WO2025155711A1

WO2025155711A1 - Lrrk2 inhibitors and compositions and uses thereof

Info

Publication number: WO2025155711A1
Application number: PCT/US2025/011861
Authority: WO
Inventors: Albert Garofalo; Thomas MONTINE
Original assignee: Leland Stanford Junior University
Current assignee: Leland Stanford Junior University
Priority date: 2024-01-17
Filing date: 2025-01-16
Publication date: 2025-07-24
Anticipated expiration: 2026-07-17

Abstract

Disclosed herein are compounds that inhibit leucine-rich repeat kinase 2 (LRRK2), pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., in a method of treating a disorder that derives in full or in part from LRRK2 kinase activity, such as neurodegenerative diseases, immune-mediated diseases, and forms of cancer.

Description

LRRK2 INHIBITORS AND COMPOSITIONS AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63/621,841, filed on January 17, 2024, and to U.S. Provisional Patent Application No. 63/688,592, filed on August 29, 2024, the disclosures of which are incorporated herein by reference in their entireties.

FIELD

Disclosed herein are compounds that inhibit leucine-rich repeat kinase 2 (LRRK2), pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., in methods of treating disorders associated with LRRK2 such as neurodegenerative diseases, immune-mediated diseases, and forms of cancer.

BACKGROUND

Parkinson's disease ("PD") is the most common form of parkinsonism, a neurodegenerative movement disorder, and the second most common age-related neurodegenerative disease estimated to affect 1-2% of the population over age 65. PD patients experience a progressive loss of dopaminergic neurons leading to disease that is characterized by tremor, rigidity, postural instability, impaired speech, and bradykinesia. Nonmotor symptoms also manifest with PD and include sleep disorders, gastrointestinal dysfunction, depression, cognitive and emotional changes, and anosmia. It is a chronic, progressive disease with increasing disability and diminished quality of life. In addition to PD, parkinsonism is exhibited in a range of conditions such as progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, PD dementia, and dementia with Lewy bodies. Current therapeutic strategies for PD are primarily palliative and focus on reducing the severity of symptoms using supplemental dopaminergic medications. At present, there is no disease-modifying therapy that addresses the underlying neurop athological cause of the disease, thus constituting a significant unmet medical need.

It has long been known that family members of PD patients have an increased risk of developing the disease compared to the general population. Leucine-rich repeat kinase 2 ("LRRK2," also known as dardarin) is a 286 kDa multi-domain protein that has been linked to PD by genome-wide association studies (Mov. Disord. 2011, 26(6), 1042). LRRK2 expression in the brain is highest in areas impacted by PD (Eur. J. Neurosci. 2006, 23 (3): 659) and LRRK2 has been found to localize in Lewy Bodies, which are intracellular protein aggregates considered to be a hallmark of the disease. Patients with point mutations in LRRK2 present disease that is indistinguishable from idiopathic patients (Lancet Neurol. 2008, 7(7), 583).

Missense mutations in LRRK2 have been shown to enhance the kinase activity of the protein (Proc. Nat. Acad. Sci. USA 2005, 102(46), 16842) suggesting that hyperphosphorylation of LRRK2 substrates may play a role in disease progression. Recent findings in brain from idiopathic PD (iPD) patients suggest that genetic and sporadic forms of PD may be linked through increased LRRK2 kinase activity. Rab GTPases, which regulate vesicular trafficking, are endogenous LRRK2 substrates. A 4-fold increase in phosphorylated Rab 10 levels has been observed in postmortem brain tissue from a cohort of iPD patients. This was correlated with a 6-fold increase in LRRK2 autophosphorylation of Ser1292; a similar effect occurs in a rotenone-induced rat model of PD (Sci. Transl. Med. 2018, 10, eaar5429). Increased Rab 10 phosphorylation also occurs in human peripheral blood neutrophils (Biochem. J. 2018, 475, 23) and increased Rab 10 phosphorylation was observed in patients with iPD in a Phase I clinical study of a LRRK2 type I KI.( https://denalitherapeutics.gcs-web.com/node/8141/pdf). Together, these findings suggest a significant role for increased LRRK2 kinase activity in the etiology and pathogenesis of LRRK2 mutation-related PD and iPD. Thereby, inhibition of LRRK2 kinase activity has become a target for the treatment of PD (Nat. Med. 2010, 16(9), 998; J. Neurosci. Res. 2009, 87(6), 1283).

In addition to PD, LRRK2 has been linked to other diseases. Among these are cancer, leprosy, and Crohn's disease (Sci. Signal., 2012, 5(207), pe2). LRRK2 mutations are also associated with diverse pathologic changes in brain, including deposits of tau, also called “tauopathy”, especially the type characteristic of Alzheimer disease (AD) (Acta Neuropathol. Commun. 7: 183 (2019)) but also a number of other neurodegenerative diseases, as well as deposits of transactive response DNA binding protein of 43 kDa (TDP-43) (Mov. Disord. 2023 Aug; 38(8): 1541-1545) suggesting that LRRK2 inhibitors may be useful for the treatment of AD or other related disorders. LRRK2 is expressed in peripheral monocytes and macrophages and inflammation increases LRRK2 activity and expression suggesting a role for LRRK2 in regulating immune cell response (J. Neurosci. 2012, 32(05), 1602). LRRK2 inhibitors may therefore be useful for the treatment of a range of immune-mediated diseases.

As there are presently limited therapeutic options for treating PD and other disorders associated with aberrant LRRK2 kinase activity, there remains a need for developing LRRK2 inhibitors. SUMMARY

In one aspect, disclosed herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from aryl and 5- or 6-membered monocyclic heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, halo, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, -(CR^a1R^b1)_m-G¹, cyano, nitro, amino, -C(O)R^c1, -C(O)OR^d1, -C(O)N(R^e1)(R^f1), - S(O)_pR^g1, -NR^h1S(O)₂Rⁱ¹, -NR^{j 1}C(O)R^k1, and -NR^{l 1}C(O)OR^m1, wherein m is 0 or 1, p is 1 or 2, and G¹ is selected from aryl, 5- or 6-membered monocyclic heteroaryl, C_3-6 cycloalkyl, 5- or 6-membered monocyclic heterocyclyl, 7- or 8-membered bicyclic heterocyclyl, and amino, wherein G¹ is unsubstituted or substituted with 1 or 2 substituents independently selected from C_1-4 alkyl, halo, C_1-4 haloalkyl, and C_1-4 alkoxy;

R² is selected from aryl and 5- or 6-membered monocyclic heteroaryl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, halo, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, - (CR^a2R^b2)_n-G², cyano, nitro, amino, -C(O)R^c2, -C(O)OR^d2, -C(O)N(R^e2)(R^f2), -S(O)_qR^g2, - NR^h2S(O)₂Rⁱ², -NR^j2C(O)R^k2, and -NR^l2C(O)OR^m2, wherein n is 0 or 1, q is 1 or 2, and G² is selected from aryl, 5- or 6-membered monocyclic heteroaryl, C_3-6 cycloalkyl, and 5- or 6- membered monocyclic heterocyclyl;

