N(104)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(103), -CH2C(0)N(102)(103), -CH2N(104)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(103), wherein C2,6alkyl, C2,6a11ceny1, C2,6a1kyny1, C3-6cycloalkyl, C2.9heterocycloalkyl, C6_20aryl, and C2_9heteroaryl are optionally substituted with one, two, or three R2Ga.
In embodiments, Rid is independently selected from hydrogen, -CN, C2_6alkyl, and C2_61ialoa1kyl, wherein Ci_6alkyl is optionally substituted with one, two, or three R2'. In embodiments, Rid is independently hydrogen. In embodiments, Rid is independently -CN.

CN
ONN,--NH2 0 S¨NH2 \ NH2 S N
S
[00446] In some embodiments, R19 is selected from: F , F
F
CN ON CN ON CN
CN
\ N \NH2 \ N \
\ N . \ N
H H . H H
N H
F F H , F , F , F
, ' ON
CN S
\ NH2 N
N
H /. N
N N ON
F H ' H F
S
, ' ON
S
')¨N H2 01 --NFI2 / __N H2 =S
el S¨NH2 \ NF12 F
S ON , F
. . . F
, N S F N F S
)¨NH2 F --NH2 ,--NH2 ¨NH2 S N S N
F , , F F F
CN

01 \>¨NH2 >¨N H2 \ NH2 / NH2 III ,--NH2 ON
F , F , F , F , 0 =
)¨N H2 NH2 ON

/ NH2 =CO N
(el (:)--19H2 \ NH2 O ON F F

,--NH2 F >¨NH2 ,--NH2 >¨NH2 F F F F
H2N CN H2Ns ,._..N H2N ON H2N CN H2N ON
¨ ¨
¨
F
, F F
, S S ..,..- F S ..- .\ S ).- TN,...
S..\
F
F F F
F
H2N CN H2Ns 33,\CN
¨
F .and F .
CN
S
\ NH2 IEEEE:fI? NH2 CN
S
\

CN

1004471 In some embodiments, le9 is selected from F , F S
ON

S \ NH2 i NH2 CN 0 i 0 \ NH2 / III-CN
CN , F , F 0 CN

¨ ¨ ¨ _ ¨
_ S S S S S
S
F , F F
. .

¨
¨
S
¨
/
SA ..---N-A
Nj , H2N\ CN H2N H2N CN H2N H2N
i S .,..... ...-.3. S
F F
F
ON ON ON
S ...,. )NN. FFs ,.., H2N CN H2N ON H2N ON S,,I. S:21A.
s&
F
F F F , and F
.
, CN
S
ON)¨NH2 JII_NH2 \ NH2 N
S
[00448] In some embodiments, R19 is selected from: F , F , F , CN ON CN ON
CN
ON
\ N \ N \
\ N \ NH2 N N
H H / H H
N H
F F H F F F
CN
ON S
\ N2 H N /
N \ \ N N.
H /
,¨NH2 N N / N H
CN
F H =H F

, , , N S
ON
S
ill ,--N H2 0 ihH 2 S

-NH rfr\ NH
S F ON F
. . . .
' ,--NH2 ¨NH2 S S N
F
F F F F
CN

1101 ¨14 H2 IP >¨ NH2 \ NH2 / N H2 N
0 ,_NH2 F , F , F , F 0 ON 0 0 )--N H2 401 , NH2 ()___ 2 NH \ NH2 O CN F F

,NH2 ¨NH2 O N --F
F F F ,and F
.

ON
0 N¨N H 2 lel S--- N H
2 \ NH2 S N S
[00449] In some embodiments, R19 is selected from F , F , F
, ON CN ON
ON S
\ NH2 \
N

N ON
F F F H F S
, -N S
ON
S 11101 ,--N H2 0 --= N H2 01 S-- N H 2 \ NH2 S ON F F
, , )¨NH2 ¨NH2 --NH2 S N S N
F F
F F F F
. . . , ON

0 )--N H2 Oil N H2 \EIII1_N

H2 / ¨N H2 1110 ,--NH2 ON F , F , F , F 0 , .

ON

'>¨N H2 0 ¨ N H2 0 0__. 2 NH \ NH2 O ON , F
F
, F F
)¨ ¨NH2 ,--NH2 --N H2 F F F F
- -¨
_____ S S¨ S S
S ¨ S
F , F F , F , F CI
-S.3,)\ S. s )\ S \ s ,,$%\
N
I '=,,õ
N
, , ¨ ¨
Sõ.-F F F
F , F F F
, , H2Ns ,....CN H2N2 ,..., :c..\\CN S ,,,- :j.. sJA .õ,.. H2NSN
../ A
N
F
H2N CN H2N\ CN HO
H2N CN ¨
SYNT
) F
HO \-, HO ''zi: 'tic H2N H2N

>:---N >z--N )--="---N
F CI S
F , F . F , S.
*F, F F , HO \-_ H2N N,.. `?2,-..- H2N N,.. 'z,.-2. H2N
N,, 'zi-a. 5'F
I
./ N
CI
I
,.., , , , '2c1 '242: N. N- N-NH N-N/
CF3 LL F HN ail V HN ,, / /

, , H
N-_ / N ,?_.,.... -4( ./
N-N N_ HNi H 0 / I

N
.2,,c HN
0 '2'-i..-IXI:v.

F CI , y H2N N 52;
H H2N 1\1,...)2i-z. .1\1.,,..N,...,..7.22 H

N N
'-2,2.-...- CF3 CF3 t., '.''''.- ....0 F3 õr 3 .

HO
'2HO 5.4-_ HO
Va.
HO =

OCF3 Ci Ci Ci CF3, or NH2.
[00450] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R" is a monocyclic ring. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof.
R" is a bicyclic ring system. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R" is a polycyclic ring system.
[00451] In select embodiments of the compound, R" is a C3_12cycloalky1 optionally substituted with one, two, three, four, five, six, or seven RH. In additional embodiments of the compound, R" is a C2_iiheterocycloa1kyl optionally substituted with one, two, three, four, five, six, or seven Rh. In further embodiments of the compound, R" is a C6_ 2aryl optionally substituted with one, two, three, four, five, six, or seven R11. In some embodiments of the compound, R" is a C?_pheteroaryl optionally substituted with one, two, three, four, five, six, or seven Rh'. In embodiments of the compound, R" is a C3_12cycloalkyl. In select embodiments of the compound, R" is a C2_ iiheterocycloalkyl. In additional embodiments of the compound, R" is a C6_12a1yl. In some embodiments of the compound, R" is a C2_12heteroaryl. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic C3_9cycloalkyl optionally substituted with one, two, three, four, five, six, or seven R''. In embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R" is a monocyclic ei_shetcrocycloalkyl optionally substituted with one, two, three, four, five, six, or seven Rh. in additional embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R" is a monocyclic phenyl optionally substituted with one, two, three, four, or five Rh. In further embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R" is a monocyclic Ci_5heteroaryl optionally substituted with one, two, three, four, or five Rh'. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R" is a spirocyclic Cs_i2cyc10a11cy1 optionally substituted with one, two, three, four, five, six, or seven R1'. In embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R" is a spirocyclic C2_iiheterocycloalkyT1 optionally substituted with one, two, three, four, five, six, or seven RH. In additional embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R" is a fused C542cycloa1kyl optionally substituted with one, two, three, four, five, six, or seven Rh. In further embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R" is a fused C2_ iiheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven RH. In further embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused C6_12aryl, optionally substituted with one, two, three, four, five, six, or seven Ru. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, 109 is a fused 5 to 12 membered heteroaryl optionally substituted with one, two, three, four, five, six, or seven Rh'.

Rid Ria N R1a h \ R1h S S
121a Ri a 1004521 In embodiments, R19 is Ria . In embodiments, R19 is Rla . In Rid Rla 0 N Ria ,--R1h \ Rill R1a R1a R 1a Rla embodiments, R19 is . In embodiments, R19 is Tn embodiments, R19 Rid Rla N Rla )¨NH2 \ NH2 S S
Rla R1a Rla ala is . In embodiments, R19 is . In embodiments, R19 is Rid R51N Rla ,--NH2 \ NH2 R1a R1a Ria . In embodiments, R" is . In embodiments, R" is Rid R1a N Rla NHC(0)0C(CH3)3 S S
Rla R1a Rla Ria . In embodiments, R19 is . In Ria N
,¨NHC(0)0C(CH3)3 Rla R1a embodiments, R19 is . In embodiments, R19 is Fed R1a Rla N
\ NHC(0)0C(CH3)3 ) O S
R1a R1a Rla Rl a . In embodiments, 109 is . In embodiments, R19 is R1d R1d R1a \ R1a N Ria ) \
S

Ria Rla R1a R1a Rla R1a . In embodiments, R19 is . In embodiments, 1119 is . In Rla S R1a 0 j Rlh lh /
N
R1a Ria Rld Ria Rla embodiments, R19 is . In embodiments, R19 is . In embodiments, 1:09 Rla 0 R1a S
z R1 h />__R1h N
Rla Rid R1a R1a R1a is . In embodiments, R19 is .
In embodiments, R19 is Ria S R1a S
>¨ NH2 N
R1a R1a R1 d R1a Ria . 141 embodiments, R19 is . in embodiments, R19 is Ria 0 R1a 0 >¨ NH2 N
Rla Rla R
Rla Wa . In embodiments, R19 is . In embodiments, R19 is R1a S R1a S
NHC(0)0C(CH3)3 / NHC(0)0C(CH3)3 N
Wa R1a Rid R1 a R1a . In embodiments, R19 is . In R1a 0 ¨NHC(0)0C(CH3)3 N
R1a Rla embodiments, R19 is . In embodiments, R19 is Ria 0 Rla 0 / NHC(0)0C(CH3)3 N
R1a R1a R1 d Rla Rla . In embodiments, 109 is . In embodiments, R19 is Ria 0 R1a S Ri a S

Wa R1a R1a R1d R1d Rla R1a Rla . In embodiments, 111 9 is . In embodiments, R" is .
OP N ,¨N H2 IS
S
O
>- NH2 S
[00453] In some embodiments, R19 is F . In some embodiments, r?29 is F . In CN

\ NH2 / NH2 S
CN
some embodiments, R19 is F . In some embodiments, R19 is F . In some embodiments, R" is 1.1 N H2 S . In some embodiments, R" is N . In some embodiments, CN S

\ NH2 R" is S . In some embodiments, R19 is CN . In some embodiments, R" is 0 N lei s ,¨N H2 S N
F . In some embodiments, R" is F . In some embodiments, R19 is N S
¨ N H2 --N H2 S N
F F
F . In some embodiments, R" is F . In some embodiments, R" is ,--N H2 >¨N H2 S N
F . In some embodiments, R19 is F . In some embodiments, R19 is ,--N H2 O N
F . In some embodiments, R" is F . In some embodiments, R" is ON

\ N H2 / NH2 C N
F . In some embodiments, R19 is F . In some embodiments, R19 is Iso N H2 0 0 ,--N N H2 O . In some embodiments, R19 is N . In some embodiments, R19 is \ N H2 O . In some embodiments, R19 is ON . In some embodiments, R19 is N
1101 )-- N H2 01 --- N H2 N
F . In some embodiments, R19 is F . In some embodiments, R19 is ,-- F N H 2 F - N H2 F . in some embodiments, R19 is F . In some embodiments, R19 is F 0 N\ F
N H2 110 I)-- N H2 F . In some embodiments, R19 is F . In some embodiments, R19 is 0 ¨
S

CN . In some embodiments, R19 is F . In some embodiments, R19 is ¨ ¨
¨
S S
S
jlII:
F F . In some embodiments. R19 is . In some embodiments, R19 is F

S S
. In some embodiments, R19 is F CI . In some embodiments, R19 is CI . In some s CN H2 N CN
S ,:ii. ..-= ::,..
/
I
N ..., embodiments, R19 is . In some embodiments, R19 is . In some embodiments, S,.... ,T.
R19 is . In some embodiments, R19 is . In some embodiments. R19 is ¨ ¨
S õ...
NX
S ,....
. In some embodiments. R19 is . In some embodiments, R19 is F
. In some embodiments, 109 is F . In some embodiments, R19 is F
. In some S ,...-, S
F
embodiments, R" is F . In some embodiments, R19 is . In some embodiments, SFS -----R19 is F . In some embodiments, R19 is F . In some embodiments, R19 is S- IA
F . In some embodiments. R19 is F . In some embodiments. R19 is S...,,f,...
F
[00454] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is:

HO
5-2(. HO
)---7-----N
S
lb 'V S
1111 'V. /,,,- F

0 µV
F , F F , F , , , HO 'z,i, 'V.
H2N N,.. '22z!' H2N N H2N H2N N1, li I .,.... I F N
----F , 410 FI-----LJi L) ,..,_ I

µ.
\:. LLL µ..
F CI H
F . F
N'N

F , , 11101 '''r / N___ N/ N-N ,NI____ ____ /0 N¨N HNli N-NH / ION µzzi_ H NI
\--._ µ. 0 µV 101µ
, HN
CI
F II CI , , , , , H
H --- N N '1õ- H2N N
1\1,..
yõ. H2N N,...(/ICL H2N N\
ij,.. CF3 ....(_.. ,v, CF3 V:

, H HO
,.. N T 1:1 1-2( H
H2N N cz,- N N 'z,- HO
....
1 ___.
.F3 .F3 CF 3 OC F 3 CI
, HO 411 "2.,'L HO .22;. F
N'''....)22;- CI 0 V.z.

, or NH2 , , , .........
x4%.****-- x10 I II
X5,. - X9 [00455] In embodiments of the subject compound, 109 is --X" wherein X4, X5, X6, X9, and Xl are as x12 x:-.7,./. =::-. x11 I I
x5,.. .....,. ... , xl10 described herein. In embodiments of the subject compound, R19 is '. X6 X9_ wherein X4, X5, x6, x9, xi , _ X11, and X12 are as described herein. In embodiments of the subject compound, 1:09 is wherein X4, .x5, .x6, Q1, and Rth are as described herein. In embodiments of the subject compound, Fe9 is ¨
x4-_-(11 1 R1 h X5' N--- 1 '-X6- Q wherein xl, xs, x6, Q', and IC are as described herein. In embodiments of the subject .........
x9õ-roZO
II
ce compound, R19 is x wherein X9, xlo. xii. Q3. ,s11.
y and Rlh are as described herein. In ¨
X9.-'CI\4 II
iiQ3 ---embodiments of the subject compound, R19 is x wherein X9, x10, x11, Q3, Q01, and Rill are as r-- , Q __ XL ...., Rfii -- ...-------- Q4 described herein. In embodiments of the subject compound, R19 is '..X8 wherein X7, X8, x12, Q3, Oy N Q3 --.R1h Q4, and Ri11 arc as described herein. In embodiments of the subjcct compound, It" is X8 wherein X', X8, Q3, Q4, and Itth are as described herein. In embodiments of the subject compound, It' is I R1 h wherein X', X8, Q3, Q4, and Itth are as described herein. In embodiments of the subject 0 Q4 N --111h compound, R" is X8 wherein X', V, Q3, Q4, and RH' are as described herein. In CI-E

h \ Q4 embodiments of the subject compound, R19 is Q wherein Q3, Q4, Q5, Q6, and Itlh are as 19 is wherein X
x6, X5-- 4 x4 described herein. In embodiments of the subject compound, R, X5, V, Q3, and Q4 Cyr,'12c I
X6, j- X4 are as described herein. In embodiments of the subject compound. R" x is wherein X4, X5, X', Q3, h and Q4 are as described herein. In embodiments of the subject compound, R49 is \ce wherein, Q3, Q4, Q5, Q6, and Rlh are as described herein. In embodiments of the subject compound, R19 is R1a 13_ IR1 h X1,4 4 X15 Q wherein, Q3, Q4, x13, )(14, x15, Rla and Rh are as described herein.

"ezr.
[00456] In embodiments of the subject compound. R19 is . In some embodiments of the subject 7,_ compound, RI' is F . In further embodiments of the subject compound, RI' is F F .In HO-additional embodiments of the subject compound, R19 is . In select embodiments of the HO-subject compound, R19 is F . In embodiments of the subject compound, R19 is uc F . In some embodiments of the subject compound, R19 is 1110 . In some H2N `2( embodiments of the subject compound, R19 is . In further embodiments of the subject H2N N.., Va.

compound, R19 is . In select embodiments of the subject compound, R19 is NH2 In embodiments of the subject compound. R19 is F . In some embodiments of the subject compound, R19 Lac.: tz2i:
CI
is . In additional embodiments of the subject compound, R19 is . In some embodiments of the subject compound, R19 is . In further embodiments of the subject compound, C I
R19 is F= In embodiments of the subject compound, R19 is F . In select embodiments of the subject compound, R19 is . In some embodiments of the subject compound, R19 is . In N¨N H
additional embodiments of the subject compound, R" is . In embodiments of the subject compound, N¨N N¨N/

109 is . In embodiments of the subject compound, R19 is F= In further embodiments of the H N
Ge.
HN
CI
subject compound, R19 is CI. In select embodiments of the subject compound, R19 is I
. In some embodiments of the subject compound, R" is . In additional embodiments of the Ny subject compound, R" is . In embodiments of the subject compound, le9 is . In some embodiments of the subject compound. R19 is . In further H2N..T:x.2t;
I

embodiments of the subject compound, R" is . In select embodiments of the subject compound, R19 is F3 . in some embodiments of the subject compound, 1119 is 'zzz.
In embodiments of the subject compound, R" is F3 In some embodiments of the subject HO aso compound, R" OC F3 is .. . In additional embodiments of the subject compound, R19 is HO
µVa. HO

CI . In further embodiments of the subject compound, R" is CI . In select HO
embodiments of the subject compound, R" is CI
. In embodiments of the subject compound, R"
N CI
is C F3 In some embodiments of the subject compound, R" is NH2 In some embodiments CN
=

of the compound, R19 is F . In some embodiments of the compound, 109 is . In CN
"N
some embodiments of the compound, R19 is F . In some embodiments of the compound, R19 is CN
CN
\ N
N
. In some embodiments of the compound, R19 is H . In some embodiments of the CN
CN
\ N

compound, R19 is . In some embodiments of the compound, R19 is F
. In some CN
embodiments of the compound, R19 is F
. In some embodiments of the compound, R19 is CN
CN
. In some embodiments of the compound, R19 is H. In some embodiments of the \ N
/ N
compound, R" is H . In some embodiments of the compound, R19 is . In S
embodiments of the compound, R19 is .
In embodiments of the compound, R19 is s H2N C N
S
. In embodiments of the compound, R19 is . In embodiments of the S
S
compound, R19 is . In embodiments of the compound, R19 is . In embodiments of the compound, is F . In embodiments of the compound, R19 is F . In S
embodiments of the compound, R19 is F
. In embodiments of the compound, R" is ;
H2N s <\\N H2N C N
S
. In embodiments of the compound, R19 is F . In embodiments of the S S
,L),µ
compound, R19 is F . In embodiments of the compound, R19 is F . In S
embodiments of the compound, R19 is F .
In embodiments of the compound, R19 is [00457] In embodiments R19 is selected from F
,,,,,,,_ ok )..rs....,, \,,,_ ii:\c-j< Fic,..),.,_ .,,,,,:q i.4 f -11--- \
----..)' `'-c: CI =
1 .2N
-CH =CH, OH L-1 .4"---j ----<1 .. . ,,,, , i ;51i .--- -r = Ci p ,N
I H N
/4 , .' '{' HN`L4.- ' , tr.N -1,4 Kt \i-i-t, Li.:-....<, ,----,-- , ..., N
Ft 1 -1/4 - - r l k).-1- - 1,5 H_õ.. 1111c A_,./
"
,N
HN ',7 __.õ.

1 -00:1k 0 g-k=,-(4-1, fr's. 'N., r-, .....:
li- 1 ,....õ....õ- ON - 4, õ..0-µ....,..õ,-.' 14, ..." ...,_<.:-' ,-, --- ..-=-=
f õLõ rac ..t.õ NI ,1,... J., --r-c-µ
, (--1 '` 1 1O.) aT) io. .,..., ... i...----1 OH -"' OH 'OH
\ /I
NH2 , . . .
r _1.
:
Br $
rc:>+
F 1-1 8 1- 'e --,..
%
--.7= Nsh i A F ....") :-*--- N I4, H2N
. . , ar , --- IF F 1 Nii _111,,,,,,,,i 1 4C:f- i ( =,:.-t..- .,..)---HO 1-107 bil --- =-...., of-1 F F
_T__)_,, c.,,,rx F Li... 1 P ph ? q pri i yy ,,,)õ,ii \ .µ 1- CI - icti-i._ ' 1-1 "--1-,i= tr ,,,,.õ
--IL
L. _..."' .... ""
, = ' t A
.,.. _,.. , -%=-=----'-{
HO
c F 3 OCF3 HO

0 ocF3 C I 0 HO

0 lei66 6, CI
CI
F F
N "---I
SCH3 -_ 0.=. CH3 CI
CI

, /-CN CN OH CI
F , F , NH HO OH
i\N ../.- .-'>= /
N
F, HO
N =---I --;.-- -=-=;-OH Br HO
I LL
..-'. / OH HN' F , , .===';.=
F Br 0 /
./
0- oF
F , NH2 , HO HO HN NI_ CI F F F
F, F, F , NI___ HN____ HO H Ni F
F , , = , , NI_ HO CI 0 H Ni F

I F c OCF3, CI OH F
' , , F, HO 0 s CI

I 0 0 0, -..,, -,.., HO

./

F
F CI

= , , , , , , F, 0 F, 0 F F,I,F F .-I.F F
-OH
\o &\ N6A 0 SOS F
I

N CI CI I
CI , N '---I
CI

F3 _ CI CF3 , , . .
F
HO
el F,---1---.F
, OH HO

HO
1111 F 0 , OH , , NI_ ...
HNI OHicit.CI up IP
CI lel NH 2, F , CF3 , , , I

F
S 1101 IP n T
, CF 3 OH , CF3 , OH
' , ' N___ HIV OH F

.1 01101 0 1 N =N'N 0 "-'1',..
, , HO
/ N
LJ-FI
IN 0.--CF3 , F , V
HO /
OH , OH 0 CI CI
/ N
F , =F
, )----=-N H2N
H2N X---N iz----N
S
rXrS S S
SI SI F , and 01 .
, 1004581 In some embodiments, R19 is selected from:

-...._ CN
N
I ,-, L-LNH HO
I ,:1\1 ------CN OH CI
N
ft LJ
OH HO
N ''',-./ I ,---;.-OH Br F , , ----' ..-;,- ---;.-/ OH
F , F Br /
NH2 n HO HO HO
CI F F F
F , , , HO D HO
/-,,,-F
F
' ' , CI
N ''" HO
Lt i 0,C F3 HO HO
0,,i,F
F F , , HO HO

F

F , F , and , .
1004591 In some embodiments, R19 is selected from:

ON ON ON T ON
ON
1101 NI,¨NH2 0 S")--NH2 \ NH2 \ NH2 10 \ \
S N S N N N
\
H H H
N
F , F , F , F , F F H
, , , , .
S

S N 0 Ns>¨N H2 0 S¨NH2 s N\
1101 >¨N H2 0 ,>-- N H 2 \ NH2 / NH2 N
CN
F S ON , F , F

3¨NH2 0 1>-_NH2 * NH2 0 --N1-12 0 )-N H2 0 ,--1\11-12 F F
F F F F , F , F
ON

N
\ NH2 /EiJI_NH2 CN o 0 C)/ NH2 0 s>--NH2 0 N"¨NH2 0 CN ,¨NH2 0 \ NI-12 F F 0 N 0 ON , F
.
, .

CN

/)--N H2 41101 .¨N H2 10 (3/>--NH2 0 \)¨NH2 .--N H2 S

F F
F F F F F , F
' ¨ ¨ ¨
--- -_ S S S S S S S
../
F F , F , F CI , CI , NI , H2N s ,...., ,.... ON x H2N ON H2N s ,.:..,C,µN H2Ns., ON H2Ns ,i...,.oj,N H2:
,,.., iCN H2N CN
-_ N'-µ
F F F F
, ..\ S ,..., S .õ,..- H2N ON

F S ,õ..., k S ,......=
\T__ N---"k F F F F F
, N ON H2N ON H2 HO '''µ. 'i HO `V. HO
s... x ....õ... ....õ...
F CI
CI
N
) F , (1100 F , F , F , F, n n >N X-=-N )--=-N HO H2N N `,,i, H2N N,.... V, H2N
N,,,, 44.
S I I
to F F 0 F F F , 0 , , , , N__ N__ N-NH
N-N't /
We ilt dal \:. FIN
I
IIP
NH2 F ' IMP

NI_ F F
N¨N/ N___ HN' ,,,i, F CF3 F

H /
Ala La,.µ N' IP ci 101\ 101µ 01\ 10\ 1.1 F , a OH OH OH OH NH2 , , F F F F
CN CN F
lw,i =\ *2,i 0 ,L,L F3C 0 `22i: F3C
NC
\ NC 0 µ
NH
NH2 OH NH2 , ON, CN, NH2, OH, NH2.
, H2N N \ H2NN,,,,A
H2N NC iTX H2N N LXCF H N N -2 \ I ;,...N..xl. \
H2N NI\
U ,-,,-CI

OH, 3 CI. CI
, H2N N H2N Nõ. \
H2N x11..:. \ H2N N., \ H2N
LC: Nõ, \ H2N N : \

-=-õ_.,--..,..' - F F CF3 F CI F , and CI .
[00460] In some embodiments, le9 is selected from:
F N._.
/ HN' Si H2N lio F 0 / NH N
/ N¨NH
/
So N
OH , 0 , CI F 0 11101 1101 110 F
IP
= , , , N¨NH OH
/ N___ HO H2N
.., N
HN' Br Br F 110 HO [41( N
I

N '-- F H2N F H2N 0 HO
I
II Oa&
Br F
isr wir III
, , O
OH H

= n n n ' n = n OH
F F
OH, OH , OH
OH
Br NH
N¨A Nit CN , 0 , ' , ' HO, F3C iss CI 0 HO 0 = OCF3 161 F 1$11 F , , , . .
. . . , ILI HO

CI SCH3 , 0 N '===
I -/- CI CI CN CN
OHftL CI
' F, F n , n n 5 n NH HO OH HO
I ,NN ,/,- ..,,'',.
/
Nr OH Br Si F , IIV
n n n n n HO
N -'- .--CI
NJ_ ,/,- % /,,, OH HN' F , . . 9 =

/
, F Br F , NH2 , , HO HO N- - HO
HN' HN
CI F F F
F n F n F n F n n N_ NH2 FI.I N

OH
n 9 n ' 5 n F F
401HO 0 401 up NH lel 0 CI

-,.., D HO HO CI
CI V
V
./.=
SI :
CI so OH , CI OH 101 1011 1110 , , V '7 F CI ill CF3 F F
---F
1110 1101 OH , OH 0 0 F 1110 IP 5 IP
.
, , , , , .
F
CI
lei Li F F,--1.,F 1101 0 F---LF F
tl\r I L../
, OH
\

* 1101 I Oil CI
I 10 1.I 1101 , H
, , CI
HO HO N 0 ___ N '-^- CF3 0 I HN' I C F3 , c 1 C F3 , , F ,,,0 HO

0,C F3 0 F HO

si- I.1 S 0 F.,L.F 0101 F F F
, , , , ' V OH HO NI_ F

0 $ F 110 S, 0 , OH , 0 CI 0 CI
0 NH2, . . . , I

0 ,,0 HO 0 HO
F 0 H NIN ¨
s IP = 0 F n CF3, n CF3n , n OH

, , IV_ HNI OH F

0 'cc,, I o n OH n CI N X
n n , n n N H
/
F
0"--, ' CF3, V VI. H2N

),---N
).----N
CI CI
S
/N )-.---N f---=.1µ1 S
.

00S0 s0 OH , OH F
, n 1 >,----N
S
and 161 .
[00461] In embodiments, R'' is a fused bicyclic C5_12cycloalkyl. In embodiments, R'' is a fused bicyclic C2.
iiheterocycloalkyl. In embodiments, R17 is a fused bicyclic C7_paryl. In embodiments, R17 is a fused bicyclic C2_ tzheteroaryl.
[00462] In embodiments, R17 is a fused bicyclic C5_12cycloalkyl substituted with one, two, three, four, five, six, or seven R1i. In embodiments, R1' is a fused bicyclic C2-1 iheterocycloalkyl substituted with one, two, three, four, five, six, or seven Rh. In embodiments, R1" is a fused bicyclic C7_12aryl substituted with one, two, three, four, five, six, or seven Rh. In embodiments, R17 is a fused bicyclic C2_12heteroaryl substituted with one, two, three, four, five, six, or seven Rh.
[00463] In embodiments, R17 is a fused bicyclic C5_12cycloa1kyl optionally substituted with one, two, three, four, five, six, or seven Rll. In embodiments, R1' is a fused bicyclic C2_iiheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven Ril. In embodiments, R17 is a fused bicyclic C7_12ary1 optionally substituted with one, two, three, four, five, six, or seven Rli. In embodiments, R17 is a fused bicyclic C242heteroary1 optionally substituted with one, two, three, four, five, six, or seven R11.
[00464] In embodiments, R17 is a C3_12eyc1oa1kyl. In embodiments, R-17 is a C2.11heterocycloa1kyl. In embodiments, R17 is a C6_12ary1. In embodiments, R17 is a C?.pheteroaryl.
[00465] In embodiments, R17 is a C342eyc10a1ky1 optionally substituted with one, two, three, four, five, six, or seven Rll. In embodiments, R17 is a C2_iiheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven Rli. In embodiments, 107 is a C642a1y1 optionally substituted with one, two, three, four, five, six, or seven R11.
In embodiments, R17 is a C2_12heteroaly1 optionally substituted with one, two, three, four, five, six, or seven R11.
[00466] In embodiments, R1-7 is a C3_12cyeloalkyl substituted with one, two, three, four, five, six, or seven Rh. In embodiments, R17 is a C24 iheterocycloalkyl substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a C642aryl substituted with one, two, three, four, five, six, or seven RE. In embodiments, R17 is a C2_12heteroaryl substituted with one, two, three, four, five, six, or seven Rh.
[00467] In embodiments, Rh is independently hydrogen. In embodiments, Rh is independently halogen. In embodiments, R' is independently oxo. In embodiments, R" is independently -CN.
In embodiments, R" is independently Ci_6allcyl. Tn embodiments, R is independently C2_6allcenyl. Tit embodiments, Ril is independently CA_ 6alkynyl. In embodiments, R11 is independently C3_10cycloalkyl. In embodiments, R11 is independently C2_ 9heterocyeloalkyl. In embodiments, R11 is independently C6_10ary1. In embodiments, R11 is independently 9heteroaryl.
[00468] In embodiments, R11 is independently Ci_6alkyl optionally substituted with one, two, or three R201. In embodiments, Rh is independently C2.6alkenyl optionally substituted with one, two, or three R20`. In embodiments, Ril is independently C2_6alkynyl optionally substituted with one, two, or three R2c)1. In embodiments, Rli is independently C3.10cycloalkyl optionally substituted with one, two, or three R20. In embodiments, Rli is independently C2.9heterocycloalkyl optionally substituted with one, two, or three fe0i. In embodiments, R11 is independently C6.ioaryl optionally substituted with one, two, or three R201.
In embodiments, R11 is independently C1_ 9heteroaryl optionally substituted with one, two, or three le`h.
[00469] In embodiments, Rli is independently -0R12. In embodiments, Rn is independently -SR12. In embodiments, Rn is independently -N(R12)(R13, ) In embodiments, finis independently -C(0)0R12. In embodiments, Rn is independently -0C(0)N(R12)(R13) . In embodiments, le is independently )C(0)N
Nc- 14, (R12)(R13, ) In embodiments, is independently -N(R14)C(0)0R15. In embodiments, R" is independently -N(Ri4)s(0)2-K 15.
In embodiments, Rn is independently -C(0)R15. In embodiments, le is independently -S(0)R15. In embodiments, R" is independently -0C(0)R15. In embodiments, R11 is independently -C(0)N(R12)(R13, ) In embodiments, le is independently -C(0)C(0)N(Ru)(R13) . In embodiments, Rli is independently -N(R14)c(0)--tc 15.
In embodiments, R11 is independently -S(0)2R15. In embodiments, R" is independently -S(0)2N(R12)(R13) . In embodiments, R" is independently S(=0)(=NH)N(Ri2)(R13, ) In embodiments, RH is independently -CH2C(0)N(R12)(Ru) . In embodiments, Rh is independently -CH2N(R11-)C(0)R15. In embodiments, R11 is independently -CH2S(0)2R15. In embodiments, Rn is independently -CH2S(0)2N(R12)(R13).

Xl I II
X
[00470] In embodiments of the subject compound, 107 is X6 wherein X4, X5, X6, X9, and X11) are as x12 x10 described herein. In embodiments of the subject compound, R17 is X X wherein X1, xs, x6, x9, x11), I
X5. Qt Xll, and X12 are as described herein. In embodiments of the subject compound, R17 is s' wherein X4, X', X6, Q1, and Rth are as described herein. In embodiments of the subject compound, R17 is XI4-1'-r-Q1 R1 h X5, N.
X6- Q wherein X4, X', X6, Q1, and Rlh are as described herein. In embodiments of the subject X5ia3 h compound, R17 is X wherein X9, )00, Q3, Q4, and R111 are as described herein. In I I --R1 h Q
embodiments of the subject compound, R17 is X wherein X9, )(10, x11, Q3, Q1, and Rill are as I R1 h described herein. In embodiments of the subject compound, R17 is X" wherein X7, X8, x12, Q3, \

Q4, and Rim are as described herein. In embodiments of the subject compound, R17 is wherein X7, X8, Q3, Q4, and R1h are as described herein. In embodiments of the subject compound, R17 is N Q4.
[

wherein X7, X8, Q3, Q4, and Rh are as described herein. In embodiments of the subject oy N
Ih X7, compound, R17 is X8Q3 wherein X7, X8, Q3, Q4, and R1h are as described herein. In cr h embodiments of the subject compound, R17 is Q6 4 wherein Q3, Q', Q5, Q6, and Rth are as '2a X6, 5-- X4 described herein. In embodiments of the subject compound, R47 is x wherein X4, X5, X6, Q3, and Q4 N¨Q4 x6 , x4 are as described herein. In embodiments of the subject compound, R17 is X
wherein X4, X5, X6, Q3, h and Q4 are as described herein. In embodiments of the subject compound, IC is \Qs Q3 wherein, ()3, Q4, Q5, Q , and RI' are as described herein. In embodiments of the subject compound, RI' is Rla I

X15 Q wherein, Q3, Q4, x'13, x-14, x-15, Rla and Rill are as described herein. In embodiments of the , X16 ________________________________________ R1h subject compound,X16 R'7 is wherein, Q3, Q4, x13, x-14, x-15, x-16, R" and RH are as described herein.

[00471] In some embodiments of the subject compound, is . In select embodiments of the N
subject compound, R17 is F. In further embodiments of the subject compound, R17 is HO '22( F . In embodiments of the subject compound, R7 is . In additional HO
embodiments of the subject compound. R17 is F= In some embodiments of the subject compound, HO 42,(. HN
R1'is F . In embodiments of the subject compound, R17 is . In select embodiments of the subject compound, R17 is . In embodiments of the subject compound, R17 H 2N 1\1 '2FXU
is . In further embodiments of the subject compound. R17 is NH2 In some embodiments of the subject compound, R1.7 is F . In additional embodiments of the subject I II I II
CI
compound, R17 is . In some embodiments of the subject compound, RI7 is . In Lzzc.

embodiments of the subject compound. R17 is . In select embodiments of the subject compound, CI
R17 is F . In further embodiments of the subject compound, R17 is F . In some N___ HN
embodiments of the subject compound, R17 is . In embodiments of the subject compound, R17 is 1\1¨ N ¨NH
HN 401,õ
tipp . In embodiments of the subject compound, 107 is . In additional embodiments of the /
N ¨ N/
N ¨N
'222:
subject compound, R1.7 is . In select embodiments of the subject compound, R1.7 is F= In N.
H N 0 µv further embodiments of the subject compound, R17 is CI. In some embodiments of the subject H
H N rat, =-zza.:, N N..., \-IIIP ,..
I
...-' CI
compound, R17 is . In embodiments of the subject compound, R17 is . In some H

....

embodiments of the subject compound. R17 is . In additional embodiments of the subject I.õ,...
compound, R17 is . In select embodiments of the subject compound, R1.7 is * \ ,.,'.'" \ ., µ.., r 3 . In further embodiments of the subject compound, R17 is . In H2N,, cix,.., I
.,-- , embodiments of the subject compound, R17 is µ.....r3 In some embodiments of the subject H
I ,...N
.11 ,õ,,,,zia.
/ I
%....1- 3 / , , ,.... r compound, R17 is . In some embodiments of the subject compound, R17 is 3.
HO
In additional embodiments of the subject compound, R17 is 0 C F3. In select embodiments of the HO
'HO 0 'di,:

subject compound, R17 is CI . In embodiments of the subject compound, R17 is CI .

\, In further embodiments of the subject compound, R17 is CI . In some embodiments of the subject N CI
compound, R17 is CF3 .In embodiments of the subjcct compound, R17 is NH2 .In some =NH
embodiments of the compound, R1.7 is F . In some embodiments of the compound, R1.7 is CN CN

. In some embodiments of the compound, 107 is F . In some embodiments of the CN
CN
\ N
\ N
compound, R1.7 is . In some embodiments of the compound, R17 is H. In some CN
\ N
embodiments of the compound, R17 is . In some embodiments of the compound, R17 is CN CN

. In some embodiments of the compound, R17 is F . In some embodiments of the CN
CN
compound, R17 is . In some embodiments of the compound, R17 is H. In some \ N
embodiments of the compound, R17 is H . In some embodiments of the compound, R17 is S
/ N
. In embodiments of the compound, R17 is . In embodiments of the compound, S S
R" is . In embodiments of the compound, R17 is . In embodiments of the H N C N

S
S
compound, R" is . In embodiments of the compound, R" is .
In embodiments of the compound, R17 is F . In embodiments of the compound, R17 is F .Ill S
embodiments of the compound, R17 is F
. In embodiments of the compound, R" is S
. In embodiments of the compound, R" is . In embodiments of the compound, R17 is F . In embodiments of the compound, R17 is F .In S
embodiments of the compound, R17 is .
In embodiments of the compound, R17 is S
[00472] In some embodiments, R17 is selected from:

ON ON ON T ON
ON
1101 NI,¨NH2 0 S")--NH2 \ NH2 \ NH2 10 \ \
S N S N N N
\
H H H
N
F , F , F , F , F F H
, , , , .
S

S N 0 Ns>¨N H2 0 S¨NH2 s N\
1101 >¨N H2 0 ,>-- N H 2 \ NH2 / NH2 N
CN
F S ON , F , F

3¨NH2 0 1>-_NH2 * NH2 0 --N1-12 0 )-N H2 0 ,--1\11-12 F F
F F F F , F , F
ON

N
\ NH2 /EiJI_NH2 CN o 0 C)/ NH2 0 s>--NH2 CN
0 N"¨NH2 SO N H2 0 \ NI-12 F F 0 N 0 ON , F
.
, .

CN

/)--N H2 41101 .¨N H2 10 (3/>--NH2 0 \)¨NH2 .--N H2 S

F F
F F F F F , F
' ¨ ¨ ¨
--- -_ S S S S S S S
../
F F , F , F CI , CI , NI , H2N s ,...., ,.... ON x H2N ON H2N s ,.:..,C,µN H2Ns., ON H2Ns ,i...,.oj,N H2:
,,.., iCN H2N CN
-_ N'-µ
F F F F
, ..\ S ,..., S .õ,..- H2N ON

F S ,õ..., k S ,......=
\T__ N---"k F F F F F
, N ON H2N ON H2 HO '''µ. 'i HO `V. HO
s... x ....õ... ....õ...
F CI
CI
N
) F , (1100 F , F , F , F, n n >N X-=-N )--=-N HO H2N N `,,i, H2N N,.... V, H2N
N,,,, 44.
S I I
to F F 0 F F F , 0 , , , , N__ N__ N-NH
N-N't /
We ilt dal \:. FIN
I
IIP
NH2 F ' IMP

NI_ / F F
N¨N N___ HN' ,,. F CF3 F

H N' 0\ 0µ 0\ 0\ 40µ 0\
ipp F , CI OH OH OH OH NH2 , , F F F F
CN CN F
0 \ 0 \ AI µ 0 0 µ 0 =-e6L F3C 0 '2ti_ F3C
\ \ NC 0 \
NH2 NH2 111" OH NH2 , ON, CN NH2 , OH, NH2 .
H2N N.,.. \ H2 N N A.
NO ''zi= H2N N H N N .. -2 \ I
' H2N N. \ H2N N,\
irx -Gx\
u .....r..,CI
cF, .õ.,..a..
-,,, OOH, CF3 CI . CI , , H2N N H2N N,...
\
H2N N :GC\
H2N N.,, \ H2N N.., \ H2N
LC\
F CF3 LI õ..L. ..,X I
- F F 0F3 F CI F,----..,_...----..,' , and CI .
F

/ NH
I. 0 F 0 [00473] In some embodiments, R17 is selected from: OH , 1101 , CI F
ill , 0 , NI_ N¨NH OH
/ N/ HNI /
N¨NH
0 17¨NH
HININ¨

/ N

. .

Br 116 NI Br I Br ll Od&
I N \ I F Ith INV NW

F H2N F H2N so HO 0 HO F F
= All n n n n n n n OH
OH
Hni 01 , F
F
F
F
OH
OH
0 , OH , OH ON , , , , Br N¨I
N---k NA N-1 0F3 . , F F so CI
ill , .

n >
o n, NJ
I-.

CO
NJ

NJ
'tj =

-n #
0, * I

-n # Cn) 0 -n * , N , 0 N
-0 .....

N
0 4C) 4,71 i i CA
cc I
1-k fil -n -n 2 cn # " 4 -n \\\ =
-z . 2 ca , - -* 4 .'µ 0 \\

' ..
i \ / \
.1.' I
=
c /
-. -n 0 * 0 4 . 1 /
0 õ --n 4 -n =
¨

,.

It /

c=-) g #
0 .
Lt i CP,.
* 0 i 4 4-n+0 -n \

. N

N
g * 0 0 *
*

7 !
\\ ..

(I) ..
-(JI
-.
--n ---OH

0 0 , HO , , , CI V 7 CI
IS S
I
, ' CI

F
HI\I___ HO
N

V IP r., 0,CF3 0 F
CF3 CI .,. 3 F 40 , F F , , .-- ilk, HO
HO V OH
CF3 = HO
S
F F
l'--. 1) 0 , , 0 0 la F 0 =-, , , , . 1/0.

NI_ F 0 HO 0 .-0 HI'!10 OH

OH , NH2, F , CF3, ' IV_ HO
F3C OH IV_ HNI OH F
HN

F (16 0 = 0 ,._=
OH OF3n n OH , CI
- N
n 5 5 /
--rL`k=Al CF3 0 /

CF3 [110 .
, .
V V
HO / CI
/ N

IJL F F CI
F , n LL F 4101 0LJ OH , OH , n n 5 H2N X-,---N H2N
H2N),---N

0 0 F ,and (100 1004741 In embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R2 is selected N---\\
from F
F
OMe v / F
/-----"-6?
v N cr's'0 N N

H
\
N---,, ,0---NN--- Ao N . ---\co H2F A0C)CC-N)1 ' 1 /0 ' 0 ' c's<0 N "' /
1-10 ---->
/..11\
õON ,,, ,,,, 0 0 ,,.
0)__o No rN \71 0 N' . , .
, F
NO-. F =-= '' .6 CY.''' "0....ome 0"
= OCF2 H
N--/
F
J
cA
I
xo.---,.,---F ciscNOJ'./3 0 y=-- 0 0....
-F
frr<
0 0 0 0Me cONO AON S \
0S ''Cl \
, F.Nik FF
,F S'0"--*0 1-- /NO r--- r-scrsa'kr=-- ,:r< ,--,,--,N,Th N--..../ N.--/
, 1---\
--1=-\N = NV I 0 =rc\-ip....OH
O_N L-(3 /
, ' /
Xo IN AO el .,.t, N--ces<0µµ 0 . 4:'j&."'' , H
['N'' =-. õ , isr-s-N--"--,-.= N ==...) _...N j._,,_ ,N ......0,,,,...) ,N
H'LI, -=-=-=-- - N 'II, N 1 --,_,..N.,.., , F
.õ--...N0---. y .-.s.'C F 3 I
p 0,0 4,(0_,01---------N----ciso r...
-'-'N `-- r -0- ..r.- 0 = F r 0 ' F
F
;sss.oNfD r14F1 NO vls NO ;f4S _______ NO
, Ilsr--------/C NO jss-:O---)CNLD<F vlss-0---)C ft........F ;rif-0"---7C 0 .
"F, F , r/ss'02C NO r:fr&CD--)c N3 rIsCY-)C. 0 rIss- -- NI '- `\/-, I
c/50-/C-NC)11 ;015:0 N3 xt-cc N cyr.cy2c ,- c'sr-0--/)CN-Th N
_______________________________________________________________ 1 , j402r CN ;rss-OWN--I vlscr.WN
`15.10Nr `isIST-D
c.55sN rcr jsr--r-NJ ,N113 ---<- 0 H z , , xs 0 I
N N
, 'XN c'ssiN 1 rrr's' NO
crss0J'= ,:prs, N,Th LT.15 r\j' rFrZ.N'-'1 N
N
L.,....., N
/ ... -,._.- , ,..-Lõ.., N , \-0Me , ' g.&.N-------) A.C)L6 r/'0 v.rcZNI\
\
Ar N No N N
\-0Me , /
, z_F
0 n isss.CY-446:1 ___GN .'s=
_Os and '0 ' .
osZo,t,..0 c:0-)1 [00475] In embodiments, R2 is / . In embodiments, R2 is . In embodiments, R2 is c'ssl'O''LO A.0j"''D rr(0 N ---/
. In embodiments, R2 is ., . In embodiments, R2 is .., . In embodiments, F
R2 is . In embodiments, R2 is . In embodiments, R2 is / . In isszr.
additional embodiments of the subject compound. R2 is . In embodiments of the subject compound, R2 is ¨C . In select embodiments of the subject compound, R2 is I . In further A.-"µ.
a embodiments of the subject compound, R2 is ..
. In some embodiments of the subject compound, R2 c:re'0 r-ss:c.
is . In some embodiments of the subject compound. R2 is . In embodiments of AO
N
the subject compound, R2 is 0, In additional embodiments of the subject compound, R2 is F
N 0 ' N
. In select embodiments of the subject compound, R2 is . In further embodiments F
F
r:r(0 N
of the subject compound. R2 is . In some embodiments of the subject compound. R2 is OM e In embodiments of the subject compound, R2 is 0 " C
N
. In some embodiments of the subject compound, R2 is . In additional embodiments of the subject H
N¨
0 "'II
compound, R2 is . In select embodiments of the subject compound, R2 is \
N ---. In further embodiments of the subject compound, R2 is (--õ...õ.....-. In embodiments of the subject compound,N R2 is L.) . In some N
embodiments of the subject compound, R2 is -----C . In embodiments of the subject compound, R2 is AN
. In additional embodiments of the subject compound, R2 is . In select embodiments of the subject compound, R2 is N ''N.'" . In embodiments of the subject compound, R2 is c3ss'0""'NO-dilF
-r . In further embodiments of the subject compound, R2 is /INC). In some F
embodiments of the subject compound, R2 is /
. In embodiments of the subject compound, R2 is OF
"'.0--'''=
0 = Nr-D.....0Me / . In additional embodiments of the subject compound, R2 is / . In embodiments of the subject compound, R2 is /
. In select embodiments of the subject 10<F
compound, R2 is / . In further embodiments of the subject compound, R2 is A.--,....,......---.N.---.õ
c:rrs'.0Nt.D 0 . In some embodiments of the subject compound, R2 is L'N./-. In some 0-Cs... .,=-= ,,, 0 ' (0 ) embodiments of the subject compound, R2 is \
. In embodiments of the subject compound, R2 is 0 ' OMe 5 6-ss:
0---)(---\ . In additional embodiments of the subject compound, R2 is N.,õ5--- . In select embodiments of the subject compound, R2 is /
. In further embodiments of the subject c3j5-00 'r-r.

compound, R2 is / . In some embodiments of the subject compound, R2 is 0 ......
N
In embodiments of the subject compound, R2 is I . In embodiments of the subject compound, R2 is N -5.-= _ z I
rc-,----__, N ,.. 0 . In additional embodiments of the subject compound, R2 is 0 . In select iss: N-Th embodiments of the subject compound, R2 is 1-,,,0 . In further embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is /
. In some embodiments of the issf, 0 = 5/-subject compound. R2 is 0---- N .
In some embodiments of the subject compound, R2 is .

In additional embodiments of the subjcct compound, R2 is . In select embodiments of the subject N
compound, R2 is I . In embodiments of the subject compound, R2 is / . In -..., ire... õ.......õ,....1-. ,N
N N
further embodiments of the subject compound, R2 is H . In some embodiments of the subject (-1\1- -..., N ----µN
compound, R2 is H . In embodiments of the subject compound, R2 is N -`1- . In -, N---N
,,,...0,...>=::-.N, additional embodiments of the subject compound. R2 is 't" . In embodiments of the subject ., ..--., compound, R2 is I . in select embodiments of the subject compound, R2 is 0N-,...
,...---....N -----..,..-0......õ
In further embodiments of the subject compound, R2 is `1.5.0'.---'-'-j . In some embodiments of the subject compound, R2 is k-) . In embodiments of the subject compound, R2 is L) .

.....----..
'0 In embodiments of the subject compound, R2 is ,--, . In additional embodiments of the subject Clj"----.'-'N '-,:ssr.
compound, R2 is 0 . In select embodiments of the subject compound, R2 is ----N
c.fir:S"--GN . In further embodiments of the subject compound, R2 is 1:ssr------') . In some (:),S) Q"---s---embodiments of the subject compound, R2 is u . In some embodiments of the subject ,1 Y
compound, R2 is / . In embodiments of the subject compound, R2 is / . In additional c:140.101 embodiments of the subject compound, R2 is . In select embodiments of the subject compound, R2 r140/'''r 0 'illy N---/
is / . In further embodiments of the subject compound, R2 is / . In some /*DWI
embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is F
c14076:SI
K.....-. In some A embodiments of the subject compound, R2 is 0 0 . In additional embodiments of the subject compound, R2 is H . In select embodiments of the subject ris.s. N NO
I ________________________ compound, R2 is 7C.
In further embodiments of the subject compound, R2 is ctrss'S.--)CNO
. In embodiments of the subject compound, R2 is . In some embodiments of the subject compound, R2 is F . In some embodiments of the subject viss-0--')CNI___D....F
compound, R2 is . In select embodiments of the subject compound, R2 is riscs'O)C NO . , %F
csisf''CY'-X. NO
. In additional embodiments of the subject compound. R2 is .. . In cls10---)C N3 embodiments of the subject compound, R2 is . in further embodiments of the subject c-rss'0"-')C NO
compound, R2 is . In some embodiments of the subject compound, R2 is sssr5-0NO ;r5s-02C-N-.1 . in embodiments of the subject compound, R2 is L----' N`-- . in select ;5ss'e)C NO
embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is I
?sr.
)c"--. In some embodiments of the subject compound, R2 is 1 . In further sls0-)CN
embodiments of the subject compound, R2 is L.õ,.0 . In additional embodiments of the subject f-srlOWCN
rkrs''ORcN"--I
compound, R2 is 0 . In some embodiments of the subject compound, R2 is 0 .
,:c.r!:06CN
In embodiments of the subject compound, R2 is 0 . In select embodiments of the subject compound, ss,cy)cCN riss'ON

R2 is . In some embodiments of the subject compound, R2 is . In further cksf.
S'..0 embodiments of the subject compound, R2 is / . In some embodiments of the subject compound, R2 is N
. In embodiments of the subject compound, R2 is NID. In additional embodiments s;5.....õ_.,..,,..õ, of the subject compound, R2 is 0H= In select embodiments of the subject compound, R2 is AC 51ss I . In some embodiments of the subject compound, R2 is I . In further õ, isi I
embodiments of the subject compound, R2 is N'-. In embodiments of the subject compound, R2 is F
:
I crsrsc-0"--446), N'''= . In embodiments of the subject compound, R2 is . In select embodiments of Or A N
the subject compound, R2 is Cr'') . In embodiments, R2 is / .
"--0-'-'"" N
iss:r.
¨c N
In embodiments, R2 is independently selected from / , ' I
, F
/-0 c'sks,. ,*skr.
---/,, tke:
0 a ,0 0-6?
N 0 ' N
N

F OMe F H
ckss.'0 0 ' -'-_ 6----) CH2F s'ssi'0 N /-0-"LQ=,,,/c3-e¨

N N
o \ 0 0 c:r(0-3 c:rr:0----3 N--/ -- .
r--- N
\7 ----A
F
N I\OF
0 = ,.6 /
z , / 11\
r'ss'"---/1----Ni....,0me 0.asiOCF2F1 `3.(0"-'''=,----\ ,F ,:sss 1-2F 'IC3NO N /N
/
' "
N----i 0--,0Me c.5:r'O'N
o'r 05 I5"-'0 , r' NO
1-=,_.,0 N/ I A,.., 101 , o N L.) = , . .. ,:s< .. -=-, ilD....OH ' -:5'5!-- C, AO 40 ¨0µµ
N
IN
0"
IN \\
CN ,zr ..õ...õ....,1N "zr_N,,õ) H
)-- -N
0,,,,,G..: ,N
c:Fssc,,,---,..CiN cx o.,-..õ,..Ø., ...,---.., ,----...N.---rls:''01\r' - N ...'C F3 5s.1:
-0 1 RµP
,.,, N
N -... NC) ..-,..N.-,,,...Sõ, AsCil o ' r-ss-ZoXN----/
i :g07.r.- rls'z0- ,-,4 -/-(IV $0--,Ti N
N---1 Y.c) 'N-.../
/ / /N----/

F
c3jC)7LCSN ,:is,,X0 rs-sHN)CNI.D ?sINI-CNLD ;''s-SCKII --I
`-----/ , ..z risslc 0 'sr's-02C NOKF c:rcf.0-.7C O,.F r' 0 .
,1F
F
, OCNO r-rre)CN3 - riss-e)c No 614C)/CN
.', csrY5-0-7CNI c=is:07\A
__________ L.,...., N N3 r1402c I s N rssi-0/\/CN 'IsnCN

, 02<CN ;r5I-OW N ---1 ;,ss,cy....x.CN , css!e)cCN

.I\O/ OH I
, , , r15s N
N......,õ....---..N.-- el I Ala, I 'r(0 I , ---46? ss, . 0 , H \
N-0 - ,1õ0 c' ' /
F
J, r..õ x0Jõ. 0 AO,J,.
_---N
'''N___./ 0-0 ,-- 0 .
, f"-oFõr_F
R
sAs 1õ ssg.0Jõ.
css: .1F
- o ,r--;s40!-- = 7 e, õ-t, N -..../
r'ss0-1'' F / ---') /- N-Th X N
N
N L_N L'n ' , --j\\--N
\-0Me \-0Me r-c3 AO"'=1\a,-F

0 , and [00476] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R5 is hydrogen.
1004771 In some embodiments, R20a is independently selected from halogen, -CN, Ci_6alkyl, C2_6alkenyl, C2-6alkynyl, C3_6cycloa1kyl, C2.9hctcrocycloalkyl, oaryl, Ci_91ictcroaryl, -OW', -N(R22)(R23), -C(0)01122, -C(0)N(R22)(R23), -0C(0)N(R22)(1223), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(1224)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein Ci_6alkyl, C2-6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2.9heterocycloa1kyl, C6_1oa1yl, and Ci_9heteroary1 are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci6haloalkyl, Ci_6alkoxy, Ci_6ha1oalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23). _N(R24)c(o)N(R22)(R23), _ N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In some embodiments, R20a is independently selected from halogen, -CN, C16alkyl, -OR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)R25, and -0C(0)R25, wherein C1_6alkyl is optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci.6a1kyl, Ci.
6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In some embodiments, R2' is independently selected from halogen, -CN, Ci_6alkyl, C2_6alkenyl, C2_6alkyny1, C3_6cycloalkyl, C2_91ieterocy eloalkyl, C6_10a1yl, Ci_9heteroatyl, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein C1.6alkyl, C2_6alkenyl, C2.6alkynyl, C3.6cycloa1kyl, C2-9heterocycloalkyl, C6.ioaryl, and C1_9heteroary1 are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), _C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In some embodiments, R2" is independently selected from halogen, -CN, C1_6alkyl, -0R21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)R25, and -0C(0)R25. wherein Ci_oalkyl is optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci.6alky1, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21; -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In some embodiments, R2" is independently selected from halogen, -CN, Ci-6alkyl, C2_6alkenyl, C2_6alkyny1, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_10aryl, Ci_9heteroary1, -0R21, -SR21, -N(R22)(R23), -C(0)0R27, -C(0)N(1172)(R73), -0C(0)N(R22)(R23), -N(1224)C(0)N(R22)(R23), -N(R24)C(0)0R25, -1\1(124)c(0)R25, _N(R24)s(0)2R25, _c(o)R25, _s(o)2R25, _s(0)21,1(R22)(R23), _ OCH2C(0)0R22, and -0C(0)R25, wherein C1_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2heterocycloalkyl, C6_10a1yl, and Ci_,heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_ 6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In some embodiments, R2' is independently selected from halogen, -CN, C1_6alkyl, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)R25, and -0C(0)R25, wherein Ci.6alkyl is optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci.6a1ky1, Ci.6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
1004781 In embodiments, Rna is independently halogen. In embodiments, R20a is independently oxo. In embodiments, R2' is independently -CN. In embodiments, R2' is independently Ci_6alkyl. In embodiments, Rna is independently C2.6a11ceny1. In embodiments, Rna is independently C2_6a1kyny1.
In embodiments, R2' is independently C3.6cycloalkyl. In embodiments, R2' is independently -CH2-C3_6cycloa1kyl. In embodiments, R20a is independently C2.9heterocycloalkyl. In embodiments, Rna is independently -C112-C2_9heterocycloalkyl. In embodiments, R2' is independently C6_10aryl. Tn embodiments, R2" is independently -CH2-C6_1oaryl. In embodiments, R2' is independently -CH2-C1_9heteroaryl. In embodiments, R2' is independently Ci_9heteroalyl. In embodiments, R2' is independently -OR'. In embodiments, R2' is independently -SR'. In embodiments, R2' is independently -N(R22)(R23) . In embodiments. Rna is independently -C(0)0R22.
In embodiments, Rna is independently -C(0)N (R22)(R23) . In embodiments, R2' is independently -C(0)C(0)N(R22)(R23). In embodiments, R2' is independently -0C(0)N(R22)(R23) . In embodiments, R2' is independently -N(R24)C(0)N(R22)(R23). In embodiments, R2' is independently -N(R21)C(0)0R25. In embodiments, Rna is independently -N(R21)C(0)R25. In embodiments, R2' is independently -N(R24)S(0)2R25. In embodiments, Rna is independently -C(0)R25. In embodiments, R2' is independently -S(0)2R25. In embodiments, R2' is independently -S(0)2N(R22)(R23) . In embodiments, R2' is independently -OCH2C(0)0R22. In embodiments, R2' is independently -0C(0)R25. In embodiments, R2'' is independently Ci_6a1ky1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci.6ha1oa1ky1, Ci_6a1koxy, Ci_61ia1oa1koxy, -01221, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2_6a1keny1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6ha1oa11y1, Ci_6a1koxy, CI
_6haloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6ha1oa1ky1, Ci_6a1koxy, Ci_6ha10a1k0xy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C3_6cy cloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1ky1, C1_6haloalkyl, Ci_6alkoxy, C1.6ha1oa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, Rna is independently -CH2-C3_6cyc1oa1ky1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloa1kyl, Ci_6alkoxy, Ci_6haloa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2_9heterocycloa1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloa1kov, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6ha1oalkox-y. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. Tn embodiments, R2' is independently -CH2-C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1.6alkyl, C1_6haloalkyl, C1.6alkoxy, C1.6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C1.9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6ha1oa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, Ci_6haloalkyl, Ci_6a1koxy, Ci.6ha1oa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00479] In embodiments, R20a is independently halogen. In embodiments, R2' is independently oxo. In embodiments, R2' is independently -CN. In embodiments, R2' is independently Ci_6alkyl. In embodiments, R2 a is independently C2.6alkenyl. In embodiments, R2' is independently C2_6alkynyl.
In embodiments, R2' is independently C3.6cycloalkyl. In embodiments, R2' is independently -CH2-C3_6cycloalkyl. In embodiments, R211a is independently C2_9heterocycloalkyl. In embodiments, R2' is independently -CH2-C2_9heterocycloalkyl. In embodiments, R2' is independently C640aryl. In embodiments, R20a is independently -CH2-C6_ioaryl. In embodiments, R2' is independently -CH2-C1_9heteroaryl. In embodiments, R2' is independently Ci.9heteroatyl. In embodiments, R2' is independently -OR'. In embodiments. R"a is independently -SR". In embodiments, R2' is independently -N(R22)(R23) . In embodiments, R2' is independently -C(0)0R22.
In embodiments, R2' is independently -C(0)N(R22)(R21) . In embodiments, R2' is independently -C(0)C(0)N(R22)(R21) . In embodiments, R2' is independently -0C(0)N(R22)(R23) . In embodiments, R2' is independently -N(R24)C(0)N(R22)(R23). In embodiments, R2' is independently -N(R24)C(0)0R25. In embodiments, R2' is independently -N(R24)C(0)R25. In embodiments, R2' is independently -N(R24)S(0)2R25. In embodiments, R20a is independently -C(0)R25. In embodiments, R20a is independently -S(0)2R25. In embodiments, R2" is independently -S(0)2N(R22)(R25) . In embodiments, R2' is independently -OCH2C(0)0R22. In embodiments, R2' is independently -0C(0)R25. In embodiments, R2' is independently C1_6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Cl_nalkyl, C1_6haloalkyl, C1_6alkoxy, CI
_6haloalkoxy. -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2fla is independently C3_6cy-cloalkyl optionally substituted with one, two, or three groups independently selected from halogen, ow, -CN, Ci_6allcyl, Ci6haloalkyl, C1_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C16alkyl, Ci_6haloalkyl, C1_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C2_9beteroeyeloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C6_1(aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6allcyl, C16haloallcyl, Ci_6alkoxy, Ci_6haloalkoxy. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R21), and -0C(0)R25. In embodiments, R2' is independently -CH2-C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently Ci_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alky1, C1_6haloalkyl, C1_6alkoxy, C1.6haloa1koxy, -SR21, -N(R22)(R23,, ) _ ¨ 22, _ C(0)1( 0 C(0)N(R22)(R23), _C(0)C(0)N(R22)(R23), _OC(0)N(R22)(R23), c(0)N (R22)(R23), N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00480] In further embodiments of the subject compound, R2" is independently halogen. In some embodiments of the subject compound, R21" is independently oxo. In some embodiments of the subject compound, R2" is independently -CN. In additional embodiments of the subject compound, R2' is independently C1_6a1ky1. In embodiments of the subject compound, R2' is independently C2_6a1kcnyl. In some embodiments of the subject compound, R2' is independently C2.6alkynyl. In further embodiments of the subject compound, R2' is independently -0R22. In select embodiments of the subject compound, R20a is independently -N(R22)(R23). In additional embodiments of the subject compound, R2' is independently -C(0)0R22. In embodiments of the subject compound, R2' is independently -0C(0)N(R22)(R23). In some embodiments of the subject compound, R20a is independently -C(0)R25. In select embodiments of the subject compound, R2' is independently -NH2. In further embodiments of the subject compound, R2" is independently -C(0)0H. In additional embodiments of the subject compound, R2' is independently -0C(0)NH2 Tn embodiments of the subject compound, R2' is independently -C(0)CH3.
[00481] In embodiments, R2' is independently halogen. In embodiments, R2' is independently oxo. In embodiments, R2' is independently -CN. In embodiments, R2' is independently Ci_6alkyl. In embodiments, R2" is independently C2_6alkenyl. In embodiments, R2' is independently C2_6alkynyl.
In embodiments, R2' is independently C1.6haloalkyl. In embodiments, R20a is independently C3_12cyc10a1ky1. In embodiments, R20a is independently -CH2-C3_12cycloalkyl. In embodiments, R2' is independently Ci_iiheterocycloalkyl. In embodiments, R2' is independently -CH2-Ci_nheterocycloalkyl. In embodiments, R20a is independently C6_12a1yl. In embodiments, R2' is independently -CH2-C6_12atyl. In embodiments, R2 13a is independently -CH2-C1_11heteromyl. In embodiments, R2' is independently Ci_iiheteroaryl. In embodiments, R2' is independently -0R22. In embodiments.
R24)a is independently -SR'. In embodiments, R2" is independently -N(R22)(R23). In embodiments, R2" is independently -C(0)0R22. In embodiments, R2' is independently -0C(0)N(R22)(R23). In embodiments, R2' is independently -N(R24)c(o)N(R22)(R23). In embodiments, R2' is independently -N(R24)C(0)0R25. In embodiments, R2' is independently -N(R24)S(0)2R25. In embodiments, R2' is independently -C(0)R25. In embodiments, R2C)a is independently -S(0)R25. In embodiments, R20a is independently -0C(0)R25. In embodiments, R20a is independently -C(0)N(R22)(R23). In embodiments, R2' is independently -C(0)C(0)N(R22)(R23).
In embodiments, R20a is independently -N(R24)C(0)R25. In embodiments, R2' is independently -S(0)2R25.
In embodiments, R2' is independently -S(0)2N(R22)(R23)-. In embodiments, R2' is independently S(=0)(=NH)N(R22)(R23). In embodiments, R2' is independently -CH2C(0)N(R22)(R23). In embodiments, R2' is independently -CH2N(R24)C(0)R25. In embodiments, R2" is independently -CH2S(0)2R25. In embodiments, R2' is independently and -CH 2S (0)2N (R22)(R23) [00482] In embodiments, R2' is independently Ci_6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_61ialoalkoxy, -N(R22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), _C(0)C(0)N(R22)(R23 _OC(0)NR22)(R23), _N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, _N(R24)c(o)R25, 4,,,T(R24)s(0)2R25, _c(0)R25, _s(0)2-25, _ S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, CI
_6haloalkoxy. -0R21, -sR21, _N(R22)(R23), _ C(0)0R22, -C(0)N(R22)(R24), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcy1, Cl6haloallcyl, Ci_6alkoxy, C1_6haloalkoxy. -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently Ci_6haloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci6alkyl, Ci_ohaloalkyl, C1_6alkoxy, Ci.ohaloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C342cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R2.4)S(0)2R25, -C(0)R2.5, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C342cycloallcyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Chaloalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Ci_iiheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C1_iiheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R2" is independently C642aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, fella is independently -CH2-C6_12aiy1 optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci6alkyl, C16haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C1_11heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Cisalkyl, CishaloaUcyl, Ci_6alkoxy, C1.6haloalkoxy, -SR21. -N(R22)(R2), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R21), -0C(0)N(R22)(R21), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Ci_llheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C16alkyl, C16haloaIkyl, Ci_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
1004831 In embodiments, R20a is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkov, Ci.6haloa1kov, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_ohaloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Clancy] optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6allcyl, Ck6haloalkyl, Ci_6alkov, Ci_6haloalkox-y, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R2')C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6a1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R2" is independently C2alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, relia is independently C3a1kenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkov, Ci_6haloalkoxy. -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Cialkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ck6haloalkyl, Ci_6alkov, Ci_6haloalkox-y, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R21), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C5alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alky1, Ci_6haloalkyl, Ci_6alkoxy, Ci_6ha1oalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -1\1(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C6a1kenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Cl_nalkyl, C1_6haloalkyl, C1_6alkoxy, CI
_6haloalkoxy. -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C3alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2fla is independently Cialkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csalkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, Ci6haloalkyl, Ci_oalkoxy, Ci_ohaloalkoxy. -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_61taloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently Cilialoalkyl. in embodiments, R20a is independently C2haloallcyl. in embodiments, R2' is independently C3haloa1kyl. In embodiments, R2' is independently C4haloalkyl. In embodiments, R2' is independently Cshaloalkyl. In embodiments, R2' is independently C6haloalkyl.
1004841 In embodiments, R2' is independently C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalicyl, Cl_falkoxy, C1.6haloalkoxy. -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently Cicycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C16haloaIkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C16haloaIkyl, Ci_6alkoxy, C1.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloa1kyl, Ci_6alkoxy, Ci_6haloa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1_6haloalkyl, Ci_6a1koxy, Ci_6haloa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, It2" is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloa1koxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C9cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6haloalkyl, Ci_Galkoxy, Ci.6haloa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R2, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25 Tn embodiments, R2' is independently Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, Cl_6alkoxy, C1.6haloalkoxy, -OR", -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00485] In embodiments, R20a is independently C2heterocycloalky1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, C1_6alkoxy, Ci_6ha1oalkoxy, -OR", -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C3heterocycloa1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ciohaloalkyl, C1_6alkoxy, Ci_61ialoalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)1\T(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Ciheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1_6haloa1koxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R20, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R20, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_Galkyl, C1_6haloa1kyl, Ci_6alkoxy, Ci_6haloa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, C1_6alkoxy, C1_6haloa1koxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, C1_6haloa1kyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R2'), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C16a1kyl, Ci_ohaloalkyl, Ci_6alkoxy, Ci_611aloa1koxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, C1ohaloa1kyl, Ci_oalkoxy, Ci_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25 In embodiments, R20a is independently C7atyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C16haloalkyl, C1_6alkoxy, Cl_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C16haloalkyl, Ck6alkoxy, Ci_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C9aiy1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C16haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -OR", -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), _N(R24)c(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C14ia1oa1ky1, C1_6alkoxy, C1_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2na is independently Cliaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci4ialoalkyl, Ci_6alkoxy, Ci_ohaloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R22), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cilaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ck6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR", -N(R22)(R21), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(1223), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, C1_6haloa1kyl, C1_6alkoxy, Ci_ohaloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C3heteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, C1_6ha1oa1kyl, Ci_6alkoxy, Ci_6haloa1koxy, -0R21, -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Ciheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_oalkoxy, Ci_ohaloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(1123), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R2', -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R21, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1_6haloa1kyl, Ci_oalkoxy, Ci_ohaloalkoxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R23. In embodiments, R2"a is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen; oxo, -CN, C1_6allcyl, C1_61taloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C7heteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1koxy, Ci_6haloa1koxy, -0R21, -SR', -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R21)C(0)N(R22)(R'), -N(R21)C(0)0R25, -N(R24)C(0)R25, -N(R21) S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6a1koxy, C1_6ha1oa1koxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R2', -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R20a is independently C9beteroaly1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci_ohaloalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cloheteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Ciiheteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6alkyl, Ci_6haloalkyl, C1_6alkoxy, Ci_6haloa1koxy, -OR', -SR', -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R2), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R2', -N(R24)C(0)R25, -N(R24)S(0)21C, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -OH. In embodiments, R20a is independently -SH. In embodiments, R20a is independently -NH2. In embodiments, R20a is independently -C(0)0H.
In embodiments, R20a is independently -0C(0)N112. In embodiments, R20a is independently -N(H)C(0)N112. In embodiments, R2l0a is independently -N(H)C(0)0H. In embodiments, R20a is independently -N(H)S(0)20113. In embodiments, R2' is independently -C(0)H. In embodiments, R2' is independently -S(0)CH3. In embodiments, R2' is independently -0C(0)C113. In embodiments, R2' is independently -C(0)NH2. In embodiments, R20a is independently -C(0)C(0)NH2. In embodiments, R2' is independently -N(H)C(0)H.
In embodiments, R20a is independently -S(0)2CH3. In embodiments, R20a is independently -S(0)2NH2-. In embodiments, R2" is independently S(=0)(=NH)NH2. In embodiments, R2' is independently -CH2C(0)NH2.
In embodiments, R2" is independently -CH2N(H)C(0)CH3. In embodiments, R20a is independently -CH2S(0)2CH3. In embodiments, R2" is independently and -CH2S(0)2NH2. In embodiments, R2' is independently -OCH3. In embodiments, R2' is independently -SCH3. In embodiments, R2' is independently -N(CH3)(H). In embodiments, R2' is independently -C(0)0CH3. In embodiments, R2' is independently -0C(0)N(CH3)(H). In embodiments, R20a is independently -N(H)C(0)N(CH3)(H). In embodiments, R2' is independently -N(H)C(0)0CH3. In embodiments, R20a is independently -N(H)S(0)2CH3. In embodiments, R20 is independently -C(0)CH3. In embodiments, R20a is independently -S(0)CH3. In embodiments, R20' is independently -0C(0)CH3. In embodiments, R2' is independently -C(0)N(CH3)(H). In embodiments, R2' is independently -C(0)C(0)N(CH3)(H). In embodiments, R2 ' is independently -N(H)C(0)CH3. In embodiments, R2 ' is independently -S(0)2CH3. In embodiments, R2' is independently -S(0)2N(CH3)(H)- Tn embodiments, 1:220a is independently S(-0)(=NH)N(CH3)(H). In embodiments, R2' is independently -CH2C(0)N(CH3)(H). In embodiments, R2" is independently -CH2N(H)C(0)C113. In embodiments, R2' is independently -CH2S(0)2CH3. In embodiments, R20' is independently and -CH2S(0)2N(CH3)(H). In embodiments, R2" is independently -0C(0)N(CH3)2. In embodiments, R2" is independently -N(H)C(0)N(CH3)2. In embodiments, R20a is independently -C(0)(CH3). In embodiments, R2' is independently -C(0)N(CH3)2. In embodiments, R20a is independently -C(0)C(0)N(CH3)2. In embodiments, R2' is independently -N(H)C(0)(CH3). In embodiments, R2' is independently -S(0)2N(CH3)2. In embodiments, R2' is independently S(=0)(=NH)N(CH3)2. In embodiments, R2' is independently -CH2C(0)N(CH3)2. In embodiments, R2' is independently and -CH2S(0)2N(CH3)2. In embodiments, R2' is independently -CH3. In embodiments, R20' is independently -CF3. In embodiments, R2' is independently -CHF2. In embodiments, R2' is independently -CFH2. In embodiments, R2 ' is independently ethyl. In embodiments, R2(1' is independently propyl. In embodiments, R20a is independently isopropyl. In embodiments, R20a is independently butyl. In embodiments, Rna is independently tert-butyl.
[00486] In embodiments, R2' is independently -CH2-C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci.6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -sR21. _N(R22)(R2.3). _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20' is independently -CH2-C4eycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Cm6haloalkyl, Ci_6alkoxy, Cm_6ha10a11c0xy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-05cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, C1_6alkoxy, C1_6haloa1koxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, C1_6haloa1kyl, C4_6alkoxy, C4_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, C4_6alkoxy, C4_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C8cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, Ci_balkyl, Ci_ohaloalkyl, C4_6alkoxy, C4_6haloa1koxy, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C9cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, C4_6alkoxy, C4_6haloalkoxy, -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)1225 In embodiments, R20a is independently -CH2-Ciocycloallcyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, Cl_6alkoxy, Cl_6haloa1koxy, -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00487] In embodiments, R20a is independently -CH2-C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6alkyl, C4_6haloa1kyl, C4_6alkoxy, C1_6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C3heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6alkyl, C4_6haloa1kyl, C4_6alkoxy, C4_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C4heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4.6alkyl, Ci.
6haloalkyl, C1_6alkoxy, C1_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22.
-C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-05heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4,6alkyl, C4_6haloalkyl, C4_6a1kov, C4_6haloalkov, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 is independently -CH2-C6heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1,6alkyl, C1.6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -0R21, -51221, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R211a is independently -CH2-C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, C1_6haloa1ky1, Ci_6a1koxy, Ci_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C8heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, It2" is independently -CH2-C9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -OR", -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00488] In embodiments, R20a is independently -CH2-Coaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6haloalkyl, Ci_Galkoxy, Ci.6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25 Tn embodiments, R2" is independently -CH2-C7a1yl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Cl_6haloalkyl, Cl_6alkoxy, Ci _6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-Csaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, C1_6alkoxy, Ci_6haloalkoxy, -0101, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C9aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci_6haloalkyl, Ci_6alkov, Ci_6haloalkox-y, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C1oaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C4_6alkyl, C16haIoalkyl, Ci_6allcoxy, Ci.6haloall(oxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C1laryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_Galkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C12aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci6alkyl, Ci6haloalicyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6allcyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-Ciheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6a1ky1, C1_6haloalkyl, Ci_6a1kov, Ci.6haloa1kov, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C4heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci6a1ky1, Ci_ohaloalkyl, C1_6a1koxy, Ci.ohaloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-05heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, Ci_ohaloalkyl, Ci_6a1koxy, Ci.ohaloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R2.4)S(0)2R25, -C(0)12,25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C6heteroatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, C1_6haloalkyl, Ci_6a1koxy, Ci_6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C7heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci_6haloalkyl, Ci_6a1kov, C1.6haloalkoxy, -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, le" is independently -CH2-Csheteroatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6a1kyl, C1_6haloalkyl, C1_6a1koxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R2" is independently -CH2-C9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, C1_6haloalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, fella is independently -CH2-C1oheteromyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6a1kyl, C1_6haloalkyl, Ci_6a1kov, Ci_6haloalkoxy, -0R21, -5R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C11heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci_6haloalkyl, Ci_6a1kov, Ci.6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R21), -0C(0)N(R22)(R21), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
1004891 In embodiments, R20b is independently halogen. In embodiments, R21b is independently oxo. In embodiments, R2 b is independently -CN. In embodiments, R2 b is independently C1_6alkyl. In embodiments, R2m is independently C2.6alkenyl. In embodiments, Rmb is independently C2_6allcynyl.
In embodiments, R20m is independently C3_6cycloa1ky1. In embodiments, R2" is independently -CH2-C3_6cyc1oalky1. In embodiments, R2 b is independently C2.9heterocyc1oalkyl. In embodiments, R2" is independently -CH2-C2_9heterocyc1oalk0. In embodiments, R2' is independently C6_10aryl. In embodiments, R2" is independently -CH2-C6_10ary1. In embodiments, R2" is independently -CH2-Ci_9heteroaryl. In embodiments, R2" is independently C1.9heteroa1yl. In embodiments, R2" is independently -OR'. In embodiments, R2" is independently -SR'. In embodiments, R2" is independently -N(R22)(R23) . In embodiments, R2" is independently -C(0)0R22.
In embodiments, R20b is independently -C(0)N(R22)(R23). In embodiments, R2' is independently -C(0)C(0)N(R22)(R23). In embodiments, R2' is independently -0C(0)N(R22)(R23) . In embodiments, R2" is independently -N(R21)C(0)N(R22)(R23) . In embodiments, R2" is independently -N(R24)C(0)0R25. In embodiments, R2' is independently -N(R24)C(0)R25. In embodiments, R2" is independently -N(R24)S(0)2R25. In embodiments, R2" is independently -C(0)R25. In embodiments, R2" is independently -S(0)2R25. In embodiments, R2" is independently -S(0)2N(R22)(R23) . In embodiments, R2" is independently -OCH2C(0)0R22. In embodiments, R20b is independently -0C(0)R25. In embodiments, R2" is independently Ci_6a1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy. -OW', -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, C1_6alkoxy, Ci_6haloalkoxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6ha1oalkyl, Cl_falkoxy, C1.6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6ha1oal1kyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloal1kyl, Ci_6alkoxy, C1.6haloalkox1y, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2(1') is independently -CH2-C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1_6haloalkyl, Ci_6a1koxy, Ci_6haloalkov, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, C1_6haloalkyl, Ci_6a1k0xy, Ci.6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201) is independently Ci_9heteroatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6ha1oa1ky1, Ci_6alkoxy, Ci.6ha1oa1koxy, -SR21, -N(R22)(R23), -C(0)0R2, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25 [00490] In embodiments, R2" is independently halogen. In embodiments, R2" is independently oxo. In embodiments, R2" is independently -CN. In embodiments, R2" is independently Cl_6alkyl. In embodiments, R2" is independently C2.6alkenyl. In embodiments, R2" is independently C2_6alkynyl.
In embodiments, R2" is independently C3.6cycloalkyl. In embodiments, R20c is independently -CH2-C3_6cycloalkyl. In embodiments, R21c is independently C2.9heterocycloalkyl. In embodiments, R2" is independently -CH2-C2_9heterocycloalkyl. In embodiments, R2" is independently C640aryl. In embodiments, R20e is independently -CH2-C6_10atyl. In embodiments, R2" is independently -CH2-C1_9heteroatyl. In embodiments, R2" is independently Ci.9heteroalyl. In embodiments, R2" is independently -0R21. In embodiments, R2" is independently -SR21. In embodiments, R20e is independently -N(R22)(R23) . In embodiments. R2" is independently -C(0)0R22.
In embodiments, R2" is independently -C(0)N(R22)(R23). In embodiments, R2" is independently -C(0)C(0)N(R22)(R23). In embodiments, R2" is independently -0C(0)N(R22)(R23) . In embodiments, R2" is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R2" is independently -N(R24)C(0)0R25. In embodiments, R2" is independently -N(R24)C(0)R25. In embodiments, R2" is independently -N(R24)S(0)2R25. In embodiments, R20c is independently -C(0)R25. In embodiments, R2" is independently -S(0)2R25. In embodiments, R2" is independently -S(0)2N(R22)(R23) . In embodiments, R2' is independently -OCH2C(0)0R22. In embodiments, R2" is independently -0C(0)R25. In embodiments, R2" is independently Ci_6a1ky1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alky1, Ci_6haloalkyl, Ci_6alkov, Ci_6haloalkoxy. -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6a1keny1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkox-y, -OR', -SR", -N(R")(R"), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R21), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6a1koxy, Ci_6ha1oa1koxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -1\1(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3_6cycloa1ky1 optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Cl_nalkyl, Cl_nhaloalkyl, Ci_6alkoxy, C1.6haloalkoxy, -0R21, -SR21, -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(1122)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R200 is independently C2_9heterocycloalkyl optionally substituted with one, two; or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1lcy1, Ci6haloa1ky1, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C640aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, Ci6haloalkyl, Ci_oalkoxy, Ci_ohaloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20' is independently -CH2-C6_10a1yl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_61taloalkyl, Ci_6alkoxy, Ci_61ialoalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C1_91ieteroaly1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
1004911 In embodiments, R202 is independently halogen. In embodiments, R202 is independently oxo. In embodiments, R2" is independently -CN. In embodiments, R2" is independently C1_6alkyl. In embodiments, R2 d is independently C2.6alkenyl. In embodiments, R2' is independently C2_6alkynyl.
In embodiments, R'd is independently C3_6cycloalkyl. In embodiments, R2' is independently -CH2-C3_6cycloalkyl. In embodiments, R2" is independently C2.9heterocycloalkyl. In embodiments, R2 d is independently -CH2-C2_9heterocycloalkyl. In embodiments, R2 d is independently C6_10aryl. In embodiments, R2 d is independently -CH2-C6_ioaryl. In embodiments, R2 d is independently -CH2-Ci_9heteroaryl. In embodiments, R2 d is independently Ci.9heteroaryl. In embodiments, R2" is independently -0R21. In embodiments, R20d is independently -SR. In embodiments, R20d is independently -N(R22)(R23) . In embodiments, R2" is independently -C(0)0R22.
In embodiments, R2e1 is independently -C(0)N(R22)(R23). In embodiments, R2 d is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20d is independently -0C(0)N(R22)(R23) . In embodiments, R20d is independently -N(R24)C(0)N(R22)(R23). In embodiments, R2" is independently -N(R24)C(0)0R25. In embodiments, R'd is independently -N(R24)C(0)R25. In embodiments, R2" is independently -N(R24)S(0)2R25. In embodiments, R2 d is independently -C(0)R25. In embodiments, R2 d is independently -S(0)2R25. In embodiments, R2" is independently -S(0)2N(R22)(R23) . In embodiments, R2" is independently -OCH2C(0)0R22. In embodiments, R2" is independently -0C(0)R25. In embodiments, It2" is independently Ci_6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C16haloallcyl, C1_6alkoxy, C1_6haloalkoxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(12_23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkox-y. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2NT(R22)(R23), and -0C(0)R25 Tn embodiments, R2 d is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Cl_6haloalkyl, Cl_6alkoxy, Ci _6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6ha1oalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloal1kyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Cishaloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR', -SR", -N(R22)(R21), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C6_i0aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6a1ky1, C1_6haloalkyl, Ci_6a1koxy, Ci.6haloa1koxy, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C16a1kyl, Ci_6haloalkyl, C1_6a1koxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(1C), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
1004921 In embodiments, R2 d is independently halogen. In embodiments, R2 d is independently oxo. In embodiments, R20d is independently -CN. In embodiments, R2 d is independently Ci_aalkyl. In embodiments, R2 d is independently C2.6alkenyl. In embodiments, R2" is independently C2_6alkynyl.
In embodiments, R20d is independently C3.6cycloalky1. In embodiments, R'd is independently -CH2-C3_6cycloa1kyl. In embodiments, R2" is independently C2_9heterocycloalkyl. Tit embodiments, R'd is independently -CH2-C2_9heterocycloallcyl. In embodiments, R2 d is independently C6_waryl. In embodiments, R2 d is independently -CH2-C6_ioaryl. In embodiments, R2" is independently -CH2-C1_9heteroaryl. In embodiments, R20d is independently C1.9heteromy1. In embodiments, IC" is independently -0R22. In embodiments, R'd is independently -SR21. In embodiments, It'd is independently -N(R22)(R23) . In embodiments. R2" is independently -C(0)0R22.
In embodiments, R2 d is independently -C(0)N(R22)(R23). In embodiments, R2" is independently -C(0)C(0)N(R22)(R23) . In embodiments, R2 d is independently -0C(0)N(R22)(R23) . In embodiments, R2 d is independently -N(R21)C(0)N(R22)(R23). In embodiments, R2" is independently -N(R24)C(0)0R25. In embodiments, R2 d is independently -N(R24)C(0)R25. In embodiments, R2" is independently -N(R24)S(0)2R25. In embodiments, R2" is independently -C(0)R25. In embodiments, R2" is independently -S(0)2R25. In embodiments, R2 d is independently -S(0)2N(R22)(R23) . In embodiments, R2" is independently -OCH2C(0)0R22. In embodiments, le" is independently -0C(0)R25. In embodiments, R2" is independently Ci_6alky-1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci_611aloalkyl, Ci_6alkoxy, Ci_6haloalkoxy. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently C2_6alkynvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alky1, C1_6haloalkyl, C1_6alkoxy, C1_6ha1oalkoxy. -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(10)C(0)N(R22)(R23), -N(R24)C(0)01225, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R21), and -0C(0)R25. In embodiments, R2 d is independently C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloal1kyl, Ci_6alkoxy, Ci.6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alky1, C1_6haloalkyl, C1_6alkoxy, C1.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alky1, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R2', -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C6_inaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R2, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-Ci_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Ci_9heteroatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
1004931 In further embodiments of the subject compound, R2cld is independently halogen. In some embodiments of the subject compound. R2 d is independently oxo. In some embodiments of the subject compound, R2 d is independently -CN. In additional embodiments of the subject compound, R2" is independently Ci_6alkyl. Iii embodiments of the subject compound, R'd is independently C2_6alkenyl. In some embodiments of the subject compound, R2" is independently C2_6alkynyl. In further embodiments of the subject compound, R2" is independently -OR'. In select embodiments of the subject compound, R2 d is independently -N(R22)(R23). In additional embodiments of the subject compound, R2cld is independently -C(0)0R22. In embodiments of the subject compound, R2" is independently -0C(0)N(R22)(R23). In some embodiments of the subject compound, R"d is independently -C(0)R23. In select embodiments of the subject compound, Rmd is independently -NH2. In further embodiments of the subject compound, R2" is independently -C(0)0H. In additional embodiments of the subject compound, R2" is independently -0C(0)NH2. In embodiments of the subject compound, R2cld is independently -C(0)CH3.