R³ is selected from 5- or 6-membered monocyclic heteroaryl, 5- or 6-membered monocyclic heterocyclyl, -O-(C_3-6 cycloalkyl), -NR^a3C(Q)OR^b3, -NR^c3C(O)N(R^d3)(R^e3), - C(O)N(R^f3)(R^g3), -NR^h3CH₂C(O)ORⁱ³, -NR^j3C(O)R^k3, and cyano, wherein Q is O or S, and wherein the heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with 1 or 2 substituents independently selected from C_1-4 alkyl and oxo;

R^a1 R^{b 1} R^{c 1} R^d1 R^e1 R^f1 R^g1 R^h1 Rⁱ¹ R^j1 R^k1 R^l1 R^m1 R^a2 R^b2 R^C2 R^d2 R^e2 R^f2 R^g2, R^h2, Rⁱ², R^j2, R^k2, R^l2, R^m2, R^a3, R^b3, R^c3, R^d3, R^e3, R^f3, R^g3, R^h3, Rⁱ³, R^j3, and R^k3 are each independently selected from H, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 haloalkyl, aryl, and C_3-6 cycloalkyl;

X¹ is CR^4a or N; X² is CR^4b or N;

X³ is CR^4C or N; and

R^4a, R^4b, and R^4c are each independently selected from H, D, C_1-4 alkyl, C_2-4 alkenyl, C _2-4 alkynyl, halo, C_1-4 haloalkyl, C_1-4 alkoxy, and C _1-4 haloalkoxy; wherein no more than two of X¹, X², and X³ are simultaneously N.

In some embodiments, R¹ is selected from phenyl and pyridinyl, which is substituted with 1, 2, or 3 substituents independently selected from C_1-4 alkyl, halo, C_1-4 haloalkyl, and - (CR^aR^b)_m-G¹, wherein m is 0 or 1, R^a and R^b are each independently hydrogen or methyl, and G¹ is a C_3-6 cycloalkyl, a 5- or 6-membered monocyclic heterocyclyl having one or two heteroatoms independently selected from N and O, a 7-membered bicyclic heterocyclyl having one or two heteroatoms independently selected from N and O, or dialkylamino, wherein G¹ is unsubstituted or substituted with 1 substituent selected from C_1-4 alkyl. In some embodiments, R¹ is selected from phenyl and pyridinyl, which is substituted with 1 or 2 substituents independently selected from C_1-4 alkyl, halo, C_1-4 haloalkyl, and -(CR_aR_b)_m-G¹, wherein m is 1, R^a and R^b are each hydrogen, and G¹ is a C_3-6 cycloalkyl, a 6-membered monocyclic heterocyclyl having one N atom, or dialkylamino. In some embodiments, R¹ is selected from:

In some embodiments, R² is aryl. In some embodiments, R² is unsubstituted phenyl.

In some embodiments, R³ is selected from: 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, S, and O; 5-membered monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, S, and O; -O-(C_3-6 cycloalkyl); -NR^a3C(Q)OR^b3; -NR^c3C(O)N(R^d3)(R^e3), -C(O)N(R^f3)(R^g3), - NR^h3CH₂C(O)ORⁱ³, -NR^j3C(O)R^k3, and cyano, wherein Q is O or S, and wherein the heterocyclyl and cycloalkyl are unsubstituted or substituted with 1 or 2 substituents independently selected from methyl and oxo, and wherein R^a3, R^b3, R^c3, R^d3, R^e3, R^f3, R^g3, R^h3, Rⁱ³, R^j3, and R^k3 are each independently selected from hydrogen, C_1-4 alkyl, and C_3-6 cycloalkyl. In some embodiments, R³ is -NR^a3C(O)OR^b3, wherein R^a3 and R^b3 are each independently C_1-4 alkyl (e.g., methyl, ethyl, isopropyl) or C_3-6 cycloalkyl.

In some embodiments, R³ is selected from:

In some embodiments: X¹ is CR^4a; X² is CR^4b; X³ is CR^4c; and R^4a, R^4b, and R^4c are each H.

In some embodiments, the compound is selected from:

and pharmaceutically acceptable salts thereof. In another aspect, disclosed herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, disclosed herein is a method of inhibiting LRRK2 in a sample, comprising contacting the sample with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, disclosed herein is a method of treating Parkinson's disease, cancer, leprosy, Crohn's disease, Alzheimer’s disease, other neurodegenerative diseases, or an immune-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is Parkinson's disease.

In another aspect, disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

In another aspect, disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treatment of Parkinson's disease, cancer, leprosy, Crohn's disease, Alzheimer’s disease, other neurodegenerative diseases, or an immune-mediated disorder. In some embodiments, the disorder is Parkinson's disease.

DETAILED DESCRIPTION

Provided herein are compounds that inhibit LRRK2 kinase activity, pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., in methods of treating disorders associated with LRRK2 such as Parkinson’s disease, other neurodegenerative diseases, immune-mediated diseases, and cancer.

Definitions

Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise.

As used herein, the term “and/or” includes any and all combinations of listed items, including any of the listed items individually. For example, “A, B, and/or C” encompasses A, B, C, AB, AC, BC, and ABC, each of which is to be considered separately described by the statement “A, B, and/or C.”

For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6- 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2^nd edition, University Science Books, Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7^th Edition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3^rd Edition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modem Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

As used herein, the term “alkyl” refers to a radical of a straight or branched saturated hydrocarbon chain. The alkyl chain can include, e.g., from 1 to 24 carbon atoms (C₁-C₂₄ alkyl), 1 to 16 carbon atoms (C₁-C₁₆ alkyl), 1 to 14 carbon atoms (C₁-C₁₄ alkyl), 1 to 12 carbon atoms (C₁-C₁₂ alkyl), 1 to 10 carbon atoms (C₁-C₁₀ alkyl), 1 to 8 carbon atoms (C₁-C₈ alkyl), 1 to 6 carbon atoms (C₁-C₆ alkyl), 1 to 4 carbon atoms (C₁-C₄ alkyl), 1 to 3 carbon atoms (C₁-C₃ alkyl), or 1 to 2 carbon atoms (C₁-C₂ alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3 -methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. As used herein, the term “alkenyl” refers to a radical of a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond and no triple bonds. The double bond(s) may be located at any position(s) with the hydrocarbon chain. The alkenyl chain can include, e.g., from 2 to 24 carbon atoms (C₂-C₂₄ alkenyl), 2 to 16 carbon atoms (C₂-C₁₆ alkenyl), 2 to 14 carbon atoms (C₂-C₁₄ alkenyl), 2 to 12 carbon atoms (C₂-C₁₂ alkenyl), 2 to 10 carbon atoms (C₂-C₁₀ alkenyl), 2 to 8 carbon atoms (C₂-C₈ alkenyl), 2 to 6 carbon atoms (C₂-C₆ alkenyl), 2 to 4 carbon atoms (C₂-C₄ alkenyl), 2 to 3 carbon atoms (C₂- C₃ alkenyl), or 2 carbon atoms (C₂ alkenyl). Representative examples of alkenyl include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, 2 -butenyl, butadienyl, 2- methyl-2-propenyl, 3 -butenyl, pentenyl, pentadienyl, hexenyl, heptenyl, octenyl, octatrienyl, and the like.

As used herein, the term “alkynyl” means a radical of a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. The alkynyl chain can include, e.g., from 2 to 24 carbon atoms (C₂-C₂₄ alkynyl), 2 to 16 carbon atoms (C₂-C₁₆ alkynyl), 2 to 14 carbon atoms (C₂-C₁₄ alkynyl), 2 to 12 carbon atoms (C₂-C₁₂ alkynyl), 2 to 10 carbon atoms (C₂-C₁₀ alkynyl), 2 to 8 carbon atoms (C₂-C₈ alkynyl), 2 to 6 carbon atoms (C₂-C₆ alkynyl), 2 to 4 carbon atoms (C₂-C₄ alkynyl), 2 to 3 carbon atoms (C₂-C₃ alkynyl), or 2 carbon atoms (C₂ alkynyl). The triple bond(s) may be located at any position(s) with the hydrocarbon chain. Representative examples of alkynyl include, but are not limited to, ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, and the like.

As used herein, the term “alkoxy” refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

As used herein, the term “amino” refers to a group -NR_xR_y, wherein R_x and R_y are selected from hydrogen and alkyl (e.g., C₁-C₄ alkyl). A group -NH(alkyl) may be referred to herein as “alkylamino” and a group -N(alkyl)₂ may be referred to herein as “dialkylamino.”

As used herein, the term “aryl” refers to a radical of a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms (“C₆-C₁₄ aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C₆ aryl,” i.e., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C₁₀ aryl,” e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄ aryl,” e.g., anthracenyl and phenanthrenyl). As used herein, the term “cycloalkyl” refers to a radical of a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl.

As used herein, the term “cyano” refers to a -CN group.

As used herein, the term “halogen” or “halo” refers to F, Cl, Br, or I.

As used herein, the term “haloalkyl” refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one, two, three, four, five, six, seven or eight hydrogen atoms) is replaced with a halogen. In some embodiments, each hydrogen atom of the alkyl group is replaced with a halogen (“perhaloalkyl”). Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.

As used herein, the term “haloalkoxy” refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2- trifluoroethoxy.

As used herein, the term “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1 -4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5 -membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazo lyl. Exemplary 5 -membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indo lyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5 -membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5 -membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1 -methylpyridin-2-onyl), and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1- methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 4-membered heterocyclyl groups fused to a 4-membered heterocyclyl ring (also referred to herein as a 4,4-bicyclic heterocyclyl ring) include, without limitation, 2- oxa-6-azaspiro[3.3]heptanyl (e.g., 2-oxa-6-azaspiro[3.3]heptan-6-yl), and the like. Exemplary 5-membered heterocyclyl groups fused to a Ck aryl ring (also referred to herein as a 5,6- bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5- membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5- bicyclic heterocyclyl ring) include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6-membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6- membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (l,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include, without limitation, azabicyclononanyl (e.g., 9- azabicyclo[3.3. l]nonanyl).

As used herein, the term “hydroxy” or “hydroxyl” refers to an -OH group.

As used herein, the term “nitro” refers to an -NO₂ group.

When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof.

As used herein, in chemical structures the indication: represents a point of attachment of one moiety to another moiety (e.g., a substituent group to the rest of the compound).

For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

The terms “administer,” “administering,” or “administration,” as used herein refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition.

As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably.

An “effective amount” of a compound or composition refers to an amount sufficient to elicit a desired biological response (e.g., treating a condition). As will be appreciated by those skilled in the art, the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of a compound or composition may reduce tumor burden or stop the growth or spread of a tumor.

A “therapeutically effective amount” of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.

A “subject” to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys).

As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

Compounds

Disclosed herein are compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein:

R³ is selected from 5- or 6-membered monocyclic heteroaryl, 5- or 6-membered monocyclic heterocyclyl, -O-(C_3-6 cycloalkyl), -NR^a3C(Q)OR^b3, -NR^c3C(O)N(R^d3)(R^e3), - C(O)N(R^f3)(R^g3), -NR^h3CH₂C(O)ORⁱ³, -NR^j3C(O)R^k3, and cyano, wherein Q is O or S, and wherein the heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with 1 or 2 substituents selected from C_1-4 alkyl and oxo;

X¹ is CR^4a or N;

X² is CR^4b or N;

X³ is CR^4C or N; and R^4a, R^4b, and R^4c are each independently selected from H, D, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, halo, C_1-4 haloalkyl, C_1-4 alkoxy, and C _1-4 haloalkoxy; wherein no more than two of X¹, X², and X³ are simultaneously N.

In some embodiments, R¹ is selected from phenyl and 6-membered monocyclic heteroaryl. In some embodiments, R¹ is selected from phenyl and pyridinyl, which is substituted with 1, 2, or 3 substituents independently selected from C_1-4 alkyl, halo, C_1-4 haloalkyl, and -(CR^aR^b)_m-G¹, wherein m is 0 or 1, R^a and R^b are each independently hydrogen or methyl, and G¹ is a C_3-6 cycloalkyl, a 5- or 6-membered monocyclic heterocyclyl having one or two heteroatoms independently selected from N and O, a 7-membered bicyclic heterocyclyl having one or two heteroatoms independently selected from N and O, or dialkylamino, wherein G¹ is unsubstituted or substituted with 1 substituent selected from C_1-4 alkyl. In some embodiments, R¹ is selected from phenyl and pyridinyl, which is substituted with 1 , 2, or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, and -(CR^aR^b)_m-G¹ wherein m is 0 or 1, R^a is hydrogen, R^b is hydrogen or methyl, and G¹ is cyclopropyl, piperidinyl, morpholino, 2-oxa-6-azaspiro[3.3]heptan-6-yl, and dimethylamino. In some embodiments, R¹ is selected from phenyl and pyridinyl, which is substituted with 1 or 2 substituents independently selected from C_1-4 alkyl, halo, C_1-4 haloalkyl, and -(CR^aR^b)_m-G¹, wherein m is 1, R^a and R^b are each hydrogen, and G¹ is a C_3-6 cycloalkyl, a 6-membered monocyclic heterocyclyl having one N atom, or dialkylamino. In some embodiments, R¹ is selected from phenyl and pyridinyl, which is substituted with one substituent selected from C_1-4 alkyl, halo, C_1-4 haloalkyl, and -(CR^aR^b)_m-G¹, wherein m is 1, R^a and R^b are each hydrogen, and G¹ is a C_3-6 cycloalkyl or a 6-membered monocyclic heterocyclyl having one N atom.