[00494] In embodiments, R20d is independently halogen. In embodiments, R2" is independently oxo. ft embodiments, R2 d is independently -CN. In embodiments, R2 d is independently C1_6a1kyl. In embodiments, R2 d is independently C2.6alkenyl. In embodiments, R2' is independently C24,allcynyl.
In embodiments, R2" is independently C1.6haloa1kyl. In embodiments. R21" is independently C3_12cycloa1kyl. In embodiments, R2" is independently -CH2-C3_12cycloa1kyl. In embodiments, R2 d is independently Ci_iiheterocycloalkyl. In embodiments, R2" is independently -CH2-Ci_iiheterocycloa1kyl. In embodiments, R202 is independently C6_12a1yl. In embodiments, R2" is independently -CH2-C6_12aryl. In embodiments, R2" is independently -CH2-Ci_iiheteroaryl. In cmbodiments, R2" is independently Ci_iihetcroaryl. In embodiments, R2" is independently -0R22. In embodiments, R2" is independently -SR22. In embodiments, R2" is independently -N(R22)(R23). In embodiments, R2.0" is independently -C(0)0R22. In embodiments, R2" is independently -0C(0)N(R22)(R23). In embodiments, R2"
is independently -N(R24)C(0)N(R22)(R23). In embodiments, R2" is independently -N(R24)C(0)0R25. In embodiments, R20d is independently -N(R24)S(0)2R25. In embodiments, R2" is independently -C(0)R25. In embodiments, R20d is independently -S(0)R25. In embodiments, R2" is independently -0C(0)R25. In embodiments, R2"d is independently -C(0)N(R22)(R23). In embodiments, R2" is independently -C(0)C(0)N(R22)(R23). In embodiments, R2 d is independently -N(R24)C(0)R25 Tn embodiments, R2 d is independently -S(0)2R25 Tn embodiments, R2 d is independently -S(0)2N(R22)(R23)-. In embodiments, R2" is independently S(=0)(=NH)N(R22)(R23). In embodiments, R2 d is independently -CH2C(0)N(R22)(R23). In embodiments, R2" is independently -CH2N(R24)C(0)R25. In embodiments, R2 d is independently -CH2S(0)2R25. In embodiments, R2 d is independently and -CH2S(0)2N(R22)(R23).
[00495] In embodiments, R2' is independently C1_6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Cimhaloalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci_6haloalkyl, Ci_6alkov, Ci_6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci_6haloalkyl, Ci_olkoxy, Ci_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Ci_6haloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloal1kyl, Ci_Galkoxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3_12cycloalky-1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_61ialoalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-C3_12cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, C14,alkoxy, C1.6haloalkoxy, -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C1_Ilheteroeyeloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alky1, C1_61taloalkyl, Ci_6alkov, Ci.6haloa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C1_iiheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci6alky1, Ci_6haloalkyl, C1_6alkoxy, Ci.6haloa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently C6_12aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, Ci_ohaloalkyl, Ci_oalkoxy, Ci_ohaloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R2.4)S(0)2R25, -C(0)R2.5, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-C6_12aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6ha1oal1kyl, Ci_6alkoxy, Ci_6haloa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-Cl_i1heteroary1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, C1.6haloalkoxy, -OR", -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently Ci_iiheteroatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
1004961 In embodiments, R2 d is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6ha1oalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkov, Ci_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6allcyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloalkox-y, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R21), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, Ci_ohaloalkyl, Ci_oalkoxy, Ci_ohaloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -1\1(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently C5alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Cl_nalkyl, C1_6haloalkyl, C1_6alkoxy, CI
_6haloalkoxy. -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R202 is independently C6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently C2alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2"d is independently C3alkenyl optionally substituted with one, two, or three groups independently selected front halogen, oxo, -CN, Ci_6allcyl, Ci6haloalkyl, Ci_6alkoxy, ei_6haloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R'd is independently C4alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alky1, Ci6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy. -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently Csalkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_61taloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently C6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently C2alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6allcyl, Cl6haloallcyl, Ci_6alkoxy, Ci_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R202 is independently C3alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alky1, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy. -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R21), and -0C(0)R25. In embodiments, R2 d is independently C4alkyny1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csalkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alky1, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Clhaloalkyl. In embodiments, R2" is independently C2haloalkyl. In embodiments, R2" is independently C3haloalkyl. In embodiments, R2" is independently C4haloalkyl. In embodiments, R2 d is independently C5haloalkyl. In embodiments, R2 d is independently C6haloalkyl.
[00497] In embodiments, R20d is independently C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6a1ky1, C1_6haloalkyl, Ci_6a1koxy, Ci.6ha1oa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2NT(R22)(R23), and -0C(0)R25 Tn embodiments, R2 d is independently C4cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Cl_6a1ky1, C1_6haloalkyl, C1_6a1koxy, C1.6ha1oa1koxy, -OR", -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -OC(0)R25. In embodiments, R2" is independently C6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, Ci_6haloalkyl, Ci_6a1koxy, Ci.6ha1oa1koxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6a1ky1, C1_6haloalkyl, Ci_6a1koxy, Ci.6ha1oa1koxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6a1k0xy, Ci.6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C9cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently Ciocycloallcyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6a1ky1, C1_6haloalkyl, C1_6alkoxy, C1.6ha1oa1koxy, -OR", -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
1004981 In embodiments, R2" is independently C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci.6alkyl, Ci_6haloalkyl, C4_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C16a1kyl, Ci6haloalkyl, Ci_oalkoxy, C1_6haloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently C4heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, Ci_6a1koxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25 In embodiments, R2 d is independently Csfieterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6alkyl, C4_6haloa1kyl, Cl_6a1koxy, Cl_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Cohetcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6alkyl, C4_6haloa1kyl, C1_6a1koxy, C1_6haloa1koxy, -0R21, -51221, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, Ci_6a1koxy, Ci_6haloa1koxy, -SR21, -N(R21)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), _N(R24)c(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6a1kyl, Ci_ohaloalkyl, C1_6alkoxy, C1_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -5R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6ary1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Cisa1kyl, Ck6haloallcyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R21), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently C7ary1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci6haloalkyl, Ci_6alkoxy, C1_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R'd is independently Caryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Cl_nalkyl, C1_6haloalkyl, Cl_nalkoxy, Ci_6haloalkox-y. -OR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C9ary1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1.4ia1oa1ky1, Ci_6a1kov, Ci_ohaloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R21, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently Cioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, C16haloalkyl, C1_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2"d is independently Cliaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci6lialoalkyl, Ci_6alkoxy, Ci_6ha1oallcoxy, -0R21, -5R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R'd is independently Cuaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C16alkyl, Ci6haloalkyl, Ci_oalkoxy, C1_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R24)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6alkyl, C4_6haloa1kyl, Ci_6alkoxy, C1_6haloalkoxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R2 d is independently C3lieteroaly1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, Ci_6a1koxy, Ci_6haloalkoxy, -OR", -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C4heteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C4_6alkyl, C4_6haloa1kyl, Ci_6alkov, C1_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, C1_6a1koxy, C1_6haloalkoxy, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently C6heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, C1_6a1koxy, Ci_6haloalkoxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently C7heteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C3_6a1kyl, C3_6haloalkyl, Cl_nalkoxy, Cl_nhaloalkoxy, -0R21, -SR2I, -N(R22)(R23). -C(0)0R22, -C(0)N(R22)(R23). -C(0)C(0)N(R22)(R23). -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R15, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_Galkyl, C3_6ha1oa1kyl, C3_6alkoxy, C3_6haloa1kov, -OR
21, _sR21, _N(R22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R213), and -0C(0)R25. In embodiments, R2" is independently C9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1kyl, C3_6haloalkyl, C3_6alkoxy, C3_6haloa1koxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), _N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1kyl, C3_6haloalkyl, C3_6a1koxy, C3_6haloalkoxy, -0R21, _sR21, _iNT(R22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R21)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently Cliheteromyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C3_6alky1, C3_6haloalkyl, Ci_oalkoxy, Ci_ohaloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R22), and -0C(0)R25. In embodiments, R2 d is independently -OH. In embodiments, R2" is independently -SH. In embodiments, R2 d is independently -NH2. In embodiments, R2" is independently -C(0)0H.
In embodiments, R2" is independently -0C(0)NH2. In embodiments, R2" is independently -N(H)C(0)NH2. In embodiments, R2 d is independently -N(H)C(0)0H. In embodiments, R2Dd is independently -N(H)S(0)2C113. In embodiments, R2" is independently -C(0)H. In embodiments, R2' is independently -S(0)CH3. In embodiments, R2 d is independently -0C(0)CH3. Tn embodiments, R2 d is independently -C(0)NH2. Tn embodiments, R2 d is independently -C(0)C(0)NH2. In embodiments, R2 d is independently -N(H)C(0)H.
In embodiments, R2Dd is independently -S(0)2CH3. In embodiments, R2" is independently -S(0)2NH2-. In embodiments, R2 d is independently S(=0)(=NH)NH2. In embodiments, R2 d is independently -CH2C(0)NH
2. In embodiments, R2" is independently -CH2N(H)C(0)CH3. In embodiments, R2cld is independently -CH2S(0)2CH3. In embodiments, R2 d is independently and -CH2S(0)2NH2. In embodiments, R2cld is independently -OCH3.
In embodiments, R2" is independently -SCH3. In embodiments, R2 d is independently -N(CH3)(H). In embodiments, R2 d is independently -C(0)0CH3. In embodiments, R20d is independently -0C(0)N(CH3)(H). In embodiments, R2 d is independently -N(H)C(0)N(CH3)(H). In embodiments, R2" is independently -N(H)C(0)0CH3. In embodiments, R21d is independently -N(H)S(0)2CH3. In embodiments, R2 d is independently -C(0)CH3.
In embodiments, R21" is independently -S(0)CH3. In embodiments, R2" is independently -0C(0)CH3. In embodiments, R2" is independently -C(0)N(CH3)(H). In embodiments, R2" is independently -C(0)C(0)N(CH3)(H). In embodiments, R2 d is independently -N(H)C(0)CH3. In embodiments, R2 d is independently -S(0)2CH3. In embodiments, R2" is independently -S(0)2N(CH3)(H)-. In embodiments, R2 d is independently S(=0)(=NH)N(CH3)(H). In embodiments, R2 d is independently -CH2C(0)N(CH3)(H). In embodiments, R2 d is independently -CH2N(H)C(0)C113. In embodiments, R20d is independently -CH2S(0)2C113. In embodiments, R20d is independently and -CH2S(0)2N(CH3)(H). In embodiments, R2" is independently -0C(0)N(CH3)2. In embodiments, R2" is independently -N(H)C(0)N(CH3)2. In embodiments, R2 d is independently -C(0)(CH3). In embodiments, R2 d is independently -C(0)N(CH3)2. In embodiments, R20d is independently -C(0)C(0)N(CH3)2. In embodiments, R2" is independently -N(H)C(0)(CH3). In embodiments, R'd is independently -S(0)2N(CH3)2. In embodiments, R2" is independently S(=0)(=NH)N(CH3)2. In embodiments, R2" is independently -CH2C(0)N(CH3)2. In embodiments, R2" is independently and -CH2S(0)2N(CH3)2. In embodiments, R2 d is independently -CH3. In embodiments, R2"
is independently -CF3. In embodiments, R2" is independently -CHF2. In embodiments, R2" is independently -CFH2. In embodiments, R2 d is independently ethyl. In embodiments, R'd is independently propyl. In embodiments, R2" is independently isopropyl. In embodiments, R2' is independently butyl. In embodiments, R2"
is independently tert-butyl.
[00499] In embodiments, R2 d is independently -CH2-C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1.6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25 In embodiments, R2 d is independently -CH2-Cicycloallcyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci6haloalkyl, Ci_6alkoxy, Cl_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-05cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloa1kyl, C1_6alkoxy, Ci_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R24)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-C6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, Ci_6haloa1kyl, Ci_6alkoxy, Ci_6haloa1koxy, -SR2', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), _N(R24)c(0)N(R22)(R23), )C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci_ohaloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C8cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, Ci_6a1kyl, C1_6haloa1kyl, Ci_6alkoxy, Ci_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-C9cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloa1kyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -N(R22)(R21), -C(0)0R22, -C(0)N(R22)(R2), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, C1_6haloa1kyl, C1_6alkoxy, C1_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00500] In embodiments, R2" is independently -CH2-C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkv1, Ci_6haloa1kyl, Ci_6alkoxy, C1_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C3heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, Ci_6a1koxy, Ci_6haloa1koxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-C4heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, 6ha1oa1ky1, Ci_6alkoxy, Ci_6ha1oalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25 In embodiments, R2 d is independently -CH2-05heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1.6alkyl, C1_611aloa1kyl, Cl_6a1koxy, Cl_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C6heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R21d is independently -CH2-Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6ha1oal1kyl, Ci_6alkoxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00501] In embodiments, R2" is independently -CH2-C6aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C7aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, CI
_6haloalkoxy. -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -M.-Caryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcy1, Ci6haloallcyl, Ci_6alkoxy, C1_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C9aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, Ci6haloalkyl, Ci_oalkoxy, Ci_ohaloalkoxy. -OR', -SR", -N(1122)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R22), -0C(0)N(R22)(R23), -N(10)C(0)N(102)(R22), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-C1oaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, Ci_ohaloalkyl, Ci_6alkoxy, Ci.ohaloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-Cliatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6ha1oalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R" d is independently -0-12-Cilaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalicyl, Ci_6alkov, Ci.6haloalkov, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(103), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R22), and -0C(0)R25. In embodiments, R2 d is independently -CH2-C2heteroaly1 optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(1222)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R2'd is independently -CH2-C3heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6ha1oalicyl, Ci_6alkoxy, Ci_6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C4heteromyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6ha1oalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-05heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalicyl, Ci_6alkov, Ci.6haloalkov, -SR22, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R21), -0C(0)N(R22)(R21), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-C6heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_oalkyl, Ci_ohaloalicyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -1\1(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-C7heteroary1 optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Cl_nalkyl, Cl_nhaloalkyl, Ci_6alkoxy, C1.6haloa1koxy, -0R21, -SR21, -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6ha1oalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 `1 is independently -CH2-C9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6ha1oalkyl, Ci_6alkoxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2"d is independently -CH2-Cloheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1lcy1, Ci6haloalkyl, Ci_6alkoxy, Ci_611aloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 d is independently -CH2-Ciiheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C16alky1, Ci_ohaloalkyl, C1_6alkoxy, Ci.ohaloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00502] In embodiments, R2" is independently halogen. In embodiments, R20 is independently oxo. In embodiments, R2" is independently -CN. In embodiments, R2' is independently C1_6a1kyl. In embodiments, R2" is independently C2,6alkenyl. In embodiments, R20 is independently C2_6alkynyl.
In embodiments, R2' is independently C3.6cycloa1kyl. In embodiments, R2' is independently -CH2-C3_6cycloalkyl. In embodiments, R20' is independently C2.9heterocycloalkyl. In embodiments, R2 e is independently -CH2-C2_9heterocycloalkyl. In embodiments, R20' is independently C640aryl. In embodiments, R20' is independently -CH2-C6_ioaryl. In embodiments, R20' is independently -CH2-C1_9heteroaryl. In embodiments, R20' is independently Ci_9heteroaryl. In embodiments, R20' is independently -0R21. In embodiments, R2 ' is independently -SR21. In embodiments, R20' is independently -N(R22)(R23). In embodiments. R2' is independently -C(0)0R22. In embodiments, R20' is independently -C(0)N(R22)(R23) . In embodiments, R20' is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20' is independently -0C(0)N(R22)(R23) . In embodiments, R2' is independently -N(R21)C(0)N(R22)(R23) . In embodiments, R2' is independently -N(R24)C(0)0R25. In embodiments, R2" is independently -N(R24)C(0)R25. In embodiments, R2" is independently -N(R24)S(0)2R25. In embodiments, R20' is independently -C(0)R25. In embodiments, R20' is independently -S(0)2R25. In embodiments, R20' is independently -S(0)2N(R22)(R23) . In embodiments, R2' is independently -OCH2C(0)0R22. In embodiments, R2" is independently -0C(0)R25. In embodiments, R2' is independently Ci_6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, C1_6alko,xy, C1_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, Ci_6haloalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, It2" is independently C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6a1kyl, C1_6haloalkyl, Ci_Galkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25 Tn embodiments, R2' is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, Cl_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C640aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6allcyl, C1_6haloalkyl, Ci_6alkov, Ci_6haloalkox-y, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_Galkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C1_9heteroa1yl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR', -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00503] In embodiments, R2" is independently halogen. In embodiments, R2" is independently oxo. In embodiments, R204- is independently -CN. In embodiments, R2" is independently Cl_nalkyl. In embodiments, R2" is independently C2_6alkenyl. In embodiments, R2' is independently C2_6alkynyl.
In embodiments, R2" is independently C3.6cycloa1ky1. In embodiments, R2" is independently -C112-C3_6cycloalkyl. In embodiments, R2' is independently C2.9heterocycloa1ky1. In embodiments, R2' is independently -CH2-C2_9heterocycloalkyl. In embodiments, R201- is independently C6_i2aryl. In embodiments, R2' is independently -CH2-C6_10ary1. In embodiments, R2" is independently -CH2-Ci_9heteroaryl. In embodiments, R2" is independently Ci_9heteroary1. In embodiments, R2" is independently -OR'. In embodiments, R202 is independently -SR21. In embodiments, R201 is independently -N(R22)(R23) . In embodiments, R2" is independently -C(0)0R22.
In embodiments, R2' is independently -C(0)N(R22)(R23). In embodiments, R2" is independently -C(0)C(0)N(R22)(R23). In embodiments, R201 is independently -0C(0)N(R22)(R23) . In embodiments, R2' is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20. is independently -N(R24)C(0)0R25. In embodiments, R2" is independently -N(R24)C(0)R25. In embodiments, R20. is independently -N(R24)S(0)2R25. In embodiments, R2Cf is independently -C(0)R25. In embodiments, R20. is independently -S(0)2R25. In embodiments, R2" is independently -S(0)2N(R22)(R23) In embodiments, R204. is independently -OCH2C(0)0R22. In embodiments, R2" is independently -0C(0)R25. In embodiments, R2' is independently Ci_6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy -SR", -N(R22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, Cm6ha1oalkyl, Ci_oalkoxy, Ci_ohaloalkoxy. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Cimhaloallcyl, Ci_6alkoxy, Ci_6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-Ccycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R2, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R21), and -0C(0)R25. In embodiments, R2" is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6_i0aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, Ci_6haloalkyl, C1_6a1koxy, C1_6haloalkoxy. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6ha1oalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)1125, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R'' is independently -CH2-Ci_91ieteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently Ci_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R21)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00504] In embodiments, R2" is independently halogen. In embodiments, R2' is independently oxo. In embodiments, R2" is independently -CN. In embodiments, R201 is independently Ci_6alkyl. In embodiments, R2" is independently C2.6alkenyl. In embodiments, R2" is independently C2_6alkynyl.
In embodiments, R2" is independently C3.6cycloa1kyl. In embodiments, R2." is independently -CH2-C3_6cycloalkyl. In embodiments, R2.1f is independently C2_9heterocyc1oa1kyl. In embodiments, R2" is independently -CH2-C2_9heterocycloa1kyl. In embodiments, R2" is independently C6_ioaryl. In embodiments, R2" is independently -CH2-C6_ioaryl. In embodiments, R2" is independently -CH2-Ci_9heteroaryl. In embodiments, R2" is independently Ci_9heteroaryl. In embodiments, R2" is independently -0R21. In embodiments, R2' is independently -SR21. In embodiments, R2" is independently -N(R22)(R23). In embodiments, R2" is independently -C(0)0R22. In embodiments, R2" is independently -C(0)N(R22)(R23) . in embodiments, R2" is independently -C(0)C(0)N(R22)(R23) . in embodiments, R2" is independently -0C(0)N(R22)(R23) . In embodiments, R2" is independently -N(R24)C(0)N(R22)(R23). In embodiments, R2" is independently -N(R24)C(0)0R25. In embodiments, R2" is independently -N(R24)C(0)R25. In embodiments, R2' is independently -N(R24)S(0)2R25. In embodiments, R2Cf is independently -C(0)R25. In embodiments, R2' is independently -S(0)2R25. In embodiments, R2" is independently -S(0)2N(R22)(R23) . In embodiments, R2" is independently -OCH2C(0)0R22. In embodiments, R2" is independently -0C(0)R23. In embodiments, R2." is independently Ci_6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2_6alkeny-1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Cmmhaloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -N(R22)(R21), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, CI
_6haloalko.xy. -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6a1ky1, C1_6haloalkyl, Ci_6a1kov, Ci.6haloa1kov, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci6a1ky1, Ci_6haloalkyl, C1_6a1koxy, Ci.6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R2.4)S(0)2R25, -C(0)12,25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C2_9heterocycloallcyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20'. is independently C6_i0ary1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloalkox-y, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R2')C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, le" is independently -CH2-C6_10myl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R2" is independently -CH2-C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently Ci_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkov, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00505] In further embodiments of the subject compound, R2" is independently halogen. In some embodiments of the subject compound, R201 is independently oxo. In some embodiments of the subject compound, R201 is independently -CN. In additional embodiments of the subject compound, R20f. is independently Ci_6alkyl. In embodiments of the subject compound, R2' is independently C2_6a1kenyl. In some embodiments of the subject compound, R2' is independently C2.6alkynyl. In further embodiments of the subject compound, R2' is independently -OR'. In select embodiments of the subject compound, R2" is independently -N(R22)(R23). In additional embodiments of the subject compound. R2" is independently -C(0)0R22. In embodiments of the subject compound, R2' is independently -0C(0)N(R22)(R23). In some embodiments of the subject compound, R2" is independently -C(0)R25. In select embodiments of the subject compound, le" is independently -NH2. In further embodiments of the subject compound, R2" is independently -C(0)0H. In additional embodiments of the subject compound, R2' is independently -0C(0)NH2. In embodiments of the subject compound, R2' is independently -C(0)CH3.
[00506] In embodiments, R2" is independently halogen. In embodiments, R2" is independently oxo. In embodiments, R2" is independently -CN. In embodiments, R2' is independently C1_6alkyl. In embodiments, R20-1 is independently C2.6alkenyl. In embodiments, R2" is independently C2_6alkynyl.
In embodiments, R2" is independently Ci.6haloa1kyl. In embodiments, R2" is independently C3_12cyeloalkyl. In embodiments, R2" is independently -CH2-C3_12cycloalkyl. In embodiments, R2" is independently Ci_iiheterocycloalkyl. In embodiments, R2" is independently -0-12-Ci_iiheterocycloa1kyl. In embodiments, R2" is independently C6_12a1yl. In embodiments, R2" is independently -C1-12-C6_12myl. In embodiments, R201 is independently -CH2-C1.1iheteroaryl. In embodiments, R2" is independently Ci_iiheteroaryl. In embodiments, R2" is independently -0R22. In embodiments, R2" is independently -SR22. In embodiments, R2()4 is independently -N(R22)(R23). In embodiments, R'''' is independently -C(0)0R22. In embodiments, R2" is independently -0C(0)N(R22)(R23) In embodiments, R20f is independently -N(R21)C(0)N(R22)(R23). In embodiments, R2' is independently -N(R24)C(0)0R25.
In embodiments, R2" is independently -N(R24)S(0)2R25. In embodiments, R2" is independently -C(0)R25.
In embodiments, R201 is independently -S(0)R25. In embodiments, R2" is independently -0C(0)R25. In embodiments, R2" is independently -C(0)N(R22)(R23). In embodiments, R2" is independently -C(0)C(0)N(R22)(R2.3).
In embodiments, R2" is independently -N(R24)C(0)R25. In embodiments, R2" is independently -S(0)2R25.
In embodiments, R20f is independently -S(0)2N(R22)(R23)-. In embodiments, R2" is independently S(=0)(=NH)N(R22)(R23). In embodiments, R2" is independently -CH2C(0)N(R22)(R23). In embodiments, R2" is independently -CH2N(R24)C(0)R25. In embodiments, R201. is independently -CH2S(0)2R25. In embodiments, R201 is independently and -CH 2 S (0)2N(R22 ) (R23).
[00507] In embodiments, R2' is independently C1_6a1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20/. is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, C1_6ha1oalkyl, C1_6a1koxy, CI
_6haloalkoxy. -0R21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R21)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Ci_6haloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloal1kyl, C1_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3_12cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6ha1oa1kyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C3_12cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6ha1oalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, It2" is independently Ci_iiheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -OR", -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-Ci_iiheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6ha1oalkyl, Ci_Galkoxy, Ci.6haloa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R2, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2NT(R22)(R23), and -0C(0)R25 Tn embodiments, R2" is independently C6_12aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Cl_6haloalkyl, Cl_6alkoxy, Ci _6haloalkoxy. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C6_12ary1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-Ci_i1heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Ci_iiheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00508] In embodiments, R2' is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_ohaloalkyl, Ci_Galkoxy, Ci.6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci6haloaIkyl, Ci_6alkoxy, Ci_6haloalkoxy, -N(Rn)(R"), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, CI
_6haloalkoxy. -01221, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R204- is independently Ctalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1lcy1, Ci6ha1oallcyl, Ci_6a1koxy, C1_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci6ha1oalkyl, Ci_6a1koxy, Ci_6haloalkoxy. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci_ohaloalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci6ha1oalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20'. is independently C3al1cenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1lcyl, Ci_6haloalkyl, Ci_6a1kov, Ci_6haloalkox-y, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R2')C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Clalkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, Ci_6ha1oalkyl, C1_6a1koxy, Ci_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R2" is independently C5alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci_6ha1oalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1ky1, Ci_6ha1oalkyl, Ci_6a1koxy, Ci_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2al1cvnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, C1_6haloalkyl, Ci_6alkov, Ci_6haloalkox-y, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R21), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alky1, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -1\1(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C4al1cvnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_nalkyl, Ci_6haloalkyl, Ci_6alkoxy, CI
_6haloalkoxy. -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csalkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6alkyl, C3_6haloalkyl, C3_6alkoxy, C3_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 4 is independently Clhaloalkyl. In embodiments, refit is independently C2haloalkyl. In embodiments, R2" is independently C3haloa1lcyl. In embodiments, R201 is independently Cilialoallcyl. In embodiments, R2" is independently Cshaloalkyl. In embodiments, R201 is independently C6haloalkyl.
[00509] In embodiments, R2" is independently C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C3_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C4cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6allcyl, C3_61ialoalkyl, C3_6alkoxy, C3_61ialoalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R204. is independently C6cycloalky1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, Ci_6alkoxy, CI
_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6alkyl, C3_6haloalkyl, C3_6alkoxy, C3_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R204- is independently Gcycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C4_6haloalkyl, C4_6alkoxy, C4_6haloalkoxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6alkyl, C1_6haloalky1, Ci_6a1koxy, C4_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00510] In embodiments, R2" is independently C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4.6alkyl, C4_6haloalkyl, C4_6alkoxy, C4_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, C4_6haloa1kyl, C4_6alkoxy, C4_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), _NT(R24)c(0)/AR22)(R23), -N(R24)C(0)0R25, -1\1(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C4heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, Cl_6a1kyl, Cl_6haloa1kyl, C4_6alkoxy, C4_6haloalkoxy, -OR", -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R211 is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, C4_6alkoxy, C4_6haloa1koxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, C4_6alkoxy, C4_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)NT(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C4_6alkyl, C4_6haloalkyl, C1_6alkoxy, C1_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R2', -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R20, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6a1kyl, C4_6ha1oa1kyl, C4_6alkoxy, C4_6haloa1koxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6alkyl, C4_6haloalkyl, C1_6alkoxy, C1_6haloa1koxy, -0R21, -5R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Cl_nalkyl, Cihaloalkyl. C1_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C7a1yl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C4_61ialoa1kyl, C4_6alkoxy, C4_6ha1oalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R22), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C16a1kyl, C4_6haloalkyl, C4_6alkoxy, C4_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C9a1yl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, C1ohaloalkyl, Ci_oalkoxy, Ci_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Cioatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C16haloalkyl, C1_6alkoxy, Cl_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently CI(aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C4_6haloallcyl, C4_6alkoxy, C4_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Cizatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C4_6haloalkyl, C4_6alkoxy, C1_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), _N(R24)c(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen; oxo, -CN, C4_6a1kyl, Ci_ohaloalkyl, C1_6allcoxy, C1_6haloall(oxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3heteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, C4_6alkoxy, C4_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R22), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C4heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, Ci_6a1koxy, Ci_61mloa1koxy, -0R21, -N(R22)(R21), -C(0)0R22, -C(0)N(R22)(R2), -C(0)C(0)N(R22)(R22), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C5heteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C4_6a1kyl, C4_6haloa1kyl, C1_6a1koxy, Ci_ohaloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6heteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, C1_6ha1oa1kyl, Ci_6a1koxy, C1_6haloa1koxy, -OR", -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C7heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, Ci_6a1koxy, Ci_ohaloalkoxy, -OR
21, _sR21, _N(R22)(R23), _ C(0)0R22, -C(0)NR22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)NR22)(R23), -N(R24)C(0)0R2', -N(R24)C(0)R29, -N(R24)S(0)2R25, -C(0)R21, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csheteroatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1_6ha1oa1kyl, Ci_oalkoxy, Ci_ohaloalkoxy, -OR", _SR21, _N(R22)(R23 _ ) C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)1*R22)(R23), _N(R24)C(0)NR22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R23. In embodiments, R2" is independently C9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen; oxo, -CN, C1_6alicyl, C1_61ta1oalky1, C1_6alkoxy, C1_6haloa1koxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kov, C1_6haloa1koxy, -OR", -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), (1=C-rr.21)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R24)C(0)R25, -N(R21) S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R22), and -0C(0)R25. In embodiments, R2" is independently CI iheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1_6haloa1kyl, C1_6alkoxy, C1_6haloa1koxy, -0R21, _sR21, _NR22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R2', -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R2" is independently -OH. In embodiments, R2" is independently -SH. In embodiments, R2' is independently -N1-12. In embodiments, R2' is independently -C(0)OH.
In embodiments, R2' is independently -0C(0)NH2. In embodiments, R2" is independently -N(H)C(0)NH2. In embodiments, R2" is independently -N(H)C(0)0H. In embodiments, R2' is independently -N(H)S(0)2CH3. In embodiments, R2" is independently -C(0)H. In embodiments, R2" is independently -S(0)CH3. In embodiments, R2' is independently -0C(0)CH3. In embodiments, R201 is independently -C(0)NH2. In embodiments, R2I1 is independently -C(0)C(0)NH2. In embodiments, R2" is independently -N(H)C(0)H.
In embodiments, R2" is independently -S(0)2CH3. In embodiments, R2" is independently -S(0)2NH2-. In embodiments, R2" is independently S(=0)(=NH)NH2. In embodiments, R2" is independently -CH2C(0)NH2.
In embodiments, R2' is independently -CH2N(H)C(0)CH3. In embodiments, R2" is independently -CH2S(0)2CH3. In embodiments, R2" is independently and -CH2S(0)2NH2. In embodiments, R2' is independently -OCH3. In embodiments, R2' is independently -SCH3. In embodiments, R2' is independently -N(CH3)(H). In embodiments, R2" is independently -C(0)0CH3. In embodiments, R2' is independently -0C(0)N(CH3)(H). In embodiments, R2' is independently -N(H)C(0)N(CH3)(H). In embodiments, R2" is independently -N(H)C(0)0CH3. In embodiments, R2' is independently -N(H)S(0)2CH3. In embodiments, R2" is independently -C(0)CH3. In embodiments, R2" is independently -S(0)Cf13. In embodiments, R2" is independently -0C(0)C1-1. In embodiments, R2" is independently -C(0)N(CH3)(H). In embodiments, R2" is independently -C(0)C(0)N(CH3)(H). In embodiments, R2" is independently -N(H)C(0)CH3. In embodiments, R2" is independently -S(0)2CH3. In embodiments, R2' is independently -S(0)2N(CH3)(H)-. In embodiments, R2' is independently S(=0)(=NH)N(CH3)(H). In embodiments, R2" is independently -CH2C(0)N(CH3)(H). In embodiments, R2" is independently -CH2N(H)C(0)CH3. In embodiments, R2" is independently -CH2S(0)2CH3. In embodiments, R2" is independently and -CH2S(0)2N(CH3)(H). In embodiments, R2" is independently -0C(0)N(CH3)2. In embodiments, R2" is independently -N(H)C(0)N(CH3)2. In embodiments, R2" is independently -C(0)(CH3). In embodiments, R2" is independently -C(0)N(CH3)2. In embodiments, R2" is independently -C(0)C(0)N(CH3)2. In embodiments, R2" is independently -N(H)C(0)(CH3). In embodiments, R201 is independently -S(0)2N(CH3)2. In embodiments, R201 is independently S(=0)(=NH)N(CH3)2. In embodiments, R2' is independently -CH2C(0)N(CH3)2. In embodiments, R2' is independently and -CH2S(0)2N(CH3)2. In embodiments, R2' is independently -CH3. In embodiments, R2" is independently -CF3. In embodiments, R2" is independently -CHF2. In embodiments, R2' is independently -CFH2.
In embodiments, R2' is independently ethyl. In embodiments, R2" is independently propyl. In embodiments, R2" is independently isopropyl. In embodiments, R2' is independently butyl. In embodiments, It'll is independently tert-butyl [00511] In embodiments, R2' is independently -CH2-C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1.6a1ky1, Cl_6haloalkyl, Ci_6alkoxy, Cl_6ha10a11c0xy, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C4cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Cishaloa1kyl, C1_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-05cycloalky1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6ha1oa1ky1, Ci_6a1k031y, Ci_6haloalkoxy, -0R21, _sR21, _N(z22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N-(R22)(R23) )C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1ky1, C1_6ha1oa1ky1, C1_6a1koxy, C1_6haloalkoxy, -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R2', -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R2', -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_Galkyl, C1_6ha1oa1ky1, Ci_6alkov, Ci_6haloalkov, -0R21 _5R21, -N(R22)(R23), _ C(0)0R22, (0)N(R22)(R23), -C(0)C(0)N(R22) (R23 ), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25 -N(R24) S (0)2R25, -C(0)R25 -S (0)2R25 , -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C8cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alky 1, Ci_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -0R21, -5R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C9cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6alkyl, C1_6haloalkyl, C4_6a1koxy, C4_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -Cf12-Clocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C4_6alkyl, C4_6haloalkyl, C4_6alkoxy, C4_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R22), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00512] In embodiments, R2' is independently -CH2-C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6alkyl, C4_6haloalkyl, C4_6alkoxy, C1_61taloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C3heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, Ci_Galkyl, C4_6haloalkyl, C4_6a1koxy, C4_6ha1oalkoxy, -OR", -SR2', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), _NT(R24)c(0)/AR22)(R23), -N(R24)C(0)0R25, -1\1(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C4heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1.6a1kyl, Cl.
6ha1oa1ky1, Ci_6a1koxy, C4_6haloalkoxy, -OR", -SR21, -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-05heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4.6alkyl, C4_6haloalkyl, C4_6a1koxy, C4_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C6heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4.6alkyl, C4.6haloalkyl, C4_6alkox-y, Ci_ehaloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20 . is independently -CH2-C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Cl_6ha1oalkyl, C1_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201. is independently -CH2-C8heterocycloalky1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6alkyl, C1_6ha1oal1kyl, Ci_6alkoxy, C4.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6ha1oal1kyl, C1_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.

[00513] In embodiments, R2' is independently -CH2-C6aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6a1kyl, C1_6haloalkyl, C1_6a1koxy, C1.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)01122, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C7aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci_6haloalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R'' is independently -CH2-Csaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci_6haloalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C9aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci_6haloalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-Cloaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R2, -N(R24)S(0)2R25, -C(0)R29, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-Clialy1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6a1koxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-Cilaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -5R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1_6haloalkyl, Cl_falkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C3heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, C1_6haloalkyl, Ci_6a1koxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R2, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R"" is independently -CH2-C1heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1_6haloalkyl, Ci_6a1koxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-05heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6ha1oa1kyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R21), and -0C(0)R25. In embodiments, R2" is independently -CH2-C6heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, C1_6haloalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, It2" is independently -CH2-C7heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci_6haloalkyl, Ci_6a1koxy, Ci.6haloalkoxy, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C8heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6a1kyl, C1_6haloalkyl, Ci_6a1koxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R2, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25 Tn embodiments, R2" is independently -CH2-C9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6a1kyl, C1_6ha1oalkyl, Cl_6a1koxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci6haloalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -OC(0)R25. In embodiments, R2" is independently -CH2-Ciiheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci6haloalkyl, Ci_6a1koxy, Ci.6haloalkoxy, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00514] In embodiments, R20g is independently halogen. In embodiments, R20g is independently oxo. In embodiments, R211g is independently -CN. In embodiments, R20g is independently C4_6alkyl. In embodiments, R20g is independently C2.6alkenyl. In embodiments, R20g is independently C2_6alkynyl.
In embodiments, R20g is independently C3.6cycloalky1. In embodiments, R20g is independently -CH2-C3_6cycloalkyl. In embodiments, R20g is independently C2_9heterocycloalkyl. In embodiments, R20g is independently -CH2-C2_9heterocyc1oalkyl. In embodiments, R20g is independently C6_10aryl. In embodiments, R20g is independently -CH2-C6_ioaryl. In embodiments, R20g is independently -CH2-Ci_9heteroaryl. In embodiments, R20g is independently Ci.9heteromy1. In embodiments, R20g is independently -OR'. In embodiments, R20g is independently -SR". In embodiments, R20g is independently -N(R22)(R23). In embodiments, R20g is independently -C(0)0R22.
In embodiments, R20g is independently -C(0)N(R22)(R21) . In embodiments, R208 is independently -C(0)C(0)N(R22)(R21) . In embodiments, R20g is independently -0C(0)N(R22)(R23) . In embodiments, R20g is independently -N(R24)C(0)N(R22)(R23). In embodiments, R20g is independently -N(R24)C(0)0R25. In embodiments, R20g is independently -N(R24)C(0)R25. In embodiments, R20g is independently -N(R24)S(0)2R25. In embodiments, R20g is independently -C(0)R25. In embodiments, R20g is independently -S(0)2R25. In embodiments, R20g is independently -S(0)2N(R22)(R23) . In embodiments, R20g is independently -OCH2C(0)0R22. In embodiments, R20g is independently -0C(0)R25. In embodiments, R20g is independently Ci_6alky1 optionally substituted with one.
two, or three groups independently selected from halogen, oxo, -CN, Cl_nalkyl, Ci_nhaloalkyl, Ci_nalkoxy, CI
_nhaloalkoxy. -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalky1, Ci_6alkoxy, Ci_6haloa1koxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently C2_6alky-nyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R21g is independently C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci6haloalkyl, C1_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C16alkyl, C1_6haloalkyl, C1_6alkoxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20s is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R210g is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently C6_,ciaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci_61taloalkyl, Ci_6alkoxy, Ci_6haloalkoxy. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently -CH2-C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(1224)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R21), and -0C(0)R25. In embodiments, R20g is independently -CH2-C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently Ci_9heteroaly1 optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alky1, C1_6haloalky1, C1_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00515] In embodiments, R201 is independently halogen. In embodiments, R2' is independently oxo. In embodiments, R2' is independently -CN. In embodiments, R2' is independently Ci_6alkyl. In embodiments, R20i is independently C2.6alkenyl. In embodiments, R20 is independently C2_6alkynyl.
In embodiments, R20 is independently C3.6cycloa1kyl. In embodiments, R2' is independently -CH2-C3_6cycloalkyl. In embodiments, R20' is independently C2.9heterocycloalky1. In embodiments, R2' is independently -CH2-C2_glieterocycloalkyl. In embodiments, R2" is independently C6_10aryl. In embodiments, R2N is independently -CH2-C6_102nyl. In embodiments, R2" is independently -CH2-Ci_9heteroaryl. In embodiments, R201 is independently Ci_9heteroaryl. Iii embodiments, R2" is independently -0R21. In embodiments, R20' is independently -SR21. In embodiments, R2 1 is independently -N(R22)(R23) . In embodiments. R2" is independently -C(0)0R22.
In embodiments, R2" is independently -C(0)N(R22)(R23). In embodiments, R'" is independently -C(0)C(0)N(R22)(R23). In embodiments, R2" is independently -0C(0)N(R22)(R23) . Tn embodiments, 1:2201 is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R2N is independently -N(R21)C(0)0R25. In embodiments, R201 is independently -N(R24)C(0)R25. In embodiments, R2th is independently -N(R24)S(0)2R25. In embodiments, R201 is independently -C(0)R25. In embodiments, R20' is independently -S(0)2R25. In embodiments, R201 is independently -S(0)2N(R22)(R23) . In embodiments, R201 is independently -OCH2C(0)0R22. In embodiments, R201 is independently -0C(0)R25. In embodiments, R2' is independently C1_6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, C1_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 1 is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, C1_6haloalkyl, Ci_6alkov, Ci_6haloalkox-y, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy. -01221, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)1125, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2N is independently C3_6cycloa1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20 is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2th is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6a1kyl, C1_6haloalkyl, Ci_6a1koxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci6ha1oalkyl, Ci_6a1koxy, Ci_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, C1_6ha1oalkyl, Ci_6a1koxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-Ci_9heteroatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1_6haloalkyl, Ci_6a1koxy, Ci_6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci_6haloalkyl, Ci_6a1kov, C1.6haloalkov, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00516] In embodiments, R2' is independently halogen. In embodiments, R2' is independently oxo. In embodiments, R2" is independently -CN. In embodiments, R2c1 is independently Ci_6a1ky1. In embodiments, R2' is independently C2.6a11ce11y1. In embodiments, R2`" is independently C2_6alkynyl. In embodiments, R2'1 is independently C3.6cyc1oa1ky1. in embodiments, R2" is independently -CH2-C3_6cycloalkyl. in embodiments, R2" is independently C2_9heterocyc1oa1kyl. In embodiments, R2" is independently -CH2-C2_9heterocycloalkyl. In embodiments, R2" is independently C6_10aryl. In embodiments, R2" is independently -CH2-C6_10aryl. In embodiments, R2 1 is independently -CH2-Ci_9heteroaryl. In embodiments, R2" is independently Ci_9heteroaryl. In embodiments, R2" is independently -OR'. In embodiments, R2.01 is independently -SR'. In embodiments, R2 1 is independently -N(R22)(R23) . In embodiments. R201 is independently -C(0)0R22.
In embodiments, R2u1 is independently -C(0)N(R22)(R23). In embodiments, R2" is independently -C(0)C(0)N(R22)(R23). In embodiments, R2" is independently -0C(0)N(R22)(R23) . In embodiments, R20 is independently -N(R24)C(0)N(R22)(R23). 111 embodiments, R2' is independently -N(R24)C(0)0R25. In embodiments, R2" is independently -N(R24)C(0)R25. In embodiments, R2" is independently -N(R24)S(0)2R25. In embodiments, R2" is independently -C(0)R25. In embodiments, R20 is independently -S(0)2R25. In embodiments, R20 is independently -S(0)2N(R22)(R24) . In embodiments, R2' is independently -OCH2C(0)0R22. In embodiments, R20' is independently -0C(0)R25. In embodiments, R2' is independently C1_6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alky1, C1_6haloalk0, C1_6alkoxy, C1_6haloalkoxy. -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2N is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R'' is independently C3_6eycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloal1kyl, Ci_6alkoxy, Ci.6haloa1koxy, -0R2', -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6haloa1kyl, Ci_6alkoxy, Ci.6haloalkoxy, -OW", -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R2, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(1123), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2h1 is independently C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci6haloalkyl, Ci_6alkoxy, Ci_61ialoalkoxy, -01221, -5R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 1 is independently -CH2-C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)01:C, -C(0)N(W2)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-Ci_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloal1kyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(1123), -N(R24)C(0)0R25, -N(R24)C(0)R2, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 is independently C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloal1kyl, Ci_6alkoxy, C1.6haloalkoxy, -5R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.

[00517] In further embodiments of the subject compound, R20' is independently halogen. In some embodiments of the subject compound, R2" is independently oxo. In some embodiments of the subject compound, R2" is independently -CN. In additional embodiments of the subject compound. R2 1 is independently C1_6alkyl. In embodiments of the subject compound, R201 is independently C2_6alkenyl. In some embodiments of the subject compound, R20' is independently C2_6a1kynyl. In further embodiments of the subject compound, R201 is independently -OR'. In select embodiments of the subject compound, R20 is independently -N(R22)(R23). In additional embodiments of the subject compound, R2' is independently -C(0)0R22. In embodiments of the subject compound, R20' is independently -0C(0)N(R22)(R23). In some embodiments of the subject compound, R2' is independently -C(0)R25. In select embodiments of the subject compound, R2' is independently -NH2. In further embodiments of the subject compound, WI is independently -C(0)0H. In additional embodiments of the subject compound, R20' is independently -0C(0)NH2. In embodiments of the subject compound, R20' is independently -C(0)CH3.
[00518] In embodiments, R201 is independently halogen. In embodiments, R2 ' is independently oxo. In embodiments, R2'" is independently -CN. In embodiments, R2'" is independently C2_6alkyl. In embodiments, R2''' is independently C2_6allceny1. In embodiments, Rni is independently C1_6alkynyl.
Tn embodiments, Rni is independently C2_6haloalkyl. In embodiments, R20' is independently C3_22cycloalkyl. In embodiments, R20' is independently -CH2-C3_12cycloalkyl. In embodiments, R20' is independently Ci., iheterocycloalkyl. In embodiments, R2' is independently -CH2-Ci_iiheterocycloalkyl. In embodiments, R2' is independently C6_22aryl. In embodiments, R201 is independently -CH2-C6_12aryl. In embodiments, R201 is independently -CH2-C1_11heteroaryl. In embodiments, R2' is independently Ci_iiheteroaryl. In embodiments, R2' is independently -OR'. In embodiments, R"' is independently -SRn. In embodiments, R2' is independently -N(R22)(R23). In embodiments, R20' is independently -C(0)0R22. In embodiments, R2' is independently -0C(0)N(R22)(R23). In embodiments, R2' is independently -N(R24)C(0)N(R22)(R23) ,.
In embodiments, R2' is independently -N(R24)C(0)0R25. In embodiments, R2' is independently -N(R24)S(0)2R25. In embodiments, R20' is independently -C(0)R25.
In embodiments, R201 is independently -S(0)R25. In embodiments, R21' is independently -0C(0)R25. In embodiments, R2.`" is independently _c(o)N(R22)(R23) .
In embodiments, Rni is independently -C(0)C(0)N(R22)(R23).
Tn embodiments, Rni is independently -N(R24)C(0)R25. In embodiments, R20' is independently -S(0)2R25.
In embodiments, R20' is independently -S(0)2N(R22)(R23)-. In embodiments, R20' is independently S(=0)(=NH)N(R22)(R23). In embodiments, R2 ' is independently -CH2C(0)N(R22)(R23) .
In embodiments, R2 ' is independently -CH2N(R24)c(o)R25. In embodiments, R201 is independently -CH2S(0)2R25. In embodiments, R2" is independently and -CH 2 S (0)2N(R22)(R23).
[00519] In embodiments, R2 ' is independently Ci_6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -0R21, _sR21n _ N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R23, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20 is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, C1_6alkoxy, Ci_6haloalkoxy, -N(R22)(R21), -C(0)0R22, _C(0)N(R22)(R23), C(0)C(0)N(R22)(R23) _ OC(0)N(R 22)(R23), -N(R24)C(0)N(R22)(R23), ( )C(0)N(R22)(R23), -N(R24)C(0)0R25, _/*R24)c(o)R25., _N(R24)s(0)2R25, _c(0)R25, _s(0)2-25, _ S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 ' is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, CI
_6haloalkoxy, -0R21, -SR24, -N(R22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -1\1(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 1 is independently CI _6ha1oa1ky1 optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_61taloalkyl, Ci_6alkov, Ci.6haloa1kov, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R23, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C3_12eye1oalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci6alkyl, Ci_6haloalicyl, C1_6alkoxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C3_12cycloalky1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, Ci_ohaloalkyl, Ci_6alkoxy, Ci.ohaloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R2.4)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, 122" is independently Ci_idieterocycloallcyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6ha1oalkyl, Ci_6alkoxy, Ci_6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R23, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Ci_ilheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalicyl, Ci_6alkov, Ci.6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R23, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C6_12ary1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, C1_6alkoxy, Ci_6haloalkoxy. -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R2" is independently -CH2-C6_12atyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6ha1oalicyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2th is independently -CH2-Ci_iiheteromyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkov, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R23, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Ci_iiheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6ha1oalicyl, Ci_6alkov, Ci.6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R21), -0C(0)N(R22)(R21), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00520] In embodiments, R2" is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_oalkyl, Ci_ohaloalicyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -1\1(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2m is independently C2a1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Cl_nalkyl, Ci_6haloalkyl, C1_6a1koxy, Cl_nhaloalkoxy. -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C3a1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6alkyl, C3_6haloalkyl, C3_6alkoxy, C3_6haloalkoxy, -OR', -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C4a1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1kyl, C3_6ha1oalkyl, C3_6a1koxy, C3_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2'" is independently Csalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6allcyl, Ci6haloalkyl, C3_6alkoxy, C3_6haloalkoxy -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20' is independently C6a1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1ky1, Ci6ha1oalkyl, Ci_6a1koxy, Ci_6ha1oalkoxy. -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C2a1kenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1kyl, C3_61taloalkyl, C3_6a1koxy, C3_6haloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1kyl, C3_6ha1oalkyl, C3_6a1koxy, C3_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2m is independently Cialkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1lcyl, C3_61ta1oalkyl, C3_6a1koxy, C3_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently Csalkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1ky1, C3_6ha1oalkyl, C3_6a1koxy, C3_6ha1oalkoxy. -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R2')C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R21), and -0C(0)R25. In embodiments, R2' is independently C6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6alkyl, C3_6haloalkyl, C3_6a1koxy, C3_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, Ci_6haloalkyl, C1_6a1koxy, C1_6haloa1koxy. -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C3a1kynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alky1, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C4a1kynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alky1, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C5a1kynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alky1, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R2', -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C6a1kynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy. -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R2, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently Clhaloalkyl. In embodiments, R20i is independently C2haloalkyl. In embodiments, R2' is independently C3haloa1ll. In embodiments, R20i is independently C4haloalkyl. In embodiments, R2' is independently C5haloa1kyl. In embodiments, R2' is independently C6haloalkyl.
[00521] In embodiments, R201 is independently C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C4cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci_6haloalkyl, Ci_olkoxy, Ci_6haloalkoxy. -01221, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C5cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ciohaloalkyl, Ci_6a1koxy, Ci_6haloalkoxy, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20 is independently C6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alky1, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -N(R22)(R21), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alky1, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -01221, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -1\1(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 1 is independently Cxcycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcy1, Ci6haloallcyl, Ci_6alkoxy, C1_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently C9cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci6haloaIkyl, Ci_6alkoxy, Ci_6haloalkoxy. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, Ci_ohaloalkyl, Ci_6alkoxy, Ci.ohaloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00522] In embodiments, R201 is independently C2heterocycloallcyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkov, Ci_6haloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C3heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, C16haloalkyl, Ck6alkoxy, Ci_6haloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R23, _N(R24)c(0)R25, _N(R24)s(0)2R25, _c(0)R25, _ S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20i is independently C4heterocycloalky1 optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, Ci_6haloa1kyl, Ci_6alkoxy, Ci_6haloa1koxy, -SR21, -N(R21)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), _N-(:0)c(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci_ohaloalkyl, Ci_6allcoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2th is independently C6heterocycloalky1 optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, Ci_6a1kyl, C1_6haloa1kyl, Ci_6alkoxy, Ci_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 ' is independently C7heterocycloalky1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1_6haloa1kyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR', -SR', -N(R22)(R21), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R22), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, C1_6haloa1kyl, C1_6alkoxy, Ci_ohaloalkoxy, -0R21, -SR", -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2N is independently C9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C3_6a1kyl, C3_6haloa1kyl, C3_6a1koxy, C3_6haloa1koxy, -0R21, -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1kyl, C3_6haloalkyl, C3_6alkoxy, C1_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(1123), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2N is independently C7a1yl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1kyl, C3_6haloalkyl, C3_6alkoxy, Ci_ohaloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R23. In embodiments, R2"1 is independently Cgaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6allcyl, C4_6haloallcyl, Ci_6alkoxy, C3_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20' is independently C9aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci6haloalkyl, Ci_6alkoxy, C3_6haloalkoxy, -SR21, -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R24)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20 is independently Cioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6alkyl, C3_6haloalkyl, C3_6alkoxy, C3_6haloalkoxy. -0R21, -5R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R2" is independently CI la tyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1kyl, C3_6haloalkyl, C3_6alkoxy, C3_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2N is independently Ci2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6alkyl, C3_61taloalkyl, Ck6alkoxy, C3_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20i is independently C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C3_6a1kyl, C3_6haloa1kyl, C3_6a1koxy, C3_6haloalkoxy, -OR', -SR', -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R2), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)21C, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C3heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C3_6a1kyl, C3_6haloa1kyl, Ci_oalkoxy, C3_6haloalkoxy, -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Clheteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C1_6a1kyl, C1_6haloalkyl, Cl_nalkoxy, Cl_nhaloalkoxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1kyl, C1_6haloa1kyl, Ci_6alkoxy, Ci_6haloalkov, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R2')C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R21 is independently C6heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, Ci_6haloa1kyl, C1_6a1koxy, C1_6haloa1koxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 1 is independently C7heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloa1kyl, ei_6alkoxy, e1_6haloalkoxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 1 is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6a1koxy, Ci_6haloa1koxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6a1koxy, C1_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R23. In embodiments, R211 is independently Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_61taloallcyl, C1_6alkoxy, C1_6haloalkoxy, -0R21, -SR2I, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 1 is independently Ciiheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1_6haloa1kyl, Ci_6a1koxy, Ci_6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R2')C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20i is independently -OH. In embodiments, R2" is independently -SH. In embodiments, R20i is independently -NH2. In embodiments, R2' is independently -C(0)0H.
In embodiments, R2' is independently -0C(0)NH2. In embodiments, R2" is independently -N(H)C(0)NH2. In embodiments, R21 is independently -N(H)C(0)0H. In embodiments, R20 is independently -N(H)S(0)2CH3. In embodiments, R2' is independently -C(0)H. In embodiments, R20' is independently -S(0)CH3. In embodiments, R2" is independently -0C(0)CH3. In embodiments, R2" is independently -C(0)NH2.
In embodiments, R201 is independently -C(0)C(0)NH2. In embodiments, R201 is independently -N(H)C(0)H.
In embodiments, R2" is independently -S(0)2CH3. In embodiments, R201 is independently -S(0)2N112-. In embodiments, R2 1 is independently S(=0)(=NH)NH2. In embodiments, R201 is independently -CH2C(0)NH2. In embodiments, R201 is independently -CH2N(H)C(0)CH3. In embodiments, R20' is independently -CH2S(0)2CH3. In embodiments, R20' is independently and -CH2S(0)2NH2. In embodiments, R20' is independently -OCH3.
In embodiments, R20' is independently -SCH3. In embodiments, R201 is independently -N(CH3)(H). In embodiments, R2" is independently -C(0)0CH3. In embodiments, R201 is independently -0C(0)N(CH3)(H). In embodiments, R20' is independently -N(H)C(0)N(CH3)(H). In embodiments, R201 is independently -N(H)C(0)0CH3. In embodiments, R2' is independently -N(H)S(0)2CH3. In embodiments, R20 is independently -C(0)CH3. In embodiments, R2' is independently -S(0)CH3. In embodiments, R20' is independently -0C(0)CH3. In embodiments, R2' is independently -C(0)N(CH3)(H). In embodiments, R2' is independently -C(0)C(0)N(CH3)(H). In embodiments, R20 is independently -N(H)C(0)CH3. hi embodiments, R2' is independently -S(0)2CH3. In embodiments, R2' is independently -S(0)2N(CH3)(H)-. In embodiments, R20' is independently S(=0)(=NH)N(CH3)(H). In embodiments, R2" is independently -CH2C(0)N(CH3)(H). In embodiments, R20' is independently -CH2N(H)C(0)CH3. In embodiments, R20' is independently -CH2S(0)2CH3. In embodiments, R20' is independently and -CH2S(0)2N(C113)(H). In embodiments, R20' is independently -0C(0)N(CH3)2.
In embodiments, R201 is independently -N(H)C(0)N(C113)2. In embodiments, R201 is independently -C(0)(CH3). In embodiments, R201 is independently -C(0)N(CH3)2. In embodiments, R201 is independently -C(0)C(0)N(CH3)2. In embodiments, R2 i is independently -N(H)C(0)(CH3). In embodiments, R20' is independently -S(0)2N(CH3)2. In embodiments, R20' is independently S(=0)(=NH)N(CH3)2. In embodiments, R2' is independently -CH2C(0)N(CH3)2. In embodiments, R20' is independently and -CH2S(0)2N(CH3)2. In embodiments, R20' is independently -CH3. In embodiments, R20' is independently -CF3. In embodiments, R201 is independently -CHF2. In embodiments, R201 is independently -CFH2.
In embodiments, R"' is independently ethyl. In embodiments, R2' is independently propyl. In embodiments, R20' is independently isopropyl. In embodiments, R2' is independently butyl. In embodiments, R20' is independently tert-butyl.
[00523] In embodiments, R2' is independently -CH2-C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1.6alkyl, C1_6haloalkyl, C4_6alkoxy, C1_6ha1oalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20' is independently -CH2-C4cycloa1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C4_4ialoalkyl, C4_6alkoxy, ci,6haloalkoxy. _0R21, _sR21, _N(R22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2th is independently -CH2-05cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C4_6alkyl, C4_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R22), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 ' is independently -CH2-C6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C4_6alkyl, C4_6haloalkyl, C1_6alkoxy, C1_61taloalkoxy, -0R21, -N(R22)(R21), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 ' is independently -CH2-C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, C4_6alkyl, C4_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -0R21, _sR24, _NR22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2N is independently -CH2-C8cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, Ca1kyl. C1_6haloa1kyl, Ci_6a1koxy, Ci_6haloa1koxy, -0R21, -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20i is independently -CH2-C9cycloa1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_oalkoxy, Ci_ohaloalkoxy, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R21, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20I is independently -CH2-Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6a1kyl, C1_6haloa1kyl, Ci_oalkoxy, Ci_ohaloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00524] In embodiments, R201 is independently -CH2-C2lieterocycloallcyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalky1, C1_6alkoxy, Ci_6ha1oalkoxy, -OR21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C3hcterocycloa1kyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, C1_6a1koxy, Ci_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R21i is independently -CH2-C4heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci.6alkyl, C1.
6ha10a11ky1, Ci_6alkov, Ci_6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20i is independently -CH2-05heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1.6alkyl, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25. -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2'1 is independently -CH2-C6heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1.6a1kyl, Ci.6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20 is independently -CH2-C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_611aloa1koxy, -01221, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2m is independently -CH2-C8heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1.6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2th is independently -CH2-Cyheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkov, Ci.6haloalkov, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
1005251 In embodiments, R2" is independently -CH2-C6arvl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci6alkyl, Ci_6haloalicyl, C1_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C7atyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R2.4)S(0)2R25, -C(0)12,25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C1atyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R211 is independently -CH2-C9aly1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, C16haloalkyl, C1_6alkov, Ci_6haloalkox-y, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R2')C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-Cioatyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. in embodiments, R2" is independently -CH2-Cliaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalicyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2th is independently -CH2-C12aiy1 optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkov, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2N is independently -CH2-C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalicyl, Ci_6alkov, Ci.6haloalkov, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R21), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C3heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalicyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -1\1(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 ' is independently -CH2-C4heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Cl_nalkyl, Cl_nhaloalkyl, C1_6alkoxy, C1.6haloa1koxy, -0R21, -SR21, -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-05heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6ha1oa1kyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 ' is independently -CH2-C6heteromyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6ha1oalkyl, Ci_6alkoxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2'" is independently -CH2-C7heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo; -CN, Ci_6allcyl, Ci6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20' is independently -CH2-C8heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C16alkyl, Ci_ohaloalkyl, C1_6alkoxy, Ci.ohaloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_61ialoalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 1 is independently -CH2-Cioheteroaly1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6ha1oal1kyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -CH2-C1Iheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00526] In embodiments, R20k is independently halogen. In embodiments, R21k is independently -CN. In embodiments, R2" is independently C1_6alkyl. In embodiments, R20k is independently C2_6alkenyl. In embodiments, R"k is independently C2_6alkynyl. In embodiments, R2" is independently C3_6cyc10a1ky1. In embodiments, R201' is independently -CH2-C3_6cycloalky1. In embodiments, feu is independently C2_9heterocycloalky1. In embodiments, R20k is independently -CH2-C2_9heterocyeloalkyl. In embodiments, R2' is independently C6.10aryl. In embodiments, R20k is independently -CH2-C6_ioaryl. In embodiments, R2" is independently -CH2-Ci_9heteroaryl. In embodiments, R2' is independently Ci_9heteroaryl. In embodiments, R20k is independently -0R21. In embodiments, R201( is independently -SR21. In embodiments, R20k is independently -N(R22)(R23) . In embodiments, R20k is independently -C(0)0R22. In embodiments, R2" is independently -C(0)N(R22)(R23). In embodiments, R2" is independently -C(0)C(0)N(R22)(R23) . In embodiments, R2" is independently -0C(0)N(R22)(R23) .
In embodiments, R2" is independently -N(R24)C(0)N(R22)(R23). In embodiments, R2' is independently -N(R24)C(0)0R25. In embodiments, R2" is independently -N(R24)C(0)R25. In embodiments, R2' is independently -N(R24)S(0)2R25. In embodiments, R2" is independently -C(0)R25. In embodiments, R2" is independently -S(0)2R25. In embodiments, R2" is independently -S(0)2N(R22)(R23) . In embodiments, R2 1' is independently -OCH2C(0)0R22. In embodiments, R2" is independently -0C(0)R25. In embodiments, R201 is independently Ci_6alkyl optionally substituted with one, two, or three groups independently selected from halogen. oxo, -CN, Ci_balkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_611aloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25 In embodiments, R201 is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, Cl_6alkoxy, Cl_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20k is independently C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, Ci_6haloalkoxy, -OR", -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R23, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R211 is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1.6alkyl, C1.
6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2 k is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25. -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1.6alkyl, Ci_Gbaloalkyl, Ci_Galkoxy, C1_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently C6.10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2" is independently -C112-C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -0R24, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2a is independently -CH2-C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alky1, Ci_6haloalkyl, Ci_6alkov, Ci_61aaloa1koxy, -0R21, -SR", -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R2' is independently Ci.9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_oalkyl, C16haloalkyl, Ci_oalkoxy, Ci_ohaloalkoxy, -OR', -SR", -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00527] In embodiments, R12' is independently hydrogen In embodiments, R12' is independently methyl. In embodiments, R12 is independently ethyl. In embodiments, R12' is independently halogen. In embodiments, R12' is independently -CN. In embodiments, R12' is independently Ci_6a11(0. In embodiments, R12' is independently C2-6a1keny1. In embodiments, R12' is independently C2_6alkynyl. In embodiments, R12' is independently C3.6cycloalkyl.
In embodiments, R12' is independently -CH2-C3_6cycloallcyl in embodiments, R12' is independently C2-9heterocycloalkyl. In embodiments, R' is independently -CH2-C2_9heterocycloa1ky1. In embodiments, R12' is independently C6.1 oaryl. In embodiments, R12` is independently -CH2-C6_1 oaryl. In embodiments, R12' is independently -CH2-Ci_9heteroaryl. In embodiments, R12" is independently Ci_9heteroaryl. In embodiments, R12 is independently -OR'. In embodiments, R12' is independently -SR'. In embodiments, R12 is independently -N(R22)(R23) . In embodiments, R12' is independently -C(0)0R22. In embodiments, R12' is independently -C(0)N(R22)(R23) . In embodiments, R12' is independently -C(0)C(0)N(R22)(R23).
In embodiments, Rue is independently -0C(0)N(R22)(R23) . In embodiments, R12' is independently -N(R24)C(0)N(R22)(R23). In embodiments, R12' is independently -N(R24)C(0)0R25. In embodiments, R12' is independently -N(R24)C(0)R25. In embodiments, R12' is independently -N(R24)S(0)2R25. In embodiments, R12' is independently -C(0)R25. In embodiments, R12' is independently -S(0)2R25. In embodiments, R12' is independently -S(0)2N(R22)(R23) . In embodiments, R12' is independently -OCH2C(0)0R22. in embodiments, R12' is independently -0C(0)R25. in embodiments, R12' is independently Ci_6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R" is independently C2_6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy. -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12' is independently C2_6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_6haloalkox-y, -0R21, -SR", -N(R')(R"), -C(0)0R22, -C(0)N(R22)(R21), -C(0)C(0)N(R22)(R21), -0C(0)N(R22)(R23), -N(R21)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12' is independently C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C1_6alkyl, C1_6haloalicyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -1\1(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently -CH2-C3_6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, Ci_nalkyl, Cl_nhaloalkyl, Ci_6alkoxy, C1.6haloa1koxy, -0R21, -SR21, -N(R')(R'), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(1('-'23), _C(0) C(0)N(R22)(R23), -0C(0)NR22) (R23 ), -N(R21 )C (0)N(R22)(R23), -N(R24)C(0)0R25, -NR211)C(0)R25, -N(R24)S(0)2R29, -C(0)R29, - S (0)2R29, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12' is independently -CH2-C2_9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci.6haloa1koxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), _C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12 is independently C610aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6allcyl, Ci6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy -0R21, -N(R22)(R23), _ C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R2')C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently -CH2-C6_10aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo. -CN, C16alkyl, Ci_ohaloalkyl, C1_6alkoxy, Ci.ohaloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), _C(0) C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R21)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12' is independently -CH2-C1_9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, Ci_6haloalkyl, Ci_6alkoxy, Ci_61ialoalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), _C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently Ci_91ieteroaly1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6alkyl, C1_6haloalkyl, Ci_6alkoxy, Ci_6haloalkoxy, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), _C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.