In some embodiments, R¹ is selected from:

In some embodiments, R² is aryl. In some embodiments, R² is unsubstituted phenyl. In some embodiments, R³ is selected from: 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, S, and O; 5-membered monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, S, and O; -O-(C_3-6 cycloalkyl); -NR^a3C(Q)OR^b3; -NR^c3C(O)N(R^d3)(R^e3), -C(O)N(R^f3)(R^g3), - NR^h3CH₂C(O)ORⁱ³, -NR^j3C(O)R^k3, and cyano, wherein Q is O or S, and wherein the heterocyclyl and cycloalkyl are unsubstituted or substituted with 1 or 2 substituents independently selected from methyl and oxo, and wherein R^a3, R^b3, R^c3, R^d3, R^e3, R^f3, R^g3, R^h3, Rⁱ³, R^j3, and R^{k 3} are each independently selected from hydrogen, C_1-4 alkyl, and C_3-6 cycloalkyl. In some embodiments, R³ is selected from: 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, S, and O; 5- or 6-membered monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, S, and O; -O-(C_3-6 cycloalkyl); and -NR^a3C(O)OR^b3; wherein the heterocyclyl and cycloalkyl are unsubstituted or substituted with 1 substituent selected from methyl and oxo. In some embodiments, R³ is selected from: 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, S, and O; 5-membered monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, S, and O; -O-(C_3-6 cycloalkyl); and -NR^a3C(O)OR^b3; wherein the heterocyclyl and cycloalkyl are unsubstituted or substituted with 1 substituent selected from methyl and oxo. In some embodiments, R³ is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N, S, and O. In some embodiments, R³ is thiazolyl, isothiazolyl, or oxazolyl. In some embodiments, R³ is thiazolyl or oxazolyl. In some embodiments, R³ is thiazolyl. In some embodiments, R³ is a 5- or 6-membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N and O. In some embodiments, R³ is a 5-membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from N and O, substituted with an oxo group and optionally further substituted with a methyl group. In some embodiments, R³ is pyrrolidinyl. In some embodiments, R³ is piperidinyl. In some embodiments, R³ is oxazolidine-2-onyl. In some embodiments, R³ is 3-methyl-2-oxoimidazolidin-1-yl. In some embodiments, R³ is -O- (C₃ cycloalkyl), wherein the cycloalkyl is substituted with 1 substituent selected from C_1-4 alkyl (e.g., methyl or ethyl). In some embodiments, R³ is selected from -NR^a3C(O)OR^b3; - NR^a3C(S)OR^b3; -NR^c3C(O)N(R^d3)(R^e3), -C(O)N(R^f3)(R^g3), -NR^h3CH₂C(O)ORⁱ³, and - NR^j3C(O)R^k3, wherein R^a3, R^b3, R^c3, R^d3, R^e3, R^f3, R^g3, R^h3, Rⁱ³, R¹', and R^k3 are each independently selected from hydrogen, C _1-4 alkyl, and C_3-6 cycloalkyl. In some embodiments, R³ is selected from -NR^a3C(O)OR^b3, -NR^a3C(S)OR^b3, -NR^c3C(O)N(R^d3)(R^e3), - C(O)N(R^f3)(R^g3), -NR^h3CH₂C(O)ORⁱ³, and -NR^j3C(O)R^k3, wherein R^a3, R^b3, R^c3, R^d3, R^e3, R^f3, R^g3, R^h3, Rⁱ³, R^j3, and R^k3 are each independently selected from hydrogen, methyl, and cyclopropyl. In some embodiments, R³ is -NR^a3C(O)OR^b3, wherein R^a3 and R^b3 are each independently C_1-4 alkyl (e.g., methyl, ethyl, isopropyl) or C_3-6 cycloalkyl (e.g., cyclopropyl). In some embodiments, R³ is cyano.

In some embodiments, R³ is selected from:

In some embodiments, R³ is selected from: In some embodiments, R3 is selected from:

In some embodiments, R³ is:

In some embodiments, the compound of formula (I) is a compound of formula (la): wherein R¹ and R³ are as defined and described herein.

In some embodiments, the compound is selected from:

and pharmaceutically acceptable salts thereof.

Additional compounds of formula (I) include: and pharmaceutically acceptable salts thereof.

Certain compounds described herein may have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers, in mixtures and as pure or partially purified compounds, are included within the scope of this disclosure.

The independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

Compounds may also possess tautomeric forms, and all tautomers also constitute embodiments of the disclosure.

The present disclosure also includes an isotopically-labeled compound, which is identical to those recited in formula (I), 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 suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively. Substitution with heavier isotopes such as deuterium (²H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated in compounds of formula (I) are ¹¹C, ¹³N, ¹⁵O, and ¹⁸F. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent.

Compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure encompass both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. a. Methods of Synthesis

Compounds disclosed herein can be prepared by a variety of methods, including those illustrated in the Examples.

Compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), by Fumiss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Reactions can be worked up in a conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.

Standard experimentation, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4^th ed.), John Wiley & Sons, NY (2006).

When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the procedures described herein using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

The synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the disclosure or the claims. Alternatives, modifications, and equivalents of the synthetic methods and specific examples are contemplated. b. Pharmaceutically Acceptable Salts

The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compound with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoro acetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. Amino groups of the compounds may also be quatemized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1 -ephenamine and N,N’ -dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

Pharmaceutical Compositions

The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or nonhuman).

The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, com starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen- free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

Thus, the compounds and their pharmaceutically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington’s Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.

Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90% by weight of the composition.

Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10% by weight of the composition.

Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as com starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50% by weight of the composition.

Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10% by weight of the composition.

Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1% by weight of the composition.

Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0. 1 to about 1.0%.

Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s), when used, in a systemic or topical composition is typically about 0.001 to about 1% by weight of the composition.

Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0. 1 to about 5% by weight of the composition.

Suitable preservatives include benzalkonium chloride, methyl paraben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5% by weight of the composition.

Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5% by weight of the composition.

Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100% by weight of the composition.

Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8% by weight of the composition.

Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington’s Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon’s Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5% by weight of the composition. Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% by weight of an active compound and 50% to 99.99% by weight of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% by weight of actives and 90% to 99.9% by weight of a carrier including a diluent and a solvent.

Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5% by weight, and more particularly from about 25% to about 50% by weight of actives. The oral dosage compositions include about 50% to about 95% by weight of carriers, and more particularly, from about 50% to about 75% by weight.

Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this disclosure.

Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (I)), or a pharmaceutically acceptable salt thereof), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this disclosure are described in the following references: Modem Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1 ,2-diol, butane- 1,3 -diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95% by weight of the composition.

Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95% by weight of the composition.

Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95% by weight of the composition.

Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5 -carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95% by weight of the composition. The amount of thickener(s) in a topical composition is typically about 0% to about 95% by weight of the composition.

Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95% by weight of the composition.

The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1% by weight of the composition.

Suitable pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.

Methods of Use

The disclosed compounds are inhibitors of LRRK2, and thus the compounds and their pharmaceutical compositions may be used in methods for treatment of disorders, including disorders associated with LRRK2. Such disorders include Parkinson’s disease, cancer, leprosy, Crohn's disease, Alzheimer’s disease, other neurodegenerative diseases, or an immune-mediated disorder. In particular embodiments, the compounds and pharmaceutical compositions are used in methods of treating Parkinson’s disease. The disclosed compounds and pharmaceutical compositions may also be used in methods for inhibiting the activity of LRRK2.

In the methods of treatment described herein, a compound or pharmaceutical composition may be administered to the subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g. through mouth or nose); rectal; vaginal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; or by implant of a depot, for example, subcutaneously or intramuscularly. In some embodiments, the administration comprises oral administration. Additional modes of administration may include adding the compound and/or a composition comprising the compound to a food or beverage, including a water supply for an animal, to supply the compound as part of the animal’s diet.

It will be appreciated that appropriate dosages of the compounds, and compositions comprising the compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present disclosure. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.

Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. In general, a suitable dose of the compound is in the range of about 100 pg to about 250 mg per kilogram body weight of the subject per day.