HN N
feL'Ov/6---SF
[00528] In some embodiments, the compound is selected from F

H
H <N,, K ==\--1) LT) /\=, 0 N
F
F 0 N N 1 'y HN 1 'IV H2N A, F
NO '= N 0 '-N
N
F
n n n H
H H N
N ( ) N
) ) 0 N
0 N 0 N -. F
H2 N H2N N 1 "` N
F F
s ,.., i )...........õ, ,...1, .....,õ N 0 =
N
N 0 = N 0 ' F
N N
F
F , F
H
N
H H eC6 N N
g (. N
0 N ¨ 0 N N 1 N F

) H2N II I
F F ''NI I N 0 S-., ..)...., .....õ,. S ..., N

N N
F F
F , F
H
N
H H
N N ) 0 0 ) 0 N

N 1 \ g F H2N
ii I
F HO N
- ''' ''' N N 0 S -..... ......-...L. ,.."õ S 1 N 0 = N 0 =
N N
F
F F
H H H
N N N
M
0 N y 0 N
H2N H2N H2N T¨L. 0 N
)--.--N N S i'' N F
--, 1,-.1....
N N N
F
F F , F
H H H
N N N
2c,:F M 0 ) ____________________ [..., 0 N 0 N 0 N

F F
F
/.1, ......,,, N = 0 ''" N 0 =
N 0 =
N N N
F
F F F
m n m H
N
H H
N N
O N ) ( F (:) 0 N
ii H2N, -,, 1 I .õ.....i., .....õ,,, 2 , CN F CN F
HO
N 0 ' -i---=N N 1 '''= i.----N N 1 ''--N

N N
, F
H H H
r ,IN N N
I<-- V M ) O N 0 N &

H2N H2N 0,,, H2N
) F
S I S -====. , S -. I
N e6----S N'...L'e '" N 0 =
N N N
F
F , F
H
N
) 0 N H H
N N
A.,., ) N I '' N F 0 N 0C N

HO*-1., N 0 N S S === s-.: , ,,,, F
N N
F
, F
H
N
) H
N H
N
O N C ) F M

H2N .A.:0,11 N

F 'S N F
''-....,,L. ....,õ
N 0 N 0 =
N N
F
, F , F
, H
N
O N
H
N H
N
( ) ==-.N y 0 y N

HO ,.., ,-,=._ , N 0,, F z D s , ...)..........õ
N 0 ''..r--N-..../
, F F .."1--7 F
..., , H
N
H M H
N
N M
( HN,V I N
F
H2N _________________________________________________ N

N 0 )------N HN-g N S ,, I
....:-.1õ ......,õ
N 0 ''==r-N 0 ' N
F F
F .r= , F

H H H
N N r , IN

F
S
''..r. F N 0 =
N N
F F KI-./ F
H H H
N N N

L..0 N 0-1 0 N

F F
N N
F , , F , H
le)1, ,Feyc:
L-7, _________________ 0 0 HO NS , N
I
H2N N -, H2N I L_ 0 N
¨
N 0 '==r--- N 0 '.r.== ¨
F
, .
, H
r õIN
H H
F F 0) 0 N
0 N ,..N
H2N H2N I 'I' õ.6---SF
F N
N 0 N 0 ===/-N
H
N
H &/ H
N N

0.II
0 @DI\II -=N;5 F N--H2N .0ii H2N Ci0 .z.g F
N 0 N 0 =
N
F N
F
F , F
.
, H H H
r_1N r , IN
F F -->
0 N 0 H2N H N .4. 0 N
N L
2 ? - H2N
)=---N N , -'N F
I
-_,-,L, õ,,õ.

N N
F F F
F F , H
N
H H
N 0 N rhl V M HO /N,g '''N 0 K¨>1 H2N c?
F N- ',',1N
F
N N
F F
F F , F
H H H
r, ,IN r re, INJ
V
/<-->1 0 N I<¨>1 ¨ 0 N 0 <--F F
S-,_ f, S -,_ ,,-; _, ,,,,õ S -= .:=,-, _õ..
__ESF
N N N
H
N
H H
( N
FµvF

I
0 N A..... ¨ N
F HO 44,4 . g N N
N F 1 -'1\1 N
.....-.1.,õ ....,õ
N 0 = N 0-'''A'''''N-' N 0 =
N I N
=
F
H
N
H
N

r ,_1N 0 N
1<-- 0 N
HO
0 N 'N '- N F HN I NI

r-.---N N N N 0 = N 0*----X¨'N"--F ¨
N
F F
H
N
H H

HO

H2N),,N
F
7:--_ N 0 = N 0 ' N N
F F
F

H
\
H y 0 N-N H
N ii N
?
0 HO N.S N 0 &Nii I
,.., F

H2 N N 0 ' H2N
F N '''N
F
F F
N 0 = ¨ ----. I
,,.L ,,,,, N 0 =
N N
F , F H
N H
M H
N
o N 0 N M
F =-.N-g F
HN 1 -` N ''' N 0 N
H2N),___N -=.,NA 1 '' N
F

N
F
, F
H
N
H H ( ) V 0 ( ) ________________________________ eµ6 0,11 --,N:S '' H2N )H2N I ,5...L., =---N '.'N- 1 '=N F I =---N NA '''' N F
N0 ' _______ N N
F
, , H
N
0 1\1) H H
N
N M0.;ii HO N-S -`N &/ 04 N
N-- '''N
F
=-,. N- ,0_,..x--,N,- H2N, FL ,Il S F
F I i=---N N 1 '=N ,õ
N 0 =
j S N
N
F
H
r ,HI
H
N NH
M o N M
H2N 02 N HN 1 '- N F
H N rIi? N
F HO ' 1...õ1, ....,,,..
2 , F
-:.=-.1,õ ,....,õ
N 0 ' F N
F
F , F
H
<N
H _____________ 0 s'N H
N L., N
V. M
0 N HOI __ N 1 1\1 ..., I ..4.1..õ F 0 N
H2N C.,g N 0- = H2N
F N >--=--N N-S 1 '-N F
N 0 ' ¨ N 0 N N

H
N H
F F ______________________________________ N
M H
N
A, .. i .N
0 N @)/
HO N,S
1 -`N 0,,, HN';S F N
I 1 '1\1 O9 No( 2 x F
F N 0 =
N sim--N FINS 1 '1\1 I

F , F F
. , H
N
H

HO ''N'S N
N O'X'' H2NW-- F F
=_- N 0 = N 0 .6--S
N N
F , F , F
' H
N
H HMrõõIN N
) .4.,F F 0 /\,0 F, F FE
F HO
N õg N N
I ''N

..õ),, ..,,,,, H2N 0 -= CN
F
)=----N N 1 N N 0 = .---N N 1 S =,, I *J., õ,,õ F N S ..., ,,õ,.
N 0 ' N 0 N N
F
, , H
N
H H
N N
( ) M N
ii , F

H2N H2N & RS? N NS 1 '''N
I
F NI N,S I"N F HO
)-,--N H N -. --,.1., ,6---- S

NI
N
N N
F
H H H
N N N
) 0 N ) ii H2N FL II
F
F
N N N
F F F
F F , F
. , H
N
H H
N N ( 0 ) ? N
F
H2N ? II N 0 )-----N N I r\il N 0 =
N 0 N 0 ''' =r----N
F F

H
N
H H
N N
ci? N
, 0 N ?¨ 1 N F
1 1 H2N L " c? HNS N I
F
N 0 ' ..71..., ,..,õ. N

N N
H H
H N N
N 0 Ki ( N ) 0 N
? 0 0,Il HO /\,. F
--.N N 1 'IV HO N's N
_.LN N---1.'0-'. "' -=,,, HO ., I
¨
¨ _ ¨ I
%
, F F
, 7 .
H
N
H H
N N ) ) , N

F
N
N 0 ==.r.- N 0 =
N
H H H
( e\C6 F F
Q--,=1 )-H2N 0.II H2N
F F H2 NhN.4. N .--.. N 0 i J., N - --r -y FL
F
F
. ,i'l=. ...-',, N N N
F F F , F
H H H
N N N
_________________ 0 ) ( HoN I L0.11 N __________ 1-1,11 09 N 1-1,N1 )==N N'-'S -CN
F
I
S =., I
..,7---1., ,...,õ S =., I
N N N
F
F F F , F
H
N
/ ,s0 H H

HO ''.N F ) M
I i 0 N
,.., ..5:-,.. H2N AF 9 ,0.II H2N ?-1,.. , N
NO 'A-1\(.-.
F
F
I
N N
F
F , F , F F

I-I
N
H H M KO <5 M
1\1_.0g N
o N
N -g F H2N

1 '"- N F
,=õ--L. õ76¨S N 0 '.=
N
N 0,,, N 0 =
N N
F F
F , F
H
N
H ) H
N N
O E1( Ocjii N ( 0 N -N,s H2N 0.11 i 'S F HO -õ N 0 1 N
i N 0 = N 0 =
N N
F
F , F
H
N

V. ( 1 0,9 N i _____________________________________ 1^, H2N Oq F H2N ,S F .. =)=,,, F I
S N -,... ..f..J..õ 0 õõ, = N 0 = ¨
N N
F F F
n n n H

0 N) H HN N
HO N T 4 ) F F
H2N ____________ F E ) 1 ' 0 N
,-, H2N 4,0z.II
le.õ0..,===N...- N
F
N 0 = S ,,, I ,) ,,, N N
H
N
H H
N
<:1) N

HN,S F

H2N 0.11 1 H2N 0,11 F HO -,, r=---N HN-S 1 '''N F _LN N 0 ' N
I-,õ, .-õ,- , .,,,,, S -=
==)=., ..,,,,,.
N 0 = N 0 N NI
F , F
H H
N N
) H
0 N /\ 0 N N
HO HO "-N 1 N
HN -'==N
I H2N--=-=.
N e*X-N-.- N 0N-- F
I __________________ I
= = N 0 N
F , F , F
, H
H N
N

HO N
F

0 61N11 HO '-N-S 1 '` N

F
N
S ¨ _ F F F
n -n H H
H N N
N
) 0 07,, 0 N
y_osõ ---N--HO F
N I ''' N 61 HO N N HO
HN_A
, -N
N 0 -..., .....-L, N N- -'0-"-X-'N".-F I ___________________ I
_ ___ _ ¨
F F F
m n n H
N
;E., ) H
N

N
N -g F F F 0 F
p N
N
N 0,, ' N
F
F n F
, , H H
N \,N H
) N, 0 C ( 0 N F./F i 0 N y .- 0 Nr-HO F HO F 4.---V.N 1 ,, N F
HO
N 1 ''' N N C" N
I F , ,.....,õ I N 0 ' --)..... ,-,õ
N 0 ' N 0 N N N
____ ____ _ _ _ F F F
m m n H H H
,N N
(N>
N/ 0 N 0 Th\J /., 0 N
HO F HO F HO F
N I ,11 HN 1 ''' N
=_ If; , ,...,õ I
.:-...&. .... N ,õ
' N 0 _ N N
____ ¨ _ _ F F F

H
H N
N
) 0 N 1:1:1 N H
N
0,11 HO N-S1 1 'N F eµ16 HO N'...S
H 1 '"'N
_.,61 H2N 0 N
'' II
N 0---X--"N--- N

F
N
F F F
n n n H
N
> H
N
H 9 N-- ) N
M
.7 0 N HO NS
''' -.., I N

HN ''s 1 CN F
I-12N N 0 ' F

N
F F
H
N

H H
N

0..,..g 0 ? 0 HO FINg N1 - N 0 ^ = ¨ ¨ ____ N
F F F
H
(N
N I -LI' H 0 -N- H
ll N
( ) HO S
N 1 "."N

....;--1,.. õ......, 0 N
H2 N N 0 ' H2N
F N F
N 0 = ' ¨ N 0 =
N N
F
F F , F
H
N H
..SZ N

N

N

,V 0 N F
HO ():1 HO N N
HO N N
N- CN''.

F F F

H
H N
N
<N> ( ) M 9 ....'N 0 0 N
HO EL.N.S , ,,N I
F HO ¨LN , ..,N F HO .N FL 0 N
I ---N
-õ
__N NO '6S
I
N 0 ' N o N N T
L--__ ¨ _ _ F F F
) , , H H
N
<N
) H
N F\ ,E
0¨L 9 N ) k -V N HO N-S , ..,1\1 I F a.., N 0 i 0 N
F HO N ''"N
.., N , N -., I
...,. 6----SF
N 0 ' N
N
_ _ ¨ _ F F
H
H
N <N>
)H 0 N

F HO /N-g 1 ''-N1 F

HN-S
I N
,..,-.1....õ ..õ,õ
H2N 4,..,001 N
'S F N. 0 = N
N
S___ N 0 ____ N
F
F F F
H H
N N H
( ) ) N
) 0 N n 0 N
HO AN-g F HO A...-:-A F y 0 N
, -"N N , '''' N 6_____s I-10 ., N-'-LO"'- "' I
N N N 0-'-`,A.-^-N-'=
F F I
z-_-_ F F F
, H H H
N N N
> Fc,F
0 N 0 N ___________ 0 N
0.11 I 4 e._____0.11 N:-"S F
HO --.NS F HO , -- N 6____sF HO , -"I\I
.'"N N
I
..., ....,--.L. ,...,õ
= N 0 ' N N
F F F
____ ____ F F F

H H
N N H

.--- N

I
0-1 C.) N 0.11 ii '' HO PLN3 N-,N HO N'S '- HO N'S N FN
..6---S
N 0,. '' N
I Xlj.
F
___ ¨ ____ F F F
H H H
<N N
(N) 0,11 YOS? r\j EI,, 011 HO NS 1N '-N F HO NS 1 ''''1\1 F HO N-S 1 N F
I I I
.., --, --_,.-.1,õõ
N 0 = N 0 ' N N N
___ F F F
H
(N>
(H) F F (11-N1 0,011 Th\J
0-1 ...., Q 'N
Ho 1 L,,u,g 4, 0 I\1 Ho HNs , '-.N F
F HO
N";.S F I
N 1 ''' N

6s ,.. ......L. ,...,õ, N
N 0 N 0-'''' N N ¨
____ ¨ ¨
¨ F
F F
, n , H
N
H F H
N
N y N N
( ) HO '= 0..011 N
=,N.S F

V N I k 'Thl /----N N- F " (:)N-- HO

S .. i _ I
F N
N 0 = ¨
N
F
F F N
H H
N H N
> N
( ) HO A.,C4 F
HO ----N N HO
..,-..L. õ..--,õ. ICI F _______ I
F m F F
n , H
H N
N
H E ) N 0 N

HO ?-1---,N 1 N HO
I
>
H2 N I N N CN,".
I
F I
N 0 "==r-- ____ ¨ ¨
F , F
, , H H H
N N N
) ) 0 N \( 0 N R N N

HO ''',N F HO HO INI N 1 -'N
I I
-=., I--; _, ,..-,õ, -,,, -,L,,,, .., ,),,, I I
F F F
n n n H
N
H H
N N
F F ) ( ) HO Li, 0 N

v_ 1:1' N N
I .i.:, H2N)õ_N N,S F F
.=
I
N 0 N 0 z-__-N N

H H
N N
) H
N F
F
) N HO
=-. CN F 0 N
1 ''-=

I
N S
_ F
F F
H
H N
N 0 ) M H

0 N e\I:6 HO N 1 -"'N
HN,g F I
-' N ( Ni? .,..
,J., N 0 = X---N HN'S
N I
, F F
H
N
H Ed N
( ) ? N
HO __________ i 1,..ug 1 /,N I ,-,N HO HO N.S -` N
F
N 1 1\1 I
...,-1..., ,õ
. N 0--)CN---F N ON N 0 = N
I ___________________ I F
¨
_ ____ _ F F F
, H H
N N
) H
HO
y N0 II _______________ 1 Q N
-S N HO __ I, N ''' N
,S F F 031 1 NON H2N 4.0 .11 - --- N o---X-'NI --- "S
F I F
S I
Z-_-_ .....,6-SF
¨
N 0 ' N
, F F
, F , H
N
H H
N (i)-1 ON

( ) \io(S
HO __ L,N,S
''' N
K' 0 N

H2N)N Nr--- F 1 1 N
S :fN ,0.' 'A. 6-SF
N 0 ¨ ' N N
F F , F 0 N
H H
H N
N
<> N) ) HO ---N-S ===== N HO
F
I HN N -...,, )CI ., HO ..., I
N N 0 ' F I
N
= =
F F

HI
<>
H H
N N

0 N.--4X,.., ,11 0.11 HO '''===-N-I' ====. N HO HO
-' N
N- -'0N"' _ F F F
, , , H
N,õ_ H ( __ /
N
H ) N .04 N
) 0 N Ho N
I 'N
F

N) IN
...:-.1.õ õ,...,õ
N 0 =
CN F HO ---. _., X--N N 1 ''== N N 0 = F
N
F
F F

H
N H
/-_\ N
E ) H
N V: N
HO N N
I ,.1 HO
HN-S 1 '. N
H2N ?-LO.,,..9 N
N
F F , F

H H
N r , IN
&' H
n0 ..-,,,i 1 HN-S 1 N F N --, F
H2N 0o N.11 1 -I
HO I ..,-.1.õ N 0 N õ...,õ.
,---N HN-S 1 N
S -,, 1 1,-.1õ.õ õ...,õ N
N 0 =
N
F
, m m H
N
) H
N
H r ) A,.. HO N __ -.` N

I J, HO /\-,NA
0 N N-0----K''N-.- N

..õ. ,J,, F N X-0-')CN"--_ _ F
F -N 0 _ N
F F

H
N
H H / \O <__>
N N
) 0 N---0 N ,..N _A 0a0,S9 N
I ____________ 1,.0 HO N

I HO N:
I .,NI
F
N
N 0 ' N
N CN-' N O'')N--F I _______________________________________________ C
F I
F F F

H
N
M H
N H
N
0 N m m ,.N F 0 N 5)¨L, 0 N
'".. N H2N
HO -.= 1 ,,,I _,,. H2N
F
F
1\1-'0 N N
H
N
H
H
N N.7 0 N
0 N 0 LS Oz..11 s''-õ- N
1 ...,C

I _et I ...õ
HO ,, ,1-õ, 1\1- '0'.--'2c N

N
F -= 0 ''.. F
¨
¨
NO

H H
N N H
) ( ) 9 N F\, N

0 N 77 0.

HO 17C),g HO __ CN.:S N HO &FC)q N 1 '''N
I
--,,, I
=_-_--_ ¨
_ _ _ F ' F F
H
H
N H / \O <N) 0 N 0_1,11 0 N -..N,S
HO A4 /\.0::....g HO 1 ''N F
N '`N
HO _______ N 1 N I
==, N 0.--)CN-' ..., õ-L.
N 0 =
N
F _______ I
_7= ¨ ¨ _ F F F
, , , H H
N N
..S.. H
N
0 ..'1\1--. FL 0 1\1 N

HO '-N HO
1 - N 1 '-N /\ -. F
I N--8 1 ''s-N
IT

I ,)=., .. I
N 0---X-.-N--- N 0=''''ANI, 1.---1.... ...õ,õ.

N
¨ _ _ F F
, H
N
,... H H
N N
0-1N ''N F 0 .1,e.' ( ) I L. 0 N 0 N
HO /N,g I1 ,,N
1 A. CN
F
N 0-')CN.I HO F N 0 ' N
= F
F
H H
N N
4F.,F

HO N 1 '1\1 I ) 9 N HO ",N
I -y N-..-.0"----X--N---NQN"--F I I I
=_-N
F , F F

H
N H
<ENI) N

HO HO __ N 1 ''' N F ?7, 0 N
N HO NLN
I -=,, I I N 0---X-^N---I
_ F F F
n n n H
N
H eµO/ N H
M 0 /\,..N 0 N N
N
1 ''' N F M
H2N H2N 4,.. 0 N
F HO
)------N HN 1 =-== N N 0 = ),---.N N 1 ."' N
......õ .......e N 0 = N
0 =
N N
F , F
H H
N N
..SZ ..SZ
2(..:F H
N
HO
0 N ( ) HO /.\'N 1 -,N

I
ek, CN F ,., eJ,,, --=
NO ---"'/C-N---¨
N
F , F F
H
N
H H
ICI: N N N
HO L.N-8 .,N ) ? .F 4F. ) I ,..),õ, ¨1 0N 0 N
-., H2N II
N 0')CN ---- H2N F ,S S F
, S_ -, .....,-.1....õ ..õ,õ
0 ' N
N
F F
F F F
H
N
____________________ F H H

HO N .-- N

,., H2N 0y N - -'0".'"/CN. H2N
CN F CN
F
F I

S S
_ N N

H
H <>N
F F C

2,., 9 N FE .: . 0 N H
N
HO N,S , .."- N F M
I HO N-- N
y 0 N

N N 0---)C-N
F F _______ I
=_ N
F F F
n n n H H
N N
H
N
________________________________________________________________ F
\( 0 N

/\.. CN F -.... õS
N N HO
N HO 1 -'== I 1 ,, .., N"--'0''K'-N-' I I
N
=_ ____ F F
I-I
N H
F F
HONcN
>
y HO N,S

N F
F
" Crc'''' 1 s F
N*.i.,Ø., _ N
F , F F
H
N
H H

HO /N,g N ) M

F N- H2N F S H2N __ I L CIII
'(/N' S
F
N N
F
, F , F
, H
N
H H
-HO '-N-S N ) i FL. 0 N OLaµ 0 N

N 0--)CN..õ- H2N N , =,_ CN F CN F
F I S .., 1 õ.- .....õ.
s)=-- N N 1 ..=-N N
F F
F F F
, , , H H

C N
TONIR N.- 1-10,91 N , - rLON9 N
HO NS ''N HO NS ''' N HO :S
N -NN
N cy-`=-A-"Nr N- -..0"'..-7CN".' F I F _______ I
I
= :-_-_ F F F
n n n H
N
H
4V 0( H
HO ) N
-0 N r , IN
0.11 N:S N A.... N

... H2 \( -')C-N-' HO F

F N 0 '''''.r---N 0 _________________________________________________________________ N 0 =
F
F , F
H H
N N
H
N
0 c) Y
I
.04 N I 0"

HO NS N
HO cNS 1 '`N
I HO

____________________ I I
= ____ ____ =
F F F
H
N
SZ H
N

H 0,11 N HO HNS
''N
I .4t .., HO "NNN
.Y., 0 H2N 1 ....., >- ____ ___ N 0 ===/----F
F , F
H H
H N N
\,,N

N A 1\1 F 0-9 1\1- A,s04 N
1 -` HO AN,N:S õN
I HO
N0 -., -..., N NO) F I ___________ F I
__ ____ F F F

H

/ \O
H
( Cio N
?¨L. iii? N N ) HO =,.N.3 1 ..,N
I F
HO N,S

V 0 N ,.õ., CN F N
N- -'0"-)C-Ne'e I
N 0 ¨ ¨ ¨
N
F
F F
, , F , H
N
H H )N N
Fy 0 0 N
4\-. 0 N

CN HO -, N '", 1 .., I CN
F

i.---_N N 1 ''', )7----N N
'',.. N 0 =
S 1õ,-,õ F N
N 0 ' N 0 ' N N
F F
F , F , , H
N
H

H

CN ) ?
ON,A N
HO N

F
N 1 '- N
1.---1..... .....,õ. N- '. H2N

),---N 'N'yN F
=_- 0 N
N
F , F , , H H H
N N N
) V 0 N n (1:1) y (?-1 0 N

F
--=---N. .µ'N,I ..6.__S. --=-.- N Ns., 1 ....LN
>-=---N NN H2N

6¨SF
S S S
0 N N e ''= 0 N N 0 f'" I.
N N N
F F F
n m m H H H
N N N
M F F eC6 N
H2N ¨lc Ys N

F H2N\ ,c,..... ...11 F S
F
>,---_N HNI I
S S
--)....õ .õ--,õ. S
N'I'O''' '.= N
0 N N 0'.. '" N 0 N N
F F F
n , n H
N H
N
) H

________________ )HO I ¨N-g '`11 /.. III
N N 6s.F CFI. N
., ,,,,- H2N
N CKs'IN HO F
____________________________ I N Ne )------N N'''.1 N
N S , I , ..,,,6s _-_-__- 0 N N 0 ' N
F , and F . In , H
N
_____________________________________________________________________ 0 H2N A.., F
N 0 ' N
F
some embodiments, the compound is selected from atropisomer 1 of F
H H
H2N ___________________________ 0 N C F3 0 N
F H2N\
N N
F
, atropisomer 2 of F F F , , H H
N
F-F __ F ) N F)--=---- N I IN
S--. ....,- ,.õõ ,..-,õ. S =-=_. ...,:-._ _.
õ,..--6-N N
F F
H
<N) H
N

N
1 .." N F H2N 0 ,-. ,-=
I -t 0 N
N 0 ' F
F
F
N -,, N 0 =
s¨(< N
F

H
N
<
../OH
CN, 0 N 0 HN

S-=. ..õ:..-,- , ,,,, S -.,. I ......,-.1..õ,õ
....--,,, N 0 = N 0 ' N N
F F
and H
N
<__) N 0 ' N
F
F . In some embodiments, the compound is selected from H H
=%y N ,_1 H
N
). N
L. ).= õ
N '", H 4. 0 H2N NC 4,N
F
' N
1 ' N

)-=-N " 1 F H2N CN,, S I ). ¨ N N ¨
,,,,, S N 0 ,, ,.
=
N N--' 010 S N 0 N
F F
F
F
F
H
r_L.IN
CO) H V=-. .) 4,-.., EC1 F H2N NC t_ N
N
ItL'011") ),--N
_.5.-. ,...õ.. _ N 1 ' N F
F F
ni ./
s N 0 S N 0 = N
N N

.
, H
N
H

(N ) N

H2N '&=, F H2N, III 0 N

ni `= N
F
-i---=--N N S S I -= ., 46----SF
N N 0 =
N 0 ' F N N
F F
F , F
F F
0õ..) N Niµla-/ CN

L.----./
0 CN.--N
H2N /\, F H2N Aõ, F
N N
F F
F , F
5(F

Yj---CN.

_ N I NNI

N
F
F . In some embodiments, the compound is selected from N
C T ,, 0 HN".-Clirr L.--...
H2N A,,, III
0 N 0 S ) Nr-F H2N A,.., F F N 1 s' N ,..., ,...-N F
N
F F
F , F , F
H
r---N ,...N...., OH
r... N ......õ;)' NC
4., 0 HN
'I., 0 N
H

F
F F 2 N \ N
sr-N
1 ' i N 0 ' N N F
F F
, F
H H
N N
,SZ c_pH

0 le 4-3,,... 0 N
4...... 0 N
H2N NC 4.N --.. N F H2N
N I ,.t , , .......õ6.____sF H2N
N
1 "1 F
N N
N
F F F
, F , F , F
:
0....õ..--.õ.=
H
cili\JH N
c,..N
NC
\ N

H2N CNI C) \

N
F
)=----N N
F
N
F F N---/ F
/ F , F
, , CY-r_--N
N , N
C T NC ,,..EiNH N
C ) H2N NC <:\====.N
F

N
I_ S...... ....,1.,õ ,,...õ, F F
F N----/
F , F , F
, H
0y---,.
F N
N
cir H2N ..., ..).õ... H2N
F N CY-LTD
F
N S--1( N
F F
F NH2 , F
.
, CI
Oy-J
N ,N
õ-- y ..-- 0 NI) 0 H2N CI\I N 'K F
F H2N &N I NI
S ---. -;:l.., ---,,õ S N 0 =

N F
I-F , and F . In some embodiments, the H
\1 N 1 ?
-N -, F
I
S ..,,, ,=,,, ,,õ, S
.-.,õ ,4.--L, ,õõ, N 0 = N 0 =
N N
F F
compound is selected from Oy-----_ -õ,.T..0 H 01,-0 kl F
0 N 0 1\
..(-.

N 1 -.`
N F
-.` N
I -I
....1, .õ...õ,. ,.-1, N 0 " N 0 N 0 =
N N
N
F F F
F F , 1 [6 H Oy-F <N N
) 0 N qv 0 The le 0 N

\
F
F
- N=

N
S
r--N
N
F F N---/ F
F , F / F

N, H * F H H
CN
<N>
__?

F S

......,õ F7 S -., ,-.,1_, ,õ
0 'N N 0 "1").-F
F F
N F F N

oyo Y F
H
N
<N N

0 N 0 1\12 F 0 N

F F
F
I
'.1\1 ,.õ,. S ..,..
õ....,õ.
NOS ' N 0 N N N
F F F
F F F
, 0..y.-----.
-..1õ,0 0y0 H H
M 0 Me0 s F
I NI F - N N
...,1 N
,..õ, ' N
F 0.-- F F

/
N-N
V, Oy H
N N
) ( ) N

1 -, N o F F ,.----õNõ---,,,O
S I., I
Ni.":-L-0.. = N
N
F
7 F , 0y0 H (F
N
N ) N
( ) c7 0 N
CN
C ) H2N CN H2N \

F
s õ
..,-.. , .......,õ. N Na, N 0 N 0 =
F F F
F I, F
' H H
NC N
>

F
..-.1.,,, N 0 = N
N e)CNOKF
F F F
F
N, H
P C

S ,.., õ.õ, S
N 0 ' N A'N''M
N
F F L,,,,.0 F F
m m r 0\
\
Y
N--"N
0y1----j>
H 0y0 N N
( NI C--) <N

H2N CN C=? H2N CN H2N CN C? N
F F
F
I
N 0 N 0 =
N 0 =
N N
N
F F F
F , CI
OF
H
N N
C ) 0 N ci 0 N

F
"rDe F F
N 0- ''=
N
F F
F /N
<Il ...,õ N
NC '( H2N ON 1 H2N CN Ii I
-_ , N
N" (:) 0 F N , , õ /-'-'1 NO'''' F F N
F
n n H S
N-CN
KN

H2N ON (---_, H2N CN N
F
S ,..., re-l'-'0 =,,i/--1 S -õ, N 0 ' F F
F

0.õ1 (ANNi ,1 H2N CN C"? N
H2N CN .S?
- N N N H2N _CN
.S?Ni N
I s I
N 0 = N 0 ' N N
N N <N
\CcToN

i- N1 N H2N CN

I
N N
F and f---0 < >r\I

- N N
I
N 0 ' In embodiments, the compound is a compound described herein (e.g., one of compounds 101 to 372). In embodiments, the compound is a compound described herein (e.g., one of compounds 101 to 442). In embodiments, the compound is a compound described herein (e.g., one of compounds 101 to 454). In cmbodimcnts, the compound is a compound described herein.
[00529] In an aspect is provided a compound having the formula A-LAB-B wherein A is a monovalent form of a compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, Ill, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, hAil, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV;
LAB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.
[00530] In an aspect is provided a compound having the formula A-LAB-B wherein A is a monovalent form of a compound of Formula I, I', IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9. IA10, IA1 1, 1Al2, 11, 11A1, 11A2, 11A3, 11A4, 11A5, 11A6, 11A7, 11A8, 11A9, 11A10, 11A1 1, 11Al2, 111, IV, V, VI, VII, V111, lx, X, XI, XII, XIII, XIV, or XV;
LAB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.
[00531] In an aspect is provided a compound having the formula A-LAB-B wherein A is a monovalent form of a compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA1 1, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, HAM, HAI 1, HAI 2, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, I', II', I", II'', I-1, I-1', I-1", I-1' ", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX;
LAB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.
[00532] A "degradation enhancer" is a compound capable of binding a ubiquitin ligase protein (e.g., E3 ubiquitin ligase protein) or a compound capable of binding a protein that is capable of binding to a ubiquitin ligase protein to form a protein complex capable of conjugating a ubiquitin protein to a target protein. In embodiments, the degradation enhancer is capable of binding to an E3 ubiquitin ligase protein or a protein complex comprising an E3 ubiquitin ligase protein. In embodiments, the degradation enhancer is capable of binding to an E2 ubiquitin-conjugating enzyme. In embodiments, the degradation enhancer is capable of binding to a protein complex comprising an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin ligase protein.
[00533] In embodiments, the degradation enhancer is capable of binding a protein selected from E3A, mdm2, AFC. EDD1, SOCS/BC-box/eloBC/CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HERS, HERC6, HUWEL
ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL (von-Hippel-Lindau ubiquitin ligase), WWP1, WWP2, Parkin, MKRN1, CMA (chaperon-mediated autophage), SCFb-TRCP (Skip-Cullin-F box (Reta-TRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAP1 (cellular inhibitor of apoptosis protein 1), APC/C (anaphase-promoting complex/cyclosome), CRBN
(cereblon), CUL4-RBX1-DDB1-CRBN (CRL4cRBN) ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBX04, FBX031, BTRC, FBW7, CDC20, PML, TR1M21, TR1M24, TR1M33, G1D4, avadomidc, ibcrdomide, and CC-885.
[00534] In embodiments, the degradation enhancer is capable of binding a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L I, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.
[00535] In embodiments, the degradation enhancer is a compound described in Ishida and Ciulli, SLAS Discovery 2021, Vol. 25(4) 484-502, which is incorporated by reference in its entirety for any purpose, for example VH032, VH101, VH298, thalidomide, bestatin, methyl bestatin, nutlin, idasanutlin, bardoxolone, bardoxolone methyl, indisulam (E7070), E7820, chloroquinoxaline sulfonamide (CQS), nimbolide, KB02, ASTX660, lenalidomide, or pomalidomide.
[00536] In embodiments, the degradation enhancer is a compound described in US20180050021, W02016146985.
W02018189554, W02018119441, W02018140809, W02018119448, W02018119357, W02018118598, W02018102067, W0201898280, W0201889736, W0201881530, W0201871606, W0201864589, W0201852949, W02017223452, W02017204445, W02017197055, W02017197046, W02017180417, W02017176958, W0201711371, W02018226542, W02018223909, W02018189554, W02016169989, W02016146985, CN105085620B, CN106543185B, US10040804, US9938302, US10144745, US10145848, U5993 8264, US9632089, US9821068, US9758522, US9500653, US9765019, US8507488, US8299057, US20180298027, US20180215731, US20170065719, US20170037004, U520160272639, US20150291562, or US20140356322, which are incorporated by reference in their entirety for any purpose.
[00537] In embodiments LAB is LA' LA' LAB3 LAB4 L'5;

LAB1, LAB2, LAB3, AB4, and LAB5 are independently a bond, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(RN)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, C1_6alkyT1ene, (-0-C1.6alk).71)z-, (-C1_ C2_6a1kenylene, C2_6alkynylene, Cl_nhaloalkylene, C3_12cycloalkylene, CI_Ilheterocycloalkylene, C6.
12arylene, or Ci_itheteromylene, wherein C1_6a1kylene, C2_6alkenylene, C2.6a1kynylene, C1_61taloalk)Tlene, C3-12cyc10a1ky1ene, Ci_iiheterocycloalkylene, C6_12arylene, or Ci_iiheteroarylene,are optionally substituted with one, two, or three R20-i: wherein each C1_6alkyl of (-0-Ci_6alkyl)z- and (-C1.6alky1-0)z- is optionally substituted with one, two, or three R20-i;
z is independently an integer from 0 to 10:
each R12 is independently selected from hydrogen, C1_6a1kyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, -CH2-C3.
6cyc10a1ky1, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10aryl, -CH2-C6_10aryl, -CH2-C1_9heteroary-1, and C1_ 9heteroaryl, wherein Ci-6a1kyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocycloa1kyl, C6_1(aryl, -CH2-C6_10a1yl, -CH2-Ci_9heteroaryl, and Ci_9heteromyl are optionally substituted with one, two, or three R20;
each RH is independently selected from hydrogen, C1_6alkyl, and Ci_6haloa1kyl;
or RH and RH, together with the nitrogen to which they are attached, form a C2_9heterocycloallcyl ring optionally substituted with one, two, or three Rafe;
each RH is independently selected from hydrogen, C1_6alkyl, and Ci_6haloa1kyk each R15 is independently selected C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyT1, C2_9heterocycloalkyl, C6_10ar0, and C1.9hetcroaryl, wherein Ci_oalkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalky1, C2.9heterocycloalkyl, Cb_loaryl, and C1_9heteroaryl are optionally substituted with one, two, or three R20;
each R2 d, woe, _R. - 20f, and R20-1 are each independently selected from halogen, -CN, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10ary-1, -CH2-C6_10aly1, -CH2-C1_9heteroaryl, C1_9heterowyl, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein Ci_6a1ky1, C2-6a1keny1, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3.6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6-ioaryl, -CH2-C6_1(aryl, -CH2-C1_9heteroary1, and Ci_9heteroary-1 are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, Ci_6haloalkyl, C1_6alkoxy, Ci_6haloalkoxy, -0R21, -SR21. -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23). -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R2', -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R21 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2_ 9heterocycloalkyl, C6_10aryl, and C1_9heteroary1;
each R22 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2_6alkenyl, C2_6a1kvnyl, C3_6cycloalkyl, C2_ 9heterocycloalkyl, C6_10aryl, and C1_9heteroary1;
each R23 is independently selected from H and C1_6alkyl;
each R24 is independently selected from H and C1_6alkyl; and each R25 is selected f7rom C1_6alkyl. C2_6a1kenyl, C2_6alkynyl, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6_10aryl, and C1_ 9heteroaryl.
[00538] In embodiments, LAB is -(0-C2a1kyl),- and z is an integer from 1 to 10.
[00539] In embodiments, LAB is -(C2alky1-0-),- and z is an integer from 1 to 10.

1005401 In embodiments, LAB is -(C1-12)zILAB2(CH2O)z2-, wherein LAB2 is a bond, a 5 or 6 membered heterocycloalkylene or heteroai-ylene, phenylene, -(C2-C4)alkynylene, -SO2- or -NH-; and zl and z2 are independently an integer from 0 to 10.
[00541] In embodiments, LAB is -(C1-12)z1(CH20)z2-, wherein zl and z2 are each independently an integer from 0 to 10.
[00542] In embodiments, LAB is a PEG linker (e.g., divalent linker of 1 to 10 ethylene glycol subunits).
[00543] In embodiments, B is a monovalent form of a compound selected from ti. PH
9 = r = 01.4 ' N
H = ..-"s= ==,'"' 1 F,x,k,t,,, N, '14 Al =,..-K, . 1........ P - ..-----('''' :t:
,.....e p 1.... ,,, ,s.
, L\ -;;....,N 6),:--µ i ) f---, -ii '>-o.... , '14 \...zny K.:,..4 0'..)-")µ ;/¨';44, = n = s 0 H s., iNt -.1 6 b Nutlin --=Nt? H 114-.\.::µ, ,y --,-õ, 0.4-,,,N,õ---HO I..
--.- -.õ--1, idasanutlin ....õ, A ..,,,, ko d 1) HI\
õ........
ke 0La ' R

e'..k. . 11 Nss., t ,;,, : '-/ '' H".51, =R
N'''',"\- .--, S.'.. ...,-3µ. -,.,-- K''''r''''''N'''kk'N'is-'-'''''' µ0-+, - =.....--' r , " 84-1) a .. ,µ
....,v4,,,,,,,...- o , .and .
Table 1 Compound Formula A B

N
I
R17- N' R2 R17------''N'NR2 R16 Formula R16 Formula (IA1) (TA2) 2 R1 o 0 \ R8õ,_ I
R1 l'-'-'''''''. N '----'"'- R2 R17N
N"pp2 ¨ Formula R16 Formula (TA4) (IA3) 3 0 R1 o o o Rlo R8, d R, s//
\ / `-,.../---':-õ, N

I
R17N /- N';'--'' R2 Formula R17N N
R2 Formula (IA5) (TA6) s R11-NR2 RI 7.----'-----'-'N R2 R16 Formula R16 Formula (IA7) (TA8) o o R10 0 R10 R8 Vc o'i . ,- R8 'R3 pp 2 ¨ Formula R16 Formula (TA 1 0) (IA9) R8 Vc> R3 R17N ,-N-pp. 2 ¨ Formula or R17 N----'''''N R2 (IA 1 1) Fomlula (IA 1 2) 7 0 Rlo 0 Rlo II

'N '--.'''.'`-- N
I I

Formula (IIA 1) Formula (IIA2) 8 0õ0 R1 0 Rl R8 \\s'c_.

''''.= N
I I I
R16 NR2 N..õ-..,-,..
,..-_-_,:-.,,, 2 N R

Formula Formula (IIA3) (IIA4) 9 0 Rlo 0 0 R1 I I I I
--,---, _.2-.,., N N ,......--..,,R2 R17 Formula Formula (IIA5) (IIA6) 0 Rlo 0 R1 R8 ..L.õ_..õ..,..õ..,,R3 R8 s Formula (IIA7) Formula (IIA8) 11 0õ0 Ri 0 R10 '-'1\1--R2 Formula Formula (IIA9) (HA 10) 12 0 Rl 0õ0 Rl ii R8 s.....,..._______I R3 ,.......
'NN/ R6 \src>

N--õ,..--,.-.... N =-=.,,,,....:____... õ..õ:"--...., N

Formula or (IIA 1 1) Formula (IIA 12) Table 2. R''' Embodiments A B C D
1 3-12 membered 5-12 membered H 3 membered nitrogen nitrogen nitrogen containing __.! (Ra)p containing ,.
containing heteroaryl '' heterocycloalkyl heterocycloalkyl optionally optionally substituted optionally substituted with one with one or more RI
substituted with or more RI and/or and/or one or more R4 one or more RI one or more R4 and/or one or more R6 and/or one or and/or one or more more 124 and/or R6 one or more R6 2 3-12 membered 5-12 membered H 4 membered nitrogen heterocycloalkyl heteroaryl bi¨(R4) containing P
optionally optionally li heterocycloalkyl ..n.tvv substituted with substituted with one optionally substituted one or more RI or more RI and/or with one or more R1 and/or one or one or more R4 and/or one or more 124 more 124 and/or and/or one or more and/or one or more R6 one or more R6 R6 3 H H N 5 membered nitrogen R
N N ....
...õ ...., < (R4 _(R4),,, containing ( 4)p ,... )p :43 1 .....
heterocycloalkyl J\AIV
optionally substituted with one or more RI
and/or one or more R4 and/or one or more R6 4 H H H 6 membered nitrogen N.. N, N
containing II N

heterocycloalkyl usfuv optionally substituted with one or more R1 and/or one or more R4 and/or one or more R6 H H H 7 membered nitrogen N
7-- ( Rel)p containing N 11 ri heterocycloalkyl optionally substituted with one or more RI
and/or one or more R4 and/or one or more R6 6 H H --NH 8 membered nitrogen HN\...N. (R4)p containing ,, ..-, ...-- P li 11 ....'-N
heterocycloalkyl optionally substituted with one or more RI
and/or one or more R4 and/or one or more R6 K/c1H H 9 membered nitrogen 6,,, )--(R4)p -----(R4)p N, C VR4)p containing ri Il heterocycloalkyl optionally substituted with one or more RI
and/or one or more R4 and/or one or more R6 8 NH /, 1---, (R4) 10 membered nitrogen 0¨(R4)p " P
(R4)p 11 ll containing I'l heterocycloalkyl optionally substituted with one or more RI
and/or one or more 124 and/or one or more R6 9 \c,CH r-N1c1 H
N 11 membered nitrogen (R4)P \s=õ,./¨(R4)P
containing 7-(RID
heterocycloalkyl ,4) N optionally substituted ' with one or more RI
and/or one or more R4 and/or one or more R6 (R4) R6 4 12 membered nitrogen containing li 2 heterocycloalkyl optionally substituted with one or more RI

and/or one or more R4 and/or one or more R6 11 R6 R6 R6 3 membered nitrogen N I
N N R4 containing monocyclic -1\r )P
heterocycloalkyl N N
1 optionally substituted with one or more R1 and/or one or more R4 and/or one or more R6 12 R6 R6 R6 4 membered nitrogen F
/
FN/
t- ¨/-1--(R I
C N) ) N___T¨(R4)p e 1\1 containing monocyclic 1.4)P
heterocycloalkyl optionally substituted with one or more RI
and/or one or more R4 and/or one or more R6 13 4 5 membered nitrogen (R4) p N--:-----µ,/ (R4)P r----"--,(R )P
r N N ,,/, containing monocyclic N L
z N
heterocycloalkyl r _......., L. N ..,----optionally substituted L. N
with one or more RI
_L.
and/or one or more R4 and/or one or more R6 14 R4 R4 6 membered nitrogen c__p....._R4 containing monocyclic - -->,(R4)P N>_õ--- (R 4)p ..j N
-1.-heterocycloalkyl optionally substituted N .-...N.-- with one or more RI
_L.
......L. and/or one or more R4 and/or one or more R6 15 R4 R4 R4 7 membered nitrogen (R ,...-p I 1 4 containing monocyclic N -- (R4) X cir.\.31õ...,,,,(R4)p )P
heterocycloalkyl ,N optionally substituted N
...L. N
_1..... with one or more Ri and/or one or more R4 and/or one or more R6 16 (R4) R4 8 membered nitrogen p N--( )p N., ,,N containing monocyclic N r N r ¨
heterocycloalkyl c T L.1\1.' optionally substituted NN ......L
.....L. _L. with one or more RI
and/or one or more R4 and/or one or more R6 17 (R4)p N:----- \-/ ("P rz---rj---- (R4)P 9 membered nitrogen F.\ -:-N, r N;..> N N .,.." containing monocyclic C
N ,....,N
heterocycloalkyl 1-... ..--l''s N *-. N optionally substituted I-.
N with one or more RI
and/or one or more R4 and/or one or more R6 18 R6 R6 4 membered nitrogen .S<
(R4)p I :IN -..... containing fused (R4)p R6 N
¨1¨ bicyclic heterocycloalkyl N optionally substituted N...N, .....L.
with one or more RI
and/or one or more R4 and/or one or more R6 19 R6 R6 R6 5 membered nitrogen X
N.:..õ----(R4)p i I r(R containing fused (R4)p ci N 4)P
bicyclic ,N
heterocycloalkyl N 4., .....L. N N optionally substituted with one or more RI
and/or one or more 124 and/or one or more R6 20 (R4) R6 6 membered nitrogen p NN N -- (R4) c )õ.- P
CNN
containing fused bicyclic L'N '''' heterocycloalkyl ... ... -L. optionally substituted with one or more RI

and/or one or more R4 and/or one or more R6 21 7 membered 8 membered 9 membered nitrogen 10 membered nitrogen nitrogen nitrogen containing containing fused containing fused containing fused fused bicyclic bicyclic bicyclic bicyclic heterocycloalkyl heterocycloalkyl heterocycloalkyl heterocycloalkyl optionally optionally substituted optionally substituted optionally substituted with one with one or more RI
with one or more R1 substituted with or more RI- and/or and/or one or more R4 and/or one or more R4 one or more RI one or more R4 and/or one or more R6 and/or one or more R6 and/or one or and/or one or more more R4 and/or R6 one or more R6 22 11 membered 12 membered 5 membered nitrogen 6 membered nitrogen nitrogen nitrogen containing containing bridged containing bridged containing fused fused bicyclic bicyclic bicyclic bicyclic heterocycloalkyl heterocycloalkyl heterocycloalkyl heterocycloalkyl optionally optionally substituted optionally substituted optionally substituted with one with one or more RI
with one or more Ri substituted with or more RI- and/or and/or one or more R4 and/or one or more R4 one or more it' one or more R4 and/or one or more R6 and/or one or more R6 and/or one or and/or one or more more R4 and/or R6 one or more R6 23 7 membered 8 membered 9 membered nitrogen 10 membered nitrogen nitrogen nitrogen containing containing bridged containing bridged containing bridged bridged bicyclic bicyclic bicyclic bicyclic heterocycloalkyl heterocycloalkyl heterocycloalkyl heterocycloalkyl optionally optionally substituted optionally substituted optionally substituted with one with one or more RI
with one or more Ri substituted with or more RI and/or and/or one or more R4 and/or one or more 124 one or more RI one or more R4 and/or one or more R6 and/or one or more R6 and/or one or and/or one or more more 124 and/or R6 one or more R' 24 11 membered 12 membered 5 membered nitrogen 6 membered nitrogen nitrogen nitrogen containing containing spirocyclic containing spirocyclic containing bridged bridged bicyclic bicyclic bicyclic bicyclic heterocycloalkyl heterocycloalkyl heterocycloalkyl heterocycloalkyl optionally optionally substituted optionally substituted optionally substituted with one with one or more RI
with one or more RI
substituted with or more RI and/or and/or one or more R4 and/or one or more R4 one or more RI one or more R4 and/or one or more R6 and/or one or more R6 and/or one or and/or one or more more R4 and/or R6 one or more 126 25 7 membered 8 membered 9 membered nitrogen 10 membered nitrogen nitrogen nitrogen containing containing spirocyclic containing spirocyclic containing spirocyclic bicyclic bicyclic bicyclic spirocyclic heterocycloalkyl heterocycloalkyl heterocycloalkyl bicyclic optionally optionally substituted optionally substituted heterocycloalkyl substituted with one with one or more RI
with one or more RI
optionally or more RI and/or and/or one or more le and/or one or more R4 substituted with one or more R4 and/or one or more R6 and/or one or more R6 one or more RI and/or one or more and/or one or R6 more R4 and/or one or more R6 26 11 membered 12 membered 3 membered nitrogen 4 membered nitrogen nitrogen nitrogen containing containing containing containing spirocyclic bicyclic heterocycloalkyl heterocycloalkyl spirocyclic heterocycloalkyl optionally substituted optionally substituted bicyclic optionally with one or more R4 with one or more R4 heterocycloalkyl substituted with one optionally or more RI and/or substituted with one or more R4 one or more RI and/or one or more and/or one or R6 more R4 and/or one or more R6 27 5 membered 6 membered 7 membered nitrogen 8 membered nitrogen nitrogen nitrogen containing containing containing containing heterocycloalkyl heterocycloalkyl heterocycloalkyl heterocycloalkyl optionally optionally substituted with one optionally substituted ..
optionally substituted substituted with or more R4 with one or more R4 with one or more R4 one or more R4 28 9 membered 10 membered 11 membered nitrogen 12 membered nitrogen nitrogen nitrogen containing containing containing containing heterocycloalkyl heterocycloalkyl heterocycloalkyl heterocycloalkyl optionally optionally substituted optionally substituted optionally substituted with one with one or more 124 with one or more R4 substituted with or more R4 one or more R4 29 3 membered 4 membered .5 membered nitrogen 6 membered nitrogen nitrogen nitrogen containing containing monocyclic containing monocyclic containing monocyclic heterocycloalkyl heterocycloalkyl monocyclic heterocycloalkyl optionally substituted optionally substituted heterocycloalkyl optionally with one or more 124 with one or more R4 optionally substituted with one substituted with or more R4 one or more R4 30 7 membered 8 membered 4 membered nitrogen 5 membered nitrogen nitrogen nitrogen containing containing fused containing fused containing monocyclic heterocycloalkyl heterocycloalkyl monocyclic heterocycloalkyl optionally substituted optionally substituted heterocycloalkyl optionally with one or more 124 with one or more R4 optionally substituted with one substituted with or more R4 one or more R4 31 6 membered 7 membered 8 membered nitrogen 9 membered nitrogen nitrogen nitrogen containing containing fused containing fused containing fused fused heterocycloalkyl heterocycloalkyl heterocycloalkyl heterocycloalkyl optionally substituted optionally substituted optionally optionally with one or more R4 with one or more R4 substituted with substituted with one one or more R4 or more R4 32 10 membered 11 membered 12 membered nitrogen 5 membered nitrogen nitrogen nitrogen containing containing fused containing bridged containing fused fused heterocycloalkyl heterocycloalkyl heterocycloalkyl heterocycloalkyl optionally optionally optionally substituted optionally substituted substituted with substituted with one with one or more R4 with one or more R4 one or more R4 or more R4 33 6 membered 7 membered 8 membered nitrogen 9 membered nitrogen nitrogen nitrogen containing containing bridged containing bridged containing bridged bridged heterocycloalkyl heterocycloalkyl heterocycloalkyl heterocycloalkyl optionally substituted optionally substituted optionally optionally with one or more 124 with one or more R4 substituted with substituted with one one or more R4 or more R4 34 10 membered 11 membered 12 membered nitrogen 5 membered nitrogen nitrogen nitrogen containing containing bridged containing spirocyclic containing bridged bridged heterocycloalkyl heterocycloalkyl heterocycloalkyl heterocycloalkyl optionally substituted optionally substituted optionally optionally with one or more 124 with one or more R4 substituted with substituted with one one or more R4 or more R4 35 6 membered 7 membered 8 membered nitrogen 9 membered nitrogen nitrogen nitrogen containing containing spirocyclic containing spirocyclic containing spirocyclic heterocycloalkyl heterocycloalkyl spirocyclic heterocycloalkyl optionally substituted optionally substituted heterocycloalkyl optionally with one or more R4 with one or more R4 optionally substituted with one substituted with or more R4 one or more R4 36 10 membered 11 membered 12 membered nitrogen nitrogen nitrogen containing containing spirocyclic containing spirocyclic heterocycloalkyl spirocyclic heterocycloalkyl optionally substituted heterocycloalkyl optionally with one or more R4 optionally substituted with one substituted with or more R4 one or more R4 Table 3. L1 Embodiments A B C
1 Bond CI-C6alkyl C2-Coalkenyl 2 C2-Galkynyl -C(0)- -NHC(0)-3 -C(0)NH- CH20 CH2NH

Table 4. R'9 Embodiments A B C D E
.........
1 C3_12cyc1oalky1 C2- C6-12aryl and C2 optionally iihetcrocycloalky optionally 1 2hete ro aryl x4."-- xi o I
II
substituted with 1 optionally substituted with optionally x5_,.. ,X9 one to seven R" substituted with one to seven R" substituted with one to seven Rh one to seven Ril ¨ ¨ ¨ ¨
2 ¨
X12 Qi x4-xii x4-1,1-- 1 )(4 '' r- \ 12' i X9'-''*"=

;_R x:10_.Q4 X6-X1 6o.z,.. _______ .., x 1 o )(5X6,.. ...õ. Q 1 XX66-. N-Q-- 1 X19---xii Q4 ' xil Q3 x -N
(:).õ,N Q3 ,N Q4 Q3 . Q3 ----- , --R
I I ¨Rill -1 )( ________________ I '-R r I Q;,3 > R
o ,N Q4 X7.=,,x8.."--Q4 7X8------04 xT.8 ¨1), w \Q6 Q4 ---x 4 Nz-_-Q3 N¨Q4 H2N H2N
yr ., ,, cyr 04 =--N )-----N
',.._ 51 Q5/ I ____ *R' 0 I I "QS Q3 S
X6,. xi- Xi X6, xi- Xi IF
H2N HO ,,... "V HO \-. HO V H2N N___ )?----N I F ./
.-= I
S
F
0 \-F . ..__ -..,, ..,_.
õ..,...,.....õ
F
IIIII
6 H2N N,, 'Liz-. H2N 1\1.. cxci 0 I
õ,- I
F F ..----CI
N
L_iiI
,õ

7 cA \--. .:J\I___.

F F

/ HN
N._ N...._ N-N N-N

HNI
\--. , 0 \-.
F
CI

9 N____ H H H2N N.,, 'L
H2N N.õ
HN0 \.- N N 5.,- N N '2,-1;Qv y -..,--CF, .-.--- CH
CI
1 H2NN,'44: H2N,..,rNyz,.-a. H H HO
.,,,...5,L.I
I ,, N 1\1A.
_,...

'.-.-r 1.,.,,..., OCF

'V:. HO 0 'Liz. HO
, Nio--F
1 ./
CF3 Lt&CF3 C I
CI
CI CI

1 Rla CN H2 Ns ..,, N

2 x13 C1 --.- \
\ NH2 X15----(14 H
F
F

_.,,.,. CN H2N ON H2N
CN

F

4 ¨
S X S ,... NX S - S
A
N' S .N___A
) F
F

,..., C;c\N H2N CN H2N CN H2N
CN
¨ _ ¨
S _ S S
./. 1 F
N .. I
F F F F F F

CN
¨ 0 S S ¨ \ NH2 / NH2 \ NH2 S
F F ON
Table 5. R2 Embodiments A B C D
1 ¨(Ci-C6alkyl)-R12b ¨(C2_6a1keny1)-R12b ¨(C2_6alkynyD-RI2b -0-R12a 2 -N(R14)-R12b -S-R'b -(C3_10cycloa1kyl)-R"b -(C2-9heterocycloalkyl)-R12b 3 -(C6_10ary1)-R12b ¨(Ci_9hctcroary1)-R12b ,ss r' -:), /
¨( 4 N¨N
N
N4> c:c<0 1 .., N
'.e10 AO F F
N N F
ifss--0"-= 6".-N N

6 OM e H
6-----S 5"ss&O'6---)--c:rc4:0-6i:
N

7 \
N¨ "--0,--3 rr(cy.."" Nr -----oNN,,..õ,.-F F
c.rfs0/"'0....0Me 10 0.--,, 2 OCF H
0 N D<F c:rcs'ONLD rrs.-F
/ /
11 o=ks,0,--,,õ r,... A --IID
0, '10-- OMe Nr -/
IV ----/

\ \

c3<CDN
,f- iss-s-o^D Na 13 I ctrrs'.N10....OH

/

1--- \N
c3s:r-0 In N

Ø...CN H
rsss'. N '''''..1N-N N N N
, /
H H
16 -..., I A \\ AO N
N,N
1 "--0--) ...
17 .õ..----...N .---...0 F 3 Cy ..õ---..., //

18 ,..---.. N -,-= .,õ....¨...N -,--,õ--0--.. 0N, P
, Y õ....--.N..--,,,S ssss-0 '"=c---c(0-) /N

Xs' cis" rls.s-0'-'"'icic....5.-/N
0 0 ogo , F
/OW j`slOK' r14 N)C NO
cIss- OW
21 rµrs'N .--)C NO
1 r S -'/C NO ;;Js'---'--)C NO
cljs'O).CNO<F
F
22 c'sr!.0-')CNO..... F cl5f0-.'-X. NO
riss'07c NO . ,µ F
rIss'02C N6 23 rls-Zes NO r4-0-)CN
cFc'CY)C NO
24 I r/ss.'0 N ':'se-)C VM cijs'0,CCN
vIrs-0-2c N --N.

___________________________________________________________________________ NO/
s.ro--"-><^.N ---- risfØ-----.x.,CN
'-js0-'7cCN

Y V
26 As ... D cf=-=¨=-"--0 /

N
OH
/

1 clsr.-1C 1 I I
28 if C1,0 H
N-----".1- n N 'IS /-'= A0'-'..6)'", /

/
30 Tr< J F riss., r x j 0,_._ 1 \j/D ,g j, 0 = 0 NO = I\
ON ' N
0¨
.., o 31 RI F.,r_F
c"ss'.0j"'=r----,,NO

Fs j F
r*
), F
/ / ,-;go "-i--- /-0,g1-\--D
AO)'==µ--(F 0 b /, csiss. _I, F c3sNI AN
L.i.5 /
\-0Me \-0Me H
S N
/ N
/
37 /N 1-).---F NO
'llo'Q==,,/(j1 Table _______ 8 1V
A B C D

1 hydrogen halogen oxo -CN
2 Ci_6alkyl optionally C2_6alkeny1 optionally C2_6alkynyl optionally C3_6cycloa1kyl substituted with one, substituted with one, substituted with one, optionally substituted two, or three R2c4t two, or three R2041 two, or three R20a with one, two, or three R20a 3 C2_9heterocyc1oalkyl C6_10aryl optionally C1_9heteroaryl optionally -OR' optionally substituted substituted with one, substituted with one, with one, two, or three two, or three R20a two, or three R20a R20a 4 -SR' -N(1212)(1213) -C(0)0R" -0C(0)N(R")(R13) - -N(R14)C(0)0R15 -N(R14)S(0)2R15 -C(0)R15 N(R14)C(0)N(R12)(Rn) 6 -S(0)R15 -0C(0)R1' -C(0)N(R12)(R") -C(0)C(0)N(R9(R13) 7 -N(R14)C(0)R15 -S(0)2R15 -S(0)2N(R12)(R13)-S(=0)(=NH)N(R12)(R13) g _cH2c(0)N(R12)(R13) _CH2N(R14)C(0)R15 -CH2S(0)2R15 -CH2S(0)2N(R9(R13) 0.õ,y------..
0....,..-----..
Oil -='¨, --' --õrO

0' 0 ¨ -. 0 0 ---:,- -..- _ ¨
10 ,,,,c,CN
c \ N-1,.
1\
OTO

N¨N
¨I¨ 01:11 ¨
cd, 0.....õ.---12 CI NC"';/ I
o 0a, , F NV
T......F N
13 r0 -C(0)R15; R15 is C6- -C(0)R15; R15 is Ca_ -C(0)R15; R15 is Ca_ \c, N õ......) ioaryl optionally ,heteroaryl optionally 6alkyl optionally substituted with one, substituted with one, substituted with one, two, or three R20f two, or three R201 two, or three R20f 14 -C(0)R15; R15 is C2_ -C(0)R15; R15 is C2_ -C(0)R15; R15 is C3- -C(0)R15; R15 is C2_ 6a1ke11y1 optionally 6a1kyny1 optionally 6cyc10a1ky1 optionally 9heterocycloalkyl substituted with one, substituted with one, substituted with one, optionally substituted two, or three R2" two, or three R2" two, or three R2"
with one, two, or three R20f Table 9 R8 A

õõP>+
NC
F F
2 >F1-F CN

,0 N \ = CN
N37\1 4 NC¨\_5 N C
sc.) Me Et n-Pr n-Bu 6 t-Bu iPR HO¨\_5 HO¨>r [00544] In embodiment the subject compound is a compound of a Formula of Table 1 (e.g., one Formula selected from 1A-12B) combined with one R' Embodiment of Table 2 (e.g., selected from 1A-9C, 10A) combined with one L' Embodiment of Table 3 (e.g., selected from 1A-3C, 4A) combined with one R'9 Embodiment of Table 4 (e.g., selected from 1A-11E)(wherein L1 and R19 combine to form R'' of the formulae of Table 1) combined with one R2 Embodiment of Table 5 (e.g., selected from 1A-27D, 28A, 28B). R3, le, and 12_16 are as described herein, including in any embodiment herein.
[00545] In embodiment the subject compound is a compound of a Formula of Table 1 (e.g., one Formula selected from 1A-12B) combined with one R1' Embodiment of Table 2 (e.g., selected from 1A-12C) combined with one L1 Embodiment of Table 3 (e.g., selected from 1A-3C, 4A) combined with one R"
Embodiment of Table 4 (e.g., selected from 1A-16E)(wherein L1 and R19 combine to form R'7 of the formulae of Table 1) combined with one R2 Embodiment of Table 5 (e.g., selected from 1A-36D). R3, R8, and R16 are as described herein, including in any embodiment herein.
1005461 In embodiment the subject compound is a compound of a Formula of Table 1 (e.g., one Formula selected from 1A-12B) combined with one 111 Embodiment of Table 2 (e.g., selected from 1A-20C) combined with one L' Embodiment of Table 3 (e.g., selected from 1A-3C, 4A) combined with one R19 Embodiment of Table 4 (e.g., selected from 1A-16E)(wherein L,1 and R19 combine to form R'' of the formulae of Table 1) combined with one R' Embodiment of Table 5 (e.g., selected from 1A-36D). R3, re, and R16 are as described herein, including in any embodiment herein.
[00547] In embodiment the subject compound is a compound of a Formula of Table 1 (e.g., one Formula selected from 1A-12B) combined with one R1`) Embodiment of Table 2 (e.g., selected from 1A-35D, 36A, 36B, 36C) combined with one L1Embodiment of Table 3 (e.g., selected from 1A-3C, 4A) combined with one R19 Embodiment of Table 4 (e.g., selected from 1A-16E)(wherein L1 and R19 combine to form R1.7 of the formulae of Table 1) combined with one R2 Embodiment of Table 5 (e.g., selected from 1A-36D, 37A, 37B), combined with one 111 Embodiment of Table 8 (e.g., selected from 1A-14D) combined with one IV
Embodiment of Table 9 (e.g., selected from 1A-6D). R3 and R16 are as described herein, including in any embodiment herein. P is an integer from 0 to 12.
In embodiments, p is 0. In embodiments, p is 1. In embodiments, p is 2. In embodiments, p is 3. In embodiments, p is 4. In embodiments, p is 5. In embodiments, p is 6.
[00548] Besides the inhibitory effect and high potency in reducing Kras signaling output by targeting Kras (including Kras mutants such as Kras G12D), compounds disclosed herein exhibit one or more advantageous DMPK
properties. Exemplary superior DMPK properties associated with the subject compounds include but are not limited to improved metabolic stability, decreased serum protein binding (hence increasing the free and available compounds circulating in a subject's blood upon administration of the compounds), and/or increased oral exposure.
Fine-tuned pharmacological properties embodied in the subject compounds are of great significance for improving efficacy and/or safety of Kras inhibitors for therapeutic clinical applications.
[00549] In sonic embodiments, a compound of Formula T, T', T", T-1, T-1', T-1", or I-1"' exhibits an increase in unbound/free compound present in plasma as compared to a compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) but with the similar or identical substituents R2. R10, R16, and R17. In an embodiment, a subject compound of Formula I, I', I", I-1, I-1', I-1", or I-1' " exhibits an increase in unbound/free compound present in plasma by at least 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700 times or more in comparison to a corresponding compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) but with the similar or identical substituents R2, R10, R16, and R17. In another embodiment, a subject compound of' Formula I, I', I", I-1, I-1', I-1", or I-1" ' exhibits an increase in unbound/free compound present in plasma by at least 10%, 20%, 30%, 40%, 50%, 100%, 200%, 300%, 400%, 500%, or even higher as compared to a corresponding compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) but with the similar or identical substituents R2, R10, R', and R17.
[00550] In an embodiment, a subject compound of Formula I", T-1, T-1', I-1", or T-1'" exhibits a decreased serum protein binding as compared to a compound having a different core scaffold but with similar or identical substituents R2, R10, R16, and R17.
[00551] In an embodiment, decreased serum protein binding is observed in compounds of Formula 1, l', 1", 1-1, 1-1', I-1", or I-1" ', as compared to a compound having the same substituents R2, R10. R16, and ic but with a different 6-membered heteroaryl bicyclic core scaffold.
[00552] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula 1, 1', 1", 1-1, 1-1', 1-1", or 1-1" ' wherein R' is -1:-R7; 1_,7 is a bond, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, _c(0)N(R24)_, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)_, _s(0)N(R24)_, _N(R24)s(0)_, _N(R14)s(0)2_, C1-C6alkyl, C2-C6alkenyl, C2-C6a1kynyl, or 2 to 4 membered heteroalkylene linker, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R2 ; and 11.7 is a 4-12 membered cycloalkyl, 3-12 membered heterocy cloalkyl, '7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aiyl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00553] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, I', I", I-1, I-1', I-1", or I-1" ' wherein R" is -L7-R7; L7 is a bond, -0-, or -N(R")-; and R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more 10, and optionally substituted with one or more R6.
[00554] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, I', I", I-1, I-1', I-1", or I-1" ' wherein R" is -L7-R7; 1_2 is a bond; and 117 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00555] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, I', I", I-1, I-1', I-1", or I-1" ' wherein RI" is -L7-R7; L7 is a bond; and R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more R4.
[00556] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, I', I", I-1, I-1', I-1", or I-1" ' wherein R17 is -1_,1-R19; L1 is selected from a bond, Cl-C6a1kyl, C2-C6alkenyl, C2-C6a1kynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(Ri4)_, _N(Riot)s(0-.)_, _, N(R14)S(0)2-, -OCON(R14)_, _ N(RN)C(0)0-, N(R1e), C(0)N(111`), S(0)2N(Rie), S(0)N(R), (Rir)(Rig)0, c(Rir)(Rig)N(Ri)c,, and C(R1f)(R1g); R19 is selected from a C3_12cycloalkyl, C2 ,,heterocycloalkyl, C6_12atyl, and C2.12heteroaryl, wherein the C342cycloalkyl, C2_iiheterocycloalkyl, C6_12aryl, and C2_12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven RH.
[00557] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, I', I", I-1, I-1', I-1", or I-1" ' wherein RI' is -L'-R'9; L' is a bond; R'9 is selected from a C642aryl and 9-10 me mbe red bete roalyl, wherein the C6_12aty1 and 9-10 membered heteroa iy1 are optionally substituted with one, two, three, four, five, six, or seven Rh.
[00558] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, I', I", 1-1, 1-1', 1-1", or 1-1"' wherein R17 is -L-F119; ['is a bond; R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaly1 are optionally substituted with one, two, three, four, five, six, or seven Rh.
[00559] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula 1, 1", 1-1, 1-1' 1-1", or 1-1" ' wherein R17 is -L'-R'9; L1 is a bond; R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven 1111; each TO is independently selected from halogen, -CN, C1_3a11(371, C1-3haloalkyl, C2_3a1kenyl, C2_3alkynyl, -OH, -NH2, wherein C1_3alkyl, C1_3ha10a1ky1, C2_3alkenyl, and C2_3alkynyl are optionally substituted with one, two, or three R20.
[00560] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula (I-1), (I'-1), (Ia-1), (Ia'-1), (lb-1), (lb'-1), (Ic-1), or (Ic'-1), wherein R2 is _0_102a; Rua is _c(Ri2c)245-8 membered heterocycloa111), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20".

[00561] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula (I-1), (I'-1), (Ia-1), (Ia'-1). (lb-1), (lb'-1), (Ic-1), or (Ic'-1), wherein R2 is _o_R12a R12a is _c(R12c)245-8 membered heterocycloalkyl), wherein -C(R1292-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R'd; R12' is independently selected from hydrogen and methyl.
[00562] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds H2N CNµP\N
N
N 0 ' Ris of Formula (XVI), F in comparison to a corresponding compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core).
[00563] In some embodiments, a compound of Formula I, I', I", I-1, I-1', I-1", or I-1" ' exhibits superior metabolic stability as compared to a compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) but with the similar or identical substituents R2, R10, R'6, and R17. For example, a subject compound exhibit significantly longer metabolic stability as ascertained by the T1/2 of liver microsomal metabolism (see Example 12 for experimental procedures). In an embodiment, improved microsomal metabolic stability is observed as compared to such a corresponding compound by at least, 10%, 20%, 30%, 40%, 50%, 100%, 200%, 300%, 400%, 500%, or even higher. In an embodiment, improved microsomal metabolic stability is observed as compared to such a corresponding compound by at least, 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, or more times higher.
[00564] In an embodiment, a subject compound of Formula I, I', I", I-1, I-1', I-1", or I-1- exhibits superior metabolic stability as compared to a compound having a different core scaffold but with similar or identical substitucnts R2, R10, R16, and R17.
[00565] In an embodiment, superior metabolic stability is observed in compounds of Formula I, I', I", I-1, I-1', I-1", or I-1' ", as compared to a compound having the same substituents R2, R10, R16, and R17, but with a different 6-membered heteroalylbicyclic core scaffold.
[00566] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, l', 1", 1-1, 1-1', 1-1", or 1-1"' wherein Rio is _L.. 7_ R7; L7 is a bond, -0-, -N(Ru)-, -C(0)-, -N(RH)C(0)-, -C(0)N(R14,_. 4s_, _ ) S-. -S(0)2-, -S(0)-, -S(0)2N(R1 ) S(0)N(Ri4)_. _NR14)s(0)_. _ N(RN)S(0)2-, CI -C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or 2 to 4 membered heteroalkylene linker, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R2 a: and R7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered hetcroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more and optionally substituted with one or more R6.
[00567] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, l', 1", 1-1, 1-1', 1-1", or 1-1- wherein R' is -L7-R7; L7 is a bond, -0-, or -N(R14)-; and R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more Rd, and optionally substituted with one or more R6.
[00568] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, I', I", I-1, I-1', I-1", or I-1" ' wherein R" is -L7-R7; L7 is a bond; and IC
is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more 10, and optionally substituted with one or more R6.
[00569] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I.
I', I", I-1, I-1', I-1", or I-1" ' wherein R" is -L7-R7; L7 is a bond; and R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more [00570] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, I', I", I-1, I-1', I-1", or I-1" ' wherein R17 is -L1-R19; L1 is selected from a bond, Ci-C6a11/1, C2-C6a1kenyl, C2-C6alkynyl, -0-, -N(R111)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(Ri4)S(0)-, -N(Ri4)sto)2_, OCON(R14)-, -N(R14)C(0)0-, N(R C(0)N(R1c), S(0)2N(R1c), S(0)N(R), C(Rif)(R1g)0, C(R1f)(R1g)N(R1c), and C(R1f)(R1g); R19 is selected from a C3_12cycloalkyl, C24 iheterocycloalkyl, C6-2aryl, and C2_12heteroalyl, wherein the C3.12cycloalkyl. C2_, iheterocycloalkyl, C6_12aryl, and C2_12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R".
[00571] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula 1, I', I", I-1, I-1', I-1", or I-1" wherein 1117 is -L1-109; 1_,1 is a bond; R19 is selected from a C5.12a1yl and 9-10 membered heteroalyl, wherein the C6_12aryl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11.
[00572] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I.
I', I", I-1, I-1', I-1", or I-1" ' wherein R17 is -L1-R19; L1 is a bond; R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11.
[00573] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, I', I", I-1, I-1', I-1", or I-1" ' wherein R17 is -L1-R19; L1 is a bond; R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, C1.3alkyl, C1_3haloalkyl, C2_ 3alkenyl, C2_3alkynyl, -OH, -M-12, wherein C1_3alkyl, C13haloallcyl, C2_3a1kenyl, and C2_3allcynyl are optionally substituted with one, two, or three R20'.
[00574] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula (I-1), (F-1), (Ia-1), (Ia'-1), (lb-1), (lb'-1), (Ic-1), or (Ic'-1), wherein R2 is R12. is _c(102)2.-(5-8 membered heterocycloalkyl), wherein -C(R12a)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R"d.
[00575] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Fommla (I-1), (I'-1), (Ia-1), (Ia'-1), (lb-1), (lb'-1), (Ic-1), or (Ic'-1), wherein R2 is -0-R12a; Rua is _c(Ri2c ) (5-8 membered heterocycloalkyl), wherein -C(R12e)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three Raw; Rue is independently selected from hydrogen and methyl.

[00576] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula H 2 N CI\N
N
I
N 0 ' Ris (XVI), F
in comparison to a corresponding compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core).
[00577] It shall be understood that different aspects of the invention can be appreciated individually, collectively, or in combination with each other. Various aspects of the invention described herein may be applied to any of the particular applications disclosed herein. The compositions of matter including compounds of any formulae disclosed herein in the composition section of the present disclosure may be utilized in the method section including methods of use and production disclosed herein, or vice versa.
100578] Further Embodiments 1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

X
R Formula (I);
Wherein W is C(0), S(0), or S(0)2;
V is C(IC) and J is C(1116), or V is C(R17) and J is N, or J is C(IC) and V is C(R16), or J is C(R17) and V is N;
R1 is -L7-R7;
L7 is a bond, -0-, -N(R14,_ ), C(0)-, _N(R14)c(0)_, _c(0)N(R14)_, S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R24)s(0, ) N(R14)S(0)2-, C2-C6alkenyl, or C2-C6alkynyl, wherein Ci-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl, are optionally substituted with one, two, or three R26a;
R7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteromyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more R1, one or more re, or one or more R6;
wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3.22cycloa1kyl, Ci.iiheterocycloalkyl, C6_12aryl, or Ci.iiheteroaryl, wherein the C3_12cycloalkvl, Ci.iiheterocycloalkyl, C6.12aryl, or Ci.iiheteroaryl are optionally substituted with one, two, or three Et'a, each R1 is independently selected from hydrogen, Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, Ci_6haloalkyl, C3_12cyc10a11cy1, -CH2-C3_12cyc10a1ky1, Ci_iiheterocycloalkyl, -CH2-Ci_iiheterocycloalkyl, C6_12ary1, -CH2-C6_12aryl, -CH2-C1-iiheteroaryl, and Ci_nheteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6haloalkyl, C3_12cycloalky1, -CH2-C3_12cycloalkyl, Ci_iiheterocycloalkyl, -CH2-Ci_iiheterocycloalkyl, C6_12aly1, -CH2-C6_12aryl, -CH2-C1-iiheteroaryl, and Ci_nheteroaryl are optionally substituted with one, two, or three Rma;
each R4 is independently selected from hydrogen, halogen, oxo, -CN. Cl_6alkyl, C2_6alkenyl, C2_6alkynyl, 6cycloalkyl, C2.9heterocycloalkyl, C6_10my1, Ci_91ieteroaryl, -0R12, _sR12, _N(R12)(R13), _ C(0)0R12, -OC(0)N(R12)(R13), 14 )C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -OC(0)R15, -C(0)N(Ru)(R13). -C(0)C(0)N(Ru)(R13), -N(R")C(0)R15, -S(0)2R15, -S(0)2N(Ru)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R", -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkyny1, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6_10my1, and C1.9heteroary1 are optionally substituted with one, two, or three R2 a;
R6 is -L2-R5;
each L2 is independently selected from a bond, Cl-C6alkyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R11)-, -S(0)N(R11)-, -N(R11)S(0)-, -N(R")S(0)2-, -000N(R1")-. -N(R14)C(0)0-, and -N(R11)C(0)N(R11)-;
each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci_6a1kyl, C2_6a1kenyl, C2_6a1kyny1, C3_6cycloalkyl, C2_9heterocycloa1kyl, C6-ioary1, Ci_9heteroaryl, -0R12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R11)C(0)N(R12)(R13), N(R11)C(0)0R1 5, -N(R11)S(0)2R15, -C(0)R15, -S(0)R1 5, -0 C(0)R' 5, -C(0)N(R12)(1C), -C(0)C(0)N(R12)(R13), _N(Ri4)c(0)Ri5, _s(0)2Ri5, _s(0)2-1,(R12)(-13µ_ ), S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R', -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, Cs_ 6cyc1oa11y1, C2.9heterocycloalkyl, C6_10ary1, and Cl_9heteroary1 are optionally substituted with one, two, or three R20e;
R17 is -L1-R19;
L1 is selected from a bond, Cl-C6a1kyl, C2-C6alkenyl, C2-C6alkyny1, -0-, -N(R")-, -C(0)-, -N(R")C(0)-, -C(0)N(1111)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R")-, -S(0)N(R11)-, -N(R11)S(0)-, -N(R11)S(0)2-, -000N(R")-, -N(R")C(0)0-, N(R1e), C(0)N(R1c), S(0)2N(R1c), S(0)N(R1c), C(R1f)(R1g)0, C(Rif)(R18)N(Ric), and C(RNR1g);
R1e, R1f, and R1g are independently selected from hydrogen, halogen, -CN, C,6a1ky1, Ci.6ha1oa1ky1, C2.6alkenyl, C2-6a11cy11y1, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6_10aryl, Ci.9heteroary1, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), 4,1(:04)c(0)-N(R12)(R13), )C(0)0R15, -N(R11)S(0)2R15, -C(0)R15, -S(0)R15, -OC(0)R15, -C(0)N(Ru)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3.6cycloal1cyl, C2_9heterocycloalkyl, C6.
loaryl. and C1.9heteroary1 are optionally substituted with one, two, or three R201; or R' and Rig are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Ric is selected from hydrogen, Ci_6a1ky1, C2_6a1kenyl, C2_6alkyny1, C3_6cycloalkyl, C2_9heterocycloa1kyl, C6toaryl, and Ci.9heteroaryl, wherein Ci_6a11cy1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2.9heterocyc1oa1kyl, C6_ioaryl, and C1.9heteroaryl are optionally substituted with one, two, or three R2 1 111' is selected from a C3_12cycloalkyl, C2_11heterocycloalkyl, C6_12aryl, and C2_12heter0a1y1, wherein the C3-12CY ClOalky 1, C2_iiheterocycloalkyl, C6_12aryl, and C242heteroaryl are optionally substituted with one, two, three, four, five, six, or seven lei;
each R1 is independently selected from halogen, -CN, Ci_6a1ky1, C1_6haloalkyl, C2_6alkenyl, C2_6alkynyl, C3_ 6cycloalkyl, C2.9heterocycloalkyl, C6_ioaryl, Ci_9heteroaryl, -0R'2, -SRu, -N(Ru)(R13), -C(0)01112, -0C(0)N(R12)(R13), _N(Riisc ) (0)N(R12)(R13), -N(R14)C(0)0R15, -N(R11)S(0)2R15, -C(0)R15, -S(0)R15, -OC(0)R15, -C(0)N(R12)(ic'"3). _C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=N1-1)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R')C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Cl_nalkyl, C2_6alkenyl, C2_6alkynyl, C3_6eycloalkyl, C2_9heterocycloallcyl, C6_ ioaryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R20';
R16 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6a1kyny1, C3_6cyc1oalky1, C2-9heterocycloalkyl, C6.10aryl, Ci_9heteroary1, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(1112)(R13), -C(0)C(0)N(Ru)(R13), -N(R11)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(-0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R'), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R1-2)(R1-3), wherein C1-6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6-ioaryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R20g;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(RH)S(0)2R15, -C(0)R35, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R"), -CH2C(0)N(R12)(R"), -CH2N(RH)C(0)105, -CH2S(0)2R15, -CH2S(0)2N(R12)(R13), -(CI-C6a1kyl)-R12b, -(C2_6a1keny1)-R12b, -(C2_6alkyny1)-R12b, -0-R12a, --1,1(R
14)-R 12b, _s_R12b, -(C3 locycloalkyl)-Rub, -(C2_6heterocycloalky1)-R12b, -(C6_10a1y1)-R12b, or -(Ci_9heteroa1y1)-R12b, wherein said Cl_ 6a1ky1, C2_6alkenyl, C2_6alkynyl, C31Ocycloalkyl, C2_9heterocycloalkyl, C6.10aryl. and Ci_9heteroaryl are optionally substituted with one, two, or three R2";
R12a is selected from Ci_oalkyl, C2_6a1kenyl, C2.6alkynyl, C3_10cycloallcyl, -CH2-C3_10cycloalkyl, C2_9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6_ioaryl, -CH2-C6_ioaryl, -CH2-Ci_9heteroary1, and Ck9heter0ary1, wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, -CH2-C3_10cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloa1kyl, C61oa1yl, -CH2-C6_10aryl, -CH2-Ci_9heteroary1, and Ci_9heteroa1y1 are optionally substituted with one, two, or three R2 d;
R12b is selected from hydrogen, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, -CH2-C3_10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_ioaryl, -CH2-C6_ioaryl, -CH2-Ci_9heteroary1, and Ci_9heteroary1, wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkyny1, C3_10cycloalkyl, -CH2-C3.1ocycloalkyl, C2.9heterocycloalkyl, -CH2-C2_9heterocycloallcyl, C6_ioaryl, -CH2-C6_10atyl, -CH2-Ci_9heteroary1, and Ci_9heteroary1 are optionally substituted with one, two, or three R20d;
X is C(R3) or N;
R3 is selected from hydrogen. halogen. -CN. C1_6alkyl. C2_6alkenyl, C2_6alkyny1. C3_6cycloalkyl, C2_9heterocycloal1cyl.
C6.10a1yl, C1_9heteroaryl, -0R12, -N(R')(1:03), -C(0)0R12, -0C(0)N(R12)(R13), -N(R")C(0)N(R12)(Rn), -N(R11)C(0)0R15, -N(RH)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(Ru)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6alkenyl, C2_6a1kynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6_i0ary1, and Ci_9heteroary1 are optionally substituted with one, two, or three R201);
each R12 is independently selected from hydrogen, Ci_6a1ky1, C2_6a1kenyl, C2_6alkyny1, C3_6cycloalkyl, -CH2-C3_ 6cycloalkyl, C2.9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6.10aryl, -CH2-C6_ioaryl, -CH2-Ci_9heteroary1, and C1.9heteroaryl, wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_ 9heterocycloalkyl, -C112-C2.9heterocycloalkyl, C6_ioaryl, -CH2-C6_i0ary1, -CH2-Ci_9heteroaryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R20";

each R13 is independently selected from hydrogen, Ci_6a1ky1, and Ci_6haloalkyl; or R12 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R2';
each RH is independently selected from hydrogen, Ci_6alky1, and C1_6haloa1kyl;
each R15 is independently selected Ci_6a1lql, C2_6a1kenyl, C2_6alkynyl, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6_10aryl, and Ci.9heteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2_9heterocycloa1kyl, C6_10aryl, and Ci.9heteroaryl are optionally substituted with one, two, or three R20;
each R20a, R20b, R20c, R2od, R20e, R2of, R20, and R201 are each independently selected from halogen, -CN, Ci_6a1kyl, C2-6alkeny 1, C2_6alky ny 1, C3_6cy cloalky 1, -CH2-C3_6cy cloalkyl, C2 _9heterocy cloalky I, -CH2-C2.9heterocy cloalky 1, C6_ ioaryl, -CH2-C6_10aryl, -CH2-C1_9heteroaryl, Ci_9heteroaryl, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), _N(R24)c(o)N(R22)(R23), )C(0)0R25, -N(R24)c(0)R25, _N(R24)s(0)2R25, _c(0)R25, _s(0)2R25, _s(0)2N(R22)(R23), _ OCH2C(0)0R22, and -0C(0)R25, wherein Ci_6a1kyl, C2_6a1kenyl, C2_6alkynyl, C3_6cycloalkyl, -C112-C3_6cycloalkyl, C2_9heterocycloalkyl, -C112-C2-9heterocycloalkyl, C6.10aryl, -CH2-C6_10aryl, -CH2-Ci_9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci6alkyl, Ci_6haloallcyl, C1_ 6a1koxy, C1_6haloalko,cyr, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -OC(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25. -N(R24)s(0)2R25, _c(o)R25, _ S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R21 is independently selected from H, Ci_oalkyl, Ci_ohaloalkyl, C2_6alkenyl, C26a1kvnyl, C3_6cyc1oalkyl, C2_ 9heterocycloalkyl, C6.10aryl, and C1_9heteroa1yl;
each R22 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2_ 9heterocycloalkyl, C6.10aryl, and C1_9heteroa1yl;
each R23 is independently selected from H and Ci_6alkyl;
each R24 is independently selected from H and Ci_6alkyl;
each R2' is selected from C1_6alkyl, C2.6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_1oa1yl, and C1.
9heteroatyl; and - indicates a single or double bond such that all valences are satisfied.
2. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R3).
3. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.
4. The compound of any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein V is C(R16) and J is C(R').
5. The compound of any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein V is N and J is C(R17).
6. The compound of any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein J is N and V is C(W7).
7. The compound of any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R16) and V is C(R17).
8. The compound of any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C(0).

9. The compound of any one of Embodiments Ito 7, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S(0).
10. The compound of any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S(0)2.
11. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure:
O Rlo 0 Rlo R8 R8, I I 1 \ N''''"N

R16 Formula (IA1), R16 Formula (IA2), R8 V 0 Ri C
NN- - N
1 R8N'''''''''''')N
R17 ---' -----'''''N'''R2 R16 Formula (IA3), R17N N---;>. R2 Formula (IA4), O Rio o o Rio I I
R8 N R8 st "---.--'`.'.', .. N
I I
R17----N-N------R2 Formula (IA5), R17---N N -'-.----- R2 Formula (IA6), RB RB II

S

Formula (IA7), R16 Formula (IA8), 0 m 0 "10 õ

\I\I'-- ''.=-----',"---, R3 Formula (IA9), Ri7N -N'-- la 2 R18 ¨ Formula (IA10), O Rlo 0 Rlo ii 0 RB s Ra 8 ,/,.. R3 RNs NI/
N

Ri7NN 2 I 7.=====. ...õ...,\,... ----,.... R 2 R Formula (IA11), or R N N Formula (IA12).
12. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure:

0 Rio 0 Rlo R8,, *

'N'''-'-''..--1 N µNN

Ri6NR2 R16 -.-'.."-------NR2 R17 Formula (IIA1), R17 Formula (IIA2), 0 Ri o i o R 8 Y>\N NN
N R

N,-:,,,,,,,,,, Ri6 N
R17 Formula (IIA3), R17 Formula (IIA4), R8s R8 s Z/

N.,,...:õ......,õ..... ,....)",-...õõ N,,,,...---, ...2--..:-...õõ

R17 Fommla (11A5), R17 Formula (IIA6), 0 Rio 0 Rio R8N ,R3 R8N s, R3 N N

R16 NR2 R16N .--''R2 R17 Formula (IIA7), R17 Formula (IIA8), 0.10 0 R10 R6 Yc 3 R RS
\ ...," NN -,c,õ R3 R16 N R2 N --..õõõ,...>õõ--....,õ

R17 Formula (IIA 9), R17 Formula (ITA10), 0 0 2 R Rl 10 ,\ /

R8,.., )R3 R8 N's-c>., R3 NN,--N

Nly-, ,,---.-- -.., R-R17 Formula (IIA11), or R17 Formula (IIA12).
13. The compound of any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is a bond.
14. The compound of any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is -NH-.
15. The compound of any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein IV is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloallcyl is optionally substituted with one or more R1, one or more R/, or one or more R6;
and wherein two substituents selected from fe, R1, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C342cyc1oalky1, Ci_llheterocycloalkyl, C642a1y1, or C14 iheteroaryl, wherein the C3-12eycloa1kyl, CI_Iiheterocycloalkyl, C6_12aryl, or Ci_iiheteromyl are optionally substituted with one, two, or three R20a.
16. The compound of any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein (R46 (R4) p X3 X3 X3 x3 117 is 1 x2 ____________________________ x2 x2 <
I I , xi _____________________________________________________ x> ____________________________________ (R4)1, (R4)õ
x3 -x3 , or - =
p is an integer from 0 to 12;
X' is selected from CH2, C(R4)(R6), C=N-0R4, C=NN(R4)(R6), C(0)N(R4), N(V), N(R6), 0, S. S(0), S(=0)(=NR4), S(0)2N(R4), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), OC(0)N(R4), N(R4)C(0)N(R4), S(0)2, CH2C(R1)(R6), CH2C(114)(R6)CH2, C(R4)(R6)C(R4)(R6)C(R4)(R6), C(R1)(R6)C=N-0R4, CH2C=NN(R4)(R6), C(R1)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R6)0.
C(R4)(R6)0C(R4)(R6), C(R4)(R6)S, C(R1)(R6)SC(10)(R6), C(R1)(R6)S(0), C(10)(R6)S(0)C(10)(R6), C(R1)(R6)S(0)2C(R1)(R6), C(R4)(R6)S(=0)(=NR4), C(R4)(R6)S(0)2N(R4), C(R4)(R6)N(R4)S(0)N(R4), C(R4)(116)N(R4)S(0)2N(R1), C(R4)(R6)S(0)N(R4), C(R4)(R6)0C(0)N(R4), C(R4)(R6)N(R4)C(0)N(R4), C(R4)(R6)S(0)2, C=NN(R1)(R6)C(R1)(R6), C(0)N(R1)C(R1)(R6), S(0)2N(R1)C(R1)(R6), S(0)N(R1)C(R1)(R6), OC(0)N(R1)C(R1)(R6), C(R1)(R1), C=N-0R1, C=NN(R4)(R4), CH2C(R1)(R1), CI-12C(R4)(R4)CH2, C(R1)(R1)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R1)(R1)C=N-0R4, CH2C=NN(R4)(R4), C(R1)(R1)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0.
C(R4)(R4)0C(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R1), C(R4)(R4)S(0)N(R1), C(R1)(R1)0C(0)N(R1), C(R1)(R1)N(R1)C(0)N(R1), C(R4)(R4)S(0)2, C=NN(R4)(R1)C(R1)(R1), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R1)(R4), S(0)N(R4)C(R4)(R4), and 0C(0)N(R4)C(R1)(R1);
X' is selected from N, C, C(R6), C(R4), CH, N(R1), N(R4), N(R6), 0, S. S(0), C(H)(R6), C(114)2, CH2, C(R1)(R'), S(=0)(=NR4), S(0)2; and X' is selected from N, C, C(R6). and C(R4).
17. The compound of Embodiment 16, or a pharmaceutically acceptable salt or solvate thereof, wherein _________X2õ..õ,_ X2 X2 .x2,, X _.(R4), ,,,õXl>¨I(R4)p s..**-"===.X1-..-----1¨(R4)P
,..j ( R4)p < .:///>

R7 is I- .1 1_ i , , , , X x2 x2_, (._k 4.
)P <
Z Xi Xi >¨(R4}p (R.4)p , ,or ----- .
18. The compound of any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, H H H H H
N,õ N.., C¨(R ¨(R) -1----(R4)p -(R) ( ,Sr(R4)P y---(R4)p wherein R7 is '"/Y" , H H H (R4) H
(R H
p (:0----(R )p K., 4 1Z )p [..-1---( R4)p AC - (R )p 11 Il N N

'Ur' 1 ' , H H
HNN,) N HN---1 R4) i.,\,1Fi &(R4 NH
1C:13(6/T-( P ----(R )P
Y Y 11 ri 11 ¨11H H
N., -,--(R )p C _,--c-i(R )p NH

) )P
il ( II V (R4)p \µ.C..õ____ (R4)p 1,1 ) ' H
N
ç5(R4)p ri Y
,or . ; and p is an integer from 0 to 12.
19. The compound of Embodiment 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is H H H H H H H H H
H
A A
( > (31\1/3 coN N 7 N .õN, N
,,N.õ N
C D
il y ii ii T 11 N N
N
..A.AAI `AriV ...s.nne ,Nfvu .nnov r' j'' ..nktv , , , CN
HN N _________ -NH
H NH õ, N) CN) NC

CN õSZ
HO C H2N 11j NH2 N)V
)1 N c51H CS
1?1 or .
20. The compound of Embodiment 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is .=
\s.
Of 21. The compound of any one of Embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R'' is independently selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6alkynvl, and C3_6cycloalkyl, wherein Ci_6alkyl, C2_6a1kenyl, C2_6alkynyl, and C3_6cycloalkyl are optionally substituted with one, two, or three R208.
22. The compound of any one of Embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R'6 is independently selected from hydrogen and halogen.
23. The compound of any one of Embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R'6 is independently selected from hydrogen and fluoro.
24. The compound of any one of Embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from halogen, -CN, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2-9heterocycloalkyl, C6_10myl, Ci.9heteroary1, -0R12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(Ri4)c(o)N(R12)(R13), (IC )C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(Ru)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R' '), -CH2C(0)N(R12) (R13), -CH2N(R14)C(0)R13, -CH2S
(0)2R13. and -CH2S (0)2N(Ru)(Rn), wherein Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9he1erocycloalkyl, C6 -wary', and Ci_9heteroa1y1 are optionally substituted with one, two, or three R2 e.
25. The compound of any one of Embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from Ci_6a1kyl, C340cycloalkyT1, and C2_9heterocycloalkO, wherein C1_6alkyl, C3-locycloalkyl, and C2_9heterocycloalkyl are optionally substituted with one, two, or three R2' independently selected from halogen, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C340cycloalkyl, and C2_9heteroeycloalkyl.
26. The compound of any one of Embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein re is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro. methyl, cyclopropyl, cyclobutyl, and oxetanyl.
27. The compound of any one of Embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
28. The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen or CN.

29. The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen.
30. The compound of any one of Embodiments 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein L' is a bond.
31. The compound of any one of Embodiments 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein Ll is selected from a Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C(0)-, -NHC(0)-, -C(0)NH-, CH20, CH2NH, and CH2.
32. The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a monocy clic ring.
33. The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a bicyclic ring system.
34. The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a polycyclic ring system.
35. The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein 1:219 is-x12 x4 x10 x4 1 h R1 h R II
x9 10 X9 NL-1 yl 0 X6 x ' X6 X9 X6 Q 11 X6' `4 Q"

I I _______________________________________ Rh h1 (N y h Ri xl 0 3 , Q -.-X8 Q4 -)(8 p-Q4 Oy N 4 õ
R h QQ6-"--Q4 ,or Q4.
Qe ;>___Rih \Qe Q3 =
Q1, Q3, and Q5 are independently N or C(R);
Wand Q6 are independently 0, S, C(R1a)(R1b), or X4, X5, X6, X9, X10, X11, and X12 are independently selected from C(R) or N;
X' and X' are independently selected from C(R1a), C(Rla)(IC lb), N, or each R. Rn. R1d, and Rth are each independently selected from hydrogen, halogen, -CN, C1_6a1kyl, 6haloalkyl, C2_6a1kenyl, C2_6alkynyl, C3_iocycloalkyl, C2_9heterocycloalkyl, C6_ioaryl, Ci_911eteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6a1keny1, C2-6alkynyl, C340cycloalkyl, C2_9heterocycloalkyl, C6_ileryl, and Ci_dieteroaryl are optionally substituted with one, two, or three R20i; or Ria and Rib bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3_10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3_10cycloa1kyl ring are optionally substituted with one, two, or three R2c1: or two Ria bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_10aryl ring, a 5-12 membered heteroaryl ring, or a C3_iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6_10a1y1 ring, 5-12 membered heteroaly1 ring, or C3_10cycloalkyl ring are optionally substituted with one, two, or three R20; or Rib and one of Rian Rib, ic -^ len and Rid bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_10aryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6_1tiaryl ring, a 5-12 membered heteroaryl ring, and C3_10cy-cloalkyl ring are optionally substituted with one, two, or three R201; and each Ric is independently selected from hydrogen, C1-6a1kyl, C2-6a1kenyl, C2_6a1kynyl, C3_10cycloalkyl, C2-9heterocycloalkyl, C6-1oa1yl, C1-9heteroaryl, wherein C1-6a1kyl, C2-6a1keny1, C2_6alkynyl, C3-1oeyeloa1kyl, C2-9heterocycloa1k¶, C6_20aryl, and C1_9heteroaryl are optionally substituted with one, two, or three R201.
36. The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is:

X-=-N )7---N )-----------N HO \-. HO
o,i:Er '2,, s, :&.7., ,õ... F
F, , F , N,., ,22;.. 0õ.._.
H 0 '1,2.. H2N Nõ. "etc H2N N,., x.
../ / F H2N / N
F I
-..., F , NH2 ,N___.

HN ,z22,.. HN / / /
"21-- 0 "2ti..= 40õ..... 0 `v H N eiz2i..

. . , H
,,N N__., =-eza-.. H2N N_ Va.
H
.N N,,, ve. H2N N.,.. va,.
y H2N ,...., N......,v2_ y ....-1 --(...,,xv cF, x, ,- .õ
,õ
µ....1-3 H HO
,,. N N '222 H
H2N N '2,- õ,.... HO 0 't2.2 1)-1. ,1õ..,...X.

, HO, HO
CI
X ,.., . F
CI
co-cF3 ..., ,._.
c, ,, , or N H2 .
37. The compound of any one of Embodiments 1-36, or a pharmaceutically acceptable salt or solvate thereof, --I
1-.
-("r(0 = N-1 '(0''''' N
.
wherein R2 is selected from I .3, F
AO A
rs4t0 c:`(0-6¨N- N 0->(-1) N N
0, '=-..-) F OMe F
0 c:rslOi"' N ':5530"'' N N C H2F r:40LCI\--H \
N --- ,,/0--t --- 0 cos, ,. . , , /0 N
--\ /0 --\< 0 N 0 6-1--? i 0 0 N
---- -----\
N.õ.....õ.= , F
F
_(.1\i Ao'"-i----j c:Nr0-''''INCID...... F `34.0 ,.6 0,,-Ø...0Me I zi\i z /

icN.D..... /

/ N) F
' r'sj-LO-i'''f- `353:-O'''' 0Me ,IN-D--1 N----/
5 5 0 csss-01 v"ssr'0/""0F 635:C'00 \ \ N ...../.-- , /N /
, csss'ON'Th /.- Na ' Nn 1 c¶0 c' '1Ci CO
/
""..
0 r\i'D....0H r¨oNs' N
R 0 4111 rss:!o IN 0 0 N
N
I N
\\
riD-'1C N
fljt. " s'N".-) ,N
0 1, ,N
, r.s4C) N -. CY--1 5:0.-r-0-"-...-) , AO01C F3, .õ-----..N ..- p -"- - õ ='-'1\l'' S-0 Z111 N ""
4 Sj sk/C rji c.f<0-') , ,A1----1 7 0 cl-rs-0X,---- cls'00 , . , , F
?4.e''''r c'so cls0 0 N1\11-'-\) H _____________________________________________________________________ "---/ , )CND riss'S --.)c- NO rIss-7C NO /0c-N<
, ;s4e)C NO,. F ce)C NO, F COC NO r:rrf'OC N3 , 7' cv,o---x----No L_,,,,11 N-L../ , C)-')C NO
I
N- rijs'ON OWCN c140-W N
0...-C N
cs4- ocCN

I, -.-= ilsr ,...õ,-----. ----N rijs 1101 I
N9 N c:s.sr , .z..F 0 n N 6 õ.....------õ. ,S/
'''=
I
., and 0 =
38. The compound of any one of Embodiments 1 to 7 and 10 to 37, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5 is independently selected from:
tl...9 pH
-H, -Nit, -OH, -NH(Ci..6 alkyl), a -,.. N PH Nis,;(1 pH
, _NH ..?<-.. Abi 1-, ..--, i "ON ;=$(..---.. . , ,,Oli NS s 4,014 /4,,,,g,1,4 ...OH
t,OT" , 'C,. , 14 , tr-oN ,kki=-f-A-N-QH
% Mtz -4111 jtai-i i f..-"N liti NH r's¨N.2 # -,,, . õ. ir--N _ _e ..,,, , ,ir is, vy--0 vi,---N 7---0 ..,----- If- ¨ µA, ><1"----"-., ' NH H H NH NH NH
HN N CN HN.,..N.,CN
,..- ..õ,,=
H N)-(NH NC.,N,J-L.NH NCN'ILNH
-4. NH 2 ' I 2 i , H I , H
I
¨ , -CN, _¨_,.__o."_¨_,.__oc'l't 4r11 014 A,..),,,,,.141-C, 'ir:''L-Aff---."-Of-1 0 , 8, 8 , o , o , o ,1 , . =0(-3 , , -N
L¨'01-1 ?a) 1 r iZr=)1,P, , , 0 r ''' IQ ' ' , '04- 0 < r e =
C, , 0 , 0 . 0 =Ft-c, i tC
:,'-''N ,--, 14, ,r-NN
ec-kkvii 1J
O Ae , 6 Ill ..."\--',....1.....r.,1..OH ,.., .C., IT
O and 0 ; and M. wilen present is 0, i, 2, ;-)r 3, 39. A compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:

R 8 W.......1.....
'N ....--R17 Formula (II);

Wherein W is C(0), S(0), or S(0)2 V is C(R16) or N;
1V is -L7-117;
L7 is a bond, -0-, -N(R")-, -C(0)-, -N(R14)C(0)-, -C(0)N(R")-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R")-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Cl-C6alkyl, C2-C6a1kenyl, or C2-C6alkynyl, wherein Cl-C6a1kyl, C2-C6a1kenyl, and C2-C6alkynyl, are optionally substituted with one, two, or three R2 a;
R7 is a 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl are optionally substituted with one or more one or more le, or one or more R6;
two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3_12cycloalkyl, Ci_iiheterocycloalkyl, C6_12aryl, or Ci_iiheteroaryl, wherein the C3_12cycloa1kyl, Ci-iiheterocycloalkyl, C642aryl, or Ci_nheteroaryl are optionally substituted with one, two, or three R2 a;
each R1 is independently selected from hydrogen, Ci_6a1ky1, C2.6a1kenyl, C2.6a1kyny1, Ci_6haloalkyl, C3_12cyc1oa1ky1, -CH2-C3_12cycloa1ky1, Ci_llheterocycloalkyl, -CH2-Ci1iheterocycloalkyl, C6_12ary1, -CH2-C6_12aryl, -CH2-Ci-iiheteroaryl, and Ci_uheteroaryl, wherein Ci_6allcyl, C2_6alkenyl, C2_6a1lcyny1, C,6ha1oa1ky1, C3_12cycloallcyl, -CH2-C3_12cycloallcyl, Ci_iiheterocycloalkyl, -CH2-Ci_iiheterocycloalkyl, C6_12a1y1, -CH2-C6_12aryl, -CH2-C1_ iheteroaryl, and Ci_li heteroaryl are optionally substituted with one, two, or three R2 a;
each R4 is independently selected from hydrogen, halogen, oxo, -CN. Ci_6a1kyl, C2_6alkeny1, C2_6alkynyl, C3_ 6cycloalkyl, C2.9heterocycloalkyl, Co_loaryl, Ci_9heteroary1, -0R12, -N(Ru)(R13), -C(0)0R12, -0C(0)N(R')(103), -N(R14)C(0)N(R12)(103), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R11)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6a1ky1, C2_6a1kenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloa1kyl, C6_10myl, and Ci.9heteroaly1 are optionally substituted with one, two, or three R2 a;
R6 is -L2-k);
each L2 is independently selected from a bond, Cl-C6allcyl, -0-, -N(R14)-, -C(0)-, -N(R")C(0)-, -C(0)N(R")-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R")-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -000N(R14)-, -N(R14)C(0)0-, and -N(R14)C(0)N(R14)-;
each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci_6a1ky1, C2_6a1kenyl, C2_6a1kyny1, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6_10aryl, Ci_9heteroaryl, -0R12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(1112)(R13), -N(R11)C(0)N(Ru)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(Ru)(R13), wherein Ci_6a1ky1, C2_6alkeny1, C2_6alkyny1, C3_ 6cyc10a11cy1, C2.9heterocycloalkyl, C6_1(aryl, and Ci_9heter0ary1 are optionally substituted with one, two, or three R20c;
R17 is -L1-R19;
L1 is selected from a bond, Cl-C6a1kyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R") ,-S-, S(0)2-, -S(0)-, -S(0)2N(R")-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -000N(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Ric), S(0)2N(R1c), S(0)N(R1c), C(R1f)(Rig)0, C(R1f)(R19N(R1c), and C(R1f)(R1g);
Rie, Rif, and Rig are independently selected from hydrogen, halogen, -CN, Ci_6alkyl, Ci.6haloalkyl, C2.6alkenyl, C2-6alkynyl, C3_6cycloalkyl. C2_9heterocyc1oalkyl, C6_10ary1, C(.9heteroaryl, -OR', -N(R12)(R13), -C(0)OR'.
-0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R11)S(0)2R15, -C(0)1115, -S(0)R15, -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R11)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_oalkyl, C2_6a1keny1, C2_6alkynyl, C3.6cyc1oa1ky1, C2_9heterocyc1oa1ky1, C6-lOarY1, and Ci.9heteroaryl are optionally substituted with one, two, or three R20; or Rif and R1g are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R2 1;
R1c is selected from hydrogen, Ci_6a1kyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloa1kyl, Catoaryl, and C1.9heteroary1, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cyc1oa1ky1, C2.9heterocycloalkyl, C6_40ary1, and C1.9heteroaryl are optionally substituted with one, two, or three R201 R19 is selected from a C3_12cycloalkyl, C2_11heterocyc1oa1ky1, C6_12ary1, and C2_12heteroaryl, wherein the C.2_ 12eye1oa1ky1, C2_oheterocycloalkyl, C6_12aryl, and C2_12heteromyl are optionally substituted with one, two, three, four, five, six, or seven Rh;
each R" is independently selected from halogen, -CN, C1_6alkyl, Ci_6haloalkyl, C2_6alkeny1, C2_6alkynyl, C3_ 6cycloalkyl, C2.9heterocyc1oa1ky1, Co_waryl, Ci_9heteroaryl, -0R12, -SR", -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(103), -N(R')C(0)N(R12)(R"), -N(R11)C(0)0R15, -N(R11)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R')(R13), -C(0)C(0)N(R12)(R13.), _N(R11)c(o)R15, -S(0)2R15, _ S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R11)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C1_6alky1, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6-ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20i;
1116 is selected from hydrogen, halogen, -CN, C1_6alkyl, C2_6alkenyl, C2.6a1kyny1, C3.6cycloalkyl, C2-9heterocycloalkyl, C6.10atyl, Ci_9heteroaty1, -0R12, _SR12, _N(R12)(R13), _ C(0)0R12, -0C(0)N(R12)(1213), -N(R11)C(0)N(R12)(R13), -N(R11)C(0)0R15, -N(R11)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13) , C(0)C(0)N(R12)(R13), -N(R11)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)( R13), -CH 2C(0)N(R12)(R13), -CH2N(R11)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13). wherein C1_6alkyl. C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl. C6_ lomyl, and Ci_9heteroatyl are optionally substituted with one, two, or three fedg;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R11)C(0)N(R12)(R13), -N(R11)C(0)0R15, -N(R11)S(0)2R15, -C(0)R1', -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R11)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R11)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R12)(R13), -(CI-C6alkyl)-R121), -(C2.6a1keny1)-R12b, -(C2_6alkyny1)-R12b, -O-R12, -NR14)_R(2b, _s_Rim, -(C3_ locycloalkyl)-Rub, -(C2.9heterocycloa1kyl)-R121), -(C6_10my1)-R121), or -(C).9heteroary1)-R"b, wherein said C1_ 6alkyl, C2_6alkenyl, C2_6alkynyl, C3-iocycloalkyl, C2_9heterocycloalkyl, C6-loaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R2 d;
R12a is selected from Ci.6alkyl, C2.6a1kenyl, C2.6a1kynyl, C340cyc1oa1ky1, -CH2-C3_10cyc10a1ky1, C2_9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6_ioaryl, -CH2-C6_1oaryl, -CH2-C1_9heteroaryl, and C1_9heteroaryl, wherein Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, C3_1(Icyc1oalkyl, -C1-12-C3_10cycloalkyl, C2_,heterocycloalkyl, -CH2-C2_,heterocycloa1kyl, C6_10ary1, -CH2-C6_11)aryl, -CH2-C1_9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20c1;
RI' is selected from hydrogen. Cl_nalkyl. C2_6a1kenyl. C2_6a1kynyl.
C3_1()cycloa1kyl. -CH2-C3.10cycloalkyl. C2-9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6_icory1, -CH2-C6_icaryl, -CH2-Ci_9heteroaryl, and Ci_9heteroaryl, wherein Ci_6a1kyl, C2_6a1kenyl, C2_6a1kynyl, C3_11)cycloalkyl, -CH2-C34c)cycloalkyl, C2_9heterocycloalkyl, -CH2-C2.9heterocycloalky1, C6_10aryl, -CH2-C6_10alyl, -CH2-Ci_9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20';
Xis C(R3) or N;
113 is selected from hydrogen, halogen, -CN, C1_6alkyl, C2_6alkenyl, C2_6alkyny1, C3_6cycloalkyl, C2_9he1erocycloalkyl, C6_10aryl, Ci_9heteroaryl, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6_10aryl, and Ci_9heteroary1 are optionally substituted with one, two, or three R2ob;
each R12 is independently selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6alkyny1, C3_6cycloalkyl, -CH2-C3_ 6cyc1oa11y1. C2.9heterocycloalkyl. -CH2-C2_9heterocycloalkyl. C6.10aryl, -CH2-C6_1(-)aryl, -CH2-C1_9heteroaryl. and Ci.9heteroaryl, wherein Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_ 9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, Co_loaryl, -CH2-C6_icaryl, -CH2-C1_9heteroaryl, and Ci_9hcteroaly1 are optionally substituted with one, two, or three R2";
each R13 is independently selected from hydrogen, C1_6alkyl, and Ci_6haloalkyl; or 1112 and R13, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R2 e;
each R14 is independently selected from hydrogen, Ci_6alkyl, and Ci_6haloa1kyl;
each R1' is independently selected Ci_6a1kyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_10aryl, and Ci.9heteroaryl, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloallcyl, C2_9heterocycloallcyl, C6_10myl, and Ci_,heteroaryl are optionally substituted with one, two, or three R20f;
each R20a, R2ob, R20c, Raki, R20e, Rag-, R20g, and Rmi are each independently selected from halogen, -CN, Ci_6alkyl, C2-6a1keny1, C2_6alkynyl. C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2.9heterocyc1oalkyl, C6_ i()aryl. -CH2-C6_1()aryl. -CH2-Ci_9heteroaryl. C1_9heteroaryl. -SR21, -N(R22)(R23). -C(0)0R22, -C(0)N(1122)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R21)C(0)R25, -N(R21)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein C1_6a1kyl, C2_6a1kenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6.10aryl, -CH2-C6_1(aryl, -CH2-C1_9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C16aIkyl, C1_6haloalkyl, Ci_ 6a1k0xy, C1_6haloalkoxy, -0R21, -SR', -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R21), -N(R24)C(0)0R25, -N(R21)C(0)R23, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R21 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2_ 9heterocycloalkyl, C6.10aryl, and Ci_9heteroaryl;

each R22 is independently selected from H, Ci_6alkyl, Ci_6haloalkyl, C2_6a1kenyl, C2_6alkynyl, C3_6cycloalkyl, C2_ 9heterocycloalkO, C6.10ary1, and Ci_9heteroaryl;
each R23 is independently selected from H and Ci_6a1kyl:
each R' is independently selected from H and Ci_6a1k0;
each R25 is selected from Ci_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_ioary1, and Ci_ 9heteroaryl; and ¨ indicates a single or double bond such that all valences are satisfied.
40. The compound of Embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R3).
41. The compound of Embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.
42. The compound of any one of Embodiments 39 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein V is C(R16).
43. The compound of any one of Embodiments 39 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein V is N.
44 The compound of any one of Embodiments 39 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C(0).
45. The compound of any one of Embodiments 39 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S(0).
46. The compound of any one of Embodiments 39 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S(0)2.
47. The compound of Embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, having the structure:
0 Rio 0 Rio NN" N
R1eNR2 R16 N
R17 Formula (IIA1), R17 Formula (IIA2), 0 Ri o Ri o ,0 R8 µsrc N R 8 N
Rie R- R2 R17 Formula (IIA3), R17 Formula (TIA4), I

R8 s R8 s//
NN

R17 Fommla (IIA5), R17 Formula (IIA6), 0 Rlo 0 Rlo .. õõ..--R3 .., S...R3 I I
R16..--......:-... N-------R2 R16 N --''' R2 R17 Formula (IIA7), R17 Formula (IIA8), 0 0 R1 0 R1 o õ
R8 \R3 R R3 I N

Rie N R2 R17 Formula (IIA 9), R17 Formula (ITA10), o R10 o o R10 R8 R3 S '...,../'-'-',,, R3 RNN -.,, I I
Nyl, R2 N-...s,,,_.--.

R17 Formula (IIA11), or R17 Formula (IIA12).
48. The compound of any one of Embodiments 39 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is a bond.
49. The compound of any one of Embodiments 39 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is -NH-.
50. The compound of any one of Embodiments 39 to 49, or a pharmaceutically acceptable salt or solvate thereof, wherein Ral is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocy-cloalkyl is optionally substituted with one or more R1, one or more R4, or one or more R6; and wherein two substituents selected from RJ, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3_12cycloalkyl, Ci_iiheterocycloalkyl, C6_12alyl, or Cit iheteroalyl, wherein the C3-ucycloalkyl, Ci_iiheterocycloalkyl, C6_12aryl, or Ci_iiheteromyl are optionally substituted with one, two, or three R20a.
51. The compound of any one of Embodiments 39 to 49, or a pharmaceutically acceptable salt or solvate thereof, wherein x2 x2 X2 X2 X1 R <___,(R4)p X1 --- (4) p 1 1 < 7 41 p -:;-2 (R4)p ., R7 is ¨1¨ _L. I_ i , , , , x2 x2 x2 / _7: (R4)p < :......, 1 , > __________________________________ (R (R
. __ (R4)p ,or ;
, p is an integer from 0 to 12;

X1 is selected from CH2, C(R4)(R6), C=N-0R4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), 0, S. S(0), S(=0)(=NR4), S(0)2N(R4), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), OC(0)N(R4), N(R4)C(0)N(R4), S(0)2, CH2C(R4)(R6), CH2C(R4)(116)CH2., C(10)(R6)C(R4)(R6)C(R4)(R6), C(R4)(R6)C=N-0R4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(10N(R6), C(R4)(R6)0.
C(R4)(100C(R4)(1V), C(R4)(R6)S, C(R4)(R6)SC(R4)(R6), C(R4)(R6)S(0), C(R4)(R6)S(0)C(R4)(R6), C(R4)(R6)S(0)2C(R4)(R6), C(R4)(R6)S(=0)(=NR4), C(R4)(R6)S(0)2N(R4), C(R4)(TON(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R4)(R6)S(0)N(R4), C(R4)(R6)0C(0)N(R4), C(R4)(R6)N(R4)C(0)N(R4), C(R4)(R6)S(0)2, C=NN(R1)(R6)C(R1)(R6), C(0)N(R1)C(R4)(R6), S(0)2N(R1)C(114)(R6), S(0)N(R1)C(R1)(R6), OC(0)N(R4)C(R4)(R6), C(R4)(R4), C=N-010, C=NN(R4)(R4), CH2C(R4)(10), CH2C(R4)(R4)CH2, C(R4)(R4)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C=N-0R4, CH2C=NN(R4)(R4), C(R4)(R4)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0.
C(R4)(R4)0C(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(1R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and OC(0)N(R1)C(R1)(R1);
X2 is selected from N, C. C(R6). C(R4), CH, N(R1), N(R4), N(R6). 0, S. S(0), C(H)(R6), C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X' is selected from N, C, C(R6). and C(R4).
52. The compound of Embodiment 51, or a pharmaceutically acceptable salt or solvate thereof, wherein X2_ _.X2_ X2 X2 .. ,../ -\.., .._, ) , ( R4p X1 1 4 'X'11-------(R4)P
eõ... >----(R ) - --p (R4) p < , .',.. .,.,.. ,..
x3 x3 x3 x3 R7 is .1 .....L i , , , , x2 x2_ x2 4,7,,,,,,...(R4)p < -\., ,..-.. 1 ==-.., __________________________________________ (R4)p ......,....õ..,....)Xi _________________________________________________________ (R4)p 1 .....L , or -, .
53. The compound of any one of Embodiments 39 to 49, or a pharmaceutically acceptable salt or solvate thereof, wherein H H H H H
( :4--(R4)p c)-(R4)p ______________________ 11 N Il IC is ''""r" JW,I I
JIAIIV
' 7 7 , , H H H H H

J-1-(R4)p \cly---(R4)P /0A,...,____(R4)p ..`_3___(R.µt)p AC ,.. j (R4)p ri 11 N N 11 u111111 'Ur 4+V I

HI\INH H ---(R4) HN-Th ,.,, Nõ, 11 N. N.9 1 6¨,)(R4)p <ctl_____H (R.4)p N
_________________________________________________________________________ ,LH
(R4)p 'C---iC 4p -' N
fVV
-NH H
N õ
--...N.9 ----- (R4)p \s=L...7-(R4)p s'N--N N
H
N
N N
,or . ; and p is an integer from 0 to 12.
54. The compound of Embodiment 51, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is H H H H H H H H H H
N N N N-, N N AcN
y CN) N
avvy ,'",'", .n.nry =-"f", .....,,,,, ---7- --; .,-knnt C
H H N -NH
HNIN /1-1 NH ____ NH ____ NC õ(tµ1) N1 ..9 ---.
N...
H
N
H (Pi H 0 CN ,R
N
( Jv N HO,...)-k...,,N) H2NN1-1) 1 , or , .
55. The compound of Embodiment 51, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is \ceicil OH
or \.
56. The compound of any one of Embodiments 39 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein R'' is independently selected from hydrogen, halogen, -CN, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, and C3_6cycloa1kyl, wherein Ci_6alkyl. C2_6a1kenyl, C2_6alkynyl, and C3_6cycloa1kyl are optionally substituted with one, two, or three R20g.
57. The compound of any one of Embodiments 39 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from hydrogen and halogen.
58. The compound of any one of Embodiments 39 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from hydrogen and fluoro.
59. The compound of any one of Embodiments 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein re is selected halogen, -CN, Cl_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C640ary1, C3_9heteroary1, -0R12, -SR12, 11)(R32), _ C(0)0R12, -0C(0)N(R12)(R13), -N(Rii)c(o)N(R12)(R33), -N(R14)C(0)0R15, -N(R')S(0)2R15, -C(0)R15, -S(0)R12, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(1113), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C2_6alkyl, C2-6a1keny1, C2_6alkynyl, C3_6cyc1oalkyl, C2_9heterocycloalky1, C6_30aryl, and C3_9heteroary1 are optionally substituted with one, two, or three R29c.
60. The compound of any one of Embodiments 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from C3_6alkyl, C34ocycloalll, and C2_9heteroeycloalkyl, wherein Ci_oalkyl, C3_ locycloalkyl, and C2_9heterocycloalkyl are optionally substituted with one, two, or three R2' independently selected from halogen, C3_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_20cycloalkyl, and C2_9heterocycloa1kyl.
61. The compound of any one of Embodiments 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R2 c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl.
62 The compound of any one of R mbod i me nts 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein re is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
63. The compound of any one of Embodiments 39 to 62, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen or CN.
64. The compound of any one of Embodiments 39 to 62, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen.
65. The compound of any one of Embodiments 39 to 64, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is a bond.
66. The compound of any one of Embodiments 39 to 64, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is selected from a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C(0)-, -NHC(0)-, -C(0)NH-, CH20, CH2NH, and CH2.
67. The compound of any one of Embodiments 39 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a monocyclic ring.
68. The compound of any one of Embodiments 39 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a bicyclic ring system.
69. The compound of any one of Embodiments 39 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a polycyclic ring system.
70. The compound of any one of Embodiments 39 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is:
x12 Qi n3 x4 x10 x4 x11 1 1 -'1 R1 h 11h % X9 __R11-1 X 5 11 X9 1 X 5,- I 1 X 1 1 X 5,- 1 Xk_ N x1 o 4 X6' X6 X9 X6 Q -x6- Q
,xii Q

rN h I R1 h /
R1 h X1) ->\ 3 Xx 8 Q4 X7-77,--x8 Q4 3 xli Q X8 Q

\)-- R1 h or QeilL h \Q6 Q3 Q1, Q3, and Q5 are independently N or Q4 and Q6 are independently 0, S, C(R1a)(R1b), or X1, X5, X6, X9, X10, X11, and X12 are independently selected from C(R1a) or N;
X' and X' are independently selected from C(R"), C(R1a)(R1b), N, or each R1 a, Rn, R", and Rth are each independently selected from hydrogen, halogen, -CN, Cima1kirl, C1 6haloalkyl, C2_6a1kcnyl, C2_6a1kynyl, C34ocycloalkyl, C2_9hetcrocycloalkyl, C6_10aryl, Ci_91tetcroary1, -Run -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(RH), wherein Ci_6a1ky1, C2_6alkenyl, C2_ 6alkynyl, C34ocycloalkyl, C2_9heterocycloalkyl, C6_ioaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R20'; or Ria and Rib bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C34ocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C340cycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3_tocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6_10aryl ring, 5-12 membered heteroaryl ring, or C3_10cycloalkyl ring are optionally substituted with one, two, or three R20; or Rth and one of Rla, Rn, Ric, and R bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6_10aryl ring, a 5-12 membered heteroaryl ring, and C3_iocy-cloalkyl ring are optionally substituted with one, two, or three R201; and each Ric is independently selected from hydrogen, Ci_6a1ky1, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, C2_ ,heterocycloalkyl, C6_10aryl, Ci_9heteroary1, wherein Ci_6a1ky1, C2_6a1keny1, C2_6alkynyl, C3_10cycloa1kyl, C2_9heterocycloa1kyl, C6_ioaryl, and Ci_9heteroary/1 are optionally substituted with one, two, or three R201.
71. The compound of any one of Embodiments 39 to 70, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is:

H2N H2N H2N HO \-:
>---=-N >:-----N >:----N
O, ,v s liwr s 0,,,r F F F , LJJ
F , , HO \..- H2N 1\1,., \-: H2N N,., .2.e2 H2N
1\1,,. '72-t.
F F /
---;=-I I I
N
LJJ L)I
-., F , NH2 ' V- \'EOI.
.<,.., F F, F, N____ N / / NI_ N¨NH N¨N N¨N HN
/ H Ni 01 H NI ,.,?? H14 \: 0 F .12C 1.I 'V' 0 µV / 11 110\.: 01 , ' , H
õAl I\I, =tiõ H2N N,, H
......N N\ H2N N µ2,- H2N N\
--rtx,I Ti),\,71, --(,_....õ1 .F, i)--., .F3 u3 , , , , , H HO
Vz. ,,N....N.,,,zz-2. H
H2N N µ2.,- 1 IX. --=-=-=-=,C F3 .. N 1\1,..)2?-,. HO, .24..
I,_,....,, , -HO 0 x HO
'-zi;. F
CI
C F3 U.,,,,......5,,,, C I C I CF3 , or NH2 .
72. The compound of any one of Embodiments 39 to 71, or a pharmaceutically acceptable salt or solvate thereof, AO---b NO _c wherein R2 is selected from F
N cs5s0 c.r(0""' N
N
0 , F OMe o F ._,.
o . -6---- cH2F
N N

\
NO
H
N ---N /0--\( ., 0...Ac----, '1&.1:) /-0/''Ø=F
rN
A
N
N
F
f:K -''''.

=Nrip,... ,0Me 0 0...
A-0 AC)-''' F
/ , r3ss'Oy' o A ,,,, ¨ F A e \---". 0 0 Nc_><
F
' , , ome o NO-0õT
A o c's'<o"-'"=i'..I 'sr'Cr-DI
L__2D

\ , _ 1 c":11\1 ANO

z N
, \.......--'-,N..-- ..Ø ......õ,,.....)õ..s...õ.õ.., ,:re:o.õ,:,.õ.......õN...õ,, 1.,,,....õ.0 , , /

N
c3-rF'0"'' OCN
AO
N
N , N\-µ 53.e_ .........õ,........,,,..--""
N . H 1,.., ,N 0,õõ,...).zz.-- ,N
N , Iii H H
p ,...0 c F3 s.,0....0 c. 0 AO
n c;\ /5') I
N
N õ.........õ.....õ..S,,,, -. õõ....-.._.N.------,õõ...-o-,-,...."..... ....----...._õ...- N-...
- N
r:"(0-) , AS , 4../\...) , = 0 , A Y,, O r- c14-C) N
N---/
, N--/ /N----./ /N , F
s:r40 N r.goK ND NCO/ A' NO
I ______________________________________________________________ ;54. S X'-' 0 /)c NO jr4- 02C NO<.F ci4- 0'-)c NO... F F
, 0 , .µF r}5.5µ0 0 j5402CN isssc'OC NO
, I
csrs'''ON A e)CN -') Acy-x--,. N
L',...-''' L,,,,, N NO ;g(cl =-.
, c:F :0-)c NL.,õ.õ-0 "TiOWCN c-53--:0N --- ;05,0,--6CN
c-555.-0-)C N 1 As c'sss c.5ss, r0 r14,o-' CN `:550-- N ----/ z N
, Crrri ;1<C
/ _.,,... , N..õ,,,,"....N. N.,.._,.-^..N..- Ill 1 cljs''IC:1,,___ I

OH I I N
N
,... =---. , .,F

4:540-.A4%LQ N
,and 0
73. The compound of any one of Embodiments 39 to 50and 56 to 72, or a pharmaceutically acceptable salt or solvate thereof, wherein each R' is independently selected from:
Y'.' q, P ci \ 11.- r ''',;.-`if..[4.fill Nrst4-1,1 PE4 .3i:'-ybk=A 1: 8 -1-1, -Nib, -OK -Nii(C1,,, ags:yi), N 109 .. s.s, µP ...0i4 A. -.oil 11 , rn `4 , , ?
At, .034 r_it 2 .,, L-s.,--1 S
tlifq /WLN-) ,.'i-vi-/N-QH **(v'kni---T-A4 L''"J ht-om 4c, = in in c-...,.,..-,,r411 e92 i -mik =---irtS-NH 111---NH' ',- . a `14 .... P )4 NH H H NH NH NH
HN N cN HN NCN
,., NC, NC'''...NANH
-µj*LNH2 ' , 7 , H2NANH , NANH
H I , H
I
, -CN, OH OH
;=cS
:
IA:1D )1r4ir 4"))) µ=,=14 8 . ) 0 m A., ,!=*0 ro N.
6 f .
y 1,1 0 am! 0 w.s.V1W prrsent, is 0, 1.2. or 3.
74. A compound having the formula A-LAB-B wherein A is a monovalent form of a compound of one of Embodiments I to 73;
LAB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.
75. The compound of Embodiment 74 wherein the degradation enhancer is capable of binding a protein selected from E3A, mdm2, APC, EDD1, SOCS/BC-box/eloBC/CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HERS, HERC6, HUWEL ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3a UBE4A, UBE4B, UBOX5, UBR5, VHL (von-Hippel-Lindau ubiquitin ligase), WVVP1, WWP2, Parkin, MKRN1, CMA (chaperon-mediated autophage), SCFb-TRCP (Skip-Cullin-F box (Beta-TRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAP1 (cellular inhibitor of apoptosis protein 1), APC/C
(anaphase-promoting complex/cyclosome), CRBN (cereblon), CUL4-RBX1-DDBI-CRBN (CRL4cRn ubiquitin ligase, XIAP, TAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBX04, FBX031, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885.
76. The compound of Embodiment 74 wherein the degradation enhancer is capable of binding a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.
77. The compound of any one of Embodiments 74 to 76, wherein LAB is LAB' LAB2 LAB3 LAB4 L5;
LAB1, LAB2, AB3, LAB4, and L5 are independently a bond, -0-, -N(R14)-, -C(0)-, -N(R")C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(RH)S(0)-, -N(Ru)S(0)2-, Ci.6a1kylene, (-0-Ci_oalky1)2-, (-Ci_oa1ky1-0)z-, C2_6a1kenylene, C2_6a1kynylene, Ci.ohaloalkylene, C3_12cycloalkylene, Ci-ilheterocycloalkylenc, Co_12ary1ene, or Ci_iiheteroarylcne, wherein Ci_oalkylene, C2_6alkeny1ene, C2.
oalkynylene, Ci6haloalkylene, C3_12cycloa1kylene, C1nheterocycloa1kylene.
Co_12arylene, or CI.

iiheteroarylene,are optionally substituted with one, two, or three R20J;
wherein each Ci_6a1kyl of (-0-C1_ 6a1ky1)z- and (-Ci_6alky1-0)z- is optionally substituted with one, two, or three R20-1;
z is independently an integer from 0 to 10:
each R12 is independently selected from hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3.6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloa1kyl, C6_10aryl, -CH2-C6_ioaryl, -CH2-C1-9heteroaryl, and Ci_9heteroaryl, wherein C1_6alkyl, C2_6a1kenyl, C2_6alkynyl, C3_6cyc1oa1kyl, -CH2-C3-6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocyc1oalky1, C6_ioary1, -CH2-C6_10aryl, -CH2-C1-9heteroaryl, and Ci_9heteroaryl are optionally substituted with one, two, or three R2";
each RH is independently selected from hydrogen, Ci_6alkyl, and C1_6haloalkyl;
or RI' and RH, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R2 e;
each R14 is independently selected from hydrogen, Ci_6alkyl, and Ci_ohaloalkyl;
each R15 is independently selected Ci_6alkyl, C2_6alkeny1, C2.6allqTnyl, C36cyc1oa1kyl, C2_9heterocycloalky1, C6_10atyl, and Ci_9heteroaryl, wherein C1_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2-9heterocycloallcyl, C6_10aiyl, and Ci_91ieteroaryl are optionally substituted with one, two, or three R20;
each R2 d, R20e, K20f, and R20-1 are each independently selected from halogen, -CN, Ci6alkyl, C2_6a1kenyl, C2-6alkynyl. C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloa1kyl, -CH2-C2_9heterocycloa1kyl, C6_10a1yl, -CH2-C6_10aryl, -CH2-C1_9heteroaryl, Ci_9heteroaryl, -0R21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -OC(0)R25, wherein Ci_6a1kyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloa1kyl, -CH2-C3_6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6_10aryl, -CH2-C6_102uyl, -CH2-Ci_9heteroaryl, and C1-9heteroatyl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, C1_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(1124)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R21 is independently selected from H, Ci_6alky1, Ci_6haloalkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloa1kyl, C2_9heterocycloalkyl, C6_1oaryl, and C1_9heteroaly1;
each R22 is independently selected from H, Ci_6alky1, C1_6haloalkyl, C2.6alkenyl, C2.6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6-1 oaryl, and C1_9heteroatyl;
each R23 is independently selected from H and Ci_6alkyl;
each R24 is independently selected from H and Ci_6alky1; and each R25 is selected from C1_6alkyl, C2_6alkenyl, C2_6a1kynyl, C3_6cycloalkyl, C2.9heterocycloa1kyl, C6_1oaryl, and C1_9heteroaryl.
78. The compound of any one of Embodiments 74 to 76, wherein LAB is -(0-C2a1kyl)z- and z is an integer from 1 to 10.
79. The compound of any one of Embodiments 74 to 76, wherein LAB is -(C2a1ky1-0-),- and z is an integer from 1 to 10.
80. The compound of any one of Embodiments 74 to 76, wherein LAB is -(CH2)z1LAB2(C1-120)z2-, wherein LAB2 is a bond, a 5 or 6 membered heterocycloalkylene or heteroarylene, phenylene, -(C2-C4)alkynylene, -SO2- or -NH-; and zl and z2 are independently an integer from 0 to 10.
81. The compound of any one of Embodiments 74 to 76, wherein LAB is -(CH2)z1(CH20)z2-, wherein zl and z2 are each independently an integer from 0 to 10.
82. The compound of any one of Embodiments 74 to 76, wherein LAB is a PEG
linker.
83. The compound of any one of Embodiments 74 to 82, wherein B is a monovalent form of a compound PH
9' IC A.,:r =
H õµ,./"Th ./.., N s 1 cs..,e.,...N.,-..r.,,, k ===.µz#:µ efA N 8 N,--.1-----,,1 i ., ............................................... sj 0 H
1....d...,1-....õõ:7----IN
,, gc ......, selected from , b ' P"
0+:, N ----= ' .
? = 0 I
.
0 N1-12 r--,----)t f.'0'.. 7"'..." \
N-- ...::,=$!:, 0 ..i. il,s, __' ,,.1,-,. .9 L=-=%`-" Al --1 õ,- ....,õ --,... -..,,, , , , \

=,... ..,.
, c r---J-N, 5.----<, .. .---d p-, < .1,..--....--,-.,0 õ.).k. H
..A---N
fr.f.'NN,,, fv...-i .4: pli rõ a c. µ
1,:õ.....õ) µ,a .-= ..,), 1-01---(-C3 Nutlin F
i 1 tti I-Idasanutlin ..,.....t.
,Aõ,....
..".õ... c ckp 0 I ,N, HA.s,A,,õ-..:; tiN-4:1 1 k.'c''' 'N' '1..'' '='-'''''''''''"
4" NY N N
- N
6 b k:i 1,1.! i.,:: ji.
....õ40,- H.z14.-S.:,-) , , = , and .....":3..-L õ.---r-,,,----s 4 b .
84. A pharmaceutical composition comprising a compound of any one of Embodiments 1 to 6583 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
85. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof.
86. A method of modulating activity of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound of any one of Embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.
87. The method of Embodiment 85 or Embodiment 86 comprising administering an additional agent or therapy.
88. A method of inhibiting cell growth, comprising administering an effective amount of a compound of one of Embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.
89. The method of one of Embodiments 85 to 88 comprising administering an additional agent to said cell.
90. A Ras protein bound by a compound of one of Embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof, wherein activity of said Ras protein is reduced as compared to a Ras protein unbound to said compound.
Further Forms of Compounds Disclosed Herein Isomers [00579] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers in some embodiments, the compounds described herein possess one or more double bonds.
The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S
configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion, are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.
Labeled compounds [00580] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H, 3H, 13C, 14C, 15N, 170, 180, 31p, 3215, 35S. 18F, and 36C1, respectively.
Compounds described herein, and pharmaceutically acceptable salts, esters, solvate, hydrates, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 13C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., 3H and carbon-14, isotopes are particularly preferred for their case of preparation and dctectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.
[00581] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts [00582] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
[00583] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Solvates [00584] In sonic embodiments, the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.
[00585] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran. or Me0H. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Synthesis of Compounds [00586] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.