The compound or composition may be administered once, on a continuous basis (e.g. by an intravenous drip), or on a periodic/ intermittent basis, including about once per hour, about once per two hours, about once per four hours, about once per eight hours, about once per twelve hours, about once per day, about once per two days, about once per three days, about twice per week, about once per week, and about once per month. The composition may be administered until a desired reduction of symptoms is achieved.

When used in methods of treatment disclosed herein, a compound or composition described herein may be used in combination with other known therapies. Administered “in combination,” as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.

Kits

For use in the therapeutic applications described herein, kits and articles of manufacture are also provided, which include a compound or pharmaceutical composition described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical comosition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof ). In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, in some embodiments the container(s) includes a compound of formula (I, or a pharmaceutically acceptable salt thereof, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.

For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

The following examples further illustrate aspects of the disclosure but, of course, should not be construed as in any way limiting its scope. Examples

Abbreviations used in the Examples include the following: ACN is acetonitrile; Ac₂O is acetic anhydride; AcOH is acetic acid; DCM is dichloromethane; DIEA is diisopropylethylamine; DMF is dimethylformamide; DMSO is dimethylsulfoxide; EtOAc is ethyl acetate; EtOH is ethanol; h is hours; HPLC is high performance liquid chromatography; i-PrOH is isopropanol; MeOD is methanol-d4; MeOH is methanol; MS-ESI is mass spectrometry - electrospray ionization; NMR is nuclear magnetic resonance; TFA is trifluoroacetic acid; THF is tetrahydrofuran; and TLC is thin layer chromatography.

Example 1 Compound Syntheses Compound 1

(Z)-5-(l -Methylcyclopropoxy)-3-(phenyl((4-(piperidin- 1 - ylmethyl)phenyl)amino)methylene)indolin-2-one

2-Bromo-4-(l -methylcyclopropoxy)-l -nitrobenzene. A mixture of 2-bromo-4-fluoro- 1 -nitro-benzene (5.00 g, 22.7 mmol) and 1 -methylcyclopropanol (1.80 g, 25.0 mmol) in DMF (70 mL) was degassed and purged with N₂ (3x) at 0 °C. NaH (1.36 g, 34.09 mmol, 60% dispersion in oil) was then added to the mixture at 0 °C and the mixture was stirred at 20 °C for 12 h under an N₂ atmosphere. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-3% EtOAc/petroleum ether gradient eluent to give the product (3.48 g, 56.3%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=9.01 Hz, 1 H), 7.34 (d, J=2.63 Hz, 1 H), 7.01-7.09 (m, 1 H), 1.57-1.59 (m, 3 H), 1.01-1.05 (m, 2 H), 0.78-0.82 (m, 2 H).

Dimethyl 2-(5-(l-methylcyclopropoxy)-2-nitrophenyl)malonate. A mixture of dimethyl malonate (6.76 g, 51.2 mmol) in DMF (55 mL) was degassed and purged with N₂ (3x) at 0 °C. NaH (2.56 g, 64.0 mmol, 60% purity) was then added to the mixture at 0 °C, and then the mixture was stirred at 40 °C for 0.5 h under an N₂ atmosphere. 2-Bromo-4-(1- methylcyclopropoxy)- 1 -nitrobenzene (3.48 g, 12.8 mmol) in DMF (5 mL) was then added to the mixture at 40 °C, and the mixture was stirred at 40 °C for an additional 11.5 h under an N₂ atmosphere. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-5% EtOAc/petroleum ether gradient eluent to give the product (730 mg, 17.6%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J=9.13 Hz, 1 H), 7.09 (dd, J=9.13, 2.50 Hz, 1 H), 7.02 (d, J=2.50 Hz, 1 H), 5.47 (s, 1 H), 3.82 (s, 6 H), 1.58 (s, 3 H), 0.99-1.06 (m, 2 H), 0.76-0.82 (m, 2 H) MS-ESI (m/z) calc’d for C₁₅H₁₈NO₇ [M+H]⁺: 324.1. Found: 324.3.

Methyl 2-(5-(l-methylcyclopropoxy)-2-nitrophenyl)acetate. To a solution of dimethyl 2-(5-(1-methylcyclopropoxy)-2-nitrophenyl)malonate (730 mg, 2.26 mmol) in DMSO (10 mL) and H₂O (1 mL) was added LiCI (191.4 mg, 4.520 mmol) at 20 °C. The mixture was stirred at 140 °C for 6 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-5% EtOAc/petroleum ether gradient eluent to give the product (353 mg, 58.9%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, .1 9.13 Hz, 1 H), 7.07 (dd, J=9.13, 2.75 Hz, 1 H), 6.87 (d, J=2.75 Hz, 1 H), 4.01 (s, 2 H), 3.73 (s, 3 H), 1.58 (s, 3 H), 1.00-1.05 (m, 2 H), 0.76-0.81 (m, 2 H) MS-ESI (m/z) calc’d for C₁₃H₁₆NO₅ [M+H]⁺:

266.1. Found: 266.4.

Methyl 2-(2-amino-5-(l-methylcyclopropoxy)phenyl)acetate. A mixture of methyl 2- (5-(1-methylcyclopropoxy)-2-nitrophenyl)acetate (353 mg, 1.33 mmol) and 10% Pd/C (99.13 mg, 93.15 μmol) in MeOH (2.5 mL) was degassed and purged with H₂ (3x), and then the mixture was stirred at 20 °C for 2.5 h under an H₂ atmosphere (15 Psi). The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the product (270 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calc’d for C₁₃H₁₈NO₃ [M+H]⁺: 236.1. Found: 236.1.

5-(l-Methylcyclopropoxy)indolin-2-one. To a solution of methyl 2-[2-amino-5-(1- methykyclopropoxy)phenyl] acetate (270 mg, 1.15 mmol) in MeOH (3 mL) was added AcOH (6.89 mg, 115 μmol) at 20 °C. The mixture was stirred at 70 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by preparative TLC (silica gel, petroleum ether/EtOAc=1/1, Rf=0.47) to give the product (216 mg, 92.6%) as a brown solid. MS-ESI (m/z) calc’d for C₁₂H₁₄NO₂ [M+H]⁺: 204.0. Found: 204.4.

(Z)-l-Acetyl-3-(methoxy(phenyl)methylene)-5-(l-methylcyclopropoxy)indolin-2-one.

A mixture of 5-(1-methykyclopropoxy)indolin-2-one (216 mg, 1.06 mmol) and trimethoxymethylbenzene (581.0 mg, 3.190 mmol) in Ac₂O (2 mL) was degassed and purged with N₂ (3x) at 20 °C, and then the mixture was stirred at 90 °C for 12 h under an N₂ atmosphere. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give the product (386 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calc’d for C₂₂H₂₂NO₄ [M+H]⁺: 364.1. Found: 364.3.