[00587] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.
[00588] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 41l Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein.
In some embodiments, the following synthetic method may be utilized [00589] In some embodiments, the compounds of the present invention exhibit one or more functional characteristics disclosed herein. For example, a subject compound binds to a Ras protein, Kras protein or a mutant form thereof. In some embodiments, a subject compound binds specifically and also inhibits a Ras protein, Kras protein or a mutant form thereof. In some embodiments, a subject compound selectively inhibits a Kras mutant relative to a wildtype Kras. In some embodiments, a subject compound selectively inhibits KrasG12D and/or KrasG12V relative to vvildtype Kras. In some embodiments, the IC50 of a subject compound for a Kras mutant (e.g., including G12D) is less than about 5 NI, less than about 1 M, less than about 50 nNI, less than about 10 nIVI, less than about 1 nNI, less than about 0.5 nNI, less than about 100 pM, or less than about 50 pM, as measured in an in vitro assay known in the art or exemplified herein.
[00590] In some embodiments, a subject compound of the present disclosure is capable of reducing Ras signaling output. Such reduction can be evidenced by one or more members of the following: (i) an increase in steady state level of GDP-bound Ras protein; (ii) a reduction of phosphoiylated AKTs473, (iii) a reduction of phosphorylated ERKT202/y204, (iv) a reduction of phosphorylated S6S235/236, and (v) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., those derived from a tumor cell line disclosed herein). In some cases, the reduction in Ras signaling output can be evidenced by two, three, four or all of (i)-(v) above.
Methods [00591] In an aspect is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., compound of Formula 1, 1A1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, hAil, I1Al2, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", I-1, I-1', I-1", I-1" ', 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject method comprises administering an additional agent or therapy.
[00592] In an aspect is provided a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IAll, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, hAll, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", II", I-1, I-1', I-1", I-1", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras (e.g., K-Ras) protein [00593] In some embodiments, the subject method comprises administering an additional agent or therapy.
[00594] In an aspect is provided a method of inhibiting cell growth, comprising administering an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA?, IA8, IA9, IA1, IA1 1, IA12, 11, HAI, IIA2, IIA3, 11A4, IIA5, 11A6, 11A7, 11A8, IIA9, HAW, HAIL IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula 1', II', I", II", I-1, I-1', I-1", I-1 " ' 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras (e.g., K-Ras) protein, thereby inhibiting growth of said cells. In embodiments, the subject method comprises administering an additional agent to said cell.
[00595] In an aspect is provided a Ras (e.g., K-Ras) protein bound by a compound described herein (e.g., compound of Formula I, IA1, IA2, 1A3, 1A4, IA5, 1A6, 1A7, IA8, IA9, IA1, IA1 1, IA12, 11, IIA1 IIA2, IIA3, IIA4, HAS, IIA6, IIA7, IIA8, IIA9, IIA1 0, IIA1 1, I1A1 2, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", II", I-1, I-1', I-1 I-1 '", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein activity of said Ras (e.g., K-Ras) protein is reduced as compared to a Ras (e.g., K-Ras) protein unbound to said compound.
[00596] In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., compound of Formula I, IA1, 1A2, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A1 0, 1A1 1, 1A1 2, 11, 11A1, 11A2, 11A3, 11A4, 11A5, 11A6, 11A7, 11A8, 11A9, IIA10, IIA1 1, IIA12, III, IV, V. VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", I-1, I-1', I-1 ", 1-1 ", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a solid tumor or a hematological cancer. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA1, IA1 1, IA12, II, HAI., IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA1 1, IIA12, III, IV, V, VI, VII, VIII, IX, X, XT, XII, XIII, XIV, or XV; compound of Formula I', TT', T", IT", T-1, 1-1', T-1", T-1 " 1-3, I-4, I1-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a solid tumor.
In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., compound of Formula 1, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IAll, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, HA7, IIA8, IIA9, IIA10, IIA1 1, I1Al2, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Fonnula I', II', I", II", I-1, I-1', I-1 ", I-1 ", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from prostate cancer, brain cancer, colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers, combinations of said cancers, and metastatic lesions of said cancers. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA 11, IA12, II, IIA 1, IIA2, IIA3, IIA4, HAS, IIA6, IIA7 n IIA8, IIA9, IIAI On HAI In I1Al2, III, IV, Vn VI, VII, VIII, IX, Xn XI, XII, XIII, XIV, or XV; compound of Formula I', II', II", I-1, I-1 ', I-1", I-1" ', I-3, I-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematological cancer. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administer* to the subject a therapeutically effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA1 1, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IA?, IIA8, IIA9, IIA10, IIA1 1, IIA12, III, IV, V, VI, VII, VIII, IX, X. XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", II", I-1, I-1 ', I-1", 1-1", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematological cancer selected from one or more of chronic lymphocytic leukemia (CLL), acute leukemias, acute lymphoid leukemia (ALT), B-cell acute lymphoid leukemia (B-ALT,), T-cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT
lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple mycloma, myclodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and pre-leukemia. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA1 1, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA1 0, IIA1 1, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", II", I-1, I-1', I-1", 1-1"', 1-3, 1-4, 11-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is one or more cancers selected from the group consisting of chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML). T-cell acute lymphoblastic leukemia (T-ALL), B cell acute lymphoblastic leukemia (B-ALL), and/or acute lymphoblastic leukemia (ALL).
[00597] Any of the treatment methods disclosed herein can be administered alone or in combination or in conjunction with another therapy or another agent. By "combination" it is meant to include (a) formulating a subject composition containing a subject compound together with another agent, and (b) using the subject composition separate from the another agent as an overall treatment regimen.
By "conjunction" it is meant that the another therapy or agent is administered either simultaneously, concurrently or sequentially with a subject composition comprising a compound disclosed herein, with no specific time limits, wherein such conjunctive administration provides a therapeutic effect.
[00598] In some embodiments, a subject treatment method is combined with surgery, cellular therapy, chemotherapy, radiation, and/or immunosuppressive agents. Additionally, compositions of the present disclosure can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunostimulants, and combinations thereof.
[00599] In one embodiment, a subject treatment method is combined with a chemotherapeutic agent.

[00600] Exemplary chemotherapeutic agents include an anthracycline (e.g., doxorubicin (e.g., liposomal doxorubicin)), a vinca alkaloid (e.g., vinblastine, vineristine, vindesine, vinorelbine), an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide), an immune cell antibody (e.g., alemtuzamab, gemtuzumab, rituximab, ofatumumab, tositumomab, brentuximab), an antimetabolite (including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)), a TNFR glucocorticoid induced TNFR related protein (GITR) agonist, a proteasome inhibitor (e.g., aclacinomycin A, gliotoxin or bortezomib), an immunomodulator such as thalidomide or a thalidomide derivative (e.g., lenalidomide).
Additional chemotherapeutic agents contemplated for use in combination include busulfan (Mylerank), busulfan injection (Busulfext), cladribine (Leustatink), cyclophosphamide (Cytoxan0 or Neosar0), cytarabine, cytosine arabinoside (Cytosar-U ), cytarabine liposome injection (DepoCyt .), daunorubicin hydrochloride (Cerubidinek), daunorubicin citrate lipo some injection (DaunoXome0), dexamethasone, doxorubicin hydrochloride (Adriamycink, Rubext), etoposide (Vepesidkz ), fludarabine phosphate (Fludarak), hydroxyurea (Hydreak), Idarubicin (Tdamycinl_t)), mitoxantrone (Novantronek), Gemtuzumab Ozogamicin (Mylotargk), anastrozole (Arimidexk), bicalutamide (Casodex0), bleomycin sulfate (Blenoxanek), busulfan injection (Busulfext), capecitabine (XelodaR), N4-pentoxycarbony1-5-deoxy-5-fluorocytidine, carboplatin (Paraplatint), carmustine (BiCNI_M), chlorambucil (Leukerank), cisplatin (Platinolk), dacarbazine (DTIC-Dome ), dactinomycin (Actinomycin D, Cosmegan), dexamethasone, docetaxel (Taxoterek), 5-fluorouracil (Admen , Efudext), flutamide (Eulexint), tezacitibine, Gemcitabine (difluorodeoxycitidine), ifosfamide (TEEM)), irinotecan (Camptosark), L-asparaginase (ELSPARCO, lcucovorin calcium, melphalan (Alkeran ), 6-mercaptopurine (Purinctholk), methotrcxatc (FolexV), mitoxantrone (Novantronet), mylotarg, paclitaxel (Taxolt), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadelk), tamoxifen citrate (Nolvadex*), teniposide (Vumont), 6-thioguanine, thiotepa, tirapazamine (Timzonek), topotecan hydrochloride for injection (Hycamptin vinblastine (Velbank), vincristine (Oncovink), and vinorelbine (Navelbinek).
[00601] Anti-cancer agents of particular interest for combinations with a compound of the present invention include: anthracyclines; alkylating agents; antimetabolites; drugs that inhibit either the calcium dependent phosphatase calcineurin or the p70S6 kinase FK506 or inhibit the p70S6 kinase;
mTOR inhibitors;
immunomodulators; anthracyclines; vinca alkaloids; proteosome inhibitors; GITR
agonists; protein tyrosine phosphatase inhibitors; a CDK4 kinase inhibitor; a BTK inhibitor; a MKN kinase inhibitor; a DGK kinase inhibitor;
or an oncolytic virus.
[00602] Exemplary antimetabolites include, without limitation, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): methotrexate (Rheumatrex , Trexallk), 5-fluorouracil (Admcil , Efudex , Fluoroplext), floxuridine (FUDFt), cytarabine (Cytosar-U , Tarabine PFS), 6-mercaptopurine (Puri-Netholt)), 6-thioguanine (Thioguanine Tabloid ), fludarabine phosphate (Fludarak), pentostatin (Nipent ), pemetrexed (Alimtak), raltitrexed (Tomudext), cladribine (Leustatink), clofarabine (Clofarex , Clolart), azacitidine (Vidazak), decitabine and gemcitabine (Gemzarl)i ). Preferred antimetabolites include, cytarabine, clofarabine and fludarabine.
[00603] Exemplary alkylating agents include, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): uracil mustard (Aminouracil Mustard , Chlorethaminacil , DemethyldopanO, DesmethyldopanO, Haemanthamine0, Nordopank, Uracil nitrogen Mustard , Uracillost , Uracilmostazat, Uramustink, Uramustinek), chlormethine (Mustargenk), cyclophosphamide (Cytoxank, Neosar , Clafen , Endoxan , Procytox , RevimmuneTm), ifosfamide (Mitoxanat), melphalan (Alkerann Chlorambucil (Leukeran0), pipobroman (Amede10. Vercytek), triethylenemelamine (Hemel . Hexalen0, Hexastatt)), triethylenethiophosphoramine, Temozolomide (Temodark), thiotepa (Thioplexk), busulfan (Busilvexk, Mylerank), carmustine (BiCNUk), lomustine (CeeNIIk), streptozocin (Zanosark), and Dacarbazine (DTIC-Domek). Additional exemplary alkylating agents include, without limitation, Oxaliplatin (Eloxatink);
Temozolomide (Temoclar(ii and Temodalk); Dactinomycin (also known as actinomycin-D, Cosmegenn Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkerank); Altretamine (also known as hexamethylmelamine (HMM), Hexalen .); Carmustine (BiCNU ); Bendamustine (Treanda ); Busulfan (Busulfexk and MyleranC); Carboplatin (Paraplatink); Lomustine (also known as CCNU, CeeNU ); Cisplatin (also known as CDDP. Platinol and Platinolk-AQ), Chlorambucil (Lcukcran)), Cyclophosphamidc (Cytoxank and Neosar0); Dacarbazine (also known as DTIC, DIC and imiclazole carboxamide, DTIC-Domet); Altretamine (also known as hexamethylmelamine (HIVIM), Hexalen ); Ifosfamide (Ilex*);
Prednumustine; Procarbazine (Matulane0); Mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, Mustargenk); Streptozocin (Zanosark); Thiotepa (also known as thiophosphoamide, IESPA and TSPA, Thioplex ); Cyclophosphamide (Endoxank, Cytoxank, Neosark, Procytox , Revimmunek); and Bendamustine HC1 (Treandak).
[00604] In an aspect, compositions provided herein can be administered in combination with radiotherapy such as radiation Whole body radiation may be administered at 12 Gy. A radiation dose may comprise a cumulative dose of 12 Gy to the whole body, including healthy tissues. A radiation dose may comprise from 5 Gy to 20 Gy. A radiation dose may be 5 Gy, 6 Gy, 7 Gy, 8 Gy, 9 Gy, 10 Gy, 11 Gy, 12, Gy, 13 Gy, 14 Gy, 15 Gy, 16 Gy, 17 Gy, 18 Gy, 19 Gy, or up to 20 Gy. Radiation may be whole body radiation or partial body radiation. In the case that radiation is whole body radiation it may be uniform or not uniform. For example, when radiation may not be uniform, narrower regions of a body such as the neck may receive a higher dose than broader regions such as the hips.
[00605] Where desirable, an immunosuppressive agent can be used in conjunction with a subject treatment method.
Exemplary inununosuppressive agents include but are not limited to cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies (e.g., muromonab, otelixizumab) or other antibody therapies, cytoxin, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation, peptide vaccine, and any combination thereof. In accordance with the presently disclosed subject matter, the above-described various methods can comprise administering at least one immunomodulatory agent. In certain embodiments, the at least one immunomodulatoly agent is selected from the group consisting of immunostimulatory agents, checkpoint immune blockade agents (e.g., blockade agents or inhibitors of immune checkpoint genes, such as, for example, PD-I, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA_ VISTA, ICOS, KIRs and CD39), radiation therapy agents, chemotherapy agents, and combinations thereof. In some embodiments, the immunostimulatory agents are selected from the group consisting of 1L-12, an agonist costimulatory monoclonal antibody, and combinations thereof. In one embodiment, the immunostimulatory agent is IL-12. In some embodiments, the agonist costimulatory monoclonal antibody is selected from the group consisting of an anti-4-1BB antibody (e.g., ii Ellab_ PIP-05082566 ), an anti-0X40 antibody (mobzunnab. ta%, PF-045.18600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, JTX-2011), and combinations thereof. In one embodiment, the agonist costimulatory monoclonal antibody is an anti-4-1 BB antibody. In some embodiments, the checkpoint immune blockade agents are selected from the group consisting of anti-PD-Li antibodies (aizzoiIkErtab, avetzmab. dun'ailumb, BMIS -936559), anti-CTLA-4 antibodies (e.g., tremc inalunah, anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti-LAG3 antibodies (e.g., C9B7W, 4)0C9), anti-M-113 antibodies (e.g., DS-5573a), anti-TIM3 antibodies (e.g.. F38-2E2), and combinations thereof. In one embodiment, the checkpoint immune blockade agent is an anti-PD-Li antibody. In some cases, a compound of the present disclosure can be administered to a subject in conjunction with (e.g., before, simultaneously or following) bone marrow transplantation. T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT). cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In some cases, expanded cells can be administered before or following surgery. Alternatively, compositions comprising a compound described herein can be administered with immunostimulants.
Immunostimulants can be vaccines, colony stimulating agents, interferons, interleukins, viruses, antigens, co-stimulatory agents, immunogenicity agents, immunomodulators, or immunotherapcutic agents. An immunostimulant can be a cytokine such as an interleukin. One or more cytokines can be introduced with modified cells provided herein. Cytokines can be utilized to boost function of modified T lymphocytes (including adoptively transferred tumor-specific cytotoxic T lymphocytes) to expand within a tumor microenvironment. In some cases, IL-2 can be used to facilitate expansion of the modified cells described herein. Cytokines such as IL-15 can also be employed.
Other relevant cytokines in the field of immunotherapy can also be utilized, such as IL-2, IL-7, IL-12, IL-15, IL-21, or any combination thereof. An interleukin can be IL-2, or aldesleukin.
Aldesleukin can be administered in low dose or high dose A high dose aldesleukin regimen can involve administering aldesleukin intravenously every 8 hours, as tolerated, for up to about 14 doses at about 0.037 mg/kg (600,000 115/kg). An immunostimulant (e.g., aldesleukin) can be administered within 24 hours after a cellular administration. An immunostimulant (e.g., aldesleukin) can be administered in as an infusion over about 15 minutes about every 8 hours for up to about 4 days after a cellular infusion. An immunostimulant (e.g., aldcsleukin) can be administered at a dose from about 100,000 1U/kg, 200,000 IU/kg, 300,000 IU/kg, 400,000 [U/kg, 500,000 IU/kg, 600,000 IU/kg, 700,000 IU/kg, 800,000 IU/kg, 900,000 IU/kg, or up to about 1,000,000 IU/kg. In some cases, aldesleukin can be administered at a dose from about 100,000 IU/kg to 300,000 IU/kg, from 300,000 IU/kg to 500,000 IU/kg, from 500,000 IU/kg to 700,000 IU/kg, from 700,000 IU/kg to about 1,000,000 IU/kg.
[00606] In some embodiments, any of the compounds herein that is capable of binding a Ras protein (e.g., KRAS) to modulate activity of such Ras protein may be administered in combination or in conjunction with one or more pharmacologically active agents comprising (1) an inhibitor of 1VFEK (e.g., IVIEK1, IvIEK2) or of mutants thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib); (2) an inhibitor of epidermal growth factor receptor (EGFR) and/or of mutants thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, olmutinib, EGF-816); (3) an immunotherapeutic agent (e.g., checkpoint immune blockade agents, as disclosed herein); (4) a taxane (e.g., paclitaxel, docetaxel); (5) an anti-metabolite (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); (6) an inhibitor of FGFR1 and/or FGFR2 and/or FGFR3 and/or of mutants thereof (e.g., nintedanib); (7) a mitotic kinase inhibitor (e.g., a CDK4/6 inhibitor, such as, for example, palbociclib, ribociclib, abemaciclib);
(8) an anti-angiogenic drug (e.g., an anti-VEGF antibody, such as, for example, bevacizumab); (9) a topoisomerase inhibitor (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, toporecan, irinotecan, mitoxantrone); (10) a platinum-containing compound (e.g. cisplatin, oxaliplatin, carboplatin); (11) an inhibitor of ALK and/or of mutants thereof (e.g. crizotinib, alectinib, entrectinib, brigatinib); (12) an inhibitor of c-MET and/or of mutants thereof (e.g., K252a, SU11274, PHA665752, PF2341066); (13) an inhibitor of BCR-ABL and/or of mutants thereof (e.g., imatinib, dasatinib, nilotinib); (14) an inhibitor of ErbB2 (Her2) and/or of mutants thereof (e.g., afatinib, lapatinib, trasturtimab, pertuzumab); (15) an inhibitor of AXL and/or of mutants thereof (e.g., R428, amuvatinib, XL-880);
(16) an inhibitor of NTRK1 and/or of mutants thereof (e.g., Merestinib); (17) an inhibitor of RET and/or of mutants thereof (e.g., BLU-667, Lenvatinib); (18) an inhibitor of A-Raf and/or B-Raf and/or C-Raf and/or of mutants thereof (RAF-709, LY-3009120): (19) an inhibitor of ERK and/or of mutants thereof (e.g., ulixertinib); (20) an MDM2 inhibitor (e.g., HDM-201, NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AIVIG-232, DS-3032, RG-7775, APG-115); (21) an inhibitor of mTOR (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (22) an inhibitor of BET (e.g., I-BET 151, I-BET 762, OTX-015, 1EN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-I, MS645); (23) an inhibitor of IGF1/2 and/or of IGF1-R (e.g., xcntuzumab, MEDI-573); (24) an inhibitor of CDK9 (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B, AT75I9, dinaciclib, SNS-032); (25) an inhibitor of farnesyl transferase (e.g., tipifarnib); (26) an inhibitor of SHIP pathway including SHIP2 inhibitor, as well as SHIP1 inhibitors; (27) an inhibitor of SRC (e.g., dasatinib); (28) an inhibitor of JAK (e.g., tofacitinib); (29) a PARP inhibitor (e.g. Olaparib, Rucaparib, Niraparib, Talazoparib), (30) a BTK
inhibitor (e.g. Ibrutinib, Acalabrutinib, Zanubrutinib), (31) a ROS1 inhibitor (e.g., entrectinib), (32) an inhibitor of SUP pathway including SHP2 inhibitor (e.g., 6-(4-amino-4-methylpiperidin-1-y1)-3-(2,3-dichlorophenyl)pyrazin-2-amine, as well as SHP1 inhibitors, (33) an inhibitor of Src, FLT3, HDAC, VEGFR, PDGFR, I,CK, Rcr-Abl or AKT
or (34) an inhibitor of KrasG12C mutant (e.g., including but not limited to AMG510, MRTX849, and any covalent inhibitors binding to the cysteine residue 12 of Kras, the structures of these compounds are publically known) (e.g., an inhibitor of Ras G12C as described in US20180334454, U520190144444, US20150239900, US10246424, U S20180086753, W02018143315, W02018206539, W020191107519, W02019141250, W02019150305, US9862701, U520170197945, US20180086753, US10144724, US20190055211, US20190092767, US20180127396, U520180273523, US10280172, US20180319775, US20180273515, U520180282307, US20180282308, W02019051291, W02019213526, W02019213516, W02019217691, W02019241157, W02019217307, W02020047192, W02017087528, W02018218070, W02018218069, W02018218071, W02020027083, W02020027084, W02019215203, W02019155399, W02020035031, W02014160200, W02018195349, W02018112240, W02019204442, W02019204449, W02019104505, W02016179558, W02016176338, or related patents and applications, each of which is incorporated by reference in its entirety), (35) a SHC inhibitor (e.g., PP2, AID371185), (36) a GAB inhibitor (e.g., GAB-0001), (37) a GRB inhibitor, (38) a P1-3 kinase inhibitor (e.g., Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, NVP-BEZ235-AN), (39) a MARPK inhibitor, (40) CDK4/6 (e.g., palbociclib, ribociclib, abemaciclib), or (41) MAPK inhibitor (e.g., VX-745, VX-702, RO-4402257, SC10-469, B1RB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB-681323, GW-856553, RW.I67657, BCT-197), or (42) an inhibitor of SHP pathway including SHP2 inhibitor (e.g., 6-(4-amino-4-methylpiperidin-l-y1)-3-(2,3-dichlorophenyl)pyrazin-2-amine, RMC-4630, TN0155 ( µõ.
)1 )1 ,s=
NH2 Vir = H2N P4 P.4 "=3 0 ), JAB-3068 ( ), IACS-13909/BBP-398 ( e-Qi N
N Cl N
), SHP099 ( ), ERAS-601, and RMC-4550 ( cti3 Cs tut;
Nt ), as well as SHP1 inhibitors. In some embodiments, any of the compounds herein that is capable of binding a Ras protein (e.g., Kras) to modulate activity of such Ras protein may be administered in combination or in conjunction with one or more checkpoint immune blockade agents (e.g., anti-PD-1 and/or anti-PD-Li antibody, anti-CLTA-4 antibody). In some embodiments, any of the compounds herein that is capable of binding a Ras protein (e.g., KRAS) to modulate activity of such Ras protein may be administered in combination or in conjunction with one or more pharmacologically active agents comprising an inhibitor against one or more targets selected from the group of: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2.
FGFR3, mitotic kinase, topoisomerase, ALK, c-MET, ErbB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, 1VIDM2, inTOR, BET, TGF1/2, IGF1-R, CDK9, SHT131, SH1P2, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, KrasG12C mutant, and ROS1. Where desired, the additional agent can be an inhibitor against one or more targets selected from the group of: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, mitotic kinase, topoisomerase, ALK, c-MET, EibB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1/2, IGF1-R, CDK9, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, KrasG12C mutant, and ROS1. In sonic embodiments, any of the compounds herein that is capable of binding a Ras protein (e.g., KRAS, mutant Ras protein) to modulate activity of such Ras mutant (e.g., Gl2C, G12D, G12S, Gl2V, Gl3C, or Gl3D) may be administered in combination or in conjunction with one or more additional pharmacologically active agents comprising an inhibitor of SOS (e.g., SOS1, SOS2) or of mutants thereof. In embodiments, the additional pharmacologically active agent administered in combination or in conjunction with a compound described herein (e.g., compound capable of binding a Ras protein) is an inhibitor of SOS (e.g., SOS1, SOS2). In embodiments, the additional pharmacologically active agent administered in combination or in conjunction with a compound (e.g., compound capable of binding a Ras protein) described herein is an inhibitor of SOS (e.g., SOS1, SOS2). In embodiments, the additional pharmacologically active agent administered in combination or in conjunction with a compound (e.g., compound capable of binding a Ras protein) described herein is an inhibitor of SOS (e.g., SOS1, SOS2) selected from RMC-5845, BI-3406 ( õk: N
CT
'11 I F

O'M HN
i N N
), BI-1701963õ TX0902 ( ), and BAY
293 ( (/
/
.L'NH
_O
, N ='=" 0 ). In embodiments, the additional pharmacologically active agent administered in combination or in conjunction with a compound described herein (e.g., compound capable of binding a Ras protein) is an inhibitor of SOS (e.g., SOS1, SOS2) described in W02021092115, W02018172250, W02019201848, W02019122129, W02018115380, W02021127429, W02020180768, or W02020180770, all of which are herein incorporated by reference in their entirety for all purposes.
[00607] In some embodiments, any of the compounds herein that is capable of binding a Ras protein (e.g., Kras) to modulate activity of such Ras protein may be administered in combination or in conjunction with one or more checkpoint immune blockade agents (e.g., anti-PD-1 and/or anti-PD-Li antibody, anti-CLTA-4 antibody).
[00608] In some embodiments, any of the compounds described herein that is capable of binding a Ras protein (e.g., KRAS) may be administered in combination or in conjunction with one or more pharmacologically active agents comprising an inhibitor of: (1) SOS1 or a mutant thereof (e.g., RMC-5845, BI-3406, BAY-293, MRTX0902, BI-1701963); (2) SHP2 or a mutant thereof (e.g., 6-(4-amino-4-methylpiperidin-l-y1)-3-(2,3-dichlorophenyppyrazin-2-amine, TN0155, RMC-4630, ERAS-601, JAB-3068, IACS-13909/BBP-398, SHP099, R_MC-4550); (3) SHC or a mutant thereof (e.g., PP2, A1D371185); (4) GAB or a mutant thereof (e.g., GAB-0001); (5) GRB or a mutant thereof; (6) JAK or a mutant thereof (e.g., tofacitinib); (7) A-RAF, B-RAF, C-RAF, or a mutant thereof (e.g., RAF-709, LY-3009120); (8) BRAF or a mutant thereof (e.g., Sorafenib, Vemurafenib, Dabrafenib, Encorafenib, regorafenib, GDC-879); (9) MEK or a mutant thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refarnetinib, AZD6244); (10) ERK or a mutant thereof (e.g., ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, ravoxertinib); (11) PI3K or a mutant thereof (e.g., Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, NVP-BEZ235-AN); (12) MAPK or a mutant thereof (e.g., VX-745, VX-702, RO-4402257, SC10-469, B1RB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB-681323, GW-856553, RW167657, BCT-197): (13) EGFR or a mutant thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, ohnutinib, EGF-816); (14) c-MET or a mutant thereof (e.g., K252a, SU11274, PHA665752, PF2341066); (15) ALK or a mutant thereof (e.g. crizotinib, alectinib, entrectinib, brigatinib); (16) FGFR1, FGFR-2, FGFR-3, FGFR-4 or a mutant thereof (e.g., nintedanib); (17) BCR-ABL or a mutant thereof (e.g., imatinib, dasatinib, nilotinib); (18) ErbB2 (Her2) or a mutant thereof (e.g., afatinib, lapatinib. trastuzumab, pertuzumab); (19) AXL or a mutant thereof (e.g., R428, amuvatinib, XL-880); (20) NTRK1 or a mutant thereof (e.g., merestinib); (21) ROS1 or a mutant thereof (e.g., entrectinib); (22) RET or a mutant thereof (e.g., BLU-667, Lenvatinib); (23) MDM2 or a mutant thereof (e.g., 1-1DM-201 , NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115); (24) mTOR or a mutant thereof (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (25) BET or a mutant thereof (e.g., I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645);
(26) IGF1, IGF2, IGF1R, or a mutant thereof (e.g., xentuzumab, MEDI-573); (27) CDK9 or a mutant thereof (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B, AT7519, dinaciclib, SNS-032);
or (28) CDK4/6 (e.g., palbociclib, ribociclib, abemaciclib).
[00609] In combination therapy, a compound provided herein and other anti-cancer agent(s) may be administered either simultaneously, concunently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
[00610] In some embodiments, the compound of the present disclosure and the other anti-cancer agent(s) are generally administered sequentially in any order by infusion or orally. The dosing regimen may vary depending upon the stage of the disease, physical fitness of the patient, safety profiles of the individual drugs, and tolerance of the individual drugs, as well as other criteria well-known to the attending physician and medical practitioner(s) administering the combination The compound of the present invention and other anti-cancer agent(s) may be administered within minutes of each other, hours, days, or even weeks apart depending upon the particular cycle being used for treatment. In addition, the cycle could include administration of one drug more often than the other during the treatment cycle and at different doses per administration of the drug.
[00611] An antibiotic can be administered to a subject as part of a therapeutic regime. An antibiotic can be administered at a therapeutically effective dose. An antibiotic can kill or inhibit growth of bacteria. An antibiotic can be a broad spectrum antibiotic that can target a wide range of bacteria.
Broad spectrum antibiotics, either a 3" or 41h generation, can be cephalosporin or a quinolone. An antibiotic can also be a narrow spectrum antibiotic that can target specific types of bacteria. An antibiotic can target a bacterial cell wall such as penicillins and cephalosporins.
An antibiotic can target a cellular membrane such as polymyxins. An antibiotic can interfere with essential bacterial enzymes such as antibiotics: rifamycins, lipiarmycins, quinolones, and sulfonamides. An antibiotic can also be a protein synthesis inhibitor such as macrolides, lincosamides, and tetracyclines. An antibiotic can also be a cyclic lipopeptide such as daptomycin, glycylcyclines such as tigecycline, oxazolidiones such as linezolid, and lipiarmycins such as fidaxomicin. In some cases, an antibiotic can be 1"
generation, 211d generation, 3rd generation, 4th generation, or 5111 generation. A first-generation antibiotic can have a narrow spectrum. Examples of 1"
generation antibiotics can be penicillins (Penicillin G or Penicillin V), Cephalosporins (Cephazolin, Cephalothin.
Cephapirin, Cephalethin, Cephradin, or Cephadroxin). In some cases, an antibiotic can be 2nd generation. 211d generation antibiotics can be a penicillin (Amoxicillin or Ampicillin), Cephalosporin (Cefuroxime, Cephamandole, Cephoxitin, Cephaclor, Cephrozil, Loracarbef). In some cases, an antibiotic can be 3' generation. A 3" generation antibiotic can be penicillin (carbenicillin and ticarcillin) or cephalosporin (Cephixime, Cephtriaxone, Cephotaxime, Cephtizoxime, and Cephtazidime). An antibiotic can also be a 41h generation antibiotic. A 41h generation antibiotic can be Cephipime. An antibiotic can also be 5'h generation. 5111 generation antibiotics can be Cephtaroline or Ceplitobiprole.
[00612] In some cases, an anti-viral agent may be administered as part of a treatment regime. In some cases, a herpes virus prophylaxis can be administered to a subject as part of a treatment regime. A herpes virus prophylaxis can be valacyclovir (Valtrex). Valtrex can be used orally to prevent the occurrence of herpes virus infections in subjects with positive HSV serology. It can be supplied in 500 mg tablets.
Valacyclovir can be administered at a therapeutically effective amount.
[00613] In some cases, a treatment regime may be dosed according to a body weight of a subject. In subjects who are determined obese (BMI > 35) a practical weight may need to be utilized.
BMI is calculated by: BMI = weight (kg)/ [height (m)12.
[00614] Body weight may be calculated for men as 50 kg+2.3*(number of inches over 60 inches) or for women 45.5kg + 2.3 (number of inches over 60 inches). An adjusted body weight may be calculated for subjects who are more than 20% of their ideal body weight. An adjusted body weight may be the sum of an ideal body weight + (0.4 x (Actual body weight - ideal body weight)). In some cases, a body surface area may be utilized to calculate a dosage. A body surface area (BSA) may be calculated by: BSA (m2) =4Height (cm) *Weight (kg)/3600.
[00615] In some embodiments, the subject method comprises administering an additional agent or therapy.
[00616] In some embodiments is a method of modulating activity of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, TA1, IA2, IA3, 1A4, IA5, IA6, 1A7, TA8, TA9, IA1, IAll, 1Al2, II, HAL ITA2, 11A3, 11A4, 11A5, 11A6, 11A7, 11A8, 11A9, IIA10, ITAll, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Fount'la I', II', I", II", I-1, I-1', I-1", I-1" ', 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein said modulating comprises inhibiting the Ras (e.g., K-Ras) protein activity. In some embodiments is a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA?, IA8, IA9, TA1, TA1 1, IA12, II, TEAL TIA2, TIA3, TIA4, TTA5, TIA6, TTA7, ITA8, ITA9, ITA10, ITAll, ITA12, ITT, TV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', II", I-1, I-1', I-1", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is a K-Ras protein. In some embodiments is a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula 1, IA1, 1A2, 1A3, IA4, 1A5, TAG, IA?, TA8, TA9, TA1, IAll, IA12, II, HA', 11A2, 11A3, 11A4, 11A5, 11A6, IIA7, IIA8, IIA9, IIA10, IlAll, I1Al2, III, IV, V, VI, VII, VIII, IX, X. XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", II", I-1, I-1', I-1", 1-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is a G12D or G12V
mutant K-Ras. In some embodiments is a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, TA1, IA2, IA3, IA4, IA5, IA6, IA7, IA, TA9, TA1, TAll, IA1 2, TT, TTA1, ITA2, ITA3, TTA4, 11A5, ITA6, 11A7, ITA8, IIA9, ITA10, TTA11, TIA12, ITT, TV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", II", I-1, I-1', I-1", 1-1", 1-3, I-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is a G12D mutant K-Ras. ln some embodiments is a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, 1A3, 1A4, IA5, IA6, 1A7, TA8, IA9, TA1, TAll, IA12, II, HAL 11A2, 11A3, 11A4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA1 1, I1Al2, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV;
compound of Formula I', II', I", II", I-1, I-1', I-1", 1-1"', 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is a G12V mutant K-Ras.
[00617] In some embodiments, provided is a method of reducing Ras signaling output in a cell by contacting the cell with a compound described herein (e.g., compound of Formula I, IA1, 1A2, IA3, 1A4, 1A5, 1A6, 1A7, 1A8, TA9, IA10, II, IA12, II, HAL IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, HAIO, hAil, I1Al2, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", II", I-1, I-1', I-1", I-1' 1-3, 1-4, II-1, XVI, XVII, XVIIL or XIX). A reduction in Ras signalling can be evidenced by one or more members of the following: (i) an increase in steady state level of GDP-bound Ras protein;
(ii) a reduction of phosphorylated AKTs473, (iii) a reduction of phosphorylated ERKT202/y204, (iv) a reduction of phosphowlated S6S235/236, and (v) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., those derived from a tumor cell line).
In some cases, the reduction in Ras signaling output can be evidenced by two, three, four or all of (i)-(v) above. In some embodiments, the reduction any one or more of (i)-(v) can be 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, or more as compared to control untreated with a subject compound. A reduction in cell growth can be demonstrated with the use of tumor cells or cell lines. A tumor cell line can be derived from a tumor in one or more tissues, e.g., pancreas, lung, ovary, bilialy tract, intestine (e.g., small intestine, large intestine (i.e.
colon)), endometrium, stomach, hematopoietic tissue (e g , lymphoid tissue), etc Examples of the tumor cell line with a K-Ras mutation may include, but are not limited to, A549 (e.g., K-Ras G12S), AGS (e.g., K-Ras G12D), ASPC1 (e.g., K-Ras G12D), Calu-6 (e.g., K-Ras Q61K), CFPAC-1 (e.g., K-Ras G12V), CL40 (e.g., K-Ras G12D), C0L0678 (e.g., K-Ras G12D), COR-L23 (e.g., K-Ras G12V), DAN-G (e.g., K-Ras G12V), GP2D (e.g., K-Ras G12D), GSU (e.g., K-Ras G12F), HCT116 (e.g., K-Ras G13D), HEC1A (e.g., K-Ras G12D), HEC1B (e.g., K-Ras G12F), HEC5OB (e.g.. K-Ras G12F), HEYA8 (e.g., K-Ras G12D or G13D), HPAC (e.g., K-Ras G12D), HPAFII (e.g., K-Ras G12D), HUCCT1 (e.g., K-Ras G12D), KARPAS620 (e.g., K-Ras G13D), KOPN8 (e.g., K-Ras G13D), KP-3 (e.g., K-Ras G12V), KP-4 (e.g., K-Ras G12D), L3.3 (e.g., K-Ras G12D), LoVo (e.g., K-Ras G13D), LS180 (e.g., K-Ras G12D), LS513 (e.g., K-Ras G12D), MCAS (e.g., K-Ras G12D), NB4 (e.g., K-Ras Al8D), NCI-H1355 (e.g., K-Ras G13C), NCI-H1573 (e.g., K-Ras G12A), NCI-111944 (e.g., K-Ras G13D), NCI-I12009 (e.g., K-Ras G12A), NCI-11441 (e.g., K-Ras G12V), NCI-H747 (e.g., K-Ras G13D), NOMO-1 (e.g., K-Ras G12D), 0V7 (e.g., K-Ras G12D), PANCO203 (e.g., K-Ras G12D), PANC0403 (e.g., K-Ras G1 2D), PANC0504 (e.g., K-Ras G12D), PANC0813 (e.g., K-Ras G1 2D), PANC1 (e.g., K-Ras G12D), Panc-10.05 (e.g., K-Ras G12D), PaTu-8902 (e.g., K-Ras G12V), PK1 (e.g., K-Ras G12D), PK45H (e.g., K-Ras G12D), P1(59 (e.g., K-Ras G12D), SK-CO-1 (e.g., K-Ras G12V), SKLU1 (e.g., K-Ras G12D), SKM-1 (e.g., K-Ras K1 17N), SNU1 (e.g., K-Ras G12D), SN1J1033 (e.g., K-Ras G1 2D), SNU1197 (e.g., K-Ras G12D), SNU407 (e.g.. K-Ras G12D), SNU410 (e.g., K-Ras G12D), SNU601 K-Ras G12D), SNU61 (e.g., K-Ras G12D), SNU8 (e.g., K-Ras G12D), SNU869 (e.g., K-Ras G12D), SNU-C2A (e.g., K-Ras G12D), SU.86.86 (e.g., K-Ras G12D), SUIT2 (e.g., K-Ras G12D), SW1990 (e.g., K-Ras G12D), SW403 (e.g., K-Ras G12V), SW480 (e.g., K-Ras G12V), SW620 (e.g., K-Ras G12V), SW948 (e.g., K-Ras Q61L), T3M10 (e.g., K-Ras G12D), TCC-PAN2 (e.g., K-Ras G12R), TGBCI1TKB (e.g., K-Ras G12D), and MIA Pa-Ca (e.g., MIA Pa-Ca 2 (e.g., K-Ras Gl2C)).
[00618] In some embodiments is a method of inhibiting activity of a KrasG12D
mutant protein, comprising contacting the KrasG12D mutant protein with a compound described herein (e.g., compound of Foninda I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IAll, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IlAl 1, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", I-1, I-1', I-1", I-1", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof.

[00619] In some embodiments is a method of inhibiting activity of a KrasG12D
mutant protein, comprising contacting the KrasG12D mutant protein with a compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA1, IAll, IA12, II, IIA1, IIA2, IIA3. IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, hAil. I1Al2, III, IV, V.
VI, VII, VIII, IX, X, XI, XII, XIII, XIV. or XV, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of inhibiting activity of a KrasG12D mutant protein, comprising contacting the KrasG12D
mutant protein with a compound of Formula I, II', IA1, IA2, IA3, IA4, 1A5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IA1, 11A2, IIA3, IIA4, 11A5, IIA6, IIA7, IIA8, IIA9, IIA10, hAl 1, ITA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of inhibiting activity of a KrasG12D mutant protein, comprising contacting the KrasG12D mutant protein with a compound of Formula I, IA1, IA2, 1A3, IA4, IA5, IA6, IA7, IA8, IA9, IA1, Ill, IA12, II, HAI, IIA2, 11A3, ITA4, HAS, IIA6, IIA7, IIA8, IIA9, TIA10, hAl 1, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV; I', II', I", II", I-1, I-1', I-1", I-1" ', I-3, I-4, II-1, XVI, XVII, XVIII, or XIX.
Pharmaceutical compositions and methods of administration [00620] In an aspect is provided a pharmaceutical composition comprising a compound described herein (e.g., compound of Formula 1, IA], IA2, IA3, IA4, TA5, IA6, IA?, TAR, IA9, TA10, IA1 1, TA12, IT, TTA1, IIA2, TIA3, TIA4, 11A5, 11A6, 11A7, IIA8, IIA9, IIA10, IIA1 1, I1Al2, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV;
compound of Formula I', II', I", II", I-1, I-1', I-1", 1-1", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
[00621] The compounds described herein (e.g., compounds of Formula 1, 1A1, 1A2, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, IA1, IAll, IA12, II, IIA1, 11A2, IIA3, 11A4, IIA5, IIA6, IIA7, IIA8, 11A9, IIA10, IlAll, I1Al2, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', I", II", I-1, I-1', I-1", I-1", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, are administered to subjects in a biologically compatible form suitable for administration to treat or prevent diseases, disorders or conditions. Administration of the compounds described herein can be in any pharmacological form including a therapeutically effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, 1A5, TA6, IA7, TA8, TA9, IA1, IA] 1, TA12, II, ITA1, TTA2, TTA3, TTA4, TIA5, TIA6, TIA7,11A8, IIA9, 1IA10, TTA1 1, 11Al2, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula I', II', IF, I-1, I-1', I-1", 1-1", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with a pharmaceutically acceptable carrier.
[00622] In certain embodiments, the compounds described herein are administered as a pure chemical. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro. 21st Ed. Mack Pub. Co., Easton. PA (2005)).
[00623] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable excipients. The excipient(s) (or carrier(s)) is acceptable or suitable if the excipient is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
[00624] In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I, IA1, 1A2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA1, IAll, IA12, II, IIA1, IIA2, 11A3, IIA4, IIA5, IIA6, ITA7, ITA8, ITA9, ITAIO, TIAI 1, ITAI 2, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I. I', II', IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA1, IA1 1, IA12, II, IA1, IIA2, IIA3, IIA4, IIA5, IIA6, 11A7, IIA8, IIA9, IIA10, IIA1 1, IIA12, III, IV, V, VI, VII; VIII, IX, X, XI, XII, XIII, XIV, or XV, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I, IAI, IA2, IA3, IA4, IA5, TAG, IA7, IA8, IA9, IA10, IAI 1, IA12, II, IIAI, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA1 0, IIA1 1, IIA1 2, III, IV, V. VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV;
I', II', I", II", I-1, I-1', I-1", I-1", 1-3, 1-4, II-1, XVI, XVII, XVIII, or XIX, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA1, or a pharmaceutically acceptable salt or solvate thereof In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA3, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA4, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA5, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA6, or a pharmaceutically acceptable salt or solvate thereof In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA7, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA8, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA9, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA10. or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA1 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA12, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IA1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IIA2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IIA3, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IIA4, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IIA5, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IIA6, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IIA7, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IIA8, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IIA9, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IIA10, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula IIAll, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula TT Al 2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula II', or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I", or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula II", or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I-1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula II-1, or a pharmaceutically acceptable salt or solvate thereof. in some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula XVI, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula XVII, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula XVIII, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula XIX, or a pharmaceutically acceptable salt or solvate thereof.
[00625] In some embodiments of the methods described herein, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.
[00626] In some embodiments of the methods described herein, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.
[00627] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
[00628] In some embodiments of the methods described herein, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[00629] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[00630] Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
EXAMPLES
[00631] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
[00632] As used herein, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
ACN or MeCN acetonitrile AcOH acetic acid Ac acetyl BINAP 2,2`-bis(diphenylphosphino)-1,1'-binaphthalene Bn benzyl BOC or Boc tert-butyl carbamate i-Bu iso-butyl t-Bu tert-butyl DCM dichloromethane (CH, C12) DIBAL-H diisobutylaluminum hydride DIPEA or DIEA diisopropylethylamine DMAP 4-(N, N-d i iiethyIaii no)pyri di ne DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMA N, N-dimethylacetamide DMSO dimethylsulfoxide Dppf or dppf 1, l'-bis(dipheny-lphosphino)ferrocene EDC or EDCI N-(3 -dimethylaminopropy1)-N'-ethylcarbodiimide hydrochloride eq equivalent(s) Et ethyl Et20 diethyl ether Et0H ethanol Et0Ac ethyl acetate HPLC high performance liquid chromatography KHMDS potassium bis(trimethylsilyl)amide NaHMDS sodium bis(trimethylsily0amide LiHIVIDS lithium bis(trimethylsilyl)amide LAI-I lithium aluminum anhydride LCMS liquid chromatography mass spectrometry Me methyl Me0H methanol MS mass spectroscopy Ms mesyl NIVIR nuclear magnetic resonance Ph phenyl iPr/i-Pr iso-propyl RP-HPLC reverse-phase high-pressure liquid chromatography RT room temperature 1B S tert-butyldimethylsilyl 1EA triethylamine TF A trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl Ts0H/p-Ts0H p-toluenesulfonic acid.
EXAMPLE 1: Synthesis of 44(1R,5S)-3,8-diazabicyclo[3.2.11octan-3-y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y0methoxy)-7-(3-hydroxynaphthalen-l-y1)pyrido[4,3-dlpyrimidin-5(6H)-one (Compound 103) Boc N,,.
Boc Boc K,N.
[-:.--) Boc (7 N.) 0 1---) =--.. --11,... ..-= 0 N

'. Y i N
' N Ft3N LDA -;r1. ----DMB, 140 C
DCM. 0C I õJ., , THF, -78 C N
S-.. dioxane =-...

1-1 1-2 1-3 Me0 OMe 1-4 HO a& B(OH)2 OMe Boc Boc Boc so C_ PdC12(dtbpf) Me0 D N
OMe 0 N OMe 0 N K3PO4 Na0Me,.. Tfc0,Et2N
11101 N,- 1 I' N
Me0H, RT dioxane-H20, 90 'C HO
-. -----'4, ..----Met) HO N S me0 Tf0 N 5-7 OMe F
H
Boc OMe (N., Boc 401 eN
HO/"
e Me0 0 6r1 0 L:7)N
meo 110 0 "NN
N
HN
i ' N
mCPBA N 1 'NA 0 NaH N 1 'N F
______________________ Ho ....., ..,....-- N 0 -DCM RT N S DMF
T N
II . RT to 50 C N U ' DCM

Compound 103 [00633] To a stirred solution of ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (1-1) (988 mg, 4 mmol) in dichloromethane (15 mL) at ice-water bath was added triethylamine (835 pL, 6 mmol) followed by tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.11octane-8-carboxylate (934 mg, 4.4 mmol).
The reaction mixture was stirred for 1 11, diluted with water, extracted with dicliloromethane. The combined organic layers were combined, dried over anhydrous Na2SO4, filtered then concentrated. The residue was purified by silica gel column chromatography eluting with 0-50% ethyl acetate/hexane to afford compound 1-2 (1.65 g). ESI-MS in/z: 423.2 [M-P1-11+.
[00634] To a stirred solution of compound 1-2 (730 mg, 1.73 mmol) in anhydrous THF (10 mL) was added a 2 M
solution of lithium diisopropylamidc in THF (3.03 mL, 6.06 mmol) under nitrogen at -78 C. The reaction mixture was stirred for 30 min, then dimethyl carbonate (262 pL, 3.1 mmol). The reaction mixture was stirred at that temperature for 30 min, then slowly warmed up for 3 h. The resulting mixture was quenched with saturated aqueous NH4C1 solution, extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, then concentrated. The residue was purified by silica gel column chromatography eluting with 0-70% ethyl acetate/hexane to afford compound 1-3 (606 mg). ESI-MS m/z: 481.2 [M+Hr.
[00635] The reaction mixture of compound 1-3 (606 mg, 1.26 mmol) and 2,4-dimethoxybenzylamine (1.14 mL, 7.58 mmol) in dioxane (5 ME) was heated at 140 C for 4 h under microwave irradiation The mixture was concentrated, the residue was purified by silica gel column chromatography eluting with 0-70% ethyl acetate/hexane to afford compound 1-4 (428 mg). ESI-MS m/z: 616.3 [M+Hr.
[00636] To a stirred solution of compound 1-4 (200 mg, 0.33 mmol) in methanol (8 mL) was added a solution of 25% sodium methoxide in methanol (150 pL, 0.65 mmol) at room temperature. The reaction mixture was stirred for 1 h, concentrate. The residue was dissolved in water, acidified with 10%
aqueous citric acid to pH 3-4. The solid was collected, washed with water and dried in vacuo to afford compound 1-5 (180 mg). ESI-MS m/z: 570.2 [M+Hr.
[00637] To a stirred solution of compound 1-5 (180 mg, 0.31 mmol) in dichloromethane (4 mL) at ice-water bath was added triethylamine (86 pL, 0.62 mmol) under nitrogen followed by a 1 M
solution of trifluoromethanesulfonic anhydride in dichloromethanc (450 pL, 0.45 mmol). The reaction mixture was stirred for 30 min, concentrated. The residue was purified by silica gel column chromatography eluting with 0-40%
ethyl acetatc/hexane to afford compound 1-6 (197 mg). ESI-MS m/z: 702.1 [M-P1-11+.
[00638] The reaction mixture of compound 1-6 (197 mg, 0.28 mmol), 3-hydroxynaphthalene-1-boronic acid (80 mg, 0.42 mmol), K3PO4 (107 mg, 0.5 mmol) and dichloro [1,1' -bis(di-tert-butylphosphino)ferrocene]palladium (II) (34 mg, 0.056 mmol) in a mixed solvent of dioxane-water (6 mL, 3:1) was heated at 90 "V for 2 h. Filtered through Celite, the filtrate was concentrated, the residue was purified by silica gel column chromatography with 0-80% ethyl acetate/hexane to afford compound 1-7 (40 mg). EST-MS m/z: 696.2 [M+H].
[00639] To s stirred solution of compound 1-7 (40 mg, 0.057 mmol) in dichloromethane (2 mL) was added 3-choroperbenzoic acid (< 77%) (38 mg, 0.17 mmol) at ice-water bath. The reaction mixture was stirred for 1 h.
Saturated aqueous NaHCO3 was added, extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered then concentrated. The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane to afford compound 1-8 (20 mg). ESI-MS m/z: 728.2 UVI+Hr.
[00640] To a stirred suspension of sodium hydride (60% dispersion in mineral oil) (4 mg, 0.11 mmol) ill DMF (0.5 mL) was added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (17 mg, 0.11 mmol) in DMF (0.5 mL) at room temperature under nitrogen. The reaction mixture was stirred for 15 min, then compound 1-8 (20 mg, 0.027 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 50 'V for 40 min Cooled down, saturated aqueous NH4C1 was added, the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2S01, filtered, then concentrated.
The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane then 0-10% ethyl acetate/Me0H to afford compound 1-9 (9 mg). ESI-MS ,n/z: 807.3 [M+Hr.
[00641] The reaction mixture of compound 1-9 (9 mg) in 50% trifluoroacetic acid in dichloromethane (2 mL) was stirred at room temperature overnight, concentrated. The residue was purified by semi preparative HPLC (5-60%
CH3CN/H20 with 0.1% formic acid) to afford compound 103 as formic acid salt (2 mg). ESI-MS nilz: 557.3 [M+141;11-INIVIR (400 MHz, d6-DMS0): 5 11.50 (s, 1H), 8.29 (s, 1H x 2) (1 formic acid), 7.78 (dd, J= 14.4 and 8.3 Hz, 2H), 7.46 (t, J= 7.3 Hz, 1H), 7.32 (t, J= 7.3 Hz, 1H) 7.27 (d, J= 2.2 Hz, 1H), 7.17 (d, J= 2.3 Hz, 1H), 6.20 (s, 1H), 5.33-5.20 (In, 1H), 4.10-3.95 (m, 3H), 4.06 (d, J= 10.3 Hz, 1H), 3.95 (d, J = 10.3 Hz, 1H), 3.60-3.50 (m, 2H), 3.35-3.25 (m, 2H), 3.14-3.06 (m, 2H), 3.05-2.98 (m, 1H), 2.85-2.78 (m, 1H), 2.14-1.95 (m, 3H), 1.88-1.60 (m, 7H).
EXAMPLE 2: Synthesis of 7-(2-amino-7-fluorobenzo[d]thiazol-4-y1)-44(1R,55)-3,8-diazabieyelo[3.2.1]oetan-3-y1)-6-eyelopropy1-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(511)-yhmethoxy)pyrido14,3-dlpyrimidin-5(611)-one (Compound 104) Boc Boc c ,)NI c INI Boc Boc Tf20, Et3N
N S xylene, 120 C A ...CN---.L'e Me0H, 50 ¨: C
ljteS DC" C TfUjjN -S

F Boc Boc Boc soSõ¨NHBoc I I PdC12(dtbpf), K3 PO4 + N S'''' mCPBA N S
________________________ . _.. N
0 u t(s dioxane/H20, 90 C F N DCM F N F N
S--IK S-4 S--/<
NHBoc NHBoc NHBoc F BOG
(IsJ, HO F F
N N
DMF. RT to 50 C F DCM F
N N
NHBoc NH2 2-7 Compound 104 [00642] The reaction mixture of compound 1-3 (480 mg, 1 mmol) and cyclopropylamine (700 pL, 10 mmol) in xylene (6 mL) was heated at 120 C overnight. The mixture was concentrated, the residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate/hexane) to afford compound 2-1 (204 mg). EST-MS miz:
506.2 [M+1-11+.
1006431 To a stirred solution of compound 2-1 (204 mg, 0.40 mmol) in methanol (8 mL) was added a solution of 25% sodium methoxide in methanol (183 pL, 0.81 mmol). The reaction mixture was stirred at 50 C for 30 min, concentrate. The residue was dissolved in water, acidified with 10% aqueous citric acid to pH 3-4. The solid was collected, washed with water then dried in vacuo to afford compound 2-2 (177 mg). ESI-MS m/z: 460.2 [M+Hr.
[00644] To a stirred solution of compound 2-2 (177 mg, 0.38 mmol) in dichloromethane (5 mL) at ice-water bath was added triethylamine (107 pL, 0.77 mmol) under nitmgen followed by a 1 M
solution of trifluoromethanesulfonic anhydride in dichloromethane (570 pL, 0.57 mmol). The reaction mixture was stirred for 30 min, concentrated. The residue was purified by silica gel column chromatography eluting with 0-50% ethyl acetate/hexane to afford compound 2-3 (150 mg). ESI-MS m/z: 592.2 [M+Hr.
[00645] The reaction mixture of compound 2-3 (150 mg, 0.25 mmol), (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[dlthiazol-4-yOboronic acid (120 mg, 0.38 nnnol), K3PO4 (80 mg, 0.38 mmol) and dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium (II) (30 mg, 0.05 mmol) in a mixed solvent of dioxane-water (6 mL, 3:1) was heated at 90 C for 2 h. Filtered through Celite, the filtrate was concentrated, the residue was purified by silica gel column chromatography with 0-50% ethyl acetate/hexane to afford compound 2-4 (70 mg). ESI-MS m,/z: 710.2 [M+Hr.
[00646] To s stirred solution of compound 2-4 (70 mg, 0.099 mmol) in dichloromethane (2 mL) was added 3-chloroperbenzic acid (< 77%) (45 mg, 0.2 mmol) at room temperature The reaction mixture was stirred for 1 h at room temperature, saturated aqueous NaHCO3 was added, extracted with dichloromethane. The combined organic layers were concentrated, the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane to afford compound 2-5 (20 mg) and compound 2-6 (45 mg).
Compound 2-5 ES1-MS ni/z: 742.2 [M+Hr. Compound 2-6 ESI-MS ,n/z: 726.2 [M+Hr.
[00647] To a stirred suspension of sodium hydride (60% in mineral oil) (10 mg, 0.26 mmol) in DMF (0.5 mL) was added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yOmethanol (43 mg, 0.26 mmol) in DMF (1 mL) at room temperature under nitrogen. The reaction mixture was stirred for 15 min, then compound 2-5 (20 mg, 0.027 mmol) and compound 2-6 (45 mg, 0.062 mmol) in DMF (1.5 mL) was added. The reaction mixture was stirred at 50 C for 40 min. Cooled down, saturated aqueous NH4C1 was added, the reaction mixture was extracted with ethyl acetate.
The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, then concentrated.
The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane then 0-10% ethyl acetate/Me0H to afford compound 2-7 (13 mg). ESI-MS m/z: 821.3 [M H].
[00648] The reaction mixture of compound 2-7 (13 mg) in 20% trifluoroacetic acid in dichloromethane (2 mL) was stirred at room temperature for 4 h, concentrated. The residue was purified by semi preparative HPLC (5-60%
CH3CN/H20 with 0.1% formic acid) to afford compound 104 as formic acid salt (3 mg). ESI-MS miz: 621.2 [M+111;11-INMR (400 MT-lz, d6-DMS0): 58.31 (s, 1H) (1 formic acid), 8.00 (s, 2H), 7.35 (dd, J= 8.4 and 5.7 Hz, 1H), 7.03 (t, J= 8.7 Hz, 1H), 6.08 (s, 1H), 5.30-5.20 (m, 1H), 4.25-4.10 (m, 1H), 4.04 (d, J= 10.3 Hz, 1H), 3.93 (d, J= 10.3 Hz, 1H), 3.56-3.30(m, 6H), 3.10-3.04 (m, 2H), 3.01-2.98 (m, 1H), 2.95-2.88 (m,1H), 2.85-2.78 (m, 1H), 2.15-1.92 (m, 3H), 1.90-1.55 (m, 7H), 0.80-0.70 (m, 1H), 0.44-0.24 (m, 3H).
Example 2a: Synthesis of 5-(7-(2-amino-7-fluorobenzo[d]thiazol-4-y1)-6-eyelopropy1-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-4-y1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-earbonitrile (Compound 453) o 0 OBn 0 OBn -=, t-BuOK,Bn0H._ --...., LiHMDS 1 I I ________ O
N ,,,I...,, /
0--iy N ,,,,I= õ__ _,,, THF,-20 C tCL _4k, ___ THF, -78 C to rt.' N
S THF, -78 C-0 C F
N a A.,NH2 A, 0 OBn A., 0 OH A, 0 CI
:* HCl/dioxane .LN * N
1-''' * N POCI3 HO N SMe HO N SMe CI N SMe F F F

9¨cN r 9----cN KNN--?---CN F
cN---?...
l\I CN
"
CN 1, HO-*-6-S
N
A
H .6....,), C:.1...,,I,1 m-CPBA
_________________ , ________________________________________________ .
TEA N I'' N DCM N
DCM,0 C -..õ, ..,,,-,k. õ,õ, F

BocHN
..
a 2 OH r.
Cs2CO3 ? 0N N .
r 57 CN

,.. L, Aõ. 0 NN A.õ. 0 N
DFEphosPdC12 BocHN

F
DMF,110 C,3h DCM
N N
F F
F F

[00649] To a solution of t-BuOK (27.2 g, 243 mmol) in THF (250 niL) at 0 C.
BnOH (26.2 g, 243 mrnol) was added, and the resulting mixture was stirred at 60 C under argon atmosphere for L5 h. The mixture was cooled to 0 C and the solution was added to the solution of compound 1-1 (50g. 202 mmol) in THF (100 mL) at -20 C under argon atmosphere. The mixture was stirred at -20 'V under argon atmosphere for 1 h. The mixture was diluted with aqueous NH4C1 (200 mL) at -20 C, extracted with Et0Ac (3 x 200 mL). The organic layers were washed with brine (200 mL), dried with Na2SO4, filtered, and the filtrate was concentrated by vacuum to give compound 3-2 (67 g, crude) which was used directly in the next step. ESI-MS nilz . 319.1 [M+Hr [00650] To a solution of compound 3-2 (81.7 g, 257 mmol) in THF (817 mL) at -78 C under argon atmosphere, LiHMDS (643 mL, 643 mmol, 1 M) was added, and the resulting mixture was stirred at this temperature for 1 h.
Dimethyl carbonate (23.1 g, 257 mmol) was added at -78 C. then the reaction mixture was warmed naturally to room temperature and stirred for 2 h. The mixture was diluted with aqueous NH4 Cl (1 L) at 0 C, extracted with Et0Ac (3 x 1 L), the organic layers were washed with brine (1 L), dried with Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column (15 %
Et0Ac in PE) to give compound 3-3 (84 g). ESI-MS iii/z: 377.1 [M+H] .
1006511 Under N2, to a suspension of compound 3-3 (1.1 g, 2.86 mmol) in THF
(15 mL) at -70 C, LiHMDS (1 M) (2.86 mL, 2.86 mmol) was added. The mixture was warmed to 0 C and was stirred at 0 C for 1 h. The mixture was cooled to -70 C and NFSI (924 mg, 2.86 mmol) in THF (5 mL) was added. The mixture was warmed to 0 C and was stirred at 0 C for 1 h. NRIC1 aqueous (5 mL) was added to quench the mixture and extracted with EA (15 mL x 3). The organic layers were concentrated, and the residue was purified by Flash Column Chromatography on silica gel (eluting with 0-15% of EA in PE) to give compound 3-4 (850 mg). ESI-MS
395.1 [M+H]t [00652] To a suspension of compound 3-4 (700 mg, 1.776mmo1) in Et0H (10 mL) was added DBU (1 mL).
Cyclopropylamine (2 niL) was then added and stirred at room temperature until the mixture became clear. The mixture was stirred at room temperature for 1 h. KOH powder (100 mg, 1.776 mmol) was added, and the mixture was stirred for 0.5 h. The mixture was poured into ice water and adjusted pH=4-5 with HCl. The resulted precipitate was filtered to give compound 3-5 (470 mg). ESI-MS m/z: 374.0 [M+Hr.
[00653] A suspension of compound 3-5 (9.0 g, 24.13 mmol) in dry DCM (450 inL), 4 M solution of HC1 in dioxane (200 mL) was added. The reaction mixture was stirred at 50 C for 3 h. The mixture was concentrated, and diluted with tert-butyl methyl ether. The solid was collected, rinsed with tert-Butyl methyl ether and dried to afford compound 3-6 (5.6 g). ESI-MS m;z: 284.2 [M+Hr.
[00654] Compound 3-6 (5.6 g) was dissolved in P0C13 (230 mL) and heated to 105 'C, and the mixture was stirred at 105 C for 3 h. The mixture was concentrated in vacuo, the residue was diluted with ice-water, and extracted with ethyl acetate The combined organic layers were washed with water, brine and then concentrated The residue was purified by silica gel column chromatography eluting with 0-70% ethyl acetate/hexane to afford compound 3-7 (2.2 g). ESI-MS m/z: 320.1 [M+H] .
1006551 To a solution of compound 3-7 (170 mg, 0.53 mmol) in DCM (10 mL), lEA
(108 mg, 1.07 mmol) and 4,5,6,7-tetrahydropyrazolo[1,5-a[pyrazine-3-carbonitrile (110 mg, 0.75 mmol) were added. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was purified by Flash Column Chromatography on silica gel (eluting with 0-60% of EA in PE) to give compound 3-8 (260 mg). ESI-MS m/z:
402.0 [M+Hr.
[00656] To a solution of compound 3-8 (240 mg, 0.56 mmol) in DCM (10 ml), m-CPBA (241 mg, 1.39 mmol) was added at room temperature and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was purified by Flash Column Chromatography on silica gel (eluting with 0-60% of EA in PE) to give compound 3-9 (240 mg). EST-MS tre/z: 464.2 [M+Hr.
[00657] Under N2, to a suspension of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethanol (106 mg, 0.66 mmol) in THF (5 ml,), Nall (27 mg, 0.66 mmol) was added, and the mixture was stirred at 0 C for 1 h.
Compound 3-9 (120 mg, 0.22 mmol) was added under N2 and the reaction mixture was stirred at 0 C for 1 h. Water ( 5 mL) was added and the residue was extracted with EA (15 mL x 3). The organic layers were concentrated, and the residue was purified by Flash Colunm Chromatography on silica gel (eluting with 0-10% of Me0H in DCM) to give compound 3-10 (70 mg). ESI-MS miz: 543.3 [M+H] .
[00658] To a solution of compound 3-10 (50 mg, 0.09 mmol) in DMF (2 mL), (2-((tert-butoxycarbonyfiamino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (72 mg, 0.23 mmol) was added under argon atmosphere, and the resulting mixture was bubbled with argon for 1 h. Cs2CO3 (90 mg, 0.28 mmol) and DPEPhosPdC12 (20 mg) were added. Then the reaction mixture was stirred at 110 C under argon atmosphere for 3 h. The mixture was filtered through celite, rinsed with ethyl acetate. The combined organic layer was concentrated, and the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/PE followed by 0-20% Me0H/DCM.
The combined fractions were concentrated and the residue was further purified by prep-TLC plate (Me0H
: DCM = 15: 1) to give compound 3-11(15 mg). ESI-MS m/z: 775.2 [M+1-11+.

[00659] To a solution of compound 3-11 (15 mg, 0.02 mmol) in DCM (3 mL), TFA
(1 mL) was added. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to afford compound 453 (6.66 mg). ESI-MS tth: 675.2 [M+H]t11-1 NMR (400 MHz, CD30D): 6 7.92 (s, 1H), 7.44 - 7.35 (m, 1H), 7.03 (t, J = 8.9 Hz, 1H), 5.49 (d, J= 52.2 Hz, 1H), 5.02 (s, 2H), 4.56 (dd, J = 30.8, 11.0 Hz, 4H), 4.27 (s, 2H), 3.67 (t, J = 67.9 Hz, 4H), 2.98 (s, 1H), 2.67 - 2.43 (m, 2H), 2.26 (dd, J=
66.7, 33.7 Hz, 4H), 0.63 (t, .1 = 65.1 Hz, 4H).
Example 2b: Synthesis of 4-(4-(3-oxa-7,9-diazabieyelo[3.3.11nonan-9-y1)-6-eyelopropy1-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-7-y1)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (Compound 447) Boc Boc Soc N N
F
N \C6 M

HO"--'''.
N
rinCPBA
N H N s'' N /\--N 1 .1\1 I ___________ ..
Et3N N SMe DCM, RT CI N.-LIS( NaOtBu, 4A MS
CI N SMe CI , µ, F DCM, RT F F 0 0 toluene, 0 C

Boc Boc H
N N N
\i01 µ01 \01 0 N F A o N õ() 0 N
F
S
BocHN NC :----.1\ H2N NC
Suzuki ... - N 1 0 F
TFA - N C-= N `,.. lil---., ,,,, =
N N DCM, RT
N
F F F
F F

[00660] To a stirred solution of compound 3-7 (50 mg, 0.16 mmol) in DCM (3 mL) was added Et3N (43 L, 0.31 mmol) followed by 3-oxa-7,9-diazabicyclo [3.3.11nonane (53 mg, 0.23 mmol) at room temperature. The reaction mixture was stirred for 30 min and then concentrated. The residue was purified by silica gel wham' chromatography eluting with 0-100% ethyl acetate/hexane to afford compound 4-1 (70 mg). ESI-MS ,n/z: 512.3 [M-hFl]t [00661] To a stirred solution of compound 4-1 (70 mg, 0.14 mmol) in DCM (3 mL) was added m-CPBA (77%) (80 mg, 0.34 mmol) at room temperature. The reaction mixture was stirred for 2.5 hand then partially concentrated. The residue was purified by silica gel column chromatography eluting with 0-100%
ethyl acetate/hexane to afford compound 4-2 (60 mg). ESI-MS ,n/z: 544.3 [M+Hr.
[00662] The reaction mixture of compound 4-2 (60 mg, 0.11 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5/1)-yl)methanol (53 mg, 0.33 mmol) and 4A molecular sieves (over-dried and cooled) in anhydrous toluene (3 mL) was stirred in ice-water bath for 40 min, then NaOtBu (32 mg, 0.33 mmol) was added. The reaction mixture was stirred at that temperature for 30 min. The mixture as diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine and concentrated. The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane with 0.5% Et3N then 0-20%
Me0H/ethyl acetate to afford compound 4-3 (58 mg). ESI-MS ,n/z: 623.4 [M-hlir.
[00663] The reaction mixture of compound 4-3 (58 mg, 0.093 mmol), tert-butyl (3-cyano-4-(5,5-dimethy1-1,3,2-dioxaborinan-2-y1)-7-fluorobenzo[b]thiophen-2-y Dcarbamate (75 mg, 0.19 imnol), DPEphosPdC12 (14 mg, 0.019 mmol) in toluene (2.5 mL) was added cesium carbonate (76 mg, 0.23 nunol). The reaction mixture was degassed and charged with nitrogen then heated at 105 C overnight. Filtered through Celite, washed with ethyl acetate. The filtrate was concentrated, the residue was purified by silica gel column chromatography with 0-20% Me0H/ethyl acetate with 0.5% Et3N then IIPLC (10-95% CH3CN/H20 with 0.1% formic acid).
The combined fractions were lyophilized to afford compound 4-4. ESI-MS in/z: 879.5 [M+Hr.
[00664] The reaction solution of compound 4-4 in 20% TFA/DCM (2 mL) was stirred at room temperature for 2 h.
and then concentrated. The residue was purified by prep.-HPLC (5-65% CH3CN/H20 with 0.1% formic acid) to afford compound 447 as formic acid salt (1.5 mg). ESI-MS /viz: 679.4 [M+H].
Example 2c: Synthesis of 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-4-(azepan-l-y1)-6-cyclopropy1-8-fluoro-2-4(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5(6H)-one (Compound 449) AT):

N N , N mCPBA
I
Et3N I I
CI N SMe CI --sme DCM, RT CI N ( NaOtBu, 4A MS
DCM, RT 0 0 toluene, 0 C

0 (Kr) 00 N) BocHN & o(\ H2N Suzuki N N
TFA N N
s CI N DCM, RI

[00665] To a stirred solution of compound 3-7 (34 mg, 0.11 mmol) in DCM (2 mL) was addcd Et3N (29 L, 0.21 mmol) followed by hexamethyleneimine (16 mg, 0.16 mmol) at room temperature.
The reaction mixture was stirred for 30 min and then concentrated. The residue was purified by silica gel column chromatography eluting with 0-60%
ethyl acetate/hexane to afford compound 5-1 (35 mg). ESI-MS m/z: 383.2 [M+Hr.
[00666] To a stirred solution of compound 5-1 (35 mg, 0.16 mmol) in DCM (2 mL) was added m-CPBA (77%) (51 mg, 0.23 mmol) at room temperature. The reaction mixture was stirred for 2.5 hand then purified by silica gel column chromatography eluting with 0-100% ethyl acetate/hexane to afford compound 5-2 (47 mg). ESI-MS rn/z:
415.2 [M+Hr.
[00667] The reaction mixture of compound 5-2 (47 mg, 0.11 mmol), ((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (54 mg, 0.34 mmol) and 4A molecular sieves (over-dried and cooled) in anhydrous toluene (3 mL) was stirred in ice-water bath for 40 min, and then NaOtBu (33 mg, 0.34 mmol) was added. The reaction mixture was stirred at that temperature for 30 min. The mixture was diluted with water, extracted with ethyl acetate.
The combined organic layers were washed with brine then concentrated. The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane with 0.5% Et3N to afford compound 5-3 (43 mg). ESI-MS ,n/z: 494.3 [M+Hr.
[00668] The reaction mixture of compound 5-3 (43 mg, 0.09 mmol), (2-((tert-butoxycarbonyfiamino)-7-fluorobenzo[d]thiazol-4-yOboronic acid (56 mg, 0.18 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol) in 1,4-dioxane (2 mL) was added a 2 M solution of Na2CO3 in water (112 L, 0.23 mmol). The reaction mixture was degassed and charged with nitrogen and then heated at 95 C overnight The mixture was filtered through Celite, washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane with 0.5% Et3N to afford compound 5-4. ESI-MS m/z:
726.5 [M+Hr.

[00669] The reaction solution of compound 5-4 in 20% TFA/DCM (2 mL) was stirred at room temperature for 3 h, and then concentrated. The residue was purified by prep-HPLC (5-60% CH3CN/H20 with 0.1% formic acid) to afford compound 449 as formic acid salt (11 mg). ESI-MS ,n/z: 626.4 [M+1-11+;
11-1NMR (400 MHz, DMSO-d6): S
8.05 (s. 2H), 7.41 (cid, J= 8.5 and 5.6 Hz, 1H), 7.07 (t, J= 8.8 Hz, 1H), 5.35-5.20 (m. 1H), 4.10-3.95 (m, 2H), 3.75-3.45 (m, 7H), 3.10-2.98 (m, 3H), 2.85-2.75 (m, 2H), 2.10-2.08 (m, 1H), 2.06-2.02 (m, 1H), 2.00-1.92 (m,1H), 1.88-1.72 (m, 4H), 1.54-1.38 (m, 4H), 0.65-0.60 (m, 1H), 0.52-0.48 (m, 1H), 0.38-0.32 (m, 2H).
Example 2d: Synthesis of 7-(2-amino-7-fluorobenzoidlthiazol-4-y1)-6-eyelopropy1-44(1R,5S)-8-(2,2-difluoroeyelopropane-1-earbony1)-3,8-diazabieyelo[3.2.11octan-3-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(511)-yOmethoxy)pyrido[4,3-d]pyrimidin-5(611)-one (Compound 452) yoc Boc yoc B BocHN
iloc N F
& 0 CI (--) L.'7-') c._,\I ,06Ns L-s-----) >----.N
S 0 B(OH)2 N 0 N 1 &,,...i.

F
F Suzuki2.1.LN
'.,1\111"N m-CPBA
DCM * N 1 --=
N .-,, I
KOtBu F CI N SM e CI N S THF

F

F F
Boc 1\1 õN.) F F
BocHN A. 0 N F A., 0 N F OyA
1-:----) ) X¨ H2N
TFA OH

N F
F F F
N
/

[00670] To a solution of compound 3-7 (315 mg, 0.99 mmol) in DCM (4 mL), tert-butyl (1R,5S)-3,8-diazabicyc1o[3.2.11octane-8-carboxylate (230 mg, 1.08 mmol) in DCM (3 mL) and Et3N (300 mg, 2.96 mmol) were added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the residue was purified by flash silica column chromatography (eluting with 0-40 % of EA in PE to give compound 6-1 (350 mg). ESI-MS in/z: 496.1 [M+Hr.
[00671] To a solution of compound 6-1 (350 mg, 0.71 mmol) in DCM (5 mL), m-CPBA (308 mg, 1.77 mmol) was added at 0 C, Then the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with aqueous HNa03S (10 mL) and extracted with DCM (3 x 20 mL). The organic layer was washed with aqueous NaHCO3 (3 x10 mL) and brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give compound 6-2 (300 mg) which was used directly in the next step. ESI-MS
m/z: 528.3 [M-411 .
[00672] To a solution of ((7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (136 mg, 0.85 mmol) in THF
(3 mL) at -20 C under argon atmosphere, t-BuOK (1.13 mL, 1.13 mmol, 1 M) was added and the resulting mixture was stirred at this temperature for 1 h. Compound 6-2 (300 mg, 0.57 mmol) in THF (5 mL) was added at -20 C, and then the mixture was stirred at this temperature for 2 h. The mixture was diluted with aqueous NH4 C1 (10 mL) at -20 C and extracted with DCM (3 x 20 mL). The organic layer was washed with brine (10 mL), dried with Na2SO4, filtered and the filtrate was concentrated in vacua The residue was purified by flash silica column chromatography (eluting with 0-15 of Me0H in DCM to give compound 6-3 (230 mg). ESI-MS rn/z:
607.3 [M-H-11 .
[00673] To a solution of 6-3 (50 mg, 0.08 mmol) in DMF (2 mL) under argon atmosphere, (2-((tert-butoxycarbonyflamino)-7-fluorobenzo Id Ithiazol-4-yl)boronic acid (66 mg, 0.21 mmol) was added, and the resulting mixture was bubbled with argon for 1 h. Cs2CO3 (81 mg, 0.25 mmol) and DPEPhosPdC12 (20 mg) were added. Then the reaction mixture was stirred at 110 C under argon atmosphere for 4 h. The mixture was filtered through celite and rinsed with ethyl acetate. The combined organic layer was concentrated, and the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/PE then 0-20% Me0H/DCM.
The combined fractions were concentrated and the residue was further purified by prep-TLC plate (Me0H :
DCM = 15: 1) to give compound 6-4 (50 mg). ES1-MS n2/z: 839.4 IM-H-11+.
[00674] To a solution of compound 6-4 (50 mg, crude) in DCM (3 mL) was added TFA (1 mL), then the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by prep-HPLC (FA) to give compound 6-5 (8 mg). ESI-MS rri/z: 639.3 [M+Hr.
[00675] To a solution of 6-5 (8 mg, 0.013 mmol) in DMF (0.1 mL), 2,2-difluorocyclopropane-1-carboxylic acid (1.5mg, 0.013 mmol), HATU (4.7 mg, 0.013 mmol) and DIEA (5 mg, 0.038 mmol) were added, and the resulting mixture was stirred at room temperature under argon atmosphere for 2 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (FA) to give compound 452 (3 mg).
ESI-MS rn/z: 743.3 IM H]+; 1H
NMR (400 MHz, CD30D): 6 8.45 (s, 2H), 7.38 (dd, J = 8.4, 5.4 Hz, 1H), 7.02 (t, J = 8.8 Hz, 1H), 5.47 (d, J = 52.7 Hz, 2H), 4.48 (dd, J = 30.4, 11.5 Hz, 3H), 3.66 (s, 4H), 3.01 (dd, J = 33.1, 22.2 Hz, 3H), 2.46 (d, J = 22.3 Hz, 2H), 2.30 (d, J = 8.8 Hz, 111), 2.21 (t, J = 12.1 Hz, 3H), 2.03 (d, J = 25.4 Hz, 4H), 1.90 (d, J = 16.4 Hz, 411), 0.79 (s, 1H), 0.50 (d, J = 37.9 Hz, 4H).
Example 2e: Synthesis of 7-(2-amino-7-fluorobenzo[d]thiazol-4-y1)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-y1)-6-cyclopropyl-8-fluoro-2-48)-148)-1-methylpyrrolidin-2-yflethoxy)pyrido[4,3-d]pyrimidin-5(6H)-one (Compound 448) 0 OBn 0 OBn 0 /N 7 Ho'l0 0 OBn N
N S DCM, 0 C DIEA N 01)1) Na0Me(25%) -. 0 1,4-Dioxane, 100 C
., ,,.= N Me0H, 50 C

Boc r. ThN
Boc 0 C') A:_i\I
I ,I, EDCM CI
N 01'''ON
HO N 0'1)1) DIA, /

Boc H
0 S¨NHBoc N A.N N
A.N B(ON)2 '"
PdC12(dtbp1), K3PO4 F F N F F N---/
N N
dioxane/H20, 90 C S-2( S-----/( NHBoc NH2 [00676] To s stirred solution of compound 3-4 (220 mg, 1.0 eq) in dichloromethane (2 mL) at 0 C, mCPBA (143 mg, 1.5) was added and the resulting mixture was stirred at 0 'V for 30 min.
The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with ethyl acetate/hexane to afford compound 7-1 (222.8 mg). ESI-MS m/z: 411.2 [M+Hr.
[00677] To a solution of compound 7-1 (222.8 mg, 1.0 eq) in 1,4-dioxane (1.0 mL), DIEA (141 ul, 1.5 eq) and (1S)-1-[(2S)-1-methylpyrrolidin-2-yll ethanol (77.2 mg, 1.1 eq) were added, and the resulting mixture was stirred at 100 C for 2 h. The mixture was concentrated, and the residue was purified by reverse phase chromatography eluting with water/CH3CN to afford compound 7-2 (88.1 mg). ESI-MS mL: 476.3 [M+Hr.
[00678] To a solution of compound 7-2 (88.1 mg, 1.0 eq) in Me0H (2.0 mL), cyclopropylamine (257 ul, 20.0 eq) and Na0Me (25%) ( 60 ul, 1.5 eq) were added, and the resulting mixture was stirred at 50 C for 1 h. The mixture was concentrated, and the residue was purified by reverse phase chromatography eluting with water/CH3CN to afford compound 7-3 (40.8 mg). ESI-MS m/z: 379.3 [M+Hr.
[00679] The compound 7-3 (40.8 mg, 1.0 eq) was dissolved in POC13 (2.0 mL) and stirred at 105 C for 24 h. The mixture was concentrated to remove the volatiles to give compound 7-4 which was used directly in the next step.
ESI-MS miz- 401.2 [M+Hr [00680] To a solution of above obtained crude compound 7-4 in DCM (5 mL) at 0 C, DIEA (177 ul, 10.0 eq) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1loctane-3-carboxylate (65 mg, 3.0 eq) were added, and the resulting mixture was stirred at 0 C for 10 min. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with ethyl acetate/hexane to afford compound 7-5 (20.5 mg). ES1-MS m/z: 577.4 [M+H]+.
[00681] The reaction mixture of compound 7-5 (20.5 mg, 1.0 eq), 2-((tert-butoxycarbonypamino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (22 mg, 2.0 eq), K2CO3(14.3 mg, 3.0 eq) and dichloro[1,1'-bis(di-tert-butylphosphino)ferrocenelpalladium (II) (8.2 rag, cat.) in a mixed solvent of dioxane-water (3 mL, 3:1) was stirred at 90 C for 2 h. The mixture was concentrated, and the residue was purified by reverse phase chromatography eluting with water/CH3CN to afford compound 7-6 (9.2 mg). ESI-MS ,n/z: 809.5 [M+Hr.
[00682] The reaction mixture of compound 7-6 (9.2 mg) in 20% trifluoroacetic acid in dichloromethane (2 mL) was stirred at room temperature for 4 h. The mixture was concentrated in vacuo.
The residue was purified by prep-HPLC
(5-60% CH3CN/H20 with 0.1% formic acid) to afford compound 448 as formic acid salt (1.96 mg). ESI-MS m/z:
609.4 [M+Hr.
Example 2f: Synthesis of 7-(2-amino-7-fluorobenzo[d]thiazol-4-y1)-6-cyclopropy1-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-4-(hexahydropyrrolo[3,4-e]pyrrol-2(1H)-yl)pyrido [4,3-d]pyrimidin-5(6H)-one (Compound 451) Boc Boc Boc 0 n A..."- rcH c , H,itV
0 CI n cr,61..,N
NN
DCM
A,...... AT._ J,C1_1 m-CPBA ,6,..., 0 N t-BuOK F
CI I
CI N S"---F DCM, rt , 30 mm ci `.. eLs.-- ==., _,,,,,.., / N ,S...., THF
CI

F F F

poc H
BocHN IV el) >----N
H n S io B(OH)2 BocHN 'cr 0 N
F H2N 'c 0 N
> F
F
I I
___________________ - s ,... ...a......,6----s DCM
N 0 = N 0 =
Suzuki N N
F F
F F

[00683] To a solution of compound 3-7 (100 mg, 0.157 mmol) in DCM (5 mL), tert-butyl hexahydropyrrolo13,4-clpyrrole-2(1H)-carboxylate (80 mg, 0.376 mmol) and Et3N (40 mg, 0.314 mmol) were added, and the resulting mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo, and the residue was purified by flash silica column chromatography (eluting with 0-60 % of EA in PE to give compound 8-1 (170 mg).
ES1-MS in/z: 496.3 [M+Hr.
[00684] To a solution of compound 8-1 (170 mg, 0.34 mmol) in DCM (5 mL) at 0 C, m-CPBA (120 mg, 0.68 mmol) was added, and the resulting mixture was stirred at room temperature for 2.5 h. The mixture was diluted with aqueous Na2S03 (10 niL) and extracted with DCM (3 A 10 niL). The organic layer was washed with aqueous NaHCO3 (3 x10 mL) and brine (10 mL), dried with Na2SO4, filtered, and the filtrate was concentrated in vacuo to give compound 8-2 (150 mg, crude) which was used in the next step. ESI-MS
in/z: 528.1 [M-I-H]t [00685] To a solution of compound 42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (120 mg, 0.75 mmol) in THF (5 mL) at -20 C under argon atmosphere, t-BuOK (0.75 mL, 0.75 mmol, 1 M) was added, and the resulting mixture was stirred at this temperature for 30 min. Compound 8-2 (200 mg, 0.37 mmol) in THF (5 mL) was added at -20 C, and the mixture was stirred at this temperature for 1 h.
The mixture was diluted with aqueous NH4C1 (20 mL) at this temperature, extracted with Et0Ac (3 x 10 mL). The organic layer was washed with brine (10 mL), dried with Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica column chromatography (eluting with 0-15 of Me0H in DCM to give compound 8-3 (150 mg). ESI-MS in/z:
607.3 1M+H1.
[00686] To a solution of 8-3 (100 mg, 0.16 namol) in DIVIF (3 inL) under argon atmosphere, (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (132 mg, 0.16 mmol) was added, and the resulting mixture was bubbled with argon for 1 h. Cs2CO3 (162mg, 0.48 mmol) and DPEPhosPdC12 (20 mg) were added, and the mixture was stirred at 110 C under argon atmosphere for 4 h.
The mixture was filtered through celite and rinsed with ethyl acetate. The combined organic layer was concentrated, and the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/PE then 0-20% Me0H/DCM.
The combined fractions were concentrated and the residue was purified by prep-TLC plate (Me0H : DCM = 15:
1) to give compound 8-4 (35 mg). ESI-MS ne,/z: 839.3 [M-hH] .

[00687] To a solution of compound 8-4 (30 mg) in DCM (3 mL), TFA (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by prep-HPLC
(FA) to give compound 451 (6.10 mg). ESI-MS in/z: 639.2 [IVI+1-11-;
[00688] 1H NAIR (400 MHz, DMSO-d6): 6 10.89 (s, 1H), 9.00 (s, 2H), 8.05 (s, 2H), 7.50 ¨7.29 (m, 1H), '7.09 (t, J
= 8.8 Hz, 1H), 5.51 (d, J= 55.1 Hz, 1H), 4.49 (s, 2H), 3.95 ¨3.67 (m, 7H), 3.57 (s, 3H), 3.08 (s, 5H), 2.83 (s, 1H), 2.12 (s, 3H), 1.99(s, 1H), 1.24 (s, 2H), 0.59 (d, J = 30.4 Hz, 2H), 0.40 (s, 2H).
[00689] The compounds in Table 6 were prepared, or can be prepared, in a similar manner as described in Examples 1 ,2, and 2a-2f.
Table 6 Compo Structure Name ESI-und MS
m/z [M+
HI+
101 7-(2-amino-7-fluorobenzo[dlthiazol-4-y1)-2-H2N F (42R,7aS)-2-fluorotetrahydro-1H-HN .11 pyrrolizin-7a(5H)-yOmethoxy)-4-F
N 0 N (piperazi n-1-yl)py rido [4,3-d[pyrimidin-5(6H)-one 555.2 102 7-(2-amino-7-f1uorobenzo[dlthiazol-4-y1)-4-H2N ((lR,5S)-3,8-HN
diazabicyclo [3 .2.1]octa n-3 -y1)-2-F
N (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yflmethoxy)pyrido [4,3 -d] pyrimidin-5(6H)-one 581.2 103 44(1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-2-F
(((2R,7aS)-2-fluorotetrahydro-1H-HN -1\1 HO pyrrolizin-7a(5H)-y1)methoxy)-7-(3-hydroxynaphthalen-1-yOpyrido[4,3-dlpyrimidin-5(6H)-one 557.2 104 7-(2-amino-7-< )1N
LT¨) fluorobenzo[dlthiazol-4-y1)-4-((1R,5S)-3,8-N N
N diazabicyclo[3.2.1]octan-3-y1)-6-F ' cyclopropy1-2-(K2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-621.2 7a(5H)-yOmethoxy)pyrido14,3-d]pyrimidin-5(6H)-one 105 H 44(1 R,5S)-3,8-diazabicyclo [3 .2.1] o ctan-3 -y1)-6-Ai cyclopropy1-2-(((2R,7aS)-2-HO I fluorotetrahydro-1H-pyrrolizin-N 0 =
7a(5H) -yl)methoxy)-7-(3 -hy dro xy naphthalen-1 -yl)py rido [4,3 -d] pyrimidin-5 (6H)-One 598.3 106 Fl 7-(2-amino-7-fluo rob enz o [d] thiazol-4-y1)-4-N
I-12N ((1R,5S)-3,8-F
I diazabicyclo [3 .2.1] o etan-3 -y1)-2-N 0 =
(((2R,7aS)-2-fluorotetrahydro-1H-F
py rroli zin-7a(5H)-yl)metho xy) -6 -methy 1py rido [4,3 -clipy rimidin-(6H)-one 595.5 107 H 7-(2-amino-7-fluo rob enz o [d] thiazol-4-y1)-4-N
H2N (( 1R,5S)-3,8-I diazabicyclo [3.2.1 o ctan-3 -y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-metlw 1py rido [4,3 -di py rimidin-5 (6H)-onc 108 H 44(1R,5S)-3,8-o diazabicyclo [3 .2.1] o etan-3 -y1)-8-N
fluoro-2-(((2R,7aS)-2-N N
HO I rel,,e6----S fluorotetrahydro-1H-pyrrohzin-N
7 a(5H) -yl)metho xy)-7-(3 -hy dro xy naphthalen-1 -yl) -6-methy 1py rido [4,3 -d] py rimidin-5 (6H)-one 109 H 7-(2-amino-7-y fluo rob enz o [d]thiazol-4-y1)-4-N
H2N ((IR,5S)-3,8-I
h-N N I
diazabicyclo [3 .2.1] o ctan-3 -y1)-6-(cyclopropylmethyl)-8-fluoro-2-F
(((2R,7 aS)-2-fluo ro te trolly dro-1H-pyrrolizin-7a(5H)-yl)methoxy)py rido 14,3 -d]pyrimidin-5(6H)-one 110 H 7-(2-amino-7-653.4 fluorobenzo [d] thiazol-4-y1)-4-Fi2N FL, N
((1R,5S)-3,8-N N=N
I diazabicyclo [3 .2.1]
octan-3 -y1)-6-cyc1obuty1-8-fluoro-2-(((2R,7aS)-F
2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -pyrimidin-5(6H)-one 111 H 8-(3 -oxa-7,9-diazabicyclo [3 .3.1] nonan-9 -y1)-2 -N cyclopropy1-6-(((2R,7aS)-2-, N
HO I 1 fluorotetrahydro-1H-pyrrolizin-N- N 7a(5H)-yl)methoxy)-3 -(3-hydroxynaphthalen-1 -y1)-211-pyrim ido [4.5-e] [1,2]thi a zine 1-oxide 112 H 3 -(2-amino-7-fluorobenzo I d I thiazol-4-y1)-8-(3-oxa-7.9-diazabicyclo [3 .3 .11nonan-I
9-y1)-2 -cy clopropy1-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4,5-el [1,21thiazine 1-oxide 113 H 7-(2-amino-7-N
fluorobenzo [d] thiazol-4-y1)-4-H2 N ((1R,5S)-3,8-I 11 diazabicyclo [3 .2.1]octan-3 -y1)-8-N 0 ' fluoro-2-(42R,7aS)-2-fluorotetrabydro-11-1-pyrrolizin-7a(5H)-y1)methoxy)-6-(oxetan-3-ylmethyDpyrido [4,3-dlpyrimidin-5(6H)-one 114 H 4-(( 1R,5S)-3,8-o diazabicyclo [3 .2.1] o etan-3 -y1)-2-N
(42R,7aS)-2-fluorotetrahydro-1H-,, N F
HO py rrolizin-7a(5H)-y Omethoxy)-7-N 0 ' (3 -hydro xy nap hthalen-l-y1)-6-methy 1py rido [4,3 -cl] py rimidin-(6H)-one 115 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-N
H2N ((1R,5S)-3,8-, diazabicyclo [3 .2.1] o etan-3 -y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-F
pyrrolizin-7a(5H)-yOmethoxy)-6-me thy 1py rido [4,3 -d] py rimidin-5 (6H)-one 116 H 7-(2-amino-7-635.5 fluorobenzo [d]thiazol-4-y1)-4-o N
H2N ((1 R,5S)-3,8-N N-N
diazabicyclo [3 .2.1] o etan-3 -y1)-6-(cyclopropylmethyl)-2-(((2R,7aS)-F
2-fluorotetrahydro-1H-pyrrohnn-7a(5H)-yflmethoxy)pyrido [4,3 -d] pyrimidin-5 (6H)-one 117 H 7-(2-amino-7-633.4 o fluorobenzo [d]thiazol-4-y1)-4-((1R,5S)-3,8-N
diazabicyclo [3 .2.1] o etan-3 -y1)-6-cyclobuty1-24((2R,7aS)-2-fluor t etrahy dro-1H-py rrolizina-7a(511)-yl)methoxy)pyrido [4,3 -d] pyrimidin-5 (6H)-one 118 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-7 o N
H2 N ((1R,5S)-3,8-N
I diazabicyclo [3 .2.1] o etan-3 -y1)-2-N 0 ' (((2R,7aS)-2-fluorotetrahydro-1H-F
py rroli zin-7a(5H)-yl)metho xy) -6 -(o xetan-3 -ylmethyl)py rido [4,3 -d]py rimidi n-5 (6H)-o lie 119 H 44(1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-2-N
(42R,7aS)-2-fluorotetrahydro-1H-HN 6_s HO pyrrolizin-7a(5H)-yOmethoxy)-7-N 0 "' (3 -hydro xynaphthalen-1-yl)py rido [4,3 -d] pyrimidin-5 (6H)-one 120 H 7-(2-amino-7-fluorobenzo [d] thiazol-4-y1)-4-H2 N 0 N cN
((1R,5S)-3,8-N , diazabicyclo [3 .2.1] octan-3 -y1)-6-N 0 ' cyclobuty1-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7 a(51{) -yl)metho xy )-5-oxo -5 ,6 -dihy dro-1,6-naphthy ridine-3 -carbonitrile 121 H 7-(2-amino-7-0 o N
fluorobenzo [d]thiazol-4-y1)-4-¨
H2 N CN ((lR,5S)-3,8-N
diazabicyclo [3 .2.1] octan-3 -y1)-2-N
(((2R,7aS)-2-fluorotetrahydro-1H-F
py rrolizin-7a(5H)-yl)metho xy) -6 -(o xetan-3 -y1)-5 -o xo-5,6-dihy dro-1,6-naphthyridi ne-3 -ca rbo nit rile 122 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-o N
H2N ((1R,5S)-3,8-HN
(((2Rdiazabicyclo [3 .2.1] octan-8-y1)-2-N 0 ' ,7aS)-2-fluorotetrahydro-1H-F
pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-5 (6H)-one 123 H 3 -(2-amino-7-Mfluorobenzo [d] thiazol-4-y1)-8-(3-N
I-12N oxa-7,9-diazabicyclo [3 .3 A] nonan-FF
9-y1) -2 -(cy clopropylmethyl)-4-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-11-1-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4,5-el [1,2] thiazine 1,1-dioxide 124 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-fl1R,5S)-3,8-N N
diazabicyclo [3 .2.1] octan-3 -y1)-6-cyclopropy1-2-(((2R,7aS)-2-F
fluorotetrahydro-1H-pyrrolizin-7a(5H) -yflmetho xy)pyrido [4,3 -d]pyrimidin-5(6H)-one 125 H 4-((1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-6-\, cyc1opropy1-8-fluo ro -2 -N
HO I (((2R,7aS)-2-fluorotetrahydro-1H-N
pyrro1izin-7a(5H)-y1)methoxy)-7-(3 -hy dro xy naphthalen-1-yl)pyrido [4,3 -d] pyrimidin-5(6H)-one 126 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-((1R,5S)-3,8-N , N
I diazabicyclo [3 .2.1]
octan-3 cyclopropy1-8-fluo ro -2 -(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)py rido [4,3 -d]pyrimidin-5(6H)-one 127 H 7-(2-amino-7-o E fluorobcnzo [d]thiazol-4-y1)-6-cyclopropy1-2-(((2R,7aS)-2-N N
fluorotetrahy 1H-pynoliziii-7a(51{)-yl)methoxy)-4-(piperazin-1-yl)pyridorido [4,3 -clipyrimidin-(6H)-one 128 H 2-(42R,7a S)-2-fluorotetrahydro-N
1H-pyrrolizin-7a(5H)-=-=,N yOmethoxy)-7-(3-N
HO I hydroxynaphthalen-1 -y1) -6-N 0 ' methy1-4-(piperazin-1-yl)pyrido [4,3 -d] pyrimidin-5(6H)-one 129 H 7-(2-amino-7-CN fluorobenzo [d]thiazol-4-y1)-2-H2N (42R,7aS)-2-fluorotetrahydro-1H-X--N '1\1 pyrrolizin-7a(5H)-yOmethoxy)-6-N methy1-4-(piperazin-1-F
yl)pyrido [4,3 -d] pyrimidin-5 (6H)-one 130 H 3 -(2-amino-7-F Co) fluorobenzo [d]thiazol-4-y1)-8-(3-N
iH2N
oxa-7,9-diazab icy clo [3 .3 .1] nonan-s I
N 0 ' 9-y1)-2 -(2,2-difluorocy clopropy1)-4-fluoro-6-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51-1)-yl)methoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1,1-dioxide 131 H 4-41R,5S)-3,8-diazabicyclo [3 .2.1] octan-3-y1)-8-N
fluoro-7-(3-hydroxynaphthalen-1--.N
y1)-6 -methyl-24( S)-1-methylpyrrolidin-2-yflmethoz)pyrido [4,3 -d]pyrimidin-5 (6H)-one 132 H 7-(2-amino-7-f1uorobenzo [d]thiazol-4-y1)-4-y 0 N
H2N ((1R,5S)-3,8-I I
\ diazabicyclo [3 .2.1]
octan-3 -y1)-6-(cyclopropylmethyl)-8-fluoro-2-F
(((S)-1-methylpy rrolidin-2-yl)methoxy)py rido [4,3 -d]pyrimidin-5 (6H)-one 133 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-y 0 N
H2N ((1R,5S)-3,8-N
I I
diazabicyclo [3 .2.1] octan-3 -y1)-6-(cyclopropylmethyl)-2-((( S )-1-methylpyrrolidin-2-yOmethoxy)pyrido [4,3 -d]py ri m idi n-5 (6H)-o lie 134 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-H1R,5S)-3,8-N

diazabicyclo [3 .2.1] octan-3 -y1)-6-N
cyclobuty1-8-fluoro-2-4(S)-1-F
methylpyrrolidin-2-yOmethoxy)pyrido [4,3 -d]pyrimidin-5 (6H)-one 135 H 7-(2-amino-7-fluorobenzo [d] thiazol-4-y1)-4-H2 N ________________________ 0 N
(( 1R,5S)-3,8-N N

diazabicyclo [3 .2.1] oetan-3 -y1)-8-fluoro-2-(((S)-1-methylpyrrolidin-F
2-yl)methoxy)-6-(oxetan-3 -yl)py rido [4,3 -di pyrimidin-5 (6H)-one 136 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-F
((1R,5S)-3,8-N
diazabicyclo [3 .2.1] octan-8-y1)-6-N 0 "
cyclobuty1-8-fluoro-2-(((2R,7aS)-F
2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]py ri m idi n-5 (6H)-o lie 137 H 7-(2-amino-7-KN

fluorobenzo [di thiazol-4-y1)-4-0 L'N>
H2 N ((1R,5S)-3,8-N
I I
diazabicyclo [3 .2.1] octan-3 -y1)-2-(((s)-1-methylpy rrolidin-2-F
yl)methoxy)-6-(oxetan-3-ylmethyl)pyrido [4,3-dlpy rimidin-(6H)-one 138 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-((1R,5S)-3,8-, I diazabicyclo [3 .2.1]
octan-3 -y1)-2-(42R,7 aS )-2-fluorotetrahy dro-1H-py rrolizin-7a(5H)-yOmetho xy) -6 -(o xeta n-3 -yl)py rido [4,3 -cl]py rimidin-5 (6H)-one 139 7-(2-amino-7-F F fluorobenzo [d]
thiazol-4-y1)-4-.2N 0 N
N
diazabicyclo [3 .2.1] octan-3 -y1)-6-(2,2 -difluorocyclopropy1)-2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cl]py rimi di n-5 (6H)-one 140 7-(2-amino-7-fluorobenzo [di thiazol-4-y1)-4-H2N o N
_______________________ NN ((1R,5S)-3,8-I I
diazabicyclo [3 .2.1] octan-3 -y1)-6-F
cyclobuty1-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido [4,3 -d]pyrimichn-5(6H)-one 141 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-?¨L 0 N
h2N ((lR,5S)-3,8-I I
diazabicyclo [3 .2.1] octan-3 -y1)-2-N 0 "=[--(((S)-1 -methylpyrrolidin-2-yl)methoxy)-6-(oxetan-3 -yl)py rido [4,3 -cllpy ri midi n-5(6H)-one 142 8-(( 1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-2-HO N
(2,2-difluorocyclopropy0-6-01 -N
I cr ((dimethylamino)methyl)cyclopro --)C
pyl)methoxy)-3-(8-ethyny1-7-=_-fluoro-3-hydroxynaphthalen-1-y1)-F
4-flu oro-2H-py rimido [4,5 -el [1,21thiazine 1,1-dioxide 143 7-(2-amino-7-F F fluorobenzo [d]thiazol-4-y1)-4-(3-oxa-7,9-diazabieyelo [3 .3 A] nonan-N N
I I 9-y1) -6 -(2,2-difluorocy clopropy1)-N 2-(((2R,7aS)-2-fluorotetrahydro-1H-py rrol izi n-7a (5H)-yl)metho xy )py rido [4,3 -d]pyrimidin-5 (6H)-one 144 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-((1R,5S)-3,8-I I
diazabicyclo [3.2.1]oetan-3 -y1)-6-FF

cyclopropy1-8-fluo ro -2 -(((S)-1-methvlpyrrolidin-2-yOmethopyrido [4,3 -d]pyrimidin-5(6H)-one 145 H 4-((1R,5S)-3,8-diazabicyclo [3.2.1] octan-8-y1)-8-N
fluoro-2-(((2R,7aS )-2-HO I õ N fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hy droxy naphthalen-1 -y1)-6-methylpyrido [4,3 -clipyrimidin-(6H)-one 146 H 3 -(2-amino-7-/0\

fluorobenzo [d]thiazol-4-y1)-8-(3-\Z N
H2N 0,11 Ioxa-7,9-diazabicyclo [3.3.1] nonan-N
I 1 9-y1)-4-fluoro-6-(K2R,7aS)-2-FL r fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(oxetan-3-ylmethyl)-2H-pyrimido [4,5-e] [1,21thiazi ne 1,1-dioxide 147 H 8-(3 -oxa-7,9-diazabicyclo [3.3.1] nonan-9-y1)-6-0,11 NSLN F
HO =
pyrrolizin-7a(5H)-yl)methoxy)-3 -(3 -hy droxy naphthalen-l-y1)-2-methy1-2H-pyrimido [4,5-e] [1,21thiazine 1,1-dioxide 148 H 3 -(2-amino-7-fluorobenzo [d]thiazol-4-y1)-8-(3-H2N 0*g oxa-7,9-diazabicyclo [3 .3.1] nonan-, N
I 9-y1)-6-4(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F
7a(5H)-yflmethoxy)-2-methyl-2H-pyrimido [4,5-e] [1,2]thiazine 1,1-dioxide 149 H 7-(2-amino-7-r, fluorobenzo [d] thiazol-4-y1)-4-H2N ((1R,5S)-3,8-diazabicyclo [3 .2.1] oetan-8-y1)-8-N 0 ' fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-methylpyrido [4,3 -d] py rimidin-(6H)-one 150 H 7-(2-amino-7-ThN
fluorobenzo [di thiazol-4-y1)-4-o o N
H2 N I ((1R,5S)-3,8-N , I diazabicyclo [3 .2.1]
o etan-8-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7 a(51{) -yl)metho xy)-6-(o xetan-3 -yOpyrido [4,3 -dlpyrimidin-5 (614)-one 151 H 7-(2-amino-7-F F fluorobenzo [d]
thiazol-4-y1)-4-N ((lR,5S)-3,8-N
I diazabicyclo [3 .2.1]
octan-8-y1)-6-(2,2-difluorocyclopropy1)-8-fluoro-2-(((2R,7a S)-2-fluorotetrahydro-1H-pyrrolizin-7 a(5H) -yl)metho xy)py rido [4,3 -cl] pyrimidin-5 (6H)-one 152 H 3 -(2-amino-7-fluorobenzo [d] thiazol-4-y1)-8-(3-w N
N oxa-7,9-diazab icyclo [3 .3 A] nonan-9-y1) -2 -(cy clopropylmethyl)-4-N 0 ' fluoro-6-4(2R,7aS)-2-fluorotetrahydro-11-1-pyrrolizin-7a(5H)-y0methoxy)-2H-pyrimido [4.5-e] [1,2] thiazine 1-oxide 153 H 2-cyclopropy1-6-(( 1-((dimethylamino)methyl)cyclopro pyl)methoxy)-3 -(8-ethyny1-7 -HO /\-- A fluoro-3-hydroxynaphthalen-1-y1)-N
I I
N 4-fluoro-8-(2,7-diazaspiro [3 .5] nonan-7-y1) -2H-pyrimido [4.5-e] [1,2] thiazine 1-F
oxide 154 H 7-(2-amino-7-,c\
fluorobenzo [d] thiazol-4-y1)-4-\/ 0 N
H2 N (( 1R,5S)-3,8-diazabicyclo [3 .2.1] octan-8-y1)-8-N 0 ' fluoro-2-(((2R,7aS)-2-fluor t etrahy dro-1H-py rrolizin-7 a(5}1) -yl)metho xy)-6-(o xetan-3 -ylmethyl)py rido [4,3-d] py rimidin-(6H)-one 155 H 7-(2-amino-7-I<->1 fluorobenzo [d]
thiazol-4-y1)-4-H2 N ((1R,5S)-3,8-N diazabicyclo [3 .2.1]
octan-8-y1)-6-(cyclopropylmethyl)-2-(((2R,7aS)-F
2-fluorotetrahydro-11-1-pyrrolizin-7a(5H)-yl)methoxy)py rido [4,3 -d] pyrimidin-5 (6H)-one 156 H 7-(2-amino-7-õ fluorobcnzo [d]thiazol-4-y1)-4-N 'NJ ((1R,5S)-3,8-diazabicyclo [3 .2.1] octan-8-y1)-6-cyclobuty1-24(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7 a(511) -yl)metho xy)py rido [4,3 -cl] pyrimidin-5 (6H)-one 157 H 7-(2-amino-7-/), fluorobenzo [d]thiazol-4-y1)-4-H2 N (( 1R,5S)-3,8-M\I , diazabicyclo [3 .2.1] octan-8-y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-F
pyrroli zi n-7a(5H)-yOmethoxy)-6-(oxetan-3-ylmethyl)pyrido [4,3 -d] pyrimidin-5 (6H)-one 158 H 8-(3-oxa-7,9-Mdiazabicyclo [3 .3.1] nonan-9 -y1)-2 -F N cyclopropy1-6-(((2R,7aS)-2-fltiorolelraliydro-1H-pynoliziii-7a(5H)-yl)methoxy)-3 -(3 -hy dro xv naphthalen-1-y1) -2H-py rimido [4.5-e] [1,2] thiazine 1,1-dioxide 159 H 2-(2,2-difluoro ey clopropy0-6-((1 -N
((dime thy lamino)me thyl)cy clopro py 1)methoxy)-3 -(8-ethy ny1-7 -N
fluoro-3-hydroxynaphthalen-1-y1)---.
N 8-(2,7-diazaspiro [3 .51 nonan-7-y1)-2H-py rimido [4,5-e] [1,2] thiazine 1,1-dioxide 160 H 44(1R,58)-3,8-r, diazabicyclo [3 .2.1] octan-8-y1)-6-cyclopropy1-2-(((2R,7a S)-2-I
HO fluorotetrahydro-1H-pyrrolizin-N
7a(5H) -yl)methoxy)-7-(3 -hy dro xv naphthalen-1 -yl)py rido [4,3 -d] pyrimidin-5 (6H)-one 161 H 7-(2-amino-7-r fluorobenzo [d]thiazol-4-y1)-4-H2N ((1R,5S)-3,8-N 'IV
diazabicyclo [3 .2.1] octan-8-y1)-6-r\r-Le N cyclopropy1-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51-1)-yl)methoxy)pyrido [4,3 -d] pyrimidin-5 (6H)-one 162 H 4-(3-oxa-7,9-diazabicyc1o[3.3.1]nonan-9-y1)-8-O N
N fluoro-2-(((2R,7aS)-2-N
I I fluorotetrahydro-1H-pyrrolizin-HO "= N
7a( 5H)-yl)methoxy )-7-(3 -hydroxvnaphthalen-1 -y1) -6-methy 1py rido [4,3 -d] py rimidin-(6H)-one 163 2-((1-S.
((dimethylamino)methyl)cyclopro o pyl)methoxy)-7-(8-ethyny1-7-HO
HN N fluoro-3 -hy droxynaphthalen-l-y1)-4-(2,7-diazaspiro [3 .5] nonan-7-yl)pyrido [4,3 -cl] pyrimidin-5 (6H)-one 164 6-cyclopropy1-2-((1-N
((dimethylamino)methyl)cyclopro pyl)methoxy )-7-(8-e thy ny1-7 -A o N
HO **- N f1uoro-3 -hy dro xynaphthalen-1-y1)-I I
N
4-(2,7-diazaspiro [3 .5] nonan-7-=_¨
yl)pyrido [4,3 -clipyrimidin-5 (6H)-One 165 7-(2-amino-7-&/ fluorobenz o[d]
thiazol-4-y1)-4-(3-H2N oxa-7,9-diazabicyclo [3 .3.11nonan-, N
I 9-y1) -8 -fluoro-2-(((2R,7aS)-2-F
N 0 ' fluorotetrahydro-1H-pyrrolizin-7a(5H)-yflmethoxy)-6-methvlpyrido [4,3 -dlpyrimidin-5(6H)-one 166 7-(2-a mi no-7-N
V
0 N fluorobenzo [d]thiazol-4-y1)-4-(3-H2N oxa-7,9-diazabicyclo p .3 .11nonan-N N, 9-y1) -6 -(cy clopropylmethyl)-8-fluoro-2-(((21L7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(511)-yl)methoxy)py rido [4,3 -d] pyrimidin-5 (6H)-one 167 7-(2-amino-7-Nc)/ fluorobenzo [di thia zol-4-y1)-4-(3-oxa-7,9-diazabicyclo ]3 .3 .1] nonan-N N , N
9-y1) -8 -fluoro-2-(((2R,7aS)-2-F
N 0 ' fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(oxetan-3-yl)pyrido [4,3 -clipyrimidin-5 (6H)-one 168 H 7-(2-amino-7-F F V.20 fluorobenzo [d]thiazol-4-y1)-4-(3 -N
oxa-7,9-diazab icyclo [3 .3 .1] nonan-N N
9-y1) -6 -(2,2-difluorocy clopropy1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H) -yflmetho xy)pyrido [4,3 -d]pyrimidin-5(6H)-one 169 H 7-(2-amino-7-<CS
0 N fluorobenzo [d]
thiazol-4-y1)-4-(3 -H2 N oxa-7,9-diazabicyclo [3 .3 .1] nonan-N
9-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F
7a(511)-yl)methoxy)-6-(oxetan-3-ylmethyl)pyrido [4,3-dlpyrimidin-(6H)-one 170 H 4-(3 -oxa-7,9-dia zabicyclo [3 .3 _1] nonan-9 (((2R,7aS)-2-fluorotetrahydro-1H-.
'11 6_s pyrro1izin-7a(5H)-y1)metho xy) -7 -N
(3 -hydro xynaphthalen-l-y1)-6-methvlpyrido [4,3 -dlpyrimidin-5 (6H)-one 171 H 7-(2-amino-7-fluorobenzo [d] thiazol-4-y1)-4-(3-H2N oxa-7,9-diazabicyclo [3 .3 A] nonan-N
9-y1)-2 -(((2R,7aS)-2-N fluorotetrahydro-1H-pyrrolizin-F
7a(511)-yl)methoxy)-6-methylpyrido [4,3 -dlpyrimidin-5 (6H)-one 172 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-(3-0¨ o N
H2 N _________________________________________________ oxa-7,9-diazabicyclo [3 .3 .1] nonan-N N
9-y1)-2 -(((2R,7aS)-2-N 0 ' fluorotetrahydro-1H-pyrrolizin-F
7a(5H)-yl)methoxy)-6-(oxetan-3-yl)pyrido [4,3 -d] pyrimidin-5(6H)-o ne 173 H 84(1R,5S)-3,8-HO
N
N' N
I I diazabicyclo [3 .2.1]
octan-3 -y1)-2-(cy clopropylmethyl)-3 -(8-ethynyl-7-flu oro-3-hy droxynaphthalen-1--y1)-6 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F 7a(5H)-yl)methoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1-oxide 174 H 7-(2-amino-7-fluorobenzo [di thiazol-4-y1)-4-(3-H2 N oxa-7,9-diazabicyclo [3 .3 A] nonan-N
9-y1)-2 -(((2R,7aS)-2-fluor t etrahy dro-1H-py rrolizin-7 a(5H) -yl)metho xy)-6-(o xetan-3 -ylmethyl)py rido [4,3-d] py rimidin-(6H)-one 175 H 4-(3 -oxa -7,9-diazabicyclo [3 .3.1] nonan-9 -y1)-2 -(42R,7 aS)-2 -fluorotetrahy dro-1H-HN., 1,..N,L1 6_s py rrolizin-7a(5H)-yl)metho xy) -7 -HO
(3 -hydro xy nap hthalen-1-yl)py rido [4,3 -d] pyrimidin-5 (6H)-one 176 H 7-(2-amino-7-fluorobenzo [di thiazol-4-y1)-4-(3-H2N oxa-7,9-diazabicyclo [3 .3 A] nonan-N H N N
N 9-y1)-2 -(((2R,7aS)-2-fluor t etrahy dro-1H-py rrolizin-7a(511)-yl)methoxy)pyrido [4,3 -d] pyrimidin-5 (6H)-one 177 H 4-(3 -oxa-7,9-dia zabicyclo [3 .3.1] nonan-9 -y1)-6 -N
F cyc1opropy1-2-(((2R,7aS)-2-HO
fluorotetrahydro-1H-pyrrolizin-N 0 ' 7a( 5H)-yl)methoxy )-7-(3 -hydroxynaphthalen-l-yl)pyrido [4,3 -d] pyrimidin-5 (6H)-o ne 178 H 7-(2-amino-7-fluorobenzo [d] thiazo1-4-y1)-4-(3-oxa-7,9-diazabicyc10 [3 .3 .1] nonan-N N

N 9-y1) -6 -cy clopropy1-2-(((2R,7aS)-N
2 -fluorotetrahydro-1H-pyrrolizin-7a(5H) -y0metho xy)py rido [4,3 -cl]pyrimidin-5(6H)-one 179 H 8-(3-oxa-7,9-diazabicyclo [3 .3.1] nonan-9 -y1)-4 -fluoro-6-(((2R,7aS)-2-HO 1 fluorotetrahydro-1H-pyrrolizin-7a(511) -yOmetho xy)-3 -(3-hy dro xynaphthalen-1 -y1) -2-me thy1-2H-py rimido [4,5-e] [1,2] thiazine 1-oxide 180 H 3 -(2 -amino-7-M fluorobenzo [d]thiazol-4-y1)-8-(3-N
H2N oxa-7,9-diazabicyclo [3 .3 .1]nonan-Xr--N N-N F
õ).., 9-y1) -4 -fluoro-6-(((2R,7aS)-2-F
N 0 ' fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-2-methyl-2H-pyrimido [4.5-e] [1,2] thiazine 1-oxide 181 H 3-(2-amino-7-s.?
fluorobenzo [d] thiazol-4-y1)-8-N
H2 N F ((lR,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-2-(cyclopropylmethyl)-6-(((2R,7aS)-F
2-flu oro te trahy dro-1H-pyrrolizin-7a(51-1)-yl)methoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1-oxide 182 H 3 -(2-amino-7-0 M fluorobenzo [d]thiazol-4-y1)-8-(3 -N¨ oxa-7,9-diazabicyc10 [3 .3 A] nonan-F
1 reLcr.õ,., 9-y1) -2 -cy elobuty1-4-fluoro-6-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-2H-py rn ido [4,5-e] [1,21thiazine 1-oxide 183 H 3 -(2-amino-7-Mfluorobenzo [d]thiazol-4-y1)-8-(3-H2 N I N oxa-7,9-diazab icyclo [3 .3 .1] nonan-9-y1) -4 -fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F
7a(5H) -yl)metho xy)-2-(o xetan-3 -yl) -2H-py rimido [4,5-e] [1,2] thiazine 1-oxide 184 H 3-(2-amino-7-F F fluorobenzo [d] thiazol-4-y1)-8-(3-N
H2N),N N-S F oxa-7,9-diazabicyc10 [3 .3 .1] nonan-N
I k N 9-y1)-2 -(2,2-difluorocy clopropy1)-4-fluoro-6-(((2R,7aS)-2-fluor t etrahy dro-1H-pyrrolizin-7a(51-1)-yl)methoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1-oxide 185 H 3-(2-amino-7-Mfluorobenzo [d]thiazol-4-y1)-8-(3-H2N oxa-7,9-diazabicyc10 [3 .3 A] nonan-9-y1) -4 -fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F
7a(5H) -yflmetho xy)-2-(o xetan-3 -yl ethyl)-2H-py ri m ido [4,5-e] [1,2] thiazine 1-oxide 186 H 8-(3-oxa-7,9-diazabicyclo [3 .3.1] nonan-9 -y1)-6 -N
(((2R,7aS)-2-fluorotetrahydro-1H-.., -s Ns., py rrolizin-7a(5H)-yl)metho xy) -3 ¨
HO

(3 -hydro xynaphthalen-l-y0-2-methy1-2H-py rimido [4,5-e] [1,2] thiazine 1-oxide 187 H 3 -(2-amino-7-fluorobenzo [d]thiazol-4-y1)-8-(3-N
H21\1 ,N F oxa-7,9-diazabicyclo [3 .3 A] nonan-9-y1)-6 -( ((2R,7aS )-2-N 0 ' fluorotetrahydro-1H-pyrrolizin-F
7a(5H)-yflmethoxy)-2-methy1-2H-pyrim ido [4,5-e] [1,2]thia zinc 1-oxide 188 H 3 -(2-amino-7-Mfluorobenzo [d]thiazol-4-y1)-8-(3-o H2N N
F
oxa-7,9-diazab icyclo [3 .3 .1] nonan-N0 9-y1)-2 -(cy clopropylmethyl)-6-N (42R,7aS)-2 -fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-py rimido [4,5-e] [1,2] thiazine 1-oxide 189 H 8-((1R,5S)-3,8-o N
diazabicyclo [3 .2.1] octan-3 -y1)-6-0.11 HO =-=. ((I-N N
((dimethylamino)methyl)cyclopro N
py1)methoxy)-3-(8-ethyny1-7-F
=
fluoro-3-hydroxynap1i11ia1en-l-y1)-4-fluoro-2-methy1-2H-pyrimido [4,5-e] [1,2] thiazine 1,1-dioxide 190 H 8-41R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-2-0o ii N
HO N N
(cy clopropylmethyl)-6-((1-I
((dimethylamino)methyl)cyclopro N
pyl)methoxy)-3-(8-ethyny1-7-=_-fluoro-3-hydroxynaphthalen-l-y1)-F
4-fluoro-2H-pyri m ido [4,5 e] [1,2] thiazine 1,1-dioxide 191 H 3 -(2-amino-7-fluorobcnzo [d]thiazol-4-y1)-8-(3-O H2N 17, N oxa-7,9-diazab icyclo [3 .3 A] nonan-N
I 9-y1)-2 -cy clobuty1-6-(((2R,7aS)-2-N 0 ' fluorotetrahydro-1H-pyrrolizin-F
7a(511)-yl)methoxy)-2H-pyrimido [4.5-e] [1,2] thiazine 1-oxide 192 H 8-(3-oxa-7,9-N
diazabicyclo [3 .3.1] nonan-9 -y1)-4 (i?
fluoro-6-(( (2R,7aS )-2-s T;,..N.t..1 6_s HO fluorotetrahydro-1H-pyrrolizin-N
7a(5H) -yl)methoxy)-3 -(3 hy dro xy naphthale -yl) py rimido [4,5-e] [1,2] thiazine 1-oxide 193 H 3 -(2-amino-7-o fluorobenzo [d]thiazol-4-y1)-8-(3-N
H2N it oxa-7,9-diazabicyclo [3 .3 .1] nonan-N HN'S F
9-y1) -4 -fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F
7a(5H)-yl)methoxy)-2H-pyrimido [4.5-e] [1,2]thiazine 1-oxide 194 H 3-(2-amino-7-fluorobenzo [d] thiazol-4-y1)-8-(3-N
oxa-7,9-diazabicyclo [3 .3 .1] nonan-9-y1) -2 -cy clopropy1-4-fluoro-6-FF
(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-2H-pyrimido [4,5-e] [1,21thiazine 1-oxide 195 H 8-(3-oxa-7,9-diazabicyclo [3 .3 _1] nonan-9 -y1)-4 -N

fluoro-6-(((2R.7aS)-2-====,N:S
HO 1 fluorotetrahydro-1H-pyrrolizin-7a(5H) -yl)metho xy)-3 -(3 -hy dro xvnaphthalen-1-y1) -2-methy1-2H-pyrimido [4,5-e] [1,2]thiazi ne 1,1-dioxide 196 H 3 -(2-amino-7-fluorobenzo [d]thiazol-4-y1)-8-(3-og N
H2N oxa-7,9-diazabicyclo [3 .3 .1] nonan-Th\JS N
I _5 ' 1., 9-y1)-4 -fluoro-6-(((2R,7aS)-2-F

fluor t etrahy dro-1H-pyrrolizin-7a(51-1)-yl)methoxy)-2-methyl-2H-pyrimido [4,5-e] [1,2]thiazine 1,1-dioxide 197 H 4-41R,5S)-3,8-ThN
diazabicyclo [3 .2.1] octan-8-y1)-2-HN N F
o N
(42R,7aS)-2-fluorotetrahydro-1H-HO pyrrolizin-7a(5H)-yOmethoxy)-7-(3 -hydro xynaphthalen-1-yl)pyrido [4,3 -d] pyrimidin-5 (6H)-one 198 H 3 -(2-amino-7-o Q M fluorobenzo [d]thiazol-4-y1)-8-(3-i..0 N
H2N I oxa-7,9-diazab icyclo [3 .3 .1] nonan-F
N0 9-y1) -4 -fluoro-6-(((2R,7aS)-2-F
fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(oxetan-3-y1)-2H-pyrimido [4,5-e] [1,2]thiazine 1,1-dioxide 199 H 3-(2-amino-7-v co) fluorobenzo [d]
thiazol-4-y1)-8-(3-N
H2N 0 oxa-7,9-diazabicyclo [3 .3 .1] nonan-9-y1) -2 -(cy elopropylmethyl)-6-F

(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-2H-pyrimido [4,5-e] [1,21thiazine 1,1-dioxide 200 H 4-41R,5S)-3,8-dia zabicyclo [3 .2_1] octan-3-y1)-6-HO
cyclobuty1-7-(8-ethyny1-7-fluoro-N C`N
3 -hydro xynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F 7a(5H)-yl)methoxy)pyrido [4,3 -d]py ri idi n-5 (6H)-o lie 201 H 3 -(2-amino-7-fluorobenzo [d]thiazol-4-y1)-8-(3-N
H2N I oxa-7,9-diazabicyclo [3 .3 .1] nonan-I 9-y1)-6 -(02R,7aS)-2-fluor t etrahy dro-1H-pyrrolizin-F
7a(51-1)-yl)methoxy)-2-(oxetan-3-y1)-2H-pyrimido [4,5-e] [1,21thiazine 1,1-dioxide 202 H 3 -(2-amino-7-\/F M fluorobenzo [d]
thiazol-4-y1)-8-(3-I-12N oxa-7,9-diazabicyclo [3 .3 A] nonan-9-y1) -2 -(2,2-difluorocy clopropy1)-6-(((2R,7aS )-2 -fluorotetrahy dro-1H-pyrrolizin-7a(5H)-y metboxy)-2H-pyrim i do [4,5-e] [1,2] thiazine 1,1-dioxide 203 H 3-(2-amino-7-N
fluorobenzo[d]thiazol-4-y1)-8-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-H2 N)õ___NN;S
N
9-y1)-6-(((2R,7aS)-2-F
N 0 "
fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(oxetan-3-ylmethyl)-2H-pyrimido[4.5-e][1,21thiazine 1,1-dioxide 204 H 8-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-y1)-6-?
HN:S N
HO os (((2R,7aS)-2-fluorotetrahydro-1H-1 pyrrolizin-7a(5H)-yl)methoxy)-3 -N 0 ' (3-hydrox-ynaphthalen-1-y0-2H-pyrimido[4,5-e][1,21thiazine 1,1-dioxide 205 H 3-(2-amino-7-N
fluorobenzo[d]thiazol-4-y1)-8-(3-in 0 oxa-7,9-diazabicyclo[3.3.11nonan-X----N
9-y1)-6-4(2R,7aS)-2-N 0 "
fluorotetrahydro-1H-pyrrolizin-F
7a(5H)-yl)methoxy)-2H-pyrimido[4.5-e][1,2]thiazine 1,1-dioxide 206 H 3-(2-amino-7-N
f1uorobenzo[d]thiazo1-4-y1)-8-0.S? N H2 N
((1R,5S)-3,8-F),N N
diazabicyclo[3.2.1]octan-3-y1)-2-N 0 "
(cyclopropylmethyl)-4-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-2H-pyrimido[4,5-e][1,21thiazine 1,1-dioxide 207 H 8-41R,5S)-3,8-F F 4 diazabicyclo[3.2.1]octan-3-y1)-2-, N
(2,2-difluorocyclopropy1)-6-41-HO N
I ((dimethylamino)methyl)cyclopro N
N
pyl)methoxy)-3-(8-ethyny1-7-¨
fluoro-3-hydroxynaphthalen-l-y1)-F
4-fluoro-2H-pyrimido[4,5-e][1,2]thiazine 1-oxide 208 H 8-(3-oxa-7,9-diazabicyclo [3 .3.1] nonan-9 -y1)-4 -os;:; N
I fluoro-6-(((2R,7aS)-2-HN N 6sF
HO fluor t etrahy dro-11-1-pyrrolizin-7a(5H) -yl)metho xy)-3 -(3 -F
hy dro xv naphthalen-1-y1) -2H-py rimido [4.5-e] [1,2] thiazine 1,1-dioxide 209 H 3 -(2-amino-7-eNc6 fluorobenzo [d]
thiazol-4-y1)-8-(3-H2N o oxa-7,9-diazabicyclo [3 .3 .1] nonan-N HN.:=S N
I 9-y1)-4 -fluoro-6-(((2R,7aS)-2-NLO
fluorotetrahydro-1H-pyrrolizin-F
7a(51-1)-yl)methoxy)-2H-pyrimido [4.5-e] [1,2] thiazine 1,1-dioxide 210 H 8-41R,5S)-3,8-dia zabicyclo [3 .2.1] octan-3-y1)-6-N
HO N N (O-I I
((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-=_-fluoro-3 -hydro xynaphthalen-l-y1)-4-fluoro-2-methy1-2H-pyrim ido [4.5-e] [1,2]thia zinc 1-oxide 211 3 -(2-amino-7-fluorobcnzo [d]thiazol-4-y1)-8-(3-.**-N oxa-7,9-diazabicyclo [3 .3 A] nonan-9-y1) -2 -cy clopropy1-6-(((2R,7aS)-N
2 -fluorotetrahy dro-1H-py ITO lizin-7a(51-1)-yl)methoxy)-2H-pyrimido [4.5-e] [1,2] thiazine 1,1-dioxide 212 H 7-(2-amino-7-fluorobenzo [d] thiazol-4-y1)-4-H2 N (( 1R,5S)-3,8-N N=N
(((2Rdiazabicyclo [3 .2.1] octan-8-y1)-2-,7aS)-2-fluorotetrahydro-1H-F
pyrroli zi n-7a(5H)-yOrnethoxy)-6-(oxetan-3-yl)pyrido [4,3 -d]pyrimidin-5 (6H)-one 213 H 7-(2-amino-7-r fluorobenzo [d]thiazol-4-y1)-4-H2N o ((1R,5S)-3,8-s diazabicyclo [3 .2.1] octan-8-y1)-6-N 0 ' (2,2 -difluorocyclopropy1)-2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido 14,3 -d]py rimi di in-5 (6H)-one 214 H 8-(3-oxa-7,9-diazabicyclo [3 .3.1] nonan-9 -y1)-2 -NS N N cy clopropy1-4-fluo ro -6 -, HO I (((2R,7aS)-2-fluorotetrahydro-1H-py rrolizin-7a(5H)-yOmetho xy) -3 -(3 -hydro xynaphthalen-1-y1)-2H-py rimido [4,5 -e] [1,2]thiazine 1,1-dioxide 215 H 7-(2-amino-7-F F 4 fluorobenzo [d]thiazol-4-y1)-4-CN , 0 N
H2N ((1R,5S)-3,8-N
I diazabicyclo [3 .2.1]
octan-3 -y1)-6-N 0 ' (2,2-difluorocyclopropy1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroli zi n-7a(5H)-yOmethoxy)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carbonitrile 216 H 7-(2-amino-7-fluorobenzo [d] thiazol-4-y1)-4-N
H2N ((1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-2-N 0 ' (((2R,7aS)-2-fluorotetrahydro-1H-F
pyrrolizin-7a(5H)-yl)methoxy)py rido 14,3 -d]py ri idi n-5 (6H)-o lie 217 H 3 -(2-amino-7-fluorobenzo [d]thiazol-4-y1)-8-(3-N S oxa-7,9-diazabicyc10 [3 .3 A] nonan-I
9-y1) -2 -cy clopropy1-4-fluoro-6-(((2R,7a S)-2-fluo rotetrahydro-1H-py rrolizin-7a(5H)-y Omethoxy)-2H-pyrimido14,5-e111,21thiazine 1,1-dioxide 21S HS-((1 c?
diazabicyclo [3 .2.1] octan-3 -y1)-4-N
N
fluoro-6-(((2R,7aS)-2-' I N fluorotetrahydro-1H-pyrrolizin-HO
7a(5H) -yl)methoxy)-3 -(3 -hydroxynaphthalen-1 -y1) -2-methy1-2H-pyrimido [4,5-e] [1,2] thiazine 1-oxide 219 H 3 -(2-amino-7-fluorobenzo [d] thiazol-4-y1)-8-((1R,5S)-3,8-, N
diazabicyclo [3 .2.1] octan-3 -y1)-4-N 0 ' fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrohzin-7a(511)-yl)methoxy)-2-methyl-2H-pyrimido [4,5-e] [1,2]thi a zinc 1-oxide 220 H 3 -(2-amino-7-fluorobenzoldlthiazol-4-y1)-8-((1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-2-N 0 ' (cyclopropylmethyl)-4-fluoro-6-F
(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4,5 -c] [1,21thiazinc 1-oxide 221 H 3 -(2-amino-7-9 fluorobenzo [d]thiazol-4-y1)-8-F
H2N 17, sH N (( 1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-2-cyclobuty1-4-fluoro-6-(((2R,7a S)-F
2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4.5 -e] [1,2]thiazine 1-oxide 222 H 3 -(2-amino-7-<5 fluorobenzo [d]
thiazol-4-y1)-8-N N
((1R,5S)-3,8->=--N
diazabicyclo [3 .2.1] octan-3 -y1)-4-fluoro-6-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7 a(5H) -yl)metho xy)-2-(o xetan-3 -ylmethyl)-2H-py rimido [4,5-e] [1,2] ihia zinc 1-oxide 223 H 7-(2-amiato-7-fluorobenzo [d] thiazol-4-y1)-4-H2 N ((1R,5S)-3,8-I diazabicyclo [3 .2.1] octan-3 -y1)-8-fluoro-6-methy1-2-(((S)-1-F
methylpyrrolidin-2-yl)methoxy)pyrido [4,3 -d]pyrimidin-5(6H)-one 224 H 8-41R,5S)-3,8-0 diazabicyclo [3 .2.1]
octan-3 -y1)-6-N
(42R,7 aS)-2 -fluorotetrahy dro-1H-N-S
HO I py rrolizin-7a(511)-yOmetho xy) -3 -N 0 ' (3 -hydro xynaphthalen-l-y1)-2-methy1-2H-pyrimido [4,5-e] [1,21thiazi ne 1-oxide 225 H 3 -(2-amino-7-0 fluorobenzo [d]thiazol-4-y1)-8-((1R,5S)-3,8-N
diazabicyclo [3 .2.1] octan-3 -y1)-6-(((2R,7aS)-2-fluorotetrahydro-1H-F
py rrolizin-7a(511)-yOmetho xy) -2 -methy1-2H-py rimido [4,5-e] [1,2] thiazine 1-oxide 226 H 3-(2-amino-7-fluorobenzo [d] thiazol-4-y1)-8-¨1 N
H2N I gF ((1R,5S)-3,8-I diazabicyclo [3 .2.1]
octan-3 -y1)-6-(42R,7 aS )-2-fluorotetrahy dro-1H-py rrolizin-7a(5H)-yl)metho xy) -2 -(o xeta n-3 -y1)-2H-py ri m i do [4,5 -e] [1,2] thiazine 1-oxide 227 H 8-(( 1R,5S)-3,8-0 diazabicyclo [3.2.1] octan-3 -y1)-6--S (42R,7aS)-2-fluorotetrahydro-1H-HN F
HO pyrrolizin-7a(5H)-yOmethoxy)-3 -N 0 ' (3 -hydroxynaphthalen-1-y1)-2H-pyrimido [4,5-e] [1,2] thiazine 1-oxide 228 H 44(1R,5S)-3,8-diazabicyclo [3.2.1] octan-3 -y1)-7-N
(3 -hy droxy naphthalen-l-y1)-6-N
I
HO I
methy1-2-MS)-1-methvlpyrrolidin-2-yflmethoxy)pyrido [4,3 -d]py rimidin-5(6H)-one 9 H 4-((1R,5S)-3,8-o diazabicyclo [3.2.1]octan-3 -y1)-6-N
HO cyclopropy1-7-(8-ethyny1-7-fluoro-, N
I 3 -hydroxynaphthalen-1-y1)-8-N 0 ' fluoro-2-(((211,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F
7a(5H)-yl)methoxy)pyrido [4,3-cl]pyrimidin-5(6H)-one 230 H 84(1R,5S)-3,8-0 ? N diazabicyclo [3.2.1] octan-3 -y1)-6-04?
HO , N (( 1 -I I
\.
((dimethylamino)methyl)cyclopro N
py1)methoxy)-3-(8-ethyny1-7-__ fluoro-3 -hydro xynaphthalen-l-y1)-2-(oxetan-3-ylmethyl)-2H-pyrimido [4,5-e] [1,2]thiazine 1,1-dioxide 231 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-N
H2N ((1R,5S)-3,8-N
I I
diazabicyclo [3 .2.1] octan-3 -y1)-6-methy1-2-(((S)-1-methylpyrrolidin-2-yOmethoxy)pyrido [4,3 -d]py ri idi n-5(6H)-o lie 232 H 3-(2-amino-7-N
o fluorobenzo[dlthiazo1-4-y1)-8-F
((1R,5S)-3,8-Xr--N N'S
I
diazabicyclo[3.2.1]octan-3-y1)-2-N 0 ' cyclopropy1-6-(K2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yflmethoxy)-2H-pyrimido[4,5-0[1,2]thiazine 1-oxide 233 H 8-((1R,5S)-3,8-diazabicyclo[3.2.1]oetan-3-y1)-2-N
/\ N N
cyclopropy1-4-fluoro-6-, HO I (((2R,7aS)-2-fluorotetrahydro-1H-N 0 ' pyrro1izin-7a(5H)-y1)met1ioxy)-3-(3-hydroxynaphthalen-1-y1)-2H-pyrimido[4,5-0[1,2]thiazine 1-oxide 234 H 3-(2-amino-7-fluorobenzo[dlthiazol-4-y1)-8-N
H2N ck,ou ((1R,5S)-3,8-N
I
diazabicyclo[3.2.1]octan-3-y1)-4-N
fluoro-6-(((2R,7aS)-2-fluorotetrahydro-11-1-pyrrolizin-7a(5H)-yflmethoxy)-2-methyl-2H-pyrimido[4,5-0[1,2[thiazine 1,1-dioxide 235 H 7-(2-amino-7-fluorobenzo[dlt1iazo1-4-y1)-4-(3-H2 N oxa-7,9-diazab icy elo p .3.1] nonan-N 1"N F
9-y1)-6-cyclobuty1-8-fluoro-2-N 0 =
(((2R,7aS)-2-fluorotetrahydro-1H-F
pyrrolizin-7a(5H)-yflmethoxy)pyrido 14,3 -d]py ri idi n-5(6H)-o lie 236 H 2-(2-amino-7-F f1uorobenzo14lt1iazo1-4-y1)-5-((lR,5S)-3,8-NjtrLN
diazabicyclo[3.2.1]octan-3-y1)-3-(2,2-dffluorocyclopropy1)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimido14,5-d]pyrimidin-4(3H)-one 237 H 3-(2-amino-7-0 fluorobenzo[d]thiazol-4-y1)-8-H2 N 1-1.011 N ((1R,5S)-3,8-diazabicyclo[3.2.1[octan-3 -y1)-2-cyc1obuty1-4-fluoro-6-(R2R,7aS)-F
2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido[4,5-e][1,2]thiazine 1,1-dioxide 238 H 3-(2-amino-7-N
0 fluorobenzo[d]thiazol-4-y1)-8-((1R,5S)-3,8-N
diazabicyclo[3.2.1[octan-3 -y1)-4-FF
fluoro-6-4(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(oxetan-3-y1)-2H-pyrimido [4,5-e][1,2]thiazine 1,1-dioxide 239 H 7-(2-amino-7-fluorobenzo[d]thiazol-4-y1)-4-ON F ((lR,5S)-3,8-N
0 diazabicyclo[3.2.1[octan-3-y1)-6-N
cyclopropy1-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carbonitrile 240 H 2-((1-fO\ 0 ((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-ethyny1-7-N
HO `.--N N tinOro-3-hydroxynaphthalen-1-y1)-6-(oxetan-3-ylmethyl)-4-(2,7-diazaspiro113.51nonan-7-=
yl)pyrido[4,3-cilpyrimidin-5(6H)-F
one 241 H 3 -(2-amino-7-F F fluorobenzo [d]thiazol-4-y1)-8-H2N N ((1R,5S)-3,8-N N
I diazabicyclo [3 .2.1]
octan-3-y1)-2-FF
N 0 ' (2,2 -difluorocyclopropy1)-4-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4.5-e] [1,2] thiazine 1,1-dioxide 242 H 3 -(2-amino-7-fluorobenzo [d] thiazol-4-y1)-8-N
N 0,11 F ((lR,5S)-3,8-, diazabicyclo [3 .2.1] oetan-3-y1)-4-N 0 ' fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(oxetan-3-ylmethyl)-2H-pyrimido [4,5-e] [1,2]thiazi ne 1,1-dioxide 243 H 84(1R,5S)-3,8-diazabicyclo [3 .2.1] oetan-3 -y1)-6-N (42R,7aS)-2-fluorotetrahydro-1H-,,N:S
N
pyrrolizin-7a(5H)-yOmetho xy) -3 -(3 -hydro xy naphtbale n-l-y1)-2-methy1-2H-pyrimido [4,5-e] [1,21thiazine 1,1-dioxide 244 H 3 -(2-amino-7-fluorobenzo [d]thiazol-4-y1)-8-H2N N ((1R,5S)-3,8-, I diazabicyclo [3 .2.1]
octan-3 -y1)-6-N 0 =
(((2R,7aS)-2-fluorotetrahydro-1H-F
pyrrolizin-7a(5H)-yl)metho xy) -2 -methy1-2H-pyrimido [4,5-e] [1,2]thiazi ne 1,1-dioxide 245 H 3-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-8-N F ((lR,5S)-3,8-N
diazabicyclo [3 .2.1] octan-3 -y1)-2-' (cyclopropyl methyl)-6-(((2R,7a S)-F
2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimidol4.5-ell 1,2Ithiazine 1,1-dioxide 246 H 3-(2-anti no-7-fluorobenzo [d] thiazol-4-y1)-8-. R,g ((1R,5S)-3,8-, diazabicyclo [3.2.1] octan-3 -y1)-2-cyclobuty1-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4,5-el [1,2] thiazine 1,1-dioxide 247 H 4-41R,5S)-3,8-F diazabicyclo [3.2.1] octan-3 4 -y1)-6-HO , 0 N
(2,2-difluorocyclopropy1)-2-41 I I
((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-l-y1)-F
8-flitoropyri do [4,3-dlpyrim idin-(6H)-one 248 H 44(1R,5S)-3,8-diazabicyclo 13.2.1 I octan-3 -y1)-2-N

HO ((I-NOçN N
I ((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-ethyny1-7-F
fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-6-(oxetan-3-ylmcthyl)pyrido 5 (6H)-one 249 H 3 -(2-amino-7-fluorobenzo [d] thiazol-4-y1)-8-H2N (( 1R,5S)-3,8-I I diazabicyclo [3 .2.1] octan-3 -y1)-6-(42R,7a S)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmetho xy) -2 -(o xetan-3 -y1)-2H-pyrimido [4,5 -e] [1,21thiazine 1,1-dioxide 250 H 3 -(2-amino-7-F F fluorobenzo [d]thiazol-4-y1)-8-H2N 51) N F ((lR,5S)-3,8-N'S
diazabicyclo [3 .2.1] octan-3-y1)-2-N 0 ' (2,2 -difluorocyclopropy1)-6-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1,1-dioxide 251 H 3 -(2-amino-7-fluorobenzo [d] thiazol-4-y1)-8-N
H2 N F ((lR,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-6-N 0' (((2R,7aS)-2-fluorote1ra1iydro-1H-F
py rrolizin-7a(5H)-yl)metho xy) -2 -(oxetan-3-ylmethyl)-2H-pyrimido [4.5-e] [1,2]thiazine 1,1-dioxide 252 H 8-41R,5S)-3,8-diazabicyclo [3 .2.1] o etan-3 -y1)-6-HN N :S (((2R,7aS)-2-fluorotetrahydro- 1H-I py rrolizin-7a(5H)-yl)metho xy) -3 -HO
N 0 ' (3 -hydro xy nap hthalen-1-y1)-2H-py ri m ido [4,5-e] [1,2]thiazine 1,1-dioxide 253 H 3 -(2-amino-7-fluorobenzo [d] thiazol-4-y1)-8-N
H2N ((1R,5S)-3,8-diazabicyclo [3 .2.1] oetan-3-y1)-6-N 0 ' (((2R,7aS)-2-fluorotetrahydro-1H-F
pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1.1-dioxide 254 H 4-41R,5S)-3,8-o diazabicyclo [3 .2.1] octan-3 -y1)-2-N
((l-=_-I
((dimethylamino)methyl)cyclopro HO HN
N o')Crr py1)methoxy)-7-(8-ethyny1-7-fluo ro-3 -hy d ro xy na phthale n-1 -yl)pyrido [4,3 -d] py rimidin-5 (6H)-one 255 H 44(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-6-HO

cyclopropy1-2-((1-/ N
I
N oKy ((dimethylanaino)methyl)cyclopro ' pyl)metho)-7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-F
yl)pyrido[4,3-dlpyrimidin-5(6H)-one 256 H 3-(2-amino-7-N
fluorobenzo[d]thiazol-4-y1)-8-H2N ((1R,5S)-3,8-N
I
diazabicyclo[3.2.1]octan-3-y1)-2-N 0 ' cyclopropy1-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(511)-yl)methoxy)-2H-pyrimido[4.5-e][1,2]thiazine 1,1-dioxide 257 H 3-(2-amino-7-Mfluorobenzo[d]thiazol-4-y1)-8-(3-oxa-7,9-diazabicyclo[3.3.1]nonan->=N , I 9-y1)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F
7a(5H)-yflmethoxy)-2-(oxetan-3-ylmethyl)-2H-pyrimido[4.5-e][1,2]thiazine 1-oxide 258 H 8-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-2-HO
FL N N cyclobuty1-64(1-I
((dimethylamino)methyl)cyclopro N orpyl)methoxy)-3-(8-ethyny1-7-=_ fluoro-3-hydroxynaphthalen-l-y1)-F
2H-pyrimido[4,5-e][1,21thiazine 1-oxide 259 H 4-41R,5S)-3 ,8-diazabicyclo[3.2.1]octan-3-y1)-7-N
(8-ethyny1-7-fluoro-3 -N
hydroxynaphthalen-1-y1)-8-fluoro-HO
N 0' 2-(((2R,7aS)-2-fluorotetrahydro-1 H-py rrol i 7i n-7a (5H)-y 1)Inellioxy )-6-me thy 1py rido [4,3 -d]pyrimidin-5(6H)-one 260 H 44(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-7-0¨L 0 N
(8-ethyny1-7-fluoro-3 -HOIN N
hydroxynaplithalen-l-y1)-8-fluoro-,, I

2-(((2R,7aS)-2-fluorotetrahydro-F
1H-pyrrolizin-7a(5H)-F yl)methoxy)-6-(oxetan-yl)pyrido[4,3-clipyrimidin-5(6H)-one 261 H 6-((1-((dimethylamino)methyl)cyclopro \/
pyl)methoxy)-3-(8-ethyny1-7-HO 1\1 o N
fluoro-3-hydroxynaphthalen-l-y1)-' I
2-(oxetan-3-ylmethyl)-8-(2,7-N
diazaspiro[3.5]nonan-7-y1)-2H-=
pyrimido[4,5-el[1,2]thiazine 1-F
oxide ((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-o N
it HO
HN,S õ N fluoro-3-hydroxynaphthalen-l-y1)-N 0-')C
2H-pyrimido[4,5-e][1,21thiazine 8-(2,7-diazaspiro[3.51n011an-7-y1)-=_¨
1-oxide 263 H 4-((1R,5S)-3,8-F
diazabicyclo[3.2.1]oetan-3-y1)-6-(2,2-difluorocyclopropy1)-7-(8-HO N
I I ethyny1-7-fluoro-3--.
hydroxynaphthalen-l-y1)-8-fluoro-F
2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cl]pyrimidin-5(6H)-one 264 H 8-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-y1)-2 -N
/N,g N F cyclopropy1-4-fluoro-HO I (((2R,7aS)-2-fluorotetrahydro-1H-N 0 ' pyrro1izin-7a(5H)-y1)methoxy)-3-(3-hydroxynaphthalen-1-y1)-2H-pyrimido[4,5-e][1,2]thiazine 1-oxide 265 H 7-(2-amino-7-F F fluorobenzo [d]thiazol-4-y1)-4-H2N 4y,õ 0 N
((1R,5S)-3,8-N N-N
diazabicyclo [3 .2.1]octan-3 -y1)-6-(2,2-difluorocyclopropy1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyridoP.1,3 -cl]py rimi di n-5(6H)-one 266 4-((1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-7-HO

(8-ethyny1-7-fluoro-3 -'N
hydroxynaphthalen-l-y1)-8-fluoro-,, =
2-(((2R,7aS)-2-fluorotetrahydro-F
1H-pyrrolizin-7a(5H)-F yl)methoxy)-6-(oxetan-ylmethyppyrido [4,3-dlpyrimidin-(6H)-one 267 H 4-41R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-6-(cyclopropylmethyl)-7-(8-ethynyl-HO
N
7-fluoro-3-hydroxynaphthalen-1-.,, y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F 7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-5(6H)-one 268 H 4-41R,5S)-3,8-F diazabicyclo[3.2.1]oetan-3-y1)-6-HO N (2,2-difluorocyclopropy1)-7-(8-, ethyny1-7-fluoro-3-N
hydroxynaphthalen-1 -y1)-2-(42R,7a8)-2-fluorotetrahydro-111-F
pyrrolizin-7a(5H)-yl)methoxy)py rido 114,3 -d]pyrimidin-5(6H)-one 269 H 44(1R,5S)-3,8-0 N)diazabicyclo [3.2.1] octan-3 -y1)-7-(8-ethyny1-7-fluoro-3 -HO
hydroxynaphthalen-l-y1)-2-,,..