(Z)-5-(l -Methylcyclopropoxy)-3-(phenyl((4-(piperidin-l - ylmethyl)phenyl)amino)methylene)indolin-2-one. To a solution of (Z)-1-acetyl-3- (methoxy(phenyl)methylene)-5-(1-methylcyclopropoxy)indolin-2-one (150 mg, 413 μmol) in MeOH (5 mL) was added 4-(1-piperidylmethyl)aniline (329.9 mg, 1.730 mmol) at 20 °C. The mixture was stirred at 70 °C for 12 h. and then concentrated to give a residue. This residue was then combined with the residue from an identical reaction mixture and the material was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 50-80% ACN/H₂O (10 mM NH₄HCO₃)) to afford the product (17.0 mg, 4.14%) as a yellow solid. ¹H NMR (400 MHz, MeOD) δ 7.43-7.62 (m, 5 H), 7.10 (br d, J=8.13 Hz, 2 H), 6.73- 6.81 (m, 3 H), 6.46-6.52 (m, 1 H), 5.78 (d, J=2.00 Hz, 1 H), 3.41 (s, 2 H), 2.26-2.47 (m, 4 H), 1.54-1.60 (m, 4 H), 1.42-1.47 (m, 2 H), 1.19 (s, 3 H), 0.60-0.66 (m, 2 H), 0.34-0.40 (m, 2 H). MS-ESI (m/z) calc’d for C₃₁H₃₄N₃O₂ [M+H]⁺: 480.2. Found. 480.4

Compound 2 (Z)-5-(l -Ethyl cyclopropoxy)-3-(phenyl((4-(piperidin- 1 - ylmethyl)phenyl)amino)methylene)indolin-2-one

2-Bromo-4-(l -ethylcyclopropoxy)-l -nitrobenzene. A mixture of 2-bromo-4-fluoro- 1 - nitrobenzene (5 g, 22.73 mmol) and 1 -ethylcyclopropanol (2.15 g, 25.0 mmol) in DMF (50 mL) was degassed and purged with N₂ (3x) at 0 °C. NaH (1.36 g, 34.1 mmol, 60% purity) was then added to the mixture at 0 °C, and then the mixture was stirred at 20 °C for 12 h under an N₂ atmosphere. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography using a 0-3% EtOAc/petroleum ether gradient eluent to give the product (4.69 g, 72.1%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=9.13 Hz, 1 H), 7.34 (d, J=2.50 Hz, 1 H), 7.03 (dd, J=9.13, 2.50 Hz, 1 H), 1.80 (q, J=7.30 Hz, 2 H), 0.98- 1.05 (m, 5 H), 0.79-0.83 (m, 2 H).

Dimethyl 2-(5-(l-ethylcyclopropoxy)-2-nitrophenyl)malonate. A mixture of dimethyl propanedioate (8.24 g, 62.4 mmol) in DMF (75 mL) was degassed and purged with N₂ (3x) at 0 °C. NaH (3.12 g, 77.9 mmol, 60% dispersion in oil) was then added to the mixture at 0 °C, and then the mixture was stirred at 40 °C for 0.5 h under an N₂ atmosphere. 2-Bromo-4-(1- ethylcyclopropoxy)-l -nitrobenzene (4.46 g, 15.6 mmol) in DMF (5 mL) was then added to the mixture at 40 °C and the mixture was stirred at 40 °C for 11.5 h under an N₂ atmosphere. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-5% EtOAc/petroleum ether gradient eluent to give the product (830 mg, 15.8%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=9.13 Hz, 1 H), 7.09 (dd, J=9.13, 2.63 Hz, 1 H), 7.03 (d, J=2.63 Hz, 1 H), 5.46 (s, 1 H), 3.82 (s, 6 H), 1.80 (q, J=7.42 Hz, 2 H), 0.97-1.05 (m, 5 H), 0.78-0.82 (m, 2 H). MS-ESI (m/z) calc’d for C₁₆H₂₀NO₇ [M+H]⁺: 338.1. Found: 338.3.

Methyl 2-(5-(l-ethylcyclopropoxy)-2-nitrophenyl)acetate. To a solution of dimethyl 2- (5-(1-ethylcyclopropoxy)-2-nitrophenyl)malonate (970 mg, 2.88 mmol) in DMSO (15 mL) and H₂O (1.5 mL) was added LiCl (243.8 mg, 5.750 mmol) at 20 °C. The mixture was then stirred at 140 °C for 6 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-8% EtOAc/petroleum ether gradient eluent to afford the product (445 mg, 55.4%) as a yellow oil. ¹ H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=9.13 Hz, 1 H), 7.06 (dd, J=9.19, 2.69 Hz, 1 H), 6.88 (d, J=2.63 Hz, 1 H), 4.01 (s, 2 H), 3.73 (s, 3 H), 1.81 (q, J=7.38 Hz, 2 H), 0.97-1.05 (m, 5 H), 0.77-0.82 (m, 2 H). MS-ESI (m/z) calc’d for C₁₄H₁₈NO₅ [M+H]⁺: 280.1. Found: 280.3.

Methyl 2-(2-amino-5-(l-ethylcyclopropoxy)phenyl)acetate. A mixture of methyl 2-[5- (1-ethykyclopropoxy)-2-nitro-phenyl] acetate (445 mg, 1.59 mmol) and 10% Pd/C (169.56 mg, 159.33 μmol) in MeOH (4 mL) was degassed and purged with H₂ (3x), and then the mixture was stirred at 20 °C for 1 h under an H₂ atmosphere (15 psi). The reaction was filtered, and the filtrate was concentrated under vacuum to give the product (310 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calc’d for C₁₄H₂₀NO₃ [M+H]⁺: 250.1. Found: 250.4.

5-(l-Ethylcyclopropoxy)indolin-2-one. To a solution of methyl 2-(2-amino-5-(1- ethykyclopropoxy)phenyl)acetate (310 mg, 1.24 mmol) in MeOH (3 mL) was added AcOH (7.47 mg, 124 μmol) at 20 °C. The mixture was then stirred at 70 °C for 12 h. The reaction mixture was concentrated to give a residue. The residue was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (silica, petroleum ether/EtOAc=1/1, Rf=0.47) to give the product (218 mg, 80.7%) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (br s, 1 H), 6.95 (s, 1 H), 6.88 (dd, J=8.44, 2.19 Hz, 1 H), 6.75 (d, J=8.50 Hz, 1 H), 3.53 (s, 2 H), 1.75 (q, J=7.38 Hz, 2 H), 0.93-1.04 (m, 5 H), 0.67-0.73 (m, 2 H). MS-ESI (m/z) calc’d for C₁₃H₁₆NO₂ [M+H]⁺: 218.1. Found: 218.5.

(Z)-l-Acetyl-5-(l-ethylcyclopropoxy)-3-(methoxy(phenyl)methylene)indolin-2-one. A mixture of 5-(1-ethylcyclopropoxy)indolin-2-one (180 mg, 828 μmol) and trimethoxymethylbenzene (452.9 mg, 2.490 mmol) in Ac₂O (3 mL) was degassed and purged with N₂ (3x) at 20 °C, and then the mixture was stirred at 90 °C for 12 h under an N₂ atmosphere. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give the product (300 mg) as a brown solid that was used without further purification. MS-ESI (m/z) calc’d for C₂₃H₂₄NO₄ [M+H]⁺: 378.1. Found: 378.3.