(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(oxetan-3-ylmethvl)pyrido [4,3-cl]pyrimidin-5(6H)-one 270 H 4-((1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3-y1)-7-N
hydroxvnaphthalen-l-y1)-2-(8-ethyny1-7-fluoro-3 -HO
HN -'1µl ,,.
(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-F yl)methoxy)pyrido 114,3 -d]pyrimidin-5(6H)-one 271 H 4-41R,5S)-3,8-<N) dia zabicyclo [3 .2.1]octan-3-y1)-6-O
N
HO
cyclopropy1-7-(8-ethyny1-7-fluoro-&N
3 -hydronaphthalen-l-y1)-2-I
N 0 =
(((2R,7aS)-2-fluorotetrahydro-1H-::_¨_ pyrrolizin-7a(5H)-yOmethoxy)pyrido 14,3 -d]py ri m idi n-.5(6H)-o lie 272 H 8-((1R,5S)-3,8-diazabicyclo [3.2.1] octan-3 -y1)-6-HO HN N ((1-N-4Ne)C
\
((dimethylamino)methyl)cyclopro -IN
py 1)methoxy )-3 -(8-e thy ny1-7-=-_ fluoro-3 -hydro xynaphthalen-l-y1)-2H-pyrimido [4,5 -el [1,21thiazine 1,1-dioxide 273 8-41R,5S)-3,8-<1-N1 diazabicyclo [3.2.1]
octan-3 -y1)-3-o M\I (8-ethyny1-7-fluoro-3 -HO ''N'S
IIJItL.S hydroxvnaphthalen-l-y1)-4-fluoro-N 0 ' 6-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-F yl) m ethoxy)-2-methy1-2H-py rimido [4,5-e] [1,2] thiazine 1-oxide 274 H 84(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-2-(cyclopropylmethyl)-3-(8-ethynyl-HO , I 7-fluoro-3-hydroxynaphthalen-1-N 0 ' y1)-4-fluoro-6-(K2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F 7a(5H)-yflmethoxy)-2H-pyrimido[4,5-e][1,2]thiazine 1-oxide 275 H 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-2-HO

(((2R,7aS)-2-fluorotetrahydro-11-1-CN
HN I
pyrrolizin-7a(5H)-yOmethoxy)-7-N e61 (3-hydroxynaphthalen-l-y1)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-earbonitrile 276 H 7-(2-amino-7-fluorobenzo[d]thiazol-4-y1)-4-N
H2N ((1R,5S)-3,8-CN
, diazabicyclo[3.2.1]octan-3-y1)-2-N
(((2R,7aS)-2-fluorotetrahydro-1H-F
pyrrolizin-7a(5H)-yflmethoxy)-6-(oxetan-3-ylmethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carbonitrile 277 H 2-cyclobuty1-6-((1-N
((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-HO
L I N
oro-3 -hy droxynaphthalen-l-y1)-I
flu4-fluoro-8-(2,7-N
diazaspiro[3.51nonan-7-y1)-2H-7_-_-pyrimido[4.5-el[1,2]thiazine 1-F
oxide 278 H 8-41R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-6-0,11 HO N , I I
((dimethylamino)methyl)cyclopro N
py1)methoxy)-3-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-F
2-methy1-2H-pyrimido [4,5-e][1,21thiazine 1,1-dioxide 279 H 7-(2-amino-7-( fluorobenzo [d] thiazol-4-y1)-4-N
H2N 1)1 0 ((1R,5S)-3,8-diazabicyclo [3.2.1]octan-3 -y1)-8-N 0 ' fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(oxetan-3 -yl)pyrido [4,3 -dlpyrimidin-5(6H)-one 280 H 8-((1R,5S)-3,8-diazabicyclo [3.2.1] octan-3 -y1)-3-HO NSI
LN (8-ethyny1-7-fluoro-3 -L.-hydroxynaphthalen-1-y1)-4-fluoro-,, N 0 ' 6-(((2R,7aS)-2-fluorotetrahydro-F
1H-pyrrolizin-7a(5H)-F yl)methoxy)-2-(oxetan-3-y1)-2H-pyrimido [4.5-e] [1,2]thiazine 1-oxide 281 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-(3-N FL, 0 N
oxa-7,9-diazabicyclo [3 .3.1] nonan-N
I Nr1,0,,,6S, 9-y1)-6-cyclobuty1-2-4(2R,7aS)-2-H2 N fluorotetrahydro-11i-pyrrolizin-F
7a(5H)-yl)methoxy)py rido [4,3 -d]pyrimidin-5(6H)-one ((dimethylamino)methyl)cyclopro \ N pyl)methoxy)-3-(8-ethyny1-7-C
HO N fluoro-3 -hy dro xy naphthalen-l-y1)-4-fluoro-2-(oxetan-3-ylmethyl)-8-N cy")C=N'' (2,7-diazaspiro [3.5]nonan-7-y1)-=
2H-pyrimido [4,5 -e] [1,21thiazine 1-oxide 283 H 8-41R,5S)-3,8-diazabicyclo [3.2.1] octan-3 -y1)-3-( 8-ethyny1-7-fluoro-3 -HO N'S N
I hydroxynaphthalen-l-y1)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroli zi n-7a(5H)-yOmethoxy)-2-F me thy1-2H-py rimido [4,5-e] [1,2]thiazine 1-oxide 284 H 84(1R,5S)-3,8-N
0 ( 5? N
diazabicyclo [3.2.1] octan-3 -y1)-6-HO
0 .
--. :SI ((1-N , N I
--... N-----0)CN"--((dimethylamino)methyl)cyclopro r-'--F I pyl)methoxy)-3 -(8-ethyny1-7 -=_-fluoro-3-hydroxynaphthalen-l-y1)-F
4-fluoro-2-(oxetan-3-vlmethyl)-2H-pyrimido [4,5-e] [1,2] thiazine 1,1-dioxide 285 H 8-((1R,5S)-3,8-N
diazabicyclo [3.2.1] clan-3 -y1)-2-I A F cyclobuty1-3-(8-ethvny1-7-fluoro -HO N , ' N
I 1 3 -hydro xynaphthalen-1-y1)-6-(((2R,7aS)-2-fluorotetrahy dro-1H-- pyrrolizin-7a(5H)-yl)methoxy)-F 2H-pyrimido [4,5-e]
[1,2] thiazine 1-oxide 286 H 4-41R,5S)-3,8-IT' N
) diazabicyclo [3.2.1]
octan-3 -y1)-7-HO ¨L 0 N
F (8-ethyny1-7-fluoro-3-hy dro xv naphthalen-l-y1) -2-õ, I ,,.

N (42R,7aS)-2-fluorotetrahydro-1H-= py rrolizin-7a(5H)-yOmetho xy) -6 -F (o xeta n-3 -yl)py rido [4,3 -d]pyrimidin-5(6H)-one 287 H 6-eyelobuty1-2-((1-N

((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-ethyny1-7-HO 'N N
.., N
fluoro-3 -hy dro xy naplithalen-l-y1)-N , --, 4-(2,7-diazaspiro [3 .51 nonan-7-_______________ I yl)pyrido [4,3 -cil pyrimidin-5(6H)-=-_ one F
288 H 8-41R,5S)-3,8-N
) diazabicyclo [3.2.1]
octan-3 -y1)-3-? ¨1 9 N (8-ethyny1-7-fluoro-3 -HO ',NJ-5 ---. N F
hydroxvnaphthalien-l-y1) -6-N (((2R,7aS)-2-fluorotetrahydro-1H-=_ py rrolizin-7a(5H)-yl)metho xy) -2 -F (o xe tan-3 -y1)-2H-py rimido [4,5 -e] [1,2] thiazine 1-oxide 289 H 44(1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 o N
cyclopropy1-2-4(2R,7aS)-2-N F
HO fluor t etrally dro-11-1-pyrrolizill-N 0 ' 7a(5H) -yflmetho xy)-7-(3 -hy dro xynaphthalen-1-yl)py rido [4,3 -d] pyrimidin-5 (6H)-one 290 H 8-((1R,5S)-3,8-diazabicyclo [3 .2.1] oetan-3 -y1)-2-HO ---N-C3g N
(2,2-difluorocyclopropy1)-3 -(8-1 I ethyny1-7-fluoro-3 N hy dro xynaphthalen-1 -y1) -6-(((2R,7aS)-2-fluorotetrahydro-1H-F
pyrrolizin-7a(5H)-yOmethoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1-oxide 291 H 3-(2-amino-7-fluorobenzo [di thiazol-4-y1)-8-H2N N ((1R,5S)-3,8-I Nej. diazabicyclo [3 .2.1]
octan-3 -y1)-2-cy clopropy1-4-fluo ro -6 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrroli zi n-7a(5H)-yOmethoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1,1-dioxide 292 H 8-41R,5S)-3,8-diazabicyclo [3 .2.1] clan-3 -y1)-3 -(8-ethyny1-7-fluoro-3 -HO -S F
hy dro xynaphthalen-1 -y1) -6-N 0 ' (((2R,7aS)-2-fluorotetrahydro-1H--pyrrolizin-7a(5H)-yflmethoxy)-2H-py rimido [4,5-e] [1,21thiazine 1-oxide 293 H 84(1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-2-HO N cyclopropy1-3-(8-ethyny1-7-fluoro-N
F
6_s 3 -hydro xynaphthalen-l-y1)-6-N 0 ' (((2R,7aS)-2-fluorotetrabydro-1H-=_ pyrrolizin-7a(5H)-yOmethoxy)-F

2H-pyrimido14,5-e l 1 1,2Ithiazine 1-oxide o N
diazabicyclo [3.2.1] octan-3 -y1)-2-HO 7\-= cyclopropy1-3-(8-ethyny1-7-fluoro-, N
3 -hydroxynaphthalen-l-y1)-4-N N
fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F
7a(5H)-yl)methoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1-oxide 295 H 8-41R,5S)-3,8-diazabicyclo [3.2.1] oetan-3 -y1)-2-cyclopropy1-3-(8-ethyny1-7-fluoro-N

3 -hydroxynaphthalen-l-y1)-6-I j =
(42R,7aS)-2-fluorotetrahydro-1H-____ pyrrolizin-7a(5H)-yOmethoxy)-2H-pyrim i do [4,5-e] [1, 21thia zinc 1,1-dioxide 296 H 44(1R,5S)-3,8-diazabicyclo I 3.2.1 I octan-3 -y1)-6-N N
y N
HO (cyclopropylmethyl)-24(1-I
((dimethylamino)methyl)cyclopro pylnnethoxy)-7-(8-ethyny1-7-fluoro-3 -hydro xynaphthalen-1-y1)-8-fluoropyrido [4,3-di pyrimidin-(6H)-onc 297 84(1R,5S)-3,8-(Ed diazabicyclo [3.2.1] octan-3 -y1)-3-0,11 (8-ethyny1-7-fluoro-3 -HO %S
F
hydroxvnaphthalen-1-y1)-4-fluoro-N 0 ' 6-(42R,7aS)-2-fluorotetrahydro-1H-pyn-oli zin-7a (5H)-yflmethoxy)-2-methy1-2H-pyrimido [4.5-e] [1,2]thiazine 1,1-dioxide 298 H 84(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-2-L
HO :04 N
cyclobuty1-3-(8-ethyny1-7-fluoro-F
I 3-hydroxynaplithalen-l-y1)-4-N 0 ' fluoro-6-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F 7a(5H)-ylnuethoxy)-2H-pyrimido[4,5-e][1,2]thiazine 1,1-dioxide 299 H 8-((1R,5S)-3,8-F diazabicyclo[3.2.1]octan-3-y1)-2-O N
(2,2-difluorocyclopropy1)-3-(8-HO N
I ethyny1-7-fluoro-3-N 0 ' hydroxynaplithalen-l-y1)-4-fluoro-F
6-(((2R,7aS)-2-fluorotetrahydro-F 1H-pyrrolizin-7a(5H)-yOmetboxy)-214-pyrimido[4,5-e][1,2]thiazine 1,1-dioxide 300 H N 2-cyclobuty1-6((1-((dimethylamino)methyl)cyclopro o pyl)methoxy)-3-(8-ethyny1-7-HO N
N fluoro-3-hydroxynaphthalen-1-y1)-I 8-(2,7-diazaspiro[3.5]nonan-7-y1)-N
2H-pyrimido[4,5-e][1,21thiazine =-_ 1-oxide ((dimethylamino)incthyl)cyclopro N
pyl)methoxy)-3-(8-ethyny1-7-HO , N
I fluoro-3-hydroxynaphthalen-1-y1)-2-(oxetan-3-y1)-8-(2,7--...-NON
diazaspirop.5]nonan-7-y1)-2H-____ pyrimido[4.5-e][1,2]thiazine 1-F
oxide 302 H 84(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-3-(8-ethyny1-7-fluoro-3-HO , N
I
hydroxvnaphthalen-l-y1)-4-fluoro-N 0 ' 6-(((2R,7aS)-2-fluorotetrahydro-=-_ 1H-pyrrolizin-7a(5H)-F yflinethoxy)-2-(oxetan-3-ylmethyl)-2H-pyrimido14,5 -e] [1,2lthiazine 1,1-dioxide Ed <

diazabicyclo [3.2.1] octan-3 -y1)-3 -(8-ethyny1-7-fluoro-3 -HO 'r\i'S N
I ,A hydroxvnaphthalen- 1 -y1)-6-W2R.7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-2-F methy1-2H-pyrimido [4,5-e] [ 1,21 thiazine 1,1-dioxide 304 H 8-41R,5S)-3,8-yin 0 diazabicyclo [3.2.1] octan-3 -y1)-2-(cyclopropylincthyl)-3 -(8-cthynyl-HO N-S
-`N
7-fluoro-3 -hydroxynaphthalen- 1 -I
N 0 ' y1)-6-(n2R,7aS)-2-fluorotetrahydro-1H-pyrrohzin-F 7a(511)-yl)methoxy)-pp-int ido [4,5-el [ 1,2]tbia zinc 1,1 -dioxide 305 84(1R,5S)-3,8-diazabicyclo13.2.11octan-3 -y1)-2-N cyclobuty1-3 -(8-ethyny1-7-fluoro -HO === N N
3 -hydroxynaphthalen- 1 -y1)-6-(((2R,7aS)-2-fluorotetrahydro- 1H-=-_ pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4,5 -el [1,21thiazine 1,1-dioxide (kli) 8-((1R,5S)-3,8-diazabicyclo [3.2.1] octan-3 -y1)-3 -N
I L-k:g (8-ethyny1-7-fluoro-3 -HO
hydroxvnaphthalen- 1 -y1)-6-(42R,7aS)-2-fluorotctrahydro-111-¨
pyn-olizin-7a(5H)-yOmethoxy)-2-F (oxetan-3 -y1)-2H-pyrimido [4,5 -el [1,2lthiazine 1,1-dioxide 307 H 84(1R,5S)-3,8-F F diazabicyclo [3 .2.1]
octan-3 -y1)-2-, 0 N
0,11 (2,2-difluorocyclopropy1)-3 -(8-NS
( ethy ny1-7-fluoro-3 -hydro xTnaphthalen-1 -y1)-6-(((2R,7aS)-2-fluorotetrahydro-1H-F pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4,5 -e] [1,21 thiazine 1,1-dioxide 308 H 8-((1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-3-0o N
(8-ethyny1-7-fluoro-3 -I hydroxynaphthalen-1 -y1)-6-(((2R,7aS)-2-fluorotetrahydro-1H-____ pyrrolizin-7a(5H)-yOmethoxy)-2H-pyrimido [4,5 -e] [1,2] thiazine 1,1-dioxide 309 H 3-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-8-H2N si? N
((1R,5S)-3,8-I Nej. diazabicyclo [3 .2.1]
octan-3 -y1)-2-cyclopropy1-4-fluo ro -6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroli zi n-7a(5H)-yOmethoxy)-2H-pyrimido [4,5 -e] [1,2] thiazine 1-oxide 310 6-(cyclopropylmethyl)-2-(( 1-((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-ethyny1-7-y 0 N
Ho N fluoro-3 -hydro xynaphthalen-1-y1)-I 8-fluoro-4-(2,7-N
diazaspiro [3.5] nonan-7-yl)pyrido [4,3 -d] pyrimidin-5(6H)-one 311 H 84(1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 N
0.11I fluoro-6-(((2R,7aS)-2-fluorotetrahydro-11i-pyrrolizin-N 0 ' 7a(5H)-y1) methoxy)-3 -(3-hy droxy naphthalen-1 -y1)-2-methv1-2H-pyrimido14,5-e] [1,21thiazine 1,1-dioxide diazabicyclo [3 .2.1] octan-3 -y1)-2-O N
HO
cyclopropy1-3-(8-ethyny1-7-fluoro-N
I 3 -hydroxynaphthalen-l-y1)-4-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F
7a(5H)-yl)methoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1,1-dioxide 313 H 4-41R,5S)-3,8-o diazabicyclo [3 .2.1] oetan-3 -y1)-2-N
HO `-= N
N (( 1 -C
((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-l-y0-F
8-flimm-6-m et hylpyrido [4,3 -d]pyrimidin-5 (6H)-one 314 H 44(1R,5S)-3,8-o diazabicyclo 13.2.1 I octan-3 -y1)-6-HO N
N
cy clobuty1-24(1 -N
((dimethylamino)methyl)cyclopro N nc-pyl)methoxy)-7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-l-y1)-F
8-fluoropyrido [4,3-dlpyrimidin-(6H)-one 315 H 7-(2-ami no-7-N
F F fluorobenzo [d]thiazol-4-y1)-4-h2N 4, N
((lR,5S)-3,8-N0 , N
diazabicyclo [3 .2.1] octan-3 -y1)-6-(2,2-difluorocyclopropy1)-2-((( S)-1 -methylpyn-ol idi n-2-yl)methoxy)py rido [4,3 -d]pyrimidin-5 (6H)-one 316 H 44(1R,5S)-3,8-diazabicyclo [3 .2.1]octan-3 -y1)-2-HO _________________ ci)¨L N
((1-N
I ), ((dimethylamino)methyl)cyclopro pyl)metho)-7-(8-ethyny1-7-F
fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-6-(oxetan-3-yl)pyrido [4,3 -d] pyrimidin-5 (6H)-one 317 H 4-((1R,58)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-2-((1-HO
NN
I I
((dimethylamino)methyl)cyclopro pyl)methoxy )-7-(8-e thy ny1-7 -=-_ fluoro-3-hydroxynaphthalen-l-y1)-F
6-methylpyrido [4,3 -dlpy rimidin-(6H)-one 318 H 4-41R,5S)-3,8-diazabicyclo [3 .2.1]octan-3 -y1)-7-N
HO (8-ethyny1-7-fluoro-3-I hy dro xv naphthalen-l-y1) -2-(42R,7aS)-2-fluorotetrahydro-1H-_ py rrolizin-7a(5H)-yOmetho xy) -6 -Inethylpy ri do [4,3 -d] py rimidi ii-5(6H)-one 319 H 4-(( 1R,5S)-3,8-HO \( o N
diazabicyclo [3 .2.1]oetan-3 -y1)-6-(cy clopropylmethyl)-24(1-I
((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-ethyny1-7-fluoro-3 -hy dro xynaphthalen- 1-yl)pyrido [4,3 -d] pyrimidin-5 (6H)-one 320 H 4-41R,5S)-3,8-diazabicyclo [3 .2.1]octan-3 -y1)-6-HO N
cyclobuty1-24( 1--`1\1 I I
((dimethylamino )methyl)cyclopro pyl)methoxy)-7-(8-ethyny1-7-fluo ro-3 -hy d ro xy na plithale n-1 -yl)pyrido [4,3 -c11 py rimidin-5 (6H)-one 321 H 3-(2-amino-7-F F
Q N
H2N N,S fluorobenzo[d]thiazol-4-y1)-8-((1R,5S)-3,8-N-N
diazabicyclo [3.2.1] octan-3-y1)-2-(2,2 -difluorocyclopropy1)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4,5 -e] [1,21thiazine 1-oxide 322 H 3 -(2-amino-7-fluorobenzo [di thiazol-4-y1)-8-N
((1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3-y1)-6-(((2R,7aS)-2-fluorote1ra1iydro-1H-F
pyrrolizin-7a(5H)-yOmethoxy)-2-(oxetan-3-ylmethyl)-2H-pyrimido [4.5-e] [1,2]thiazine 1-oxide 323 H 4-41R,5S)-3,8-o diazabicyclo [3.2.1] octan-3-y1)-2-N
HON ((I-I ((dimethylamino)methyl)cyclopro py1)methoxy)-7-(8-ethyny1-7-fluo ro-3-hyd ro xy naphthale n-l-y1)-6-(oxetan-3-yOpyrido [4,3 -d]pyrimidin-5(6H)-one 324 H 4-41R,5S)-3,8-diazabicyclo [3 .2.1] octan-3-y1)-8-N
CN F fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-HO
N
7a(51-1)-yl)methoxy)-7-(3 -hydroxynaphthalen- 1-y1)-6-methyl-5 -oxo-5.6-dihydro- 1,6-napirthy rid i ne-3-ca tho n it rile 325 H 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-4-N
H2N ((lR,5S)-3,8-CN
N
diazabicyclo [3.2.1] octan-3-y1)-8-fluoro-2-(((2R,7aS)-2-fluor tetrahy dro- 1H-py rrolizin-7a(5H)-yOmethoxy)-6-methy1-5 -oxo-5,6-dihydro-1,6-naphthyridine-3-carbonitrile 326 H 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-6-, N
HO (2,2-duorocyclopropy1)-2-41-N , N,I
((dimethylamino)methyl)cyclopro N ifl pyl)methoxy)-7-(8-ethyny1-7-F
=-_ fluoro-3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-5(6H)-one 327 H 8-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-y1)-6-HNg N (((2R,7aS)-2-fluorotctrahydro-1H-, HO 1 N pyrrolizin-7a(5H)-yOmetho xy) -3-(3-hydroxynaphthalen-1-y1)-2H-pyrimido[4,5-el [1,2]thiazine 1-oxide 328 H 3-(2-amino-7-N
fluorobenzo[d]thiazol-4-y1)-8-(3-o H2N 1, HN oxa-7,9-diazabicyclo[3.3.11nonan-'S
F
s I 9-y1)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F
7a(5H)-yl)methoxy)-2H-pyrimido[4,5-e][1,2]thiazine 1-oxide 329 H 4-41R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-2-HO *--.N , N

((dimethylamino)methyl)cyclopro N e)CN"
pyHmethoxy)-7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-l-y1)-F
6-(oxctan-3-ylmethyl)pyrido [4,3-d]pyrimidin-5(6H)-one 330 H 44(1R,5S)-3,8-o N
diazabicyclo[3.2.1]octan-3-y1)-6-A, HO cyclopropy1-2-((1-N
o'r ((dimethylamino)methyl)cyclopro )<Th pyl)methoxy)-7-(8-ethyny1-7-F
fluoro-3-hydroxynaphthalen-l-y1)-8-fluoropyrido[4,3-d]pyrimidin-5(6H)-one 331 H 6-( (1-O
((dimethylamino)methyl)cyclopro L N pyl)methoxy)-3-(8-ethyny1-7-HO ¨o N
I =:s flu o ro-3 -hy dro xy naplithalen-l-y1)-I I
2 -(o xetan-3 -y1)-8-(2,7-N
diazaspiro [3 .5[ nonan-7-y1) -2H-pyrimido [4.5-e] [1,2] thiazine 1,1-F
dioxide 332 H 8-((1R,5S)-3,8-NI
0 Q diazabicyclo [3 .2.1]
octan-3 -y1)-3-(8-ethyny1-7-fluoro-3 -HO S
I hy dro xv naphthalen-1 -y1) -4-fluo ro-N 0 =
6-(((2R,7aS)-2-fluorotetrahydro-1H-py rrolizin-7a(5H)-F
yl)methoxy)-2-(oxetan-3-y1)-2H-pyrimido [4,5-e] [1,2] thiazine 1,1-dioxide 333 H 8-41R,5S)-3,8-HO
,V diazabicyclo [3.2.1] o ctan-3 -y1)-2-N
(cy elopropy lmethyl)-64(1-, I I
((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-_-fluoro-3-hydroxynaphthalen-1-y1)-F
4-fluoro-2H-py ri m i do [4,5 -e] [1,2] thiazine 1-oxide 334 H 8-(( 1R,5S)-3,8-diazabicyclo [3 .2.1] o ctan-3 -y1)-2-N cy clobuty1-64(1 -HO
I I ((d ime thy lamino)methyl)cy clopro N
pyl)methoxy)-3-(8-ethyny1-7-z-_-_ fluoro-3-hydroxynaphthalen-l-y1)-F
4-flu o ro-2H-py rimid o [4,5 -e] [1,2] thiazine 1-oxide 335 H 8-41R,5S)-3,8-diazabicyclo [3.2.1] o ctan-3 -y1)-6-(:1)1 N
HO , N (( I I
((dimethylamino)methyl)cyclopro N
py1)methoxy)-3-(8-ethyny1-7-:=
fluoro-3-hydroxynaplithalen-1-y1)-F
4-fluo ro-2-(o xe tan-3-y1)-2H-PYrimido I 4,5-e l 1,2Ithiazine 1-oxide 336 H 2-(2-amino-7-fluorobenzo [d] thiazol-4-y1)-5 -N
H2 N)((1R,5S)-3,8-õ.= diazabicyclo [3 .2.1[
octan-3 -y1)-7-W2R.7aS)-2-fluorotetrahydro-1H-F
pyrrolizin-7a(5H)-yl)methoxy) -3 -(o xetan-3 -ylmethy 1)py rimido [4,5 -d] py rimidin-4(3H)-one 337 H 5-41R,5S)-3,8-o diazabicyclo [3.2.1] octan-3 -y1)-7-N
(((2R,7aS)-2-fluorotctrahydro-1H-HN)1.1".
F
HO pyrrolizin-7a(5H)-yOmethoxy) -2 -IN (3 -hydro xy nap hthalen-1-yl)pyrimido [4,5-d] pyrimidin-4(3H)-one 338 H 8-((1R,5S)-3,8-1? N
diazabicyclo [3.2.1] octan-3 -y1)-6-NC ((1 -HO N
I I
((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-=
fluoro-3-hydroxynaphthalen-l-y1)-F
4-fluoro-2-(oxetan-3-ylmethyl)-2H-py rimido [4,5 -e] [1,2] thiazine 1-oxide 339 H 8-41R,5S)-3,8-diazabicyclo [3 .2.1] octa n-3-y1)-6-N
HO , N ((1-1 ((dimethylamino)methyl)cyclopro N 02c r pyl)methoxy)-3-(8-ethyny1-7-=_-fluoro-3-hydroxynaphthalcn-l-y1)-F
2-m ethy1-2H-pyri mi do [4,5-e] [1,2] thiazine 1-oxide 340 H 84(1R,5S)-3,8-V N diazabicyclo [3.2.1]
octan-3 -y1)-2-Ho N s N
(cy clopropy lmethyl)-64(1-I I
((dimethylamino)methyl)cyclopro N
pyl)methoxy)-3-(8-ethyny1-7-__ fluoro-3 -hy dro xynaphthalen-l-y1)-2H-pyrimido14,5-e111,21thiazine 1-oxide F 4 diazabicyclo [3 .2.1] octan-3 -y1)-2-HO N
, 9 N
(2,2-difluorocyclopropy1)-6-41 -,S
I ((dimethylamino)methyl)cyclopro N c!)CN=='' pyl)methoxy)-3-(8-ethyny1-7-____ fluoro-3 -hydro xynaphthalen-l-y1)-2H-pyrimido [4,5 -e] [1,21 thiazine 1-oxide 342 H 6-((1-((dimethylamino)methyl)cyclopro pyl)methoxy)-3 -(8-cthyny1-7 -HO NS (N

fluoro-3 -hydro xynaphthalen-l-y1)-'''` ===== 1 N
2-methyl-8-(2,7-N
diazaspiro [3 .5] nonan-7-y1) -2H-pyrimido [4.5 -e] [1,2]thiazine 1,1-F
dioxide 343 H 7-(2-amino-7-O fluorobenzo [d]thiazol-4-y1)-4-CN

((1R,5S)-3,8-N
diazabicyclo [3 .2.1[ octan-3 -y1)-6-N
cyclopropy1-8-fluo ro -2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5 -oxo-5,6-dihy dro-1,6-naphthyridinc-3-carbonitrilc 344 H 5-((1 R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-7-N
(((2R,7aS)-2-fluorotetrahydro-1H-N-jk'N
HO Iy pyrrolizin-7a(5H)-yl)methoxy) -2 -N N 0 ' (3 -hydroxynaphthalcn-1-y0-3 -methyl pyri m ido [4, 5-d] pyri m idin-4(3H)-one 345 H 84(1R,5S)-3,8-N) diazabicyclo [3 .2.1] octan-3 -yl)-2-HO (cy clopropylmethyl)-3 -(8-ethynyl-NJ.8 , N
7-fluoro-3-hydroxynaphthalen-1-õ, N 0 ' yl) -4 -fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-F 7a(5H)-yl)methoxy )-2H-pyrimidol4.5-ell 1,2Ithiazine 1,1-dioxide diazabicyclo [3.2.1] octan-3-y1)-6-( HO
N_S(LN

(1-k ((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-=_ fluoro-3-hydroxynaphthalen-l-y1)-F
2-(oxetan-3-ylmethyl)-2H-py rimido [4,5-e] [1,2] thiazine 1-oxide 347 H 8-41R,5S)-3,8-diazabicyclo [3.2.1] oetan-3-y1)-6-N
HO
HN,S ((1-"
IN ((dimethylamino)methyl)cyclopro N c0C/J-pyl)methoxy)-3-(8-ethyny1-7-=
fluoro-3-hydroxynaphthalen-l-y1)-F
2H-pyrim i do [4,5 -el [1,21thia zinc 1-oxide 348 H 44(1R,5S)-3,8-<¨> diazabicyclo I 3.2.1 I octan-8-y1)-2-(((2R.7aS)-2-fluorotetrahydro-1H-,,N
I pyrrolizin-7a(5H)-yOmethoxy)-7-(3-hydroxynaphthalen-l-y1)-6-methylpyrido [4,3 -dlpyrimidin-5(6H)-one 349 H 7-(2-amino-7-o fluorobenzo [d]thiazol-4-y1)-4-N
H2N ((1R,5S)-3,8-, I diazabicyclo [3 .2.1] octan-8-y1)-2-N
W2R,7aS)-2-fluorotetrahydro-1H-F
pyrrolizin-7a(5H)-yOmethoxy)-6-methyl pyri do [4,3 -dlpyrimi di n-5(6H)-one 350 H 84(1R,5S)-3,8-diazabicyclo [3.2.1] octan-3-y1)-2-= N
N
HO cyclopropy1-6-41-I
N )N (D M
((dimethylamino)methyl)cyclopro X\r pyl)methox-T)-3 -(8-ethyny1-7-fluoro-3-hydroxynaphthalen-l-y1)-F 2H-pyrimido [4,5 -e]
[1,21thiazine 1-oxide 351 H 8-((1R,5S)-3,8-NJ
diazabicyclo [3.2.1] octan-3-y1)-2-= N
Z\--, cyclopropy1-6-((1-N
I
((dimethylamino)methyl)cyclopro HO N
N
py1)methoxy)-3 -(8-ethyny1-7-F
fluoro-3-hydroxynap1i11ia1en-l-y1)-4-fluoro-2H-pyrimido [4,5-e] [1,21th1azi11e 1-oxide 352 H 8-41R,5S)-3,8-dia zabicyclo [3 .2.1]octan-3-y1)-2-Ho N
= N
cyclobuty1-641-I
((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-=_ f1uoro-3-hydroxynaphthalen-l-y1)-F
4-fluoro-2H-pyrimido [4,5-e] [1,21thiazine 1,1-dioxide 353 H 84(1R,5S)-3,8-diazabicyclo [3.2.1] octan-3-y1)-6-?¨L N
HO N (O-N
N
((dimethylamino)methyl)cyclopro py 1)methoxy )-3 -(8-e thy ny1-7-F
fluoro-3-hydroxynaphthalen-1-y1)-4-fluoro-2-(oxetan-3-y1)-2H-pyrimido [4.5-e] [1,2]thiazine 1,1-dioxide 354 H 8-41R,5S)-3,8-0 diazabicyclo [3.2.1]
octan-3-y1)-3-N
( 8-ethyny1-7-fluoro-3 -HO INõ., -TX F
hydroxynaphthalen-l-y1)-6-N 0 ' (((2R,7aS)-2-fluorotetrahydro-1H-= pyrroli zin-7a(5H)-yOmethoxy)-2-F (oxetan-3-y lmethyl)-PYrimido I 4,5-e l 1,2Ithiazine oxide diazabicyclo[3.2.1[octan-3-y1)-2-O N
N N
cyclopropy1-4-fluoro-6-I N (((2R,7aS)-2-fluorotetrahydro-1H-HO
pyrrolizin-7a(5H)-yl)methoxy)-3-(3-hydroxynaphthalen-1-y1)-2H-pyrimido[4,5-e][1,2]thiazine 1,1-dioxide 356 H 7-(2-amino-7-fluorobenzo[d]thiazol-4-y1)-4-o N
H2N ((1R,5S)-3,8-N , 1 1 diazabicyclo[3.2.1[octan-3-y1)-2-'' (((S)-1-methylpyrrolidin-2-F
yl)methoxy)-6-(oxetan-3-ylmethyl)pyrido[4,3-d]pyrimidin-5(6H)-one 357 H 6-((1-e0 ((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-HO
Xo4 N
N
fluoro-3-hydroxynaphthalen-1-y1)-, 2-(oxetan-3-ylmethyl)-8-(2,7-diazaspiro[3.51nonan-7-y1)-2H-=_-pyrimido[4,5-e][1,2]thiazine 1,1-F
dioxide 358 H 8-41R,5S)-3,8-diazabicyclo[3.2.1[octan-3-y1)-2-HO I Ls N cyclobuty1-64(1-N , ((dimethylamino)methyl)cyclopro WIN
pyl)methoxy)-3-(8-ethyny1-7-fluoro-3-hydroxynaphthalcn-l-y1)-F
2H-pyrimido[4,5-e][1,21thiazine 1,1-dioxide 359 H 84(1R,5S)-3,8-diazabicyclo[3.2.1[octan-3-y1)-6-N
(O-HO 1\16 N

((dimethylamino)methyl)cyclopro N
____________________________________ 1 pyl)methoxy)-348-ethynyl-7-____ fluoro-3-hydroxynaphthalen-l-y1)-F

2-(oxetan-3-y1)-2H-pyrimido I 4,5-e] [1,21thiazine 1,1-dioxide diazabicyclo[3.2.1]octan-3-y1)-2-4ko,9 N
HO 1::S (2,2-difluorocyclopropy1)-6-41-N
((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-F
=_ fluoro-3-hydroxynaphthalen-l-y1)-2H-pyrimido [4,5 -e] [1,21thiazine 1,1-dioxide 361 H 8-41R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-2-o N
HO / Ni ,N cyclopropy1-6-((1-N
I
((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-=_ fluoro-3-hydroxynaphthalen-l-y1)-F
2H-pyrimido [4,5 -e] [1,21thiazine 1,1-dioxide 362 H 84(1R,5S)-3,8-o diazabicyclo[3.2.1]octan-3-y1)-2-N
4 N cyclopropy1-6-((1-N , ((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-F
fluoro-3-hydroxynaphthalen-l-y1)-4-fluoro-2H-pyrimido [4,5-el [1,21thiazine 1,1-dioxide 363 H 8-41R,5S)-3,8-diazabicyclo [3.2.1]octan-3-y1)-3-0 (13 N (8-ethyny1-7-fluoro-3-HO -.NS .."'N
hydroxynaphthalen-l-y1)-6-W2R,7aS)-2-fluorotetrahydro-1H-___ pyrrolizin-7a(5H)-yOmethoxy)-2-(oxetan-3-ylmethyl)-2H-pyrimido[4,5-e][1,2]thiazine 1,1-dioxide 364 H 2-(0-((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-ethyny1-7-0 Nr-HON '`N fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-6-methyl-4-(2,7-N
diazaspiro113.5]nonan-7-=_-yl)pyrido[4,3-d]pyrimidin-5(6H)-F
one 365 H 6-cyclobuty1-2-((1-((dimethylamino)methyl)cyclopro pyflmethoxy)-7-(8-ethyny1-7-HO N N fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-4-(2,7-N 0)Crr diazaspiro[3.5]nonan-7-=
yl)pyrido[4,3-d]pyrimidin-5(6H)-F
one 366 H 8-41R,5S)-3,8-diazabicyclo[3.2_1[oetan-3-y1)-2-A,,C4 cyclopropy1-6-4(2R,7aS)-2-N
HO I fluorotetrahydro-1H-pyrrolizin-N 0 ' 7a(5H)-yOmethoxy)-3-(3-hydroxvnaphthalen-1-y1)-2H-pyrimido[4,5-e][1,2]thiazine 1,1-dioxide 367 H 2-((1-((dimethylamino)methyl)cyclopro 7¨L
pyl)methoxy)-7-(8-cthyny1-7-s fluoro-3-hydroxynaphthalen-1-y1)-I k 8-fluoro-6-(oxetan-3 -y1)-4-(2,7-N'e)<The diazaspiro[3.5]nonan-7-=
yl)pyrido[4,3-d]pyrimidin-5(6H)-F
one 368 H 4-41R,5S)-3,8-diazabicyclo[3.2.1]octan-3-y1)-6-N
N CNF cyclopropy1-8-fluoro-1 (((2R,7aS)-2-fluorotetrahydro-1H-HO
N 0-'6S
pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphtha1en-l-y1)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carbonitrile 369 H 84(1R,5S)-3,8-O diazabicyclo [3 .2.1]
octan-3 -y1)-2-O N
cyclopropy1-6-(((2R,7aS)-2-s 111, F
fluoroteOrally dro- 1H-pynoliziii-7a(5H)-yl)methoxy)-3 -(3 -hy dro xv naphthalen-1-y1) -2H-py rimido [4.5-e] [1,2] thiazine 1-oxide 370 H 6-(2,2-difluorocyclopropy0-2-((1-N
((dimethylamino)methyl)cyclopro ;\s.: o pyflmethoxy)-7-(8-ethyny1-7-1\1"
HO N N fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-4-(2,7-diazaspiro [3.5] nonan-7-yl)pyrido [4,3 -c11 pydin-5(6H)-one 371 H 3 -(2-amino-7-fluorobenzo [d]thiazol-4-y1)-8-HNS ((1R,5S)-3,8-- , F
I
diazabicyclo [3 .2.1] octan-3 -y1)-6-F
NI 0 ' (((2R,7aS)-2-fMorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-py rimido [4,5-e] [1,21thiazine 1-oxide 372 H 2-((1-((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-cthyny1-7-N
fluoro-3-hydroxynaphthalen-1-y1)-6-me thy1-4-(2,7-N
diazaspiro [3.5] nonan-7-yl)pyrido [4,3 pyrimidin-5(6H)-one 373 H 6-(cyclopropylmethyl)-24(1 ((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-ethyny1-7-O
HO fluoro-3-hydroxynaphtha1en-l-y1)-N
I 4-(2,`7-diazaspiro [3 .5] nonan-7-c,rr yl)pyrido [4,3 -c11 pyrimidin-5(6H)-one 374 H 4-(( 1R,5S)-3,8-< N diazabicyclo [3 .2.1]
octan-3 -y1)-6-L.., 0 N
cyclobuty1-7-(8-ethyny1-7-fluoro-HO N 1 ' N F
3 -hy dro xy naphthalen-l-y1)-2-N (42R,7aS)-2-fluorotetrahydro-1H-= pyrrolizin-7a(5H)-F yOmethoxy)pyrido [4,3 -d] pyrimidin-5 (6H)-one 375 H 2-((1-N
((dimethylamino)methyl)cy clopro pyflmethoxy)-7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-l-y1)--'N
I
6-(oxetan-3-y1)-4-(2,7-N 0-------A-^-I
= diazaspiro [3 .5]
nonan-7-F yl)pyrido [4,3 -d]
pyrimidin-5 (6H)-one 376 H 6-(2,2-difluorocyclopropy0-2-01-N
F F ((dimethylamino)methyl)cyclopro v0 pyl)methoxy)-7-(8-ethyny1-7-HO N ....""lq fluoro-3-hydroxynaphtha1en-l-y1)-4-(2,7-diazaspiro [3 .5] nonan-7-=-_ yl)pyrido [4,3 -d]
pyrimidin-5 (6H)-F one 377 H 7-(2-amino-7-N

fluorobenzo [d] thiazol-4-y1)-4-H2N F ((lR,5S)-3,8-I
diazabicyclo [3 .2.1] octan-3 -y1)-2-N (((2R,7aS)-2-fluorotetrahydro-1H-F
py rrolizin-7a(5H)-yl)metho xy) -5 -o xo-5,6-dihy dro-1,6-naphthyridine-3-carbonitrile 378 H 6-cyclopropy1-2-((1-N
M ((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-ethyny1-7-HO I fluoro-3 -hy dro xynaphthalen-l-y1)-''.- I
N
---..
N----:----'0-)CT - 8-fluoro-4-(2,7-F
=_ diazaspiro [3 .5]
nonan-7-F yl)pyrido [4,3 -d]
pyrimidin-5 (6H)-one 379 6-((1-((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-HO ,N fluoro-3-hydroxynaphthalen-1-y1)-4-fluoro-2-methyl-8-(2,7-diazaspiro[3.5]nonan-7-y1)-2H-__ pyrimido[4.5-e][1,2]thiazine 1-F
oxide 380 H 3-(2-amino-7-N

fluorobenzo[d]thiazol-4-y1)-8-N
F
H2N sit ((1R,5S)-3,8-diazabicyclo[3.2.1]oetan-3-y1)-4-N 0 ' fluoro-6-(((2R,7aS)-2-fluor tetrahy dro-1H-pyrrolizin-7a(514)-yl)methoxy)-2-(oxetan-3-y1)-2H-pyrimido [4,5-e][1,21thiazine 1-oxide 381 H 3-(2-amino-7-F F fluorobenzo[d]thiazol-4-y1)-8-H2N ,s11 ((1R,5S)-3,8-N
I a, diazabicyclo[3.2.1[octan-3-y1)-4-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-11i-pyrrolizin-7a(5H)-yl)methoxy)-2-(oxetan-3-ylmethyl)-2H-pyrimido[4,5-e][1,21th1azi11e 1-oxide 382 H 2-(cyclopropylmethyl)-6-((1-N
((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-_V N
HO N fluoro-3-hydroxynaphtha1en-1-y1)-4-fluoro-8-(2,7-N
diazaspiro[3.51nonan-7-y1)-211-__ pyrimido[4.5-el[1,2]thiazine 1-F
oxide 383 H 7-(2-amino-7-fluorobenzo[d]thiazol-4-y1)-4-N
H2N ((1R,5S)-3,8-CN
diazabicyclo [3 .2.1] octan-3 -y1)-2-N
(((2R,7aS)-2-fluorotetrahydro-1H-F
pyrrolizin-7a(5H)-yOmethoxy)-6-methyl-5 -o xo-5,6-dihy dro-1,6-naphthyrid ine-3-carbonitrile 384 H 7-(2-ami no-7-fluo rob enz o [d]thiazol-4-y1)-4-H2N ((1R,5S)-3,8-CN
diazabicyclo [3.2.1 J o ctan-3 -y1)-6-N 0 ' (cyclopropylmethyl)-2-(((2R,7aS)-F
2-fluorotetrahydro-1H-pyrrolizin-7 a(5H) -yl)metho xy)-5-oxo -5 ,6 -dro-1,6-naphthy ridine-3 -carbonitrile 385 H 8-41R,5S)-3,8-F F A diazabicyclo [3 .2.1]
o ctan-3 -y1)-2-, 9 HO N
(2,2-difluorocyclopropy1)-3 -(8-N,S
'N
ethyny1-7-fluoro-3-hy dro xv naphthalen-1 -y1) -4-fluo ro-6-(42R,7aS)-2-fluorotetrahydro-1H-pyn-oli zin-72(5H)-yflmetho xy)-2H-py rimido [4,5-e] [1,2] thiazine 1-oxide 386 H 2-(2,2-difluo ro cy clopropy1)-64(1-((dimethylamino)methyl)cyclopro F pyl)methoxy)-3-(8-ethyny1-7-C
N
HO N N -S fluoro-3-hydroxynaphtha1en-1-y1)-4-fluoro-8-(2,7-N
diazaspiro [3 .51 nonan-7-y1) -2H-=-_ pyrimido [4.5-e] [1,2] thiazinc 1-F
oxide 387 H 7-(2-amino-7-v Co) fluo rob enz o [d]thiazol-4-y1)-4-(3-N
H2N F oxa-7,9-diazabicyc10 [3 .3 .11nonan-N N
9-y1) -6 -(cy clopropylmethyl)-2-N-1µ06S
(42R,7a S)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido 14,3 -d] py rimidin-5 ( 6H)-one 388 H 4-(( 1R,5S)-3,8-O
diazabicyclo [3 .2.1] o ctan-3 -y1)-6-N
N CN cyclopropy1-2-(((2R,7aS)-2-flu o ro t e trahy dro-1H-py rrolizin-HO
N
7 a(5H) -yl)metho xy)-7-(3 -hy dro xv naphthalen-1 -y1) -5 -oxo-5,6-dihy dro-1,6 -naphthy ridine-3 -carbonitrile 389 H 6 -((1-((dime thy lamino)methyl)cy clopro py 1)methoxy )-3 -(8-ethy ny1-7 -N
HO ''N'S N fluo ro-3 -hy dro xynaphthalen-1-y1)-2 -methy1-8-(2,7-N
diazaspiro [3.5] nonan-7 -y1) -2H-pyrimido [4,5-e] [1,2] thiazine 1-F
oxide 390 H2 -(cy clopropylmethyl)-64(1-((dimethylami no)methyl)cyclopro py flmethoxy)-3 -(8-ethy ny1-7 -HO NS N fluoro-3-hydro x/naphthalen-1-y1)-8-(2,7-diazaspiro [3 .51 nonan-7-y1)-N 0/Cir 2H-py rimido [4,5-e]
[ 1,2] thiazine 1-oxide 391 H 2 -(2,2-difluo ro cy clopropy0-6 -((1-((dimethylamino)methyl)cyclopro F 4 pyl)methoxy)-3-(8-ethyny1-7-, N
HO
N fluo ro-3 -hy dro xynaphthalc n-1-y1)-N 8-(2,7-diazaspiro [3 .51 nonan-7-y1)-2H-py rimido [4,5-e] [1,2] thiazine 1-oxide 392 H 3 -(2 -amino-7 -fluorobenzo [d] thia zol-4 -y1)-8-(3-H2 N 0,z9 N
oxa-7,9-diazab icyclo [3 .3 .1] nonan-N 0 = 9-y1) -2 -cy clobuty1-6-(42R,7aS)-2 -fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4.5-c] [1,2] thiazinc 1,1-dioxide 393 H 4-((1R,5S)-3,8-y diazabicyclo [3 .2.1] octan-3 -y1)-6-N
(cy clopropylmethyl)-7-(8-ethynyl-HO
7-flu oro-3-hy droxynaphthalen-1-,s, I

yl) -8 -fluoro-2-(K2R,7aS)-2 -fluorotetrahydro-1H-pyrrolizin-F 7 a(5H) -yl)metho xy)py rido [4,3 -d] pyrimidin-5 (6H)-one 394 H 2-cyclopropy1-6-((1-N
o ((dime thy lamino)me thyl)cy clopro pyl)methoxy)-3-(8-ethyny1-7-N
HO NN

fluoro-3 -hy dro xynaphthalen-1-y1)-8-(2,7-diazaspiro [3 .5] nonan-7-y1)-2H-py rimido [4,5-e] [1,2] thiazine 1-oxide 395 H 3-(2-amino-7-N fluorobenzo [d]thiazol-4-y1)-8-i 12N FL, 9 N
N'S ((1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-2-cyclobuty1-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1-oxide 396 H 3 -(2-amino-7-fluorobenzo [d]t1iazo1-4-y1)-8-(3-H2N I L, 0õV N oxa-7,9-diazab icyclo [3 .3 .1] nonan-9-y1) -2 -cy clobuty1-4-fluoro-6-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yOmethoxy)-2H-pyrimido [4,5-e] [1,2] thiazine 1,1-dioxide 397 H 6-((1-S?
((dimethylamino)methyl)cyclopro pyl)methoxy)-3 -(8-ethyny1-7 -HO N fluoro-3-hydroxynaphthalen-1-y1)-, I I
4-fluoro-2-methyl-8-(2,7-N
diazaspiro 113 .51 nonan-7-y1) -2H-=¨_ py rimido [4,5-e] [1,2] Elnaziiie 1,1-F
dioxide 398 7-(2-amino-7-fluorobenzo [d] thiazol-4-y1)-4-H2 N)=-- FL, 0 N
CN F ((1R,5S)-3,8-N N
N diazabicyclo [3 .2. 1] octan-3 -y 1)-6-cyclobuty1-8-fluoro-2 -(((2R,7a S)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H) -yl)metho xy)-5 -oxo -5 ,6 -dihy dro- 1,6-naphthy ridine-3 -carbonitrile 399 7-(2-amino-7-fluorobenzo [d] thiazol-4-y1)-4-CN ((1R,5S)-3,8-N
I
N'O>LN> diazabicyclo [3 .2. 1] octan-3 -y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51-1)-yl)methoxy)-6-(oxetan-3 -y1)-5 -o xo-5,6-di hydro- 1 ,6-naphthyridine-3-cathonitrile 400 2-(cy clopropylmethyl)-64( 1-((dimethylamino)methyl)cyclopro pyl)methoxy)-3 -(8-ethyny1-7-HO N
0 'it N
fluoro-3 -hydro xynaphthalen- 1-y1)-'"=-rsj-=
NON 4-fluoro-8-(2,7-diazaspi ro [3 .5] no nan-7-y1)-2H-pyrimido [4,5-e] [ 1,2] thiazine 1,1-F
dioxide 401 2-cy clobuty1-64( 1 -((dimethylamino)methyl)cyclopro N
pyl)methoxy)-3 -(8-e thy ny1-7 -o N:S
HO , N fluoro-3 -hy dro xynaphthalen- 1-y1)-I
4-fluoro-8-(2,7-diazaspiro [3 . 5] nonan-7-y1) -211-pyrimido [4.5-e] [ 1,2] thiazine 1, 1-diox ide 402 6-((1-F (dimethylamino )methyl)cyclopro pyl)methoxy )-3 -(8-ethy ny1-7 -HO ?¨ 1 N N fluoro-3 -hy dro xynaphthalen- 1-y1)-N
r\r"---0"/CNII' 4-fluoro-2-(oxeta n-3 -y1)-8-(2,7 -diazaspiro [3 . 5] nonan-7-y 1) -2H-pyrimidol4.5-ell 1,2Ithiazine 1,1-dioxide 203 H 2-(2,2-di fl tiorocyclopropy1)-6-01 -N
((dimethylamino)methyl)cyclopro pyl)methoxy)-3-(8-ethyny1-7-0,1 HO N'S , N fluoro-3 -hydro xynaphthalen-1-y1)-I
N 4-fluoro-8-(2,7-diazaspiro [3.5] nonan-7-y1)-2H-=_¨

pyrimido [4,5-e] [1,2]thiazine 1,1-F
dioxide 404 H 4-41R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-6-eyelopropy1-8-fluoro-7-(3-HO N I N
hydroxynaphthalen-1 -y1)-2-(((S)-1 -methylpyrrolidin-2-yOmethoxy)pyrido 14,3 -d]pyrimidin-5(6H)-one 405 H 7-(2-amiato-7-ThN
fluorobenzo [d]thiazol-4-y1)-4-H,N y N
((lR,5S)-3,8-N
diazabicyclo 13.2.1 I octan-8-y1)-6-(cyclopropylmethyl)-8-11noro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-5(6H)-one 406 H 2-(cyclopropylmethyl)-64( 1-M
((di methyla m i no) methyl)cyclop ro o N pyl)methoxy)-3 -(8-ethyny1-7-.11 HO NS fluoro-3 -hydro xynaphthalen-l-y1)-8-(2,7-diazaspiro [3 .51nonan-7-y1)-=¨_ 2H-pyrimido [4,5 -c]
[1,21thiazinc 1,1-dioxide 407 H 2 -cyclobuty1-6-1(1-((dinacthylamino)mcthyl)cyclopro pyl)methoxy)-3-(8-ethynyl -7-HO I L N Ckq N N Cluoro-3 -hy dro xy hal en-1-y1)-N)N-=
8-(2,7-diazaspiro [3 .5] nonan-7-y1)-2H-pyrimido [4,5 -el [1,21thiazine 1,1-dioxide 408 H 84(1R,5S)-3,8-N
v ) diazabicyclo [3 .2.1]
o ctan-3 -y1)-2-HO N

(cy clopropylmethyl)-64(1-I '',N, ====. I
---, ((d ime thy lamino)me thyl)cy clopro Nrt----0---A----T-pyl)methoxy)-3-(8-ethyny1-7--fluoro-3-hydroxynaphthalen-l-y1)-F
2H-pyrimido [4,5-e] [1,21thiazine 1,1-dioxide 409 H 7-(2-amino-7-N
F F fluorobenzo [d]
thiazol-4-y1)-4-(( 1R,5S)-3,8-H,N
s,....., I
- N Cr'''''"=r-- diazabicyclo [3 .2.1] o ctan-3 -y1)-6-F .-- (2,2-difluorocyclopropy0-8-fluoro-2-(((S)-1-me thy 1py rro Win-2 -yl)methoxy)py rido [4,3 -cl] pyrimidin-5 (6H)-one 410 H 6-((1-N
((dimethylamino)methyl)cyclopro py 1)methoxy)-3 -(8-ethy ny1-7 -HO HNIS N
fluoro-3 -hy dro x/naphthalen-1-y1)-, ."-I I
8-(2,7-diazaspiro [3 .5] nonan-7-y1)-N e)CN"
________________ I 2H-pyrimido [4,5-e] [1,21thiazine ¨
1,1-dioxide F
411 H 2 -((1 -N

6 ((dimethylamino)methyl)cyclopro pyl)methoxy)-7-(8-ethynyl -7-? o N
HO
' N fluoro-3-hydroxynaphtha1en-1-y1)-N
I
----..
F T- 8-fluoro-6-(oxetan-3-Amethyl)-4-¨ (2,7-diazaspiro [3.5 1 nonan-7-F yl)pyrido [4,3 -d]
pyrimidin-5 (6H)-one 412 hi 8-((1R,5S)-3,8-N
) diazabicyclo [3 .2.1]
o ctan-3 -y1)-2-,... fi N
cy clobuty1-3 -(8-ethy ny1-7-fluoro -HO F

3 -hydro xy naphthalen-l-y1)-4-... i ,.
N fluoro-6-(((2R,7aS)-2-F
____ ¨ fluorotetrahydro-1H-pyrrolizin-F 7a(511)-yl)methoxy)-PYrimido 1 4,5-e l 1,2Ithiazine 1-oxide 413 H 2-cyclopropy1-64(1 -N
F ((dimethylamino)methyl)cyclopro pyl)methoxy)-3 -(8-ethyny1-7 -HO g fluoro-3-hydroxynaphthalen-1-y1)-N N
I I
N 8-(2,7-diazaspiro [3 .5] nonan-7-y1)-1 2H-pyrimido [4,5 -e]
[1,21thiazine 1,1-dioxide 414 H N 2-cyclopropy1-6-((1-F ((dimethylamino)methyl)cyclopro pyl)methoxy)-3 -(8-ethyny1-7 -N
HO /VA N fluoro-3-hydroxynaphtbalen-l-y1)-N
I õ1, 4-fluoro-8-(2,7-N c;irr diazaspiro [3 .5] nonan-7-y1) -2H-pyrimido [4.5 -e] [1,2]thiazine 1,1-F
dioxide 415 H 7-(2-amino-7-fluorobenzo[d]thiazol-4-y1)-4-H2N \( N
CN F ((1R,5S)-3,8-N
N 0 diazabicyclo [3.2.1 octan-3 -y1)-6-(cy clopropylmethyl)-8-fluoro-2-(((2R,7a S)-2-fluo rotetrahydro-1H-pyrrolizin-7a(5H)-yl)metho xy) -5 -o xo-5,6-dihy dro-1,6-naphthyridine-3-earbonitrile 416 H 8-41R,5S)-3,8-dia zabicyclo [3 .2.1] octa n-3-y1)-3-N
(8-ethyny1-7-fluoro-3 -HO N'S
hy dro xynaphthalen-1 -y1) -4-fluoro-N 0 ' 6-( ((2R,7aS)-2 -fluorotetrahy dro-11-1-pyrroli zin-7a (5H)-yOmethoxy)-2-(oxetan-3-ylmethyl)-2H-pyrimido [4.5-e] [1,2lthiazine 1-oxide 417 H 6-((1-N
C

0 :
((dimethylamino)methyl)cyclopro pyl)methoxy)-3 -(8-ethyny1-7 -HO 7 ii? N
L., ,S fluoro-3 -hy dro xy naphthalen-l-y1)-N , --*N
I I
Cy 4-fluoro-2-(oxetan-3-y1)-8-(2,7-.-diazaspiro [3 .5[ nonan-7-y1) -2H-pyrimido [4.5-e] [1,2]thiazine 1-F
oxide 418 H 7-(2-amino-7-N
F F ) fluorobenzo [d]
thiazol-4-y1)-4-H2N )=--- A N ..., 0 N
ON F (( 1R,5S)-3,8-N \
I
N 0 ' diazabicyclo [3 .2.1] octan-3 -y1)-6-N
F
F (2,2-difluorocyclopropy1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51-1) -yl)metho xy)-5-oxo -5,6 -dihydro-1,6-naphthyridine-3 -carbonitrile 419 H 7-(2-amino-7-N
<:) ) fluorobenzo [d]thiazol-4-y1)-4-o N

CN F ((lR,5S)-3,8-)----N N
S I
N o--6S diazabicyclo [3 .2.1] octan-3 -y1)-8-N
F
F fluoro-2-(((2R,7aS)-2-fluo rot et ra hydro-11-1-py rrol i zi n-7a(5H) -yl)metho xy)-6-(o xetan-3 -ylmethyl)-5-o xo-5,6-dihy dro -1,6 -naphthyridine-3-carbonitrile 420 H 4-41R,5S)-3,8-N

diazabicyclo [3 .2.1] octan-3 -y1)-2-N
F
(((2R,7aS)-2 -fluorotetrahy dro-1H-I py rrolizin-7a(5H)-yl)metho xy) -7 -N (3 -hydro xynaphthalen-l-y1)-6-methy1-5 -o xo-5,6-dihy dro-1,6-naplithy rid i ne-3-ca tbo n it rile 421 H 6-cyclopropy1-2-(((2R,7aS)-2-N
(N ) fluorotetrahydro-1H-pyrrolizin-A, N F
N , 7a(5H)-yl)methoxy 1-743-, '' hy dro xynaphthalen-1 -y1) -4-N 0 ' N (piperazi n-1-yl)py rido [4,3-d]py rimidin-5 (6H)-one 422 6-( (1-((dimethylamino)methyl)cyclopro e,C\
pyl)methoxy)-3-(8-ethyny1-7-µ"' 0.õ11 HO N fluoro-3 -hy dro xy naphthalen-l-y1)-I NQçN 1 4-fluoro-2-(oxetan-3-ylmethyl)-8-(2,7-diazaspiro [3.5 Jnonan-7-y1)-_¨=
2H-py rimido [4,5-e] [1,21thiazine 1,1-dioxide 423 2-(2-amino-7-O N
fluorobenzo [d] thiazol-4-y1)-5-(( 1R,5S)-3,8-I
so'IV Nr 0 N diazabicyclo [3 .2.1] octan-3 -y1)-7-(((2R,7aS)-2-fluorotetrahydro-1H-py rrolizin-7a(5H)-yOmetho xy) -3 -methylpy rimido [4, 5-d] py rimidin-4(3H)-one 424 2-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-5-,H2N 7 0 N
((lR,5S)-3,8-= NO5SN )LXLI
N diazabicyclo [3 .2.1] octan-3 -y1)-3 -(cy clopropylmethyl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7 a(5H) -yflmetho xy)py rimido [4,5 -d]py ri m idi n-4(3H)-o ne 425 2-(2-amino-7-fluorobenzo [di thiazol-4-y1)-5-((1R,5S)-3,8-N N
= 0 N diazabicyclo [3 .2.1] octan-3 -y1)-3 -cy clob u ty1-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7 a(511) -yflmetho xy)py rimido [4,5 -d]pyrimidin-4(3H)-one 426 2-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-5-H2N 5:2_õ1 ((1R,5S)-3,8-N N
-'1N1 NO5SN diazabicyclo [3 .2.1] octan-3 -y1)-7-(42R,7 aS )-2-fluorotetrahy dro-1H-py rrolizin-7a(5H)-yOmetho xy) -3 -(o xeta n-3 -yl)py rim ido [4,5-d] py rimidin-4 (3H)-one 427 H 2-(2-amino-7-fluorobenzo [dlthiazol-4-y1)-5-N

((lR,5S)-3,8-)=--N HN-JI.XL-N
S -.),J reL0'-'6SN diazabicyclo [3 .2.1]octan-3-y1)-7-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmetho x,T)py rimido [4,5-d]pyrimidin-4(3H)-one 428 H 3 -(2-amino-7-fluorobenzo [(1.1 thiazol-4-y1)-8-(3-o o N
H2N g oxa-7,9-diazabicyclo [3 .3 .1] nonan-9-y1)-6 -4(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51-1)-yl)methoxy)-2-(oxetan-3-y1)-2H-pyrimido [4,5-e] [1,21thiazine 1-oxide 429 H 3-(2-amino-7-FF M fluorobenzo 11dlthiazol-4-y1)-8-(3-h2N N
-S oxa-7.9-diazabicyclo [3 .3 A] nonan-9-y1)-2 -(2,2-difluorocy clopropy1)-64((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-21-1-pyrimido [4,5-e] [1,21thia zi ne 1-oxide 430 H 8-((1R,5S)-3,8-N
diazabicyclo [3 .2.1] octan-3 -y1)-6-HO
(0-N
,S
NI I "1 ((dimethylamino)methyl)cyclopro py 1)methoxy -(8-e thy ny1-7-fluoro-3 -hydro xynaphthalen- 1-y1)-2-(oxetan-3-y1)-2H-pyrimido [4,5-e] [1,21thiazine 1-oxide 431 H 5-41R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-3-O
N
cyclopropy1-7-4(2R,7aS)-2-HO I
N N05IS fluorotetrahydro-1H-pyrrolizin-' 7a(5H)-yl)methoxy)-2-(3-hydroxynaphthalen-1-yppyri m ido [4,5-dlpyri m idi n-4 (3H)-one 432 H 2-(2-amino-7-"
N
fluorobenzo[d]thiazo1-4-y1)-5-)-N\''Nf-F ((1R,5S)-3,8-=-4ij S 0 INJ N' O N
diazabicyclo[3.2.1]octan-3-y1)-3-F cyclopropy1-7-(((2R,7aS)-2-=
fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimido [4,5-d]pyrimidin-4(3H)-one 433 H Atropisomer 1 of 7-(2-amino-7- 639.2 __ fluorobenzo[d]thiazo1-4-y1)-4-((1R,5S)-3,8-F
diazabicyclo [3 .2.1] octan-3-y1)-6-N cyclopropy1-8-fluoro-F
F atropisomc r 1 (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido 14,3 -cl]pyrimidin-5(6H)-one 434 H Atropisomer 2 of 7-(2-amino-7- 639.2 Q------= fluorobenzo[d]thiazol-4-y1)-4-((1R,5S)-3,8-F
diazabicyclo [3.2.1] octan-3-y1)-6-N 0 ' N cyclopropy1-8-fluoro-F
F atropisomer 2 (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-5(6H)-one 435 H 7-(2-amino-7-681.4 ( .N
C..--.7:- fluorobenzo[d]thiazol-4-y1)-4-CF3 0 N ((1R,5S)-3,8-H2N>_,N L.N F
1 ' N diazabicyclo [3 .2.1]
octan-3-y1)-8-N fluoro-2-(((2R,7aS)-2-F
F fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(2,2,2-trifluoroethyl)pyrido [4,3-cl]pyrimidin-5(6H)-one 436 1 7-(2-amino-7-613.5 (NF fluorobenzo [d]
thiazol-4-y1)-4-) H2 N ((1R,5S)-3,8-F
diazabicyclo [3 .2.1]octa n-3-y1)-8-N fluoro-2-(((2R,7aS)-2-F
F fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-6-methylpyrido [4,3 -dlpyrimidin-5(6H)-one 437 H 7-(2-amino-7-F F fluorobenzo [d]
thiazol-4-y1)-4-(( 1R,5S)-3,8-N
diazabicyclo [3 .2.1] octan-3 -y1)-6-N
(2,2-difluoroethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)pyrido [4,3 -d] pyrimidin-5 (6H)-one 663.4 438 H 3 -(7-(2-amino-7-fluorobenzo [d] thiazol-4-y1)-4-((1R,5S)-3,8-diazabicyclo [3 .2.1]oetan-3 -y1)-8-N 0 ' 0 ' fluoro-2-(42R,7aS)-2-fluorot etra by dro-1H-py ITO] Zill-NH2 7a(5H)-yl)methoxy)-5-o xopyrido [4,3-d] py rimidin-6 (5H)-yppropane nitrile 652.4 439 H 2-(7-(2-amino-7-H2N0 o fluorobenzo [d]thiazol-4-y1)-4-H2N ((1R,5S)-3,8-N diazabicyclo [3 .2.1] 0cta11-3 -y1)-8-fluoro-2-(((2R,7aS)-2-fluorotctrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-5-o xopy rido [4,3-d] py (5H)-yl)acetamide 656.4 440 H 4-(4-41R,5S)-3,8-L7') diazabicyclo [3 .2.1] octan-3 -y1)-6-cycl opropy1-8-fluo ro -2-N
S N I (((2R,7aS)-2-fluorotetrahydro-1H-N 0 ' py rrolizin-7a(514)-yOmetho xy) -5 -F
oxo-5,6-dihydropyrido [4,3 -d] pyrimidin-7-y1)-2-amino-7-fluorobenz o [b]thiophene-3-ca rbonitrile 663.4 441 _C, ir 7-(2-amino-7-,c 0 HN fluorobenzo [d]
thiazo1-4-y1)-6-cy clopropy1-8-fluo ro -2 -N -----0 6S (42R,7aS)-2-fluorotetrally dro-1H-N
F
F py rrolizin-7a(5H)-yl)metho xy) -4 -(piperidin-4-ylamino)py rido [4,3-d] pyrimidin-5 (6H)-one 627.4 442 H 2-(7-(2-amino-7-(,..N.., fluorobenzo [d]thiazo1-4-y1)-4-H2 1\1_______ F ((1R,5S)-3,8-diazabicyclo [3 .2.1] octan-3 -y1)-8-N
F fluoro-2-(42R,7aS)-2-F
fluorotetrahydro-1H-pyrrolizin-7a(51-1) -yl)metho xy )-5-oxopyrido [4,3-d] pyrimidin-6 (5H)-ypacetonitrile 638.5 443 H 7-(2-amino-7-N j., fluorobenzo [d]thiazol-4-y1)-6-N "" cyclopropy1-4-((2S,5R)-2,5-F dimethylpiperazin-l-y1)-8-fluoro -S -N, N 0 ' 2-(((2R,7aS)-2-fluorotetrahydro-N 1H-pyrrolizin-7a(5H)-F
F yl)methoxy)pyrido [4,3 -d]py rimidi n-5 (6H)-o lie 641.4 444 H 4-(4-(3-oxa-7,9-N
--- -....
diazabicyclo [3 .3.1] nonan-9 -y1)-6 -0 N cy clopropy1-8-fluo ro -2 -((S)-1 -((S)-1-methylpy rrolidin-2 -yl)ethoxy)-5-oxo-5,6--N.
dihydropyrido 114,3 -d] py rimidin-7-F N
F / yl) -2 -amino-7-fluo robe n z o [b]thiophene-3-carbonitrile 649.4 445 H 2-amino-4-(6-cyclopropy1-4-N
((2 S,5R)-2,5-dimethylpiperazin-1-yl) -8 -fluoro-2-(((2R,7aS)-2-H2N NC ---C. F
1 ' N fluor t etrahy dro-11-1-pyrrolizin-- I
N 0 = 7a(5H) -yl)metho xy)-5-oxo -5,6 -N
F dihydropyrido [4,3 -d]py rimidin-7-F
y1) -7 -fluorobenzo [b] thiophene-3 -carbonitrile 665.4 446 (-0 7-(2-amino-7-==-.N,-) fluorobenzo [d]
thiazo1-4-y1)-6-4... 0 ' N F cy clopropy1-8-fluo ro -2 -(42R,7aS)-2-fluorotetrahydro-1H

-N
N '-'-'0 = pyrrolizin-7a(5H)-yOmethoxy)-4-N
F (1,4-o xazepan-4-y Opy rido [4,3-F
d]pyrimidin-5(6H)-one 628.4 447 H 4-(4-(3-oxa-7,9-N
diazabicyclo [3 .3.1] nonan-9 -y1)-6 -0 N cy cl opropy1-8-flito ro -2 -¨ I '25...LN (((2R,7aS)-2-fluorotetrahydro-1H-S ,.õ..
N 0 =5IS py rrolizin-7a(5H)-yl)metho xy) -5 -N
F oxo-5,6-dihydropyrido [4,3-F
d]pyrimidin-7-y1)-2-amino-7-fluorobenzo [b]thiophene-3-ca rbonitrile 679.4 448 H 7-(2-amino-7-1,, N
fluorobenzo [d]thiazol-4-y1)-4-41R,5S)-3,8-diazabicyclo [3 .2.1] octan-8-y1)-6-N 0-..
N 1 ''' N I
I cy clopropy1-8-fluo ro -2 -((S)-1--:'L--.)''"
((S)-1-methylpyrrolidin-2-F
F N /N ¨j yl)ethoxy)pyrido [4,3 -c1.1 py rimidin-S ---/-( 5(6H)-one 653.4 449 ( N ) 7-(2-amino-7-fluorobenzo [d]thiazo1-4-y1)-4-& 0 I
(azepan-1-y1)-6-cyclopropy1-8-)=N N T.....N F fluoro-2-(((2R,7aS)-2-N 0 ' N fluorotetrahydro-1H-pyrrolizin-F
F 7a(511) -yl)metho xy)py rido 14,3 -d]pyrimidin-5(6H)-one 626.4 450 H 7-(2-amino-7-..,...N ,..1 7 0 <N fluorobenzo [di thiazol-4-y1)-4-H 2N ((1R,5S)-3,8-F diazabicyclo ) [3.2.1] oetan-8-y1)-6-S ...,. ...¨..,, ..õ.õ. cyclopropy1-8-fluo ro -N 0 ' N (((2R,7aS)-2-fluorotetrahydro-1H-F
F
pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]py rimi di in-5(6H)-one 639.3 451 H 7-(2-amino-7-(, ,N
C fluorobenzo RH thiazol-4-y1)-6-cyclopropy1-8-fluo ro -2 -H2N 0 N (((2R,7aS)-2-fluorotetrahydro-1H-F
)--:----N N I IN py rrolizin-7a(5H)-yOmethoxy) -4 -S =-. <,-_ __ ......,,, (hexahydropyrrolo [3 ,4-c]pyrro1-N 0 ' N
F 2 (1H)-yl)pyrido [4,3-d] pyrimidin-F
(6H)-one 639.2 452 F F 7-(2-amino-7-fluorobenzo [d]thiazol-4-y1)-6-cyclopropy1-4-((1R,5S)-8-(2,2-Kõ ...,iN
1-7.- difluorocyclopropane-1-carbonyl)-3 ,8-diazabicyclo [3.2.1]octan-3 -H2N A, F yl) -8 -fluoro-24((2R,7aS)-2-S ...,. ...,-: , ..õ...,õ fluo rot et rahydro-11-1-py rrol i zi n-N 0 ' N 7a(5H)-yl)methoxy)pyrido [4,3-F
F
d]pyrimidin-5(6H)-one 743.3 453 li 5-(7-(2-amino-7-N C N
__ fluorobenzo [di thiazol-4-y1)-6-C cy clopropy1-8-fluo ro -2-F
/., 0 N ---(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5 -S -.. .,,,,=_ , õõ...,õ
N ' N oxo-5,6-dihydropyrido [4,3-F
F d]pyrimidin-4-y0-4,5.6,7-tetrahydropy razolo [1 ,5-alpyrazine-3-carbonitrile 675.2 454 F F 2-amino-4-(6-cyclopropy1-4-y2c ((1R,5S)-8-(2,2-difluorocyclopropane-l-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-CN 0 N y1)-8-fluoro-2-(K2R,7aS)-2-H2N N fluorotetrahydro-1H-pyrrolizin-7a(5H)-yflmethoxy)-5-oxo-5,6-N 0 ' dihydropyrido[4,3-d]pyrimidin-7-F
y1)-7-fluorobenzo[b]thiophene-3-carbonitrile 767.4 EXAMPLE 3: Ras sequence [00690] Human K-Ras4b (SEQ ID NO. 1):
1 M ______________ FEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET

EXAMPLE 4: Protein expression [00691] DNA expression constincts encoding one or more protein sequences of interest (e.g., Kras fragments thereof, mutant variants thereof, etc.) and its corresponding DNA sequences are optimized for expression in E. coli and synthesized by, for example, the GeneArt Technology at Life Technologies.
In some cases, the protein sequences of interest are fused with a tag (e.g., glutathione S-transferase (GST), histidine (His), or any other affinity tags) to facilitate recombinant expression and purification of the protein of interest. Such tag can be cleaved subsequent to purification. Alternatively, such tag may remain intact to the protein of interest and may not interfere with activities (e.g., target binding and/or phosphorylation) of the protein of interest [00692] A resulting expression construct is additionally encoded with (i) art-site sequences at the 5'and 3' ends for subcloning into various destination vectors using, for example, the Gateway Technology, as well as (ii) a Tobacco Etch Virus (TEV) protease site for proteolytic cleavage of one or more tag sequences. The applied destination vectors can be a pET vector series from Novagen (e.g., with ampicillin resistance gene), which provides an N-term inal fusion of a GST-tag to the integrated gene of interest and/or a pET
vector series (e.g., with ampicillin resistance gene), which provides a N-terminal fusion of a HIS-tag to the integrated gene. To generate the final expression vectors, the expression construct of the protein of interest is cloned into any of the applied destination ventors. The expression vectors are transformed into E. coli strain, e.g., BL21 (DE3). Cultivation of the transformed strains for expression is performed in 10 L and 1 L fermenter. The cultures are grown, for example, in Terrific Broth media (ATP Biomedicals, Kat. #113045032) with 200 ug/mL
ampicillin at a temperature of 37 C to a density of 0.6 (0D600), shifted to a temperature of ¨27 C (for K-Ras expression vectors) induced for expression with 100 mM IPTG, and further cultivated for 24 hours. After cultivation, the transformed E. coli cells are harvested by centrifugation and the resulting pellet is suspended in a lysis buffer, as provided below, and lysed by passing three-times through a high pressure device. The lysate is centrifuged (49000g, 45 min, 4 C) and the supernatant is used for further purification.
EXAMPLE 5: Ras protein purification [00693] A Ras (e.g., K-Ras wildtype or a mutant such as K-Ras G12S, K-Ras G12D, K-Ras G12V or K-RasG12C) construct or a variant thereof is tagged with GST. E. coli culture from a 10L
fermenter is lysed in lysis buffer (50m1\4 Tris HCI 7.5, 500mNI NaCI,1 mM DTT, 0,5% CHAPS, Complete Protease Inhibitor Cocktail-(Roche)). As a first chromatography step, the centrifuged lysate is incubated with 50mL
Glutathione Agarose 4B (Macherey-Nagel; 745500.100) in a spinner flask (16 h, 100). The Glutathione Agarose 4B
loaded with protein is transferred to a chromatography column connected to a chromatography system, e.g., an Akta chromatography system. The column is washed with wash buffer (50naM Tris HCI 7.5, 500mNI NaCI, 1 mI\4 DTT) and the bound protein is cluted with elution buffer (50mM Tris HCI 7.5, 500mNI NaCI, 1 mNIDTT, 15mM
Glutathione). The main fractions of the elution peak (monitored by 0D280) are pooled. For further purification by size-exclusion chromatography, the above dilate volume is applied to a column Superdex 200 HR prep grade (GE
Healthcare) and the resulting peak fractions of the eluted fusion protein is collected. Native mass spectrometry analyses of the final purified protein construct can be performed to assess its homogeneous load with GDP.
EXAMPLE 6: HTRF (homogenous time-resolved fluorescence resonance energy transfer assay [00694] The ability of a compound of the present disclosure to reduce a Ras signaling output can be demonstrated by an HTRF assay. This assay can be also used to assess a selective inhibition or reduction of signaling output of a mutant Ras protein (e.g., G12D, G12S, G12C, G12V, G13D, G13S, G13C, or G13V) relative to a wildtype, or relative to a different mutant Ras protein. For example, the equilibrium interaction of wildtype Kras or K-Ras mutant (e.g., wildtype or a mutant thereof) with SOS1 (e.g., hS0S1) can be assessed as a proxy or an indication for a subject compound's ability to bind and inhibit Ras protein. HTRF assay detects from (i) a fluorescence resonance energy transfer (FRET) donor (e.g., antiGST-Europium) that is bound to GST-tagged K-Ras mutant to (ii) a FRET
acceptor (e.g., anti-6His-XL665) bound to a His-tagged hS0S1.
[00695] The assay buffer can contain ¨5 mNI HEPES pH 7.4, ¨150 m1\71 NaCI, ¨ 1 mNI DTT, 0.05% BSA and 0.0025% (v/v-) Igepal. A Ras working solution is prepared in an assay buffer containing typically a suitable amount of the protein construct (e.g., GST-tagged K-Ras mutant) and the FRET donor (e.g., antiGST-Eu(K) from Cisbio, France). A SOS1 working solution is prepared in an assay buffer containing suitable amount of the protein construct (e.g., His-liSOS1) and the FRET acceptor (e.g., anti-6His-XL665 from Cisbio, France). A suitable amount of the protein construct will depend on the range of activity or range of IC50 values being detected or under investigation. For detecting IC50 within a range of 500 nI\4, the protein constructs of the same range of molarity can be utilized. An inhibitor control solution is prepared in an assay buffer containing comparable amount of the FRET
acceptor without the SOS1 protein.
[00696] A fixed volume of DMSO with or without test compound is transferred into a 384-well plate. Ras working solution is added to all wells of the test plate. SOS1 working solution is added to all wells except for those that are subsequently filled the inhibitor control solution. Upon incubation for about 10 minutes or longer, the fluorescence is measured with a M1000Pro plate reader (Tecan) using HTRF detection (excitation 337nm, emission 1 : 620nm, emission 2: 665nm). Compounds are tested in duplicates at different concentrations (for example, 10 1\4, 2.5 jtM, 0.63 1\4, 0.16 M, 0.04 jtM, 0.01 uM test compound). The ratiometric data (i.e., emission 2 divided by emission 1) is used to calculate IC50 values against Ras using GraphPad Prism (GraphPad software). Following this general procedure, samples were tested with or without a subject compound disclosed herein including compounds exemplified in Table 6 to assess their abilities to inhibit a K-Ras mutant relative to another mutant or WT. Signaling output measured in terms of IC50 values can be obtained, a ratio of IC50 against one mutant relative to another mutant can be calculated. For instance, a selective reduction of K-Ras G12D
signaling output can be evidenced by a ratio greater than one. In particular, a selective reduction of K-Ras G12D
signaling relative to K-Ras WT signaling is evidenced as the ratio of IC50 (against K-Ras WT) to IC50 (against K-Ras G12D) is greater than 1. In embodiments, one or more subject compounds disclosed herein are expected to exhibit selective inhibition of a Ras mutant (e.g., G12C, G12D, G12S, G1V, G13C, or G13D) over WT by at least 1-fold, and in some instances greater than 2-, 3-, 4- or 5-fold. In embodiments, the compounds listed below in Table 7 exhibit the indicated IC50 values against KRas mutant G12D. In embodiments, subject compounds are expected to exhibit an 1050 against KRas mutants (e.g., G12C, G12D, G12S, G1V, G13C, or G13D) less than 500 nI\4, less than 100 nI\4, 50 nM, 10 nIV1 or even less.
Table 7 IC50 ac.ainst IC50 ac,ainst IC50 acYainst mutant IC50 apainst Compound s s Compound s s mutant Kras wildtype Kras Kras wildtype Kras 101 ++ ++ 440 102 +++ ++ 441 +++
-HP+
103 +++ ++ 442 +++
++
104 +++ +++ 443 105 +++ ++ 444 +++
-HP+
106 +++ ++ 445 110 +++ +++ 446 +++
H¨HP
116 +++ ++ 447 +++
H¨F+
117 +++ ++ 448 433 +++ +++ 449 +++
H¨HP
434 +++ +++ 450 +++
H¨F+
435 +++ +++ 451 +++
t¨+
436 +++ +++ 452 +++
H¨HP
437 +++ +++ 453 +++
H¨HP
438 +++ ++ 454 +++
t¨+
439 +++ ++
`+++' means IC50 at or less than about 1.5 !AM, C++' means 1050 greater than about 1.5 M.
EXAMPLE 7: GTPase activity assay [00697] The ability of any compound of the present disclosure to inhibit a Ras protein signalling can be demonstrated by a reduced GTPase activity. This assay can be also used to assess a selective inhibition of a mutant Ras protein relative to a wildtype, or relative to a different mutant Ras protein. For instance, the assay can be used to establish a subject compound's ability to selectively inhibit Kras G12D
relative to wildtype, G12S relative to wildtype, Kras G12V relative to wildtype, KrasG12S relative KrasG12V, KrasG12S
relative KrasG12D, KrasG12D
relative KrasG12S, or KrasG12D relative KrasG12V. in particular, intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity for K-Ras construct or a mutant thereof can be measured using EnzCheck phosphate assay system (Life Technologies). For example, K-Ras WT, K-Ras Dl 54Q mutant, K-Ras G12D mutant, K-Ras G12S mutant, and K-Ras G12D/D154Q mutant proteins (2.5 mg/ml) in buffer (20 mmol/L Tris, pH 8.0, 50 m1V1 NaCl) is loaded with GTP at room temperature for 2 hours by exposing to exchange buffer containing EDTA.
Proteins are buffer exchanged to assay buffer (30 mM Tris, pH 7.5, 1 mM DTT) and the concentration is adjusted to 2 mg/ml. GTP loading is verified by back extraction of nucleotide using 6M
urea and evaluation of nucleotide peaks by HPLC using an ion-exchange column. The assay is performed in a clear 384-well plate (Costar) by combining GTP-loaded K-Ras proteins (50 mM final) with 2-amino-6-mercapto-7-methylpurine ribonucleoside (MESG) (200 ml\/1 final), and purinc nucleotide phosphorylasc (5 U/ml final). GTP
hydrolysis is initiated by the addition of MgCl2 at a working concentration of 40 mM. For GAP stimulation, Ras p21 protein activator 1 (P120GAP) can be included at 50 mM. Absorbance at 360 nm can be measured every 8 to 15 s for 1,000 s at 20 C. Samples are tested with or without a subject compound disclosed herein to assess each compound's ability to inhibit signaling of a given Ras protein (e.g., a given mutant Kras) of interest.
EXAMPLE 8: Nucleotide exchange assay [00698] The ability of a compound of the present disclosure to inhibit a Ras protein signaling can be demonstrated by a reduced nucleotide exchange activity. This assay can be also used to assess a selective inhibition of a mutant Ras protein relative to a wildtype, or relative to a different mutant Ras protein. For example, 250 nNI or 500 nN1 GDP-loaded K-Ras proteins (e.g., wildtypc or a mutant thereof including those mentioned in Example 7), each is incubated with different concentrations of compounds (for example ¨60 M, ¨20 M, ¨6.7 M, ¨2.2 M, ¨0.7 NI, ¨0.2 M subject compound). A control reaction without subject compound is also included. SOS1 (catalytic domain) protein is added to the K-Ras protein solution. The nucleotide exchange reaction is initiated by adding fluorescent labelled GDP (Guanosine 5'-Diphosphate, BODIPYTM FL 2' -(or-3')-0-(N-(2-Aminoethyl) Urethane) to a final concentration of 0.36 rt1VI. Fluorescence is measured every 30 s for 70 minutes at 490nm/515nm (excitation/emission) in a M1000Pro plate reader (Tecan). Data is exported and analyzed to calculate an IC50 using GraphPad Prism (GraphPad Software) Sample(s) can be tested with or without a subject compound disclosed herein including compound(s) exemplified in Table 1 to assess compound's ability to inhibit K-Ras signaling or its IC50 against a given Ras protein (e.g., a given mutant K-Ras) of interest.
EXAMPLE 9: Testing for modification of Ras protein [00699] Test compounds arc prepared as 10 mIV1 stock solutions in DMSO (Fisher cat#BP231-100). KRAS protein (e.g., His-tagged GDP-loaded wildtype 1-169, His-tagged GDP-loaded Gl2C 1-169, His-tagged GDP-loaded G12D
1-169, or His-tagged GDP-loaded Gl2S 1-169) is diluted to ¨2 itiM in appropriate buffer (e.g., a Hepes buffer at physiological conditions). For testing KRAS modification, compounds are diluted to 50X final test concentration in DMSO in 96- well storage plates. 1 1 of the diluted 50X compounds are added to appropriate wells in the PCR
plate (Fisher cat#AB-0800). ¨49 al of the stock protein solution is added to each well of the 96-well PCR plate.
Reactions are mixed carefully. The plate is sealed well with aluminum plate seal, and stored in drawer at room temperature for 24hrs. 5 1 of 2% formic acid (Fisher cat#A117-50) in MilliQ
H20 is then added to each well followed by mixing with a pipette. The plate is then resealed with aluminum seal and stored until mass spectrometry analysis.
The extent of covalent modification of KRAS proteins can be determined by liquid chromatography electrospray mass spectrometry analysis of the intact proteins on a Thermo Q-Exactive Plus mass spectrometer. 20 1 of sample is injected onto a bioZen 3.6 m Intact C4 colunm (Phenomenex cat#00B-4767-AN) placed in a column oven set to 40 C and separated using a suitable LC gradient from ¨20% to ¨60% solvent B.
Solvent A isis 0.1% formic acid and solvent B is 0.1% formic acid in acetonitrile. HES1 source settings are set to 40, 5 and 1 for the sheath, auxiliary and sweep gas flow, respectively. The spray voltage is 4 kV, and the capillary temperature is 320 C. S-lens RF level is 50 and auxiliary gas heater temperature is set to 200 C. The mass spectrometry is acquired using a scan range from 650 to 1750 In/z using positive polarity at a mass resolution of 70,000, AGC target of 1e6 ions and maximum injection time of 250ms. The recorded protein mass spectrum is deconyoluted from the raw data file using Protein Deconvolution v4.0 (Thermo). The protein mass and adduct masses are exported with their peak intensities.
The peak intensities for the unmodified and modified protein are used to calculate the percent covalent modification of the KRAS protein based on the following equation: %KRAS protein modification = ((KRAS-compound) /
(KRAS) + (KRAS-Compound)) *100.

EXAMPLE 10: Ras cellular assay [00700] The ability of any compound of the present disclosure to inhibit a Ras protein signalling can be demonstrated by inhibiting growth of a given Kras mutant cells. For example, this assay can be also used to assess a selective growth inhibition of a mutant Ras protein relative to a wildtype, or relative to a different mutant Ras protein.
a. Growth of cells with K-Ras GI2C mutation [00701] MIA PaCa-2 (ATCC CRL-1420) and NCI-H1792 (ATCC CRL-5895) cell lines comprise a G12C
mutation and can be used to assess Ras cellular signaling in vitro, e.g., in response to a subject inhibitor compounds of the present disclosure. This cellular assay can also be used to discern selective inhibition of a subject compounds against certain types of Kras mutants, e.g., more potent inhibition against KrasG12D relative to KrasG12C mutant, by using MIA PaCa-2 (G1 2C driven tumor cell line) as a comparison. MIA PaCa-2 culture medium is prepared with DMEM/Ham's F12 (e.g., with stable Glutamine, 10% FCS, and 2.5% Horse Serum. NCI-H1792 culture medium is prepared with RPMI 1640 (e.g., with stable Glutamine) and 10% FCS.
[00702] On a first day (e.g., Day 1), Softagar (Select Agar, Invitrogen, 3% in ddH20 autoclaved) is boiled and tempered at 48 C Appropriate culture medium (i e , medium) is tempered to 37 C
Agar ( is diluted 1-3 in medium (=0.6%) and 50 ml/well plated into 96 well plates (Corning, #3904), then incubated at room temperature for agar solidification. A 3% agar is diluted to 0.25% in medium (1:12 dilution) and tempered at 42 C. Cells are trypsinized, counted, and tempered at 37 C. The cells (e.g., MIA PaCa-2 at about 125-150 cells, NCI-H1792 at about 1000 cells) are resuspended in 100 mL 0.25% Agar and plated, followed by incubation at room temperature for agar solidification. The wells are overlaid with 50 mL of the medium.
Sister wells in a separate plate are plated for time zero determination. All plates are incubated overnight at 37 C and 5% CO2.
[00703] On a second day (e.g., Day 2), time zero values are measured. A 40 mL
volume of Cell Titer 96 Aqueous Solution (Promega) is added to each well and incubated in the dark at 37 'V
and 5% CO2. Absorption can be measured at 490 nm and reference wavelength 660 nm. DMSO-prediluted test compounds are added to wells of interest, e.g., with HP Dispenser, to one or more desired concentrations (e.g., a final DMSO concentration of 0.3%).
[00704] On a tenth day (e.g., Day 10), absorption by wells treated with the test compounds and control wells are measured with, for example, Cell Titer 96 AQueous and analyzed in comparison to the time zero measurements. The IC50 values are determined using the four parameter fit. The resulting IC50 value is a measurement of the ability of the compounds herein to reduce cell growth of Ras-driven cells (e.g., tumor cell lines) in vitro and/or in vivo.
b. Growth of cells with K-Ras G 12D mutation [00705] ASPC-1 (ATCC CRL-1682), Panc-10.05 (ATCC CRL-2547), A427, GP2d cell lines or any other cell lines comprising a G12D mutation and can be used to assess Ras cellular signaling in vitro, e.g., in response to the compounds herein. For example, ASPC-1 culture medium is prepared with RPM1-1640 and 10% heat-inactivated FBS. Panc-10.05 culture medium is prepared with RP1VI-1640, 10 Units/ml human recombinant insulin, and 10%
FBS. A427 cell culture is prepared with RPMI-1640 and 10% heat-inactivated FBS. A CellTiter-Glo (CTG) luminescent based assay (Promega) is used to assess growth of the cells, as a measurement of the ability of the compounds herein to inhibit Ras signaling in the cells. The cells (e.g., 800 per well) are seeded in their respective culture medium in standard tissue culture-treated 384-well format plates (Falcon #08-772-116) or ultra-low attachment surface 384-well format plates (S-Bio # MS-9384UZ ). The day after plating, cells are treated with a dilution series (e.g., a 9 point 3-fold dilution series) of the compounds herein (e.g., approximately 40 jil final volume per well). Cell viability can be monitored (e.g., approximately 5 days later) according to the manufacturer's recommended instructions, where the CellTiter-Glo reagent is added (e.g., approximately 10 jt1), vigorously mixed, covered, and placed on a plate shaker (e.g., approximately for 20 min) to ensure sufficient cell lysis prior to assessment of luminescent signal. The IC50 values are determined using the four parameter fit. The resulting IC50 value is a measurement of the ability of the compounds herein to reduce cell growth of Ras-driven cells (e.g., tumor cell lines) in vitro and/or in vivo. The IC50 values are determined using the four parameter fit. The resulting IC50 value is a measurement of the ability of the compounds herein to reduce cell growth of Ras-driven cells (e.g., tumor cell lines) in vitro and/or in vivo. The ability of one or more compounds exemplified in Table 6 to inhibit growth of one or more cell lines comprising a given Kras mutation is demonstrated utilizing the procedures described above.
Corresponding assays for other mutants (e.g., G12S, G12C, G12V, G13D, G13S, G13C, or G13V) are conducted in a similar manner with appropriate cell lines.
EXAMPLE 11: In vivo Ras inhibition [00706] The in vivo reduction in Ras signaling output by a compound of the present disclosure is determined in a mouse tumor xenograft model, (e.g., in a K-Ras mutant (G12D, G12S, G12C, G12V, G13D, G13S, G13C, or Gl3V) model utilizing cells including a KRas G12D mutant (e.g., G12D, G12S, G12C, G12V, G13D, G13S, G13C, or G1 3V) to generate a xenograft model comparable to the xenograft model exemplified below.
Xenograft with K-Ras G12C mutation [0001] In an example, tumor xenografts are established by administration of tumor cells with K-Ras G12C
mutation (e.g., MIA PaCa-2 cells) into mice, e.g., injection of the tumor cells into the right flanks of female BomTacN1V1R1-Foxnlnu mice with an age between 6 to 8 weeks.
[0002] In case of the subcutaneous (s.c.) MIA PaCa-2 xenograft mouse models, MIA PaCa-2 cells are grown in cell culture flasks in appropriate medium. Cultures are incubated at 37 C and 5 % CO2 in a humidified atmosphere, with medium change or subcultivation performed 2-3 times a week. For injection, the cultured tumor cells are mixed with PBS including 5% FCS and Matrigel in a 1:1 ratio. About lx10E7 cells in a volume of 100 jtL is injected s.c. in each mouse to establish tumors. Mice are randomized into treatment groups of 7-10 mice, once tumors reach a desirable size (e.g., between about 86 to about 170 mm3, or between about 115 to about 170 mm3). Treatment with a subject compound disclosed herein or controls (e.g., vehicle control) may start on the day of randomization and can be continued until end of the study (e.g., 22 days). The test samples are administered intragastrically using a gavage needle at an application volume of 10 mL/kg in a volume of 10 mL/kg per mouse daily twice with a 6 h difference.
In some cases, the test compounds are dissolved in 0.5 % DM SO (or 0.5% and 0.5 % Natrosol) in sterile PBS.
[0003] Mice are housed under standardized conditions at 21.5 1.5 C and 55 10% humidity. Standardized irradiated diet and autoclaved tap water is provided ad libitum. In some cases, tags (e.g., ear tags, microchips implanted subcutaneously under isoflurane anesthesia) are used to identify each mouse. The tumor diameter is measured two or three times a week with a caliper. The volume of each tumor (in mm3) is calculated according to the formula "tumor volume = (7c * length * width2) / 6." To monitor side effects of treatment, mice are inspected daily for abnormalities and body weight is determined, e.g., daily. Animals are sacrificed at the end of the study.
Animals with necrotic tumors or tumor sizes exceeding 1500 mm3 are sacrificed early during the study for ethical reasons.
Xenograft with K-Ras G12D mutation [0004] In another example, tumor xenografts are established by administration of tumor cells with K-Ras mutation (e.g. G12D, G12S, G12C, G12V, G13D, G13S, G13C, or G13V) (e.g., ASPC-1 cells) into mice. Female 6- to 8-week-old athymic BALB/c nude (NCr) nu/nu mice are used for xenografts.
The tumor cells (e.g., approximately 5x106) are harvested on the day of use and injected in growth-factor-reduced Matrigel/PBS (e.g., 50% final concentration in 100 n1). One flank is inoculated subcutaneously per mouse. Mice are monitored daily, weighed twice weekly, and caliper measurements begin when tumors become visible. For efficacy studies, animals are randomly assigned to treatment groups by an algorithm that assigns animals to groups to achieve best case distributions of mean tumor size with lowest possible standard deviation.
Tumor volume can be calculated by measuring two perpendicular diameters using the following formula: (L x w2) /2 in which L and w refer to the length and width tumor diameter, respectively. Percent tumor volume change can be calculated using the following formula: (Vfimi ¨Vinitial)/Vinitial X 100. Percent of tumor growth inhibition (%TG1) can be calculated using the following formula: %TG1 = 100 x (1 ¨ (average Vfinal ¨Vinitial of treatment group) / (average Vfinal ¨Vinitial of control group). When tumors reach a threshold average size (e.g., approximately 200-400 mm3), mice are randomized into 3-10 mice per group and are treated with vehicle (e.g., 100% Labrasol0) or a subject compound disclosed herein using, for example, a daily schedule by oral gavage. Results can be expressed as mean and standard deviation of the mean.
Example 12: Metabolic (Microsomal) Stability Assay [0005] The metabolic stability of the test compound is assayed at 37 C using pooled liver microsomes (mouse or human liver microsomes). An aliquot of 10 L of 50 1\4 test compound is mixed with 490 pL of 0.611 mg/mL
liver microsomes, and then, 50 [IL of the mixtures are dispensed to the 96 well tubes and warmed at 37 C for 10 minutes. The reactions are initiated by adding 50 riL of the pre-warmed NADPH
regeneration system solution (add 1.2 pL solution, 240 1 solution B, mix with 10.56 ml KPBS) and then incubated at 37 C. The final incubation solution contains 100 mA4 potassium phosphate (pH 7.4), 1.3 mM NADP+, 3.3 mM
glucose 6-phosphate, 0.4 Unit/mL of glucose 6-phosphate dehydrogenase, 3.3 mM magnesium chloride, 0.3 mg/mL liver microsomes and 0.5 iuM test article. After 0, 15, 30 and 60 minutes in a shaking incubator, the reactions are terminated by adding 100 pL of acetonitrile containing 200 nI\4 buspirone as an internal standard. All incubations are conducted in duplicate.
Plates are vortexed vigorously by using Fisher Scientific microplate vortex mixer (Henry Troemner, US). Samples are then centrifuged at 3500 rpm for 10 minutes (4 C) using Sorvall Legend XRT Centrifuge (Thermo Scientific, GE). Supernatants (40 nL) are transferred into clean 96-deep well plates. Each well is added with 160 fiL of ultrapure water (Milli-Q, Millipore Corporation) with 0.1% (v/v) formic acid (Fisher Chemical), mixed thoroughly and subjected to LC/MS/MS analysis in MRM positive ionization mode.
[0006] All the samples are measured using a mass spectrometer (QTrap 5500 quadrupole/ion trap) coupled with a Shimadzu HPLC system. The HPLC system consisted of a Shimadzu series degasser, binary quaternary gradient pumps, column heater coupled to an autosampler, and a Phenomenex Gemini-NX, C18, 3.0 p.m or Phenomenex Lunar, C8, 5.0 tiM HPLC column (Phenomenex, Torrance, CA), and eluted with a mobile phase gradient consisting of Solution A (0.1% formic acid water) and Solution B (0.1% formic acid acetonitrile). The column temperature is maintained at 40 C. All the analytes are detected with positive-mode electrospray ionization (ES+).
[0007] The half-life for the metabolic degradation of the test compound is calculated by plotting the time-course disappearance of the test compound during the incubation with liver microsomes. Each plot is fitted to a first-order equation for the elimination of the test compound (% remaining compound) versus lime using non-linear regression (Equation 1).
Equation 1:
Ct ___________ ¨ e¨kt Co where CI is the mean relative substrate concentration at time t and Co is the initial concentration (0.5 !AM) at time 0.
Note that the area ratio of the substrate peak to an internal standard peak is proportional to the analyte concentration and are used for regression analysis to derive a value of k.
[0008] The half-life t112 for metabolic (microsome) stability is derived from the test compound elimination constant k using Equation 2 below.
Equation 2:
0.693 tv2 -Example 13: Mouse and Human Protein Binding Assay to Assess Free Drug Concentration [0009] The assay is to determine the plasma protein binding of the test compound in the plasma of human and animal species using a Rapid Equilibrium Dialysis (RED) device for equilibrium dialysis and LC-MS/MS for sample analysis. Test compound is spiked in. The stock solution of the test compound is prepared at 5 mN1 concentration. One tiL of 5 mN1 working solution into 1000 1 plasma. The final concentration is 5 M. The spiked plasma is placed on a rocker, and gently agitated for approximately 20 minutes. A volume of 300 ILL of the plasma sample containing 5 M test compound from each species is added to designate RED device donor chambers followed by addition of 500 L of potassium phosphate buffer to the corresponding receiver chambers in duplicate.
The RED device is then sealed with sealing tape and shaken at 150 RPM for 4 hours at 37 'C. Post-dialysis donor and receiver compartment samples are prepared for LC-MS/MS analysis, including spiking samples with an internal standard for the bioanalytical analysis. Warfarin and propranolol are purchased from Sigma-Aldrich (St. Louis, MO), and used as positive controls for low and high plasma protein binding, respectively.
[0010] All the samples are analyzed using an Agilent Technologies 6430 Triple Quad LC/MS system. The HPLC
system consisted of Agilent 1290 Infinity Liquid Chromatograph coupled to an autosampler (Agilent 1290 Infinity LC Injector HTC), and a Phenomenex Gemini-NX, C18, 3.0 m or Phenomenex Lunar, C8, 5.0 uNI HPLC column (Phenomenex, Torrance, CA), and eluted with a mobile phase gradient consisting of Solution A (0.1% formic acid water) and Solution B (0.1% formic acid acetonitrile). The column temperature is maintained at 40 C. All the analytes are detected with positive-mode electrospray ionization (ES+). The percentage of the test compound bound to plasma is calculated following Equation 3 and 4.
Equation 3 test compound Peak ratio ( receiver compartment 'Internal standard)' % Free test compound = * 100 Peak rati.a )' test compound donor compartment -Internal standard Equation 4 % Plasma protein bound test compound = 100 ¨ % Free test compound [0011]

Claims (52)

WHAT IS CLAIMED IS:
1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Wherein W is C(0), S(0), or S(0)2;
V is C(R47) and J is C(R16), or V is C(FC) and J is N, or J is C(R'7) and V is C(106), or J is C(R'7) and V is N;
Rl is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(0)-, -N(11")C(0)-, -C(0)N(104)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R")-, -S(0)N(R14)-, -N(104)S(0)-, -N(R44)S(0)2-, C2-C6alkeny1, or C2-C6alkynyl, wherein Cl-C6alkyl, C2-C6alkenyl, and C2' C6alkynyl, are optionally substituted with one, two, or three R2oa;
R7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl, wherein the 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more RI, optionally substituted with one or more R4, and optionally substituted with one or more R6;
wherein two substituents selected from 121, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C342cycloalkyl, Cl_llheterocycloalkyl, C6_12aryl, or C1_11heteroaryl, wherein the C3_12cycloalkyl, Cl_ilheterocycloalkyl, C6-12aryl, or Cl.11heteroaryl are optionally substituted with one, two, or three R2oa;
each RI is independently selected from hydrogen, C1_6alkyl, C2.6a1keny1, C2.6alkynyl, C1_6haloalkyl, C3_12cyc1oa1ky1, -C112-C3_12cycloalkyl, -CH2-CI_Iihetcrocycloalkyl, C6_12awl, -CH2-C6_12aryl, -CH2-C,-llheteroaryl, and CI_Hheteroaryl, wherein Cl_6alkyl, C2_6a1ke11y1, C2_6alkyny1, C1_6haloalkyl, C3_12cycloalkyl, -CH2-C3_12cycloalkyl, Cl_llheterocycloalkyl, -CH2-Cl_liheterocycloalkyl, C642aryl, -CH2-C642aryl, -CH2-C1-11heteroaryl, and CI_Hheteroaryl are optionally substituted with one, two, or three R2oa;
each R4 is independently selected from hydrogen, halogen, oxo, -CN. C1_6alkyl, C2_6alkeny1, C2_6alkyny1, C3_ 6cycloalkyl, C2.9heterocyc1oalky1, C6_10ar0, C1_9heteroary1, -SR', -N(R42)(R13), -C(0)01112, -0C(0)N(R'2)(R"), -N(Rm)C(0)N(R'2)(R"), -N(R")C(0)0R", -N(Rm)S(0)2R", -C(0)R", -S(0)R", -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2105, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R42)(R13), -CH2C(0)N(R12)(103), -CH2N(Rm)C(0)R45, -CH2S(0)2R1 , and -CH2S(0)2N(R'2)(103), wherein Cl_oalkyl, C2_6a1keny1, C2_6a1kyny1, C3_6cyc1oalky1, C2_9heterocyc1oa1ky1, C6_10alyl, and C1.9heteroaly1 are optionally substituted with one, two, or three R2';
R6 is -L2-R5;
each L2 is independently selected from a bond, Cl-C6alky1, -0-, -N(R44)-, -C(0)-, -N(R")C(0)-, -C(0)N(R")-, -S-, -S(0)2-, -S(0)-, -S(0)2N(RH)-, -S(0)N(R11)-, -N(R")S(0)-, -N(RH)S(0)2-, -000N(R11)-, -N(R")C(0)0-, and -N(RH)C(0)N(104)-;
each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;

R is selected from halogen, -CN, C1_6alkyl, C2_6a1keny1, C2_6a1kyny1, C3_6cyc1oa1ky1, C2_9heterocyc1oa1ky1, C6_waryl, C1.9heteroary1, -0R12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(1114)C(0)N(R12)(R13), -N(R'4)C(0)0R-'5, -N(R14)S(0)2R'5, -C(0)Rb, -S(0)Rb, -0C(0)R'5, -C(0)N(R12)(R13), -C(0)C(0)N(R11)(1113), -N(Rm)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R-'2)(R13), -CH2C(0)N(R11)(R-'3), -CH2N(R14)C(0)R13, -CH2S(0)2R'5, and -CH2S(0)2N(R12)(R13), wherein C1_6alkyl, C2_6a1keny1, C2_6a1kyny1, C3_ 6cycloalkyl, C2.9heterocyc1oa1ky1, C6_loaryl, and C1_9heter0ary1 are optionally substituted with one, two, or three R2k;
1117 is -L'-1119;
1_," is selected from a bond, Cl-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(Rm)-, -C(0)-, -N(Rm)C(0)-, -C(0)N(RH)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -000N(R14)-, -N(RH)C(0)0-, N(R1e), C(0)N(R'e), S(0)2N(R1c), S(0)N(R1c), C(Rif)(R1)0, C(Rif)(R1g)N(R1c), and C(Rif)(R1g);
R1e, Ril., and RIg are independently selected from hydrogen, halogen, -CN, C1_6alkyl, C1.6haloalkyl, C2_6a1keny1, C2-6alkynyl, C3_6cyc1oa1ky1, C2_9heterocyc1oa1ky1, C6-maryl, C1_9heter0ary1, -OR'', -SR", -N(R'2)(R'3), -C(0)OR'2, -0C(0)N(R120 13), _N(R14)(7(0)N(R12)(R13), 14s )C(0)OR 15, -1\1(R11) S(0)2R 15, -C(0)R 15, -S(0)R 15, -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(RH)C(0)105, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NE)N(R12)(R13), -CH2C(0)N(R'2)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R'2)(103), wherein C1_6alkyl, C2_6a1keny1, C2_6a1kyny1, C3_6cyc1oa1ky1, C2_9heterocyc1oa1ky1, C6-loaryl, and C1.9heteroary1 arc optionally substituted with one, two, or three R201; or Rif and Rlg arc joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R2';
111 is selected from hydrogen, Cl_oalkyl, C24a1keny1, C2_6a1kyny1, C3_6cyc1oa1ky1, C2_9heterocyc1oa1ky1, C64oary1, and C1.91eteroary1, wherein C1_6alkyl, C2_6a1keny1, C2_6a1kyny1, C3_6cyc1oa1ky1, C2.9heterocyc1oa1ky1, C6-loaryl, and C1.9heteroary1 are optionally substituted with one, two, or three R2"
R" is selected from a C3_12cycloalkyl, C241heterocycloalkyl, C6_12aryl, and C242heteroaryl, wherein the C3_ r2cycloalkyl, C2_11heterocycloalkyl, C6-12aryl, and C2- piheteroa tyl are optionally substituted with one, two, three, four, five, six, or seven Rli;
each R1 is independently selected from halogen, -CN, C1_6alkyl, C1_6haloalkyl, C2_6a1keny1, C2_6a1kyny1, C3_ 6cycloalkyl, C2.9heterocyc1oa1ky1, C6,oaiyl, C14heteroalyl, -0R12, -S R12, _N(R12)(R13), _ C(0)0R12, -OC(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0105, -N(R14)S(0)2R15, -C(0)1113, -S(0)1113, -0C(0)R15, -C(0)N(R'2)(R1-3). -C(0)C(0)N(R1-2)(R1-3), -N(RH)C(0)R1-5, -S(0)2R15, -S(0)2N(R1-2)(R'3)-, S(=0)(=NH)N(R12)(R13), _CH2C(0)N(R12)(R13), -CH2N(RH)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C1_6alkyl, C2_6a1keny1, C2_6alkyny1, C3_6cyc1oa1ky1, C2_9heterocyc1oa1ky1, C6-loaryl, and C1_9heteroary1 are optionally substituted with one, two, or three R2";
1116 is selected from hydrogen, halogen, -CN, C1_6alky1, C2_6alkeny1, C2.6a1kyny1, C3_6cyc1oa1ky1, C2-heterocycloalkyl, C6Joaryl, Cl_dreteroaryl, -OR'2, -SR", -N(R'2)(R13), -C(0)0R12, -0C(0)N(R12)(Rn), -N(R'4)C(0)N(R13)(R13), -N(R14)C(0)0R15, -N(R'4)S(0)2R' -C(0)R15, -S (0)1115, -0C(0)R15, -C(0)N(R1-2)(103), -C(0)C(0)N(10-2)(R13), -N(104)C(0)R15, -S(0)210-5, -S(0)2N(102)(103)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)105, -CH2S(0)2105, and -C1-12S(0)2N(R12)(R13), wherein C1-6alky1, C24alkeny1, C2_6alkyny1, C3_6cyc1oa1ky1, C2_9heterocyc1oa1ky1, C6-ioaryl, and C1_9heteroary1 are optionally substituted with one, two, or three R2Og, R2 is -C(0)0R12, -0C(0)N(R12)(R13); -N(R14)C(0)N(R12)(R13); -N(R14)C(0)0R45, -N(R44)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R44)C(0)R15. -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R", -CH2S(0)2R15, -CH2S(0)2N(R12)(R43), -(C1-C6alkyl)-R121', -(C2.6alkeny1)-R121', -(C2_6alkynyl)-R121', -0-R12a, -N(R14)-R121', -S-R121'. -(C3_ tocycloalky1)-R12", -(C2_9heterocyc1oalky1)-R121', -(C64,3ary1)-R42b, or -(C1_9heter0ary1)-R121', wherein said Cl_ 6alkyl, C2_6a1keny1, C2_6alkynyl, C3_10cycloalkyl, C2_9heterocycloalkyl, C6.1oaryl, and C1_9heteroa3y1 are optionally substituted with one, two, or three R2";
R12a is selected from Cl_oalkyl, C2_6alkcnyl, C2.6alkynyl, C3_1ocycloalkyl, -CH2-C3_1ocycloalkyl, C2_9heterocycloalkyl, -CH2-C2.9heterocy cloalky 1, C6_10ary 1, -CH2 -C6_ wary 1, -CH2-C1_91leteroary I, and Ck9heteroary 1, wherein C1_6 alky 1, C2_6a1keny1, C2_6alkyny1, C34acycloalkyl, -CH2-C3_1ocycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocycloalkyl, C6-loaryl, -CH2-C6_maryl, -CH2-C1_9heteroaryl, and C1_9heteroaryl are optionally substituted with one, two, or three R2Od;
Rub is selected from hydrogen, C1_6a1ky1, C2_6a1keny1, C2_6alkyny1, C3_Ncycloalkyl, -CH2-C34ocyc1oalky1, C2-9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6-loaryl, -CH2-C6_icaryl, -CH2-C1_9heteroaryl, and C1_9heteroaryl, wherein C1_6alkyl, C2_6a1keny1, C2_6a11yny1, C34ocycloalkyl, -CH2-C3_10cyc10a1ky1, C2_91ieterocyc1oalky1, -CH2-C2_9heterocycloalkyl, C6_ioaryl, -CH2-C6_ioary1, -CH2-C1_9heteroaryl, and C1_9heteroaryl are optionally substituted with one, two, or three R2";
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, C1_6a1ky1, C2_6alkeny1, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6-toatiyl, Cl_9heteroaryl, -0R12, -N(R12)(103), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(Rm)C(0)0R15, -N(R11)S(0)2R15, -C(0)R15, -S(0)R'5, -0C(0)R'5, -C(0)N(R12)(R13), -C(0)C(0)N(R'2)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)FC, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein C1_6a1ky1, C2_6alkeny1, C2_6alkyny1, C3-6cycloalkyl, C2.9heterocyc1oa1kv1, C6_ioaryl, and C1_9heteroaryl are optionally substituted with one, two, or three R2oh;
each R12 is independently selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3.
6cycloalkyl, C2_9heterocyc1oa1ky1, -C1-12-C2._,heterocycloalkyl, C6_ioaryl, -CH2-C6_ioaryl, -CH2-C1_9heteroaryl, and C1_9heteroaryl, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_ 9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6_ioaryl, -CH2-C6_i0aryl, -CH 2-C1_9heteroary1, and C1_9heteromyl are optionally substituted with one, two, or three R2";
each Rn is independently selected from hydrogen, C1_6alkyl, and C1_6haloalkyL
or 1112 and RH, together with the nitrogen to which they are attached, form a C2_9heterocycloalkyl ring optionally substituted with one, two, or three R2oe;
each R14 is independently selected from hydrogen, C1_6alkyl, and C1_6haloalkyl;
each R15 is independently selected C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_toaryl, and C1.9heteroaryl, wherein C1_6alkyl, C2_6a1kenyl, C2_6alkynyl, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_10alyl, and C1_91e1eroary 1 are optionally substituted with one, two, or three R20;
each R2oa, Rzob; R2OC; R2od; R2oe; R20f, _tc -=-=20g, and R2" are each independently selected from halogen, oxo, -CN, CI_ 6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3_6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2-sheterocycloalkyl, C6_loaryl, -CH2-C6_loaryl, -CH2-C1_9heteroaryl.
C1_9heteroaryl, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein C1_6alkyl, C2_6a1keny1, C2_6a1kyny1, C3_6cyc1oa1ky1, -CH2-C3_6cyc1oa1ky1, C2-9heterocycloalkyl, -CH2-C2.yheterocycloalkyl, C6_10ary1, -CH2-C6_1((aryl, -CH2-C1_9heteroary1, and C1_9heteroary1 are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Cl.
6alkyl, C1_6haloalkyl, C1_6a1koxy, C1_6haloalkoxy, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R23;
cach R21 is independently selected from H, C2_6a1keny1, C2_6a1kyny1, C3_6cyc1oa1ky1, C2_ yheterocycloalkyl, C6.1oary1, and Cl_yheteroaryl;
each R22 is independently selected from H, C1_6alkyl, C1_6haloalky1, C2_6alkeny1, C2_6a1kyny1, C3_6cyc1oa1ky1, C2_ 9heterocycloalkyl, C6-loawl, and C1_9heteroary1;
each R23 is independently selected from H and C1_6alky1;
each R24 is independently selected from H and C1_6alkyl;
each R2' is independendy selected from Cl_6alkyl, C2_6a1keny1, C2_6alkyny1, C3_6cycloalkyl, C2_9heterocycloalkyl, C6_ wary], and CI4heteroaryl, and - indicates a single or double bond such that all valences are satisfied.
2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R3).
3. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.
4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein J
is C(R16) and V is C(R17).
5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C(0).
6. The compound of clainl 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure:
7.
The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the stmcture:
8. The compound of clahn 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure:
9. The compound of any one of' claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is a bond.
10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is -NTT-.
11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R', optionally substituted with one or more R4, and optionally substituted with one or more R6; and wherein two substituents selected from R',10, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3_12.cycloalkyl, Ci_iiheterocycloalkyl, C6_12ary1, or Ci_liheteroaryl, wherein the C3-12cycloalkyl, Cmtheterocycloalkyl, CO42aryl, or Ci_itheteroaryl are optionally substituted with one, two, or three R2o..
12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein p is an integer from 0 to 12;
X1 is selected from CH2, C(R4)(R6), C=N-OR4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), 0, S, S(0), S(=0)(=NR4), S(0)2N(R4), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), OC(0)N(R4), N(R4)C(0)N(R4), S(0)2, CH2C(R4)(fe), CH2C(R4)(116)CH2, C(R4)(10C(R4)(10C(R4)(R6), C(R4)(W)C=N-0R4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R6)0, C(R4)(R6)0C(R4)(R6), C(R4)(R6)S, C(R4)(FOSC(R4)(R6), C(R4)(R6)S(0), C(R4)(R6)S(0)C(R4)(10, C(R4)(R6)S(0)2C(R4)(R6), C(R4)(fe)S(=0)(=NR4), C(R4)(R6)S(0)2N(R4), C(R4)(R6)N(10S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(114)(116)S(0)N(R1), C(11'1)(R6)0C(0)N(R"), C(10)(R6)N(111)C(0)N(R"), C(R4)(10S(0)2, C=NN(R4)(fe)C(R4)(R6), C(0)N(10)C(R4)(fe), S(0)2N(R4)C(R0)(R), S(0)N(R4)C(10)(R6), OC(0)N(R4)C(R4)(R6), C(R4)(R4), C=N-0R4, C=NN(R4)(R4), CH2C(R4)(R4), CH2C(R4)(R4)CH2, C(R4)(R4)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C=N-0R4, CH2C=NN(R4)(R4), C(R4)(R4)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0, C(R4)(R4)0C(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R1)(R1), C(0)N(R1)C(R1)(R1), S(0)2N(R4)C(R4)(R4), S(0)N(10)C(R4)(R4), and OC(0)N(R4)C(R4)(R4);
X2 is selected from N, C, C(R4), CH, N(10), N(R4), N(R'), 0, S, S(0), C(H)(W), C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X' is selected from N, C, C(R'). and C(R4).
13. The compound of any one of' claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein ; and p is an integer from 0 to 12.
14. The compound of any one of claims 143; or a pharmaceutically acceptable salt or solvate thereof, wherein R" is independently selected from hydrogen and halogen.
15. The compound of any one of claims 1-13. or a pharmaceutically acceptable salt or solvate thereof, wherein R" is independently selected from hydrogen and fluoro.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from C1.6alkyl, C3.iocycloalkyl, and C2_9heterocyc1oa1ky1, wherein C1_6alkyl, C34ocycloalkyl, and C2_9heterocyc1oa1ky1 are optionally substituted with one, two, or three R20 independently selected from halogen, Cl_talkyl, Calkenyl, C2_6alkyny1, C3_1ticycloalkyl, and C2_9hetcrocyc1oa1ky1.
17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein re is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl.
18. The compound of any one of claims 1-15. or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
19 The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen or CN.
20. The compound of any one of claims 1-19. or a pharmaceutically acceptable salt or solvate thereof, wherein Ll is a bond.
21. The compound of any one of claims 1-19. or a pharmaceutically acceptable salt or solvate thcrcof, wherein Ll is selected from a Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C(0)-, -NHC(0)-, -C(0)NH-, CH20, CH2NH, and CH2.
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a monocyclic ring.
23. The compound of any one of claims 1-21. or a pharmaceutically acceptable salt or solvate thereof, wherein R'9 is a bicyclic ring system.
24. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R39 is a polycyclic ring system.
25. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is:
Qi, Q3, and Q5 are independently N or C(Rid);
Q4 and Q6 are independently 0, S. C(Ria)(Rlb), or N(Ric);
X4, X5, X6, X9, X10, X", X13, and X16 are independently selected from C(R") or N;
X' and X8 are independently selected from C(Ria), C(Ria)(Rib), N, or X" is selected from a bond, C(0). C(Ria)(10), C(0)C(Ria)(Rib), C(Rla)(RIb)C(Rla)(R1b), C(Rla)(R1b)N(R1c), and N(Ric);
X" and Xi5 are independently selected from a bond, C(0), C(Ria)(Rib), and N(Ric);
each Ria, Rd), Rld, Rlg, and Rib are each independently selected from hydrogen, halogen, -CN, Cl_nalkyl, Cl_ 6haloalkyl, C2_6a1keny1, C2_6alkynyl, C3_10cycloalkyl, C2_sheterocycloalkyl, C6.ioary1, Cl_9heteroary1, -0R12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R18, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(103), -CH2N(R14)C(0)R15, -C1-12S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Cl_balkyl, C2_6alkcnyl.
C2_6alkynyl, C340cycloalkyl. C2-sheterocycloalkyl, C6.1oaly1, and C1_9heteroary1 are optionally substituted with one, two, or three R21; or RIa and Rib bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C34ocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3_iocycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6_, oaryl ring, a 5-12 membered heteroaryl ring, or a Cl_locycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6_ioaryl ring, 5-12 membered heteroaryl ring, or C3_, ocycloalkyl ring are optionally substituted with one, hvo, o r three R2d1, or RH' and one of Rh`, Rlb, Ric, and Rid bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-loaryl ring, a 5-12 membered heteroaryl ring, or a C34ocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a Cs_loaryl ring, a 5-12 membered heteroawl ring, and Cs_iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rif and Rig arc joined to form a 4-7 membered hacrocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R21:8; and each Ric is independently selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6a1kyny1, C3_iocycloalkyl, C2-9heterocycloalkyl, C6_10awl, C1_9heterowy1, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_iocycloalkyl, C2-9heterocycloalkyl, C6_10aw1, and C1_9heteroary1 are optionally substituted with one, two, or three R2(8.
26. The compound of any one of claims 1-21. or a pharmaceutically acceptable salt or solvate thereof, wherein
27. The compound of any one of claims 1-26. or a pharmaceutically acceptable salt or solvate thereof, wherein Fe is selected from
28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each 1_,2 is independently a bond.
29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5 is independently selected from:

; and m.1154Vn rtteVq31. ic= 0, i, 17!, or 3.
30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, whereinR4 is independently -C(0)R15.
31. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein said R15 is independently selected from C2_6a1keny1, C2_6alkyny1, C2_9heterocyc1oa1ky1, and Ci_9heteroary1, wherein Cy_ 6alkenyl, C2_6alkynyl, C2_9heterocyc1oa1ky1, and C1_9heteroary1 are optionally substituted with one, two, or three R2".
32. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein said R15 is independently C2_6a1keny1, wherein C2_6a1keny1 is optionally substituted with one, two, or three R20.
33. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein said R15 is independently C2_9heterocyc1oa1ky1, wherein C2_9heterocyc1oa1ky1 is optionally substituted with one, two, or three R2".
34. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein said R15 is independently C1_9heteroary1, wherein Ci_9heteroary1 is optionally substituted with one, two, or three 1220.
35. The compound of one of claims 30-34, or a pharmaceutically acceptable salt or solvate thereof, wherein said R4 is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein.
36. A compound having the formula A-1_,AB-B wherein A is a monovalent form of a compound of one of claims 1 to 35;

1.AB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.
37. The compound of claim 36 wherein the degradation enhancer is capable of binding a protein selected from E3A, mdm2, APC, EDD1, SOCS/BC-box/eloBC/CULS/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HERS, HERC6, HUWEI, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBRS, VHL (von-Hippcl-Lindau ubiquitin ligasc), WWP1, WWP2, Parkin, MKRN1, CMA (chaperon-inediated autophage), SCFb-TRCP (Skip-Cullin-F box (Beta-TRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAP1 (cellular inhibitor of apoptosis protein 1), APC/C (anaphase-promoting complex/cyclosome), CRBN (cereblon), CUL4-RBX1-(CRL4cRBN) ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBX04, FBX031, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885.
3/3 The compound of claim 36 wherein the degradation enhancer is capable of binding a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.
39. The compound of any one of claims 36 to 38, wherein LAB is -LAB1-LAB2-LAB3-LAB4-LAB5-;
LA131, LAB2, LAB3, LAB'', and L5 are independently a bond, -0-, -N(1311)-, -C(0)-, -N(1314)C(0)-, -C(0)N(1311)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(1314)-, -S(0)N(104)-, -N(1314)S(0)-, -N(R14)S(0)2-, Cl.balkylcne, (-C1-6a1ky1-0)z-, C2_6a1keny1ene, C2_6a1kyny1ene, C1.6haloalkylene, C3_12cycloalkylene, Ci-Iiheterocycloalkylene, C6_12arylene, or Cl_illieteroarylene, wherein C1_6alkylene, C2_6alkenylene, C2-6alkyny lene, C1_6haloalkylene, C3_12cycloalkylene, Cl-Ilheterocycloalkylene, C6_12arylene, or Ci-liheteroarylene,are optionally substituted with one, two, or three R2.01;
wherein each C1_6alkyl of (-0-6alkyl)z- and (-C1-6alky1-0)z- is optionally substituted with one, two, or three R201;
z is independently an integer from 0 to 10;
each R12 is independently selected from hydrogen, C1_6alkyl, C2_6a1keny1, C2_6alkynyl, C3.6cyc1oa1ky1, -CH2-C3_6cycloalkyl, C2_9heterocycloalkyl, -CH2-C2_9heterocyc1oa1ky1, C6_ioaryl, -CH2-C6_10awl, -CH2-Ci-9heteroaryl, and C1_9heteroary1, wherein C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, -CH2-C3-6cycloalkyl, C2_9heterocyc1oa1ky1, -CH2-C2_9heterocyc1oa1ky1, C64oalyl, -CH2-G_loaryl, -CH 2-C1-9heteroaryl, and C1_9heteroary1 are optionally substituted with one, two, or three R'd;
each RH is independently selected from hydrogen, C1_6alkyl, and C1_6ha1oa1ky1;
or ft12 and RH, together with the nitrogen to which they are attached, form a Cmheterocycloalkyl ring optionally substituted with one, two, or three R20e;
each R"is independently selected from hydrogen, C1_6alkyl, and C1_6haloalkyl;
each R15 is independently selected C1_6alkyl, C2_6alkenyl, C2.6alkynyl, C3_6cycloalkvl, Cmheterocycloalkyl, C64oaryl, and Cl.oheteroaryl, wherein C1_6alkyl, C2_6alkenyl, C2_6a1kyny1, C3_6cycloalkyl, C2.
sheterocycloalkyl, C6_loaryl, and C1_91ieteroaryl are optionally substituted with one, two, or three le";

each R2Od, Rale, R20f, and R201 are each independently selected from halogen, -CN, C1_6alkyl, C2_6a1keny1, C2-6alkynyl, C3_6cyc1oa1ky1, -CH2-C3_6cyc1oa1ky1, C2_9heterocyc1oa1ky1, -CH2-C2_9heterocyc1oa1ky1, C6_1oary1, -CH2-C6-mary1, -CH2-C1_9heteroary1, Cl_vheteromyl, -0R21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -OCH2C(0)0R22, and -0C(0)R25, wherein Cl.oalkyl, C2_6a1keny1, C2_6a1kyny1, C3.6cyc1oa1ky1, -CH2-C3_6cyc1oa1ky1, 9heterocycloalkyl, -CH2-C2_9heterocyc1oa1ky1, C6_ioary1, -CH2-C6_ioaryl, -CH2-Ci.9heteroary1, and C1-9heteroaryl arc optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci_6a1ky1, C1_6haloalkyl, Ci_6a1koxy, Ci_6ha1oa1koxy, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25;
each R" is independently selected from H, C1-6alkyl, Ci_6haloalkyl, C2.6alkeny1, C2.6a1kyny1, C3_6cyc1oa1ky1, C2_9heterocyc1oa1ky1, C64oaryl, and Ci_9heteroary1;
each R" is independently selected from H, C1-6alkyl, Ci_6haloalkyl, C2.6allceny1, C2.6a1kyny1, C3_6cyc1oa1ky1, C2_9heterocyclnalkyl, C6-ioaryl, and Ci_Aeteroaryl;
each R23 is independently selected from H and C1_6allcy1;
each R24 is independently selected from H and Cl_6allcy1: and each R25 is selected from Ci_6a1ky1, C2_6a1keny1, C2_6a1kymT1, C3_6cyc1oa1ky1, C2.9heterocyc1oa1ky1, C6_loaryl, and C1_9heteroary1.
40. The compound of any one of claims 36 to 38, wherein LAB is -(0-C2a1ky1)z-and z is an integer from 1 to 10.
41. The compound of any one of claims 36 to 38, wherein LAB is -(C2alky1-0-)z-and z is an integer from 1 to 10.
42. The compound of any one of' claims 36 to 38, wherein LAB is -(CH2),11_,AB2(CH20)z2-, wherein LAB2 is a bond, a 5 or 6 membered heterocycloalkylene or heteroarylene, phenylene, -(C2-C4)alkynylene, -S02- or -NH-; and zl and z2 are independently an integer from 0 to 10.
43. The compound of any one of claims 36 to 38, wherein L" is -(CH2),I(CH20)z2-, wherein zl and z2 are each independently an integer from 0 to 10.
44. The compound of any one of claims 36 to 38, wherein LAB is a PEG linker.
45. The compound of any one of claims 36 to 44, wherein B is a monovalent form of a compound selected from
46. A pharmaceutical composition comprising a compound of any one of claims 1 to 45 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
47. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any onc of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof.
48. A method of modulating activity of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.
49. The method of one of claims 47-48 comprising administering an additional agent or therapy.
50. A method of inhibiting cell growth, comprising administering an effective amount of a compound of one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.
51. The method of claim 50 comprising administering an additional agent to said cell.
52. A Ras protein bound by a compound of one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof, wherein activity of said Ras protein is reduced as compared to a Ras protein unbound to said compound.
CA3221608A 2021-06-14 2022-06-13 Fused heteroaryl compounds useful as anticancer agents Pending CA3221608A1 (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US202163210474P 2021-06-14 2021-06-14
US63/210,474 2021-06-14
US202163291320P 2021-12-17 2021-12-17
US63/291,320 2021-12-17
US202263313132P 2022-02-23 2022-02-23
US63/313,132 2022-02-23
PCT/US2022/033305 WO2022266015A1 (en) 2021-06-14 2022-06-13 Fused heteroaryl compounds useful as anticancer agents

Publications (1)

Publication Number Publication Date
CA3221608A1 true CA3221608A1 (en) 2022-12-22

Family

ID=82483189

Family Applications (1)

Application Number Title Priority Date Filing Date
CA3221608A Pending CA3221608A1 (en) 2021-06-14 2022-06-13 Fused heteroaryl compounds useful as anticancer agents

Country Status (5)

Country Link
EP (1) EP4355751A1 (en)
JP (1) JP2024521473A (en)
AU (1) AU2022293663A1 (en)
CA (1) CA3221608A1 (en)
WO (1) WO2022266015A1 (en)

Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3191279A1 (en) 2020-08-28 2022-03-03 Yi Liu Heterocyclic compounds and uses thereof
JP2025510572A (en) 2022-03-08 2025-04-15 レボリューション メディシンズ インコーポレイテッド Methods for treating immunorefractory lung cancer
CN119031916A (en) * 2022-04-08 2024-11-26 米拉蒂治疗股份有限公司 Combination therapy containing SOS1 inhibitors and EGFR inhibitors
AU2023250314A1 (en) * 2022-04-08 2024-10-03 Mirati Therapeutics, Inc. Combination therapies comprising a sos1 inhibitor and a mek inhibitor
CA3247639A1 (en) 2022-05-06 2023-11-09 PAQ Therapeutics Inc. Kras g12d proteolysis targeting chimeras
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
CN117327102B (en) * 2022-06-30 2026-04-28 重庆华森英诺生物科技有限公司 KRAS inhibitors, their preparation methods and applications
IL318647A (en) 2022-08-05 2025-03-01 Kumquat Biosciences Inc Heterocyclic compounds and uses thereof
WO2024152247A1 (en) * 2023-01-18 2024-07-25 Nikang Therapeutics , Inc. Bifunctional compounds for degrading kras g12d via ubiquitin proteasome pathway
TW202430179A (en) 2022-11-21 2024-08-01 美商樹線生物科學公司 Spirocyclic dihydropyranopyrimidine kras inhibitors
AU2024241633A1 (en) 2023-03-30 2025-11-06 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
CR20250420A (en) 2023-04-07 2025-11-20 Revolution Medicines Inc MACROCYCLIC RAS INHIBITORS
AR132338A1 (en) 2023-04-07 2025-06-18 Revolution Medicines Inc RAS INHIBITORS
CN121464140A (en) 2023-04-14 2026-02-03 锐新医药公司 Crystalline forms of RAS inhibitors, compositions containing the same, and methods of use thereof
CN121100123A (en) 2023-04-14 2025-12-09 锐新医药公司 Crystalline forms of Ras inhibitors
TW202508595A (en) 2023-05-04 2025-03-01 美商銳新醫藥公司 Combination therapy for a ras related disease or disorder
US20250049810A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025038936A1 (en) 2023-08-17 2025-02-20 Treeline Biosciences, Inc. Spirocyclic dihydropyranopyrimidine kras inhibitors
US20250109147A1 (en) 2023-09-08 2025-04-03 Gilead Sciences, Inc. Kras g12d modulating compounds
TW202528315A (en) 2023-09-21 2025-07-16 美商樹線生物科學公司 Spirocyclic dihydropyranopyridine kras inhibitors
AU2024360465A1 (en) 2023-10-12 2026-04-09 Revolution Medicines, Inc. Macrocyclic ras inhibitors
WO2025168051A1 (en) * 2024-02-08 2025-08-14 润佳（苏州）医药科技有限公司 Bifunctional compound and use thereof
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
TW202547461A (en) 2024-05-17 2025-12-16 美商銳新醫藥公司 Ras inhibitors
WO2025245127A1 (en) 2024-05-21 2025-11-27 Treeline Biosciences, Inc. Spirocyclic dihydropyranopyrimidine kras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025265060A1 (en) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Therapeutic compositions and methods for managing treatment-related effects
WO2026006747A1 (en) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Ras inhibitors
WO2026015796A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015801A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015790A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015825A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Use of ras inhibitor for treating pancreatic cancer
WO2026050446A1 (en) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Ras inhibitors
WO2026072904A2 (en) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions and methods for treating lung cancer

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016119707A1 (en) * 2015-01-29 2016-08-04 Hutchison Medipharma Limited Novel heteroaryl and heterocycle compounds, compositions and methods
EP3908283A4 (en) * 2019-01-10 2022-10-12 Mirati Therapeutics, Inc. Kras g12c inhibitors
CN112552294B (en) * 2019-09-10 2023-12-19 上海翰森生物医药科技有限公司 Piperazine-containing heterocyclic derivative inhibitors, preparation methods and applications thereof
EP4204412A4 (en) * 2020-08-26 2024-10-09 InventisBio Co., Ltd. Heteroaryl compounds, preparation methods and uses thereof

Also Published As

Publication number Publication date
JP2024521473A (en) 2024-05-31
AU2022293663A1 (en) 2023-12-21
EP4355751A1 (en) 2024-04-24
WO2022266015A1 (en) 2022-12-22

Similar Documents

Publication Publication Date Title
CA3221608A1 (en) Fused heteroaryl compounds useful as anticancer agents
US11648254B2 (en) Substituted pyrido[2,3-d]pyrimidines as inhibitors of Ras pathway signaling
US12365676B2 (en) Heterocyclic compounds and uses thereof
US20240109918A1 (en) Heterocyclic compounds and uses thereof
WO2023141300A1 (en) Heterocyclic compounds and uses thereof
US20240390389A1 (en) Heterocyclic compounds and uses thereof
JP7372255B2 (en) Heterocyclic compounds as immunomodulators
CN119032096A (en) Heterocyclic compounds and uses thereof
EP4291199A1 (en) Heterocyclic compounds and uses thereof
CA3086763A1 (en) Irak degraders and uses thereof
WO2023205701A1 (en) Macrocyclic heterocycles and uses thereof
IL303458A (en) Irak degraders and uses thereof
CN117120058A (en) Heterocyclic compounds and their uses
CA3225285A1 (en) Pi3k.alpha. inhibitors and methods of use thereof
CN119095849A (en) Macrocyclic heterocycles and uses thereof
EP4685142A1 (en) Triazine compound and use thereof
CN117794940A (en) Fused heteroaryl compounds as anticancer agents
TW202438056A (en) Heterocyclic compounds and uses thereof
CN119137118A (en) Adenosine receptor antagonists
TW202434589A (en) Macrocyclic heterocycles and uses thereof

Legal Events

Date Code Title Description
B11 Application withdrawn

Free format text: ST27 STATUS EVENT CODE: A-1-1-B10-B11-B206 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: WITHDRAWAL REQUEST RECEIVED

Effective date: 20250627

W00 Other event occurred

Free format text: ST27 STATUS EVENT CODE: A-1-1-W10-W00-W111 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: CORRESPONDENT DETERMINED COMPLIANT

Effective date: 20250702

W00 Other event occurred

Free format text: ST27 STATUS EVENT CODE: A-1-1-W10-W00-W100 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: LETTER SENT

Effective date: 20251201

B11 Application withdrawn

Free format text: ST27 STATUS EVENT CODE: T-1-6-B10-B11-B202 (AS PROVIDED BY THE NATIONAL OFFICE); EVENT TEXT: WITHDRAWN

Effective date: 20251210