(Z)-5-(l -Ethylcyclopropoxy)-3-(phenyl((4-(piperidin-l - ylmethyl)phenyl)amino)methylene)-indolin-2-one. To a solution of (Z)-1-acetyl-5-(1- ethylcyclopropoxy)-3-(methoxy(phenyl)methylene)indolin-2-one (150 mg, 397 μmol) in MeOH (6 mL) was added 4-(1-piperidylmethyl)aniline (378.1 mg, 1.990 mmol) at 20 °C. The mixture was stirred at 70 °C for 12 h and then concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 55-85% ACN/H₂O (10 mM NH₄HCO₃)) to afford the product (5.80 mg, 2.92%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1 H), 10.48 (s, 1 H), 7.43-7.62 (m, 5 H), 7.03 (d, J=8.38 Hz, 2 H), 6.71 (dd, J=8.44, 2.56 Hz, 3 H), 6.46 (dd, J=8.38, 2.38 Hz, 1 H), 5.62 (d, J=2.25 Hz, 1 H), 3.26 (s, 2 H), 2.22 (br s, 4 H), 1.44 (quin, J=5.28 Hz, 4 H), 1.22- 1.36 (m, 4 H), 0.76 (t, J=7.32 Hz, 3 H), 0.50-0.58 (m, 2 H), 0.30-0.39 (m, 2 H). MS-ESI (m/z) calc’d for C₃₂H₃₆N₃O₂ [M+H]⁺: 494.2. Found. 494.4

Compound 3

(Z)-3-(3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5-yl)oxazolidin-2- one

(Z)-l-Acetyl-3-(methoxy(phenyl)methylene)-5-nitroindolin-2-one. A mixture of 5- nitroindolin-2-one (2.00 g, 11.2 mmol), trimethoxymethylbenzene (6.14 g, 33.7 mmol) in Ac₂O (20 mL) was degassed and purged with N₂ (3x) at 20 °C, and then the mixture was stirred at 90 °C for 12 h under an N₂ atmosphere. The reaction mixture was filtered, and the solid was washed with H₂O (2x) and dried under vacuum to give the product (2.3 g) as a yellow solid that was used without further purification. MS-ESI (m/z) calc’d for C₁₈H₁₅N₂O₅ [M+H]⁺: 339.0. Found. 339.2

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-nitroindolin-2-one. To a solution of (Z)-1-acetyl-3-(methoxy(phenyl)methylene)-5-nitroindolin-2-one (1.00 g, 2.96 mmol) in DMF (10 mL) was added 2-methylpyridin-4-amine (335.6 mg, 3. 100 mmol) at 20 °C. The mixture was stirred at 100 °C for 12 h. The reaction mixture was poured into 5 mL of a solution of H₂O/i-PrOH (10:1). A red solid formed which was collected by filtration and washed with H₂O (2x) and dried under vacuum to give the product (1. 1 g) as a red solid that was used without further purification. MS-ESI (m/z) calc’d for C₂₁H₁₇N₄O₃ [M+H]⁺: 373.1. Found: 373.2.

(Z)-5-Amino-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2-one. To a solution of (Z)-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-5-nitroindolin-2-one (500 mg, 1.34 mmol) in EtOH (6.8 mL) and H₂O (1.7 mL) were added Fe (374.9 mg, 6.710 mmol) andNH₄Cl (359.1 mg, 6.710 mmol) at 20 °C. The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried with anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give the product (385 mg) as a brown solid that was used without further purification. MS-ESI (m/z) calc’d for C₂₁H₁₉N₄O [M+H]⁺: 343.1. Found: 343.3. (Z)-3-(3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)oxazolidin-2-one. To a solution of (Z)-5-amino-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one (50.0 mg, 146 μmol) in THF (2 mL) were added K₂CO₃ (60.55 mg, 438.1 μmol) and 2-chloroethyl carbonochloridate (22.97 mg, 160.6 μmol) in THF (0.5 mL) at 0 °C. The mixture was stirred at 70 °C for 12 h. t-BuOK (24.58 mg, 219.0 μmol) was then added to the mixture at 20 °C and the mixture was stirred at 70 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 20-50% ACN/H₂O (10 mM NH₄HCO₃)) to afford the product (6.61 mg, 10.9%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1 H), 10.84 (s, 1 H), 8.03 (d, .1 5.63 Hz, 1 H), 7.60-7.68 (m, 3 H), 7.54 (dd, J=7.50, 1.63 Hz, 2 H), 7.26 (dd, J=8.50, 2.25 Hz, 1 H), 6.86 (d, J=8.38 Hz, 1 H), 6.53 (d, J=1.88 Hz, 1 H), 6.28 (dd, J=5.75, 2.00 Hz, 1 H), 5.96 (d, J=2.13 Hz, 1 H), 4.24-4.31 (m, 2 H), 3.54-3.61 (m, 2 H), 2.24 (s, 3 H). MS-ESI (m/z) calc’d for C₂₄H₂₁N₄O₃ [M+H]⁺: 413.1. Found. 413.1

Compound 4

(Z)-l-Acetyl-5-iodo-3-(methoxy(phenyl)methylene)indolin-2-one. A mixture of 5- iodoindolin-2-one (3.00 g, 11.6 mmol) and trimethoxymethylbenzene (6.33 g, 34.7 mmol) in Ac₂O (30 mL) was degassed and purged with N₂ at 20 °C. The mixture was stirred at 90 °C for 12 h under an N₂ atmosphere and filtered. The solid was washed with H₂O (2x) and dried under vacuum to give the product (2 g) as a white solid that was used without further purification. ¹H NMR (400 MHz, CD₃CN) δ 7.91 (dd, J=4.94, 3.69 Hz, 2 H), 7.46-7.57 (m, 4 H), 7.41 (s, 1 H), 7.32-7.36 (m, 1 H), 3.79 (s, 3 H), 3.59-3.67 (m, 3 H). MS-ESI (m/z) calc’d for C₁₈H₁₅IN₄O₃ [M+H]⁺: 420.0. Found. 420.1

(Z)-5-\odo-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2-one. A mixture of (Z)-1-acetyl-5-iodo-3-(methoxy(phenyl)methylene)indolin-2-one (1.00 g, 2.39 mmol) and 2-methylpyridin-4-amine (644.9 mg, 5.960 mmol) in MeOH (10 mL) was degassed and purged with N₂ at 20 °C. The mixture was stirred at 70 °C for 12 h under an N₂ atmosphere and then concentrated to give a residue. The residue was extracted with H₂O and EtOAc (3x). The combined organic phases were dried with anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. This material was then combined with material from a separate reaction run at 1/3 scale and the combined extracts were purified by silica gel chromatography using a 0-56% EtOAc/petroleum ether gradient eluent to give the product (150 mg, 13.9%) as a yellow solid. MS-ESI (m/z) calc’d for C₂₁H₁₇IN₃O [M+H]⁺: 454.0.

Found. 454.1.

(Z)-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-5-(thiazol-4-yl)indolin-2- one. A mixture of (Z)-5-iodo-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2- one (100 mg, 221 μmol), tributyl(thiazol-4-yl)stannane (123.82 mg, 330.93 μmol), and Pd(PPh₃)₄ (12.75 mg, 11.03 μmol) in toluene (2 mL) was degassed and purged with N₂ at 20 °C. The mixture was then stirred at 100 °C for 12 h under an N₂ atmosphere. The mixture was concentrated to give a residue that was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 10-35% ACN/H₂O (0.1% TFA)) to give the product (41 mg, 35%) as a yellow, solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 11.93-12.09 (m, 1 H), 10.96-11.18 (m, 1 H), 9.04 (d, J=1.75 Hz, 1 H), 8.18-8.28 (m, 1 H), 7.57-7.84 (m, 6 H), 7.35 (d, J=1.75 Hz, 1 H), 6.87-7.01 (m, 2 H), 6.48-6.71 (m, 2 H), 2.39-2.45 (m, 3 H). MS-ESI (m/z) calc’d for C₂₄H₁₉N₄OS [M+H]⁺: 411.1. Found. 411.2

Compound 5

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-(thiazol-5-yl)indolin-2-one

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-(thiazol-5-yl)indolin-2- one. A mixture of (Z)-5-iodo-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2- one (120 mg, 265 μmol), 4-(tributylstannyl)thiazole (148.59 mg, 397.11 μmol), Pd(PPh₃)₄ (15.30 mg, 13.24 μmol) in toluene (3 mL) was degassed and purged with an N₂ at 20 °C. The mixture was stirred at 100 °C for 12 h under an N₂ atmosphere. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 10-40% ACN/H₂O (0.1% TFA)-ACN) to give the product (21.67 mg, 15.45%) as a yellow, solid TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s, 1 H), 11.17 (s, 1 H), 8.92 (s, 1 H), 8.28 (d, J=6.88 Hz, 1 H), 7.68-7.85 (m, 6 H), 7.44 (dd, J=8.13, 1.75 Hz, 1 H), 6.93-7.04 (m, 2 H), 6.66 (dd, J=6.82, 2.31 Hz, 1 H), 6.11 (d, J=1.50 Hz, 1 H), 2.44 (s, 3 H). MS-ESI (m/z) calc’d for C₂₄H₁₉N₄OS [M+H]⁺: 411.1. Found. 411.2. Compound 6

Methyl (Z)-methyl(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)carbamate

(Z)-5-(Methylamino)-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2- one. To a solution of (Z)-5-amino-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one (180 mg, 526 μmol) in MeOH (2.5 mL) was added paraformaldehyde (18 mg) at 0 °C. The mixture was then stirred at 20 °C for 6 h. NaBH₃CN (82.59 mg, 1.31 mmol) was added to the mixture at 20 °C and the mixture was then stirred at 40 °C for 12 h. The mixture was concentrated to give a residue that was purified by preparatory HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 20-50% ACN/H₂O (10 mM NH₄HCO₃)) to give the product (37 mg, 20%) as a red solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 1 H), 10.41 (s, 1 H), 8.00 (d, J=5.75 Hz, 1 H), 7.60- 7.72 (m, 3 H), 7.47-7.57 (m, 2 H), 6.60 (d, J=8.25 Hz, 1 H), 6.46 (d, J=2.00 Hz, 1 H), 6.18- 6.27 (m, 2 H), 5.15 (d, J=2.00 Hz, 1 H), 4.84 (q, J=5.17 Hz, 1 H), 2.18 - 2.27 (m, 6 H). MS- ESI (m/z) calc’d for C₂₂H₂₁N₄O [M+H]⁺: 357.1. Found: 357.2. Methyl (Z)-methyl(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin- 5-yl)carbamate. To a solution of (Z)-5-(methylamino)-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one (37.0 mg, 104 μmol) in DCM (2 mL) was added DIEA (40.25 mg, 311.4 μmol) and methyl chloroformate (11.77 mg, 124.6 μmol) at 0 °C. The mixture was stirred at 20 °C for 1 h and then concentrated to give a residue. The residue was purified by preparatory HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 20-50% ACN/H₂O (10 mM NH₄HCO₃)) to afford the product (9.8 mg, 22%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1 H), 10.89 (s, 1 H), 8.03 (d, .1 5.63 Hz, 1 H), 7.62-7.72 (m, 3 H), 7.52-7.57 (m, 2 H), 6.79-6.90 (m, 2 H), 6.54 (d, J=2.00 Hz, 1 H), 6.27 (dd, J=5.69, 2.19 Hz, 1 H), 5.59 (d, J=1.63 Hz, 1 H), 3.47 (s, 3 H), 2.92 (s, 3 H), 2.24 (s, 3 H). MS-ESI (m/z) calc’d for C₂₄H₂₃N₄O₃ [M+H]⁺: 415.1. Found. 415.2

Compound 7

(Z)-5-(Isothiazol-3-yl)-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2-one

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indolin-2-one. A mixture of (Z)-5-iodo-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one (300 mg, 661.85 μmol), bis(pinacolato)diboron (252.10 mg, 992.78 μmol), KOAc (194.86 mg, 1.99 mmol), and Pd(amphos)Cl₂ (46.86 mg, 66.19 μmol) in EtOH (4 mL) and H₂O (0.4 mL) was degassed and purged with N₂ at 20 °C. The mixture was then stirred at 80 °C for 2 h under an N₂ atmosphere. The mixture was concentrated to give a residue and purified by silica gel chromatography using a 0-80% EtOAc/petroleum ether gradient eluent to give the product (170 mg, 56.6%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1 H), 11.01 (s, 1 H), 8.04 (d, J=5.63 Hz, 1 H), 7.61-7.74 (m, 3 H), 7.55 (d, J=6.88 Hz, 2 H), 7.29 (d, J=7.75 Hz, 1 H), 6.85 (d, J=7.75 Hz, 1 H), 6.53 (d, J=2.00 Hz, 1 H), 6.26-6.35 (m, 2 H), 2.24 (s, 3 H), 1.15-1.19 (m, 12 H). MS-ESI (m/z) calc’d for C₂₇H₂₉BN₃O₃ [M+H]⁺: 454.2. Found: 454.2.

(Z)-5-(Isothiazol-3-yl)-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2- one. A mixture of (Z)-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (80 mg, 176.47 μmol), 3 -bromoisothiazole (43.42 mg, 264.70 μmol), Pd(amphos)Cl₂ (12.50 mg, 17.65 μmol), and KOAc (51.96 mg, 529.40 μmol) in EtOH (2 mL) and H₂O (0.2 mL) was degassed and purged with N₂ at 20 °C. The mixture was then stirred at 80 °C for 12 h under an N₂ atmosphere. The mixture was concentrated to give a residue that was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 20-50% ACN/H₂O (0.1% TFA)) to give the product as a yellow solid of insufficient purity. The residue was further purified by supercritical fluid chromatography (Daicel Chiralpak IG 250 mm x 30 mm, 10 um; 55:45% CO₂/EtOH (0.1% NH₄OH) isocratic elution). The first eluting fraction was further purified by preparative HPLC (Phenomenex Luna C18, 100 mm x 30 mm, 5 um; 20-45% H₂O (0.1% TFA)/ACN gradient) to give the product (1.47 mg, 12.5%) as a yellow solid. ¹H NMR (400 MHz, MeOD) δ 8.82 (d, J=4.75 Hz, 1 H), 8.09 (d, J=6.88 Hz, 1 H), 7.74-7.90 (m, 4 H), 7.63-7.72 (m, 2 H), 7.16 (d, J=4.75 Hz, 1 H), 7.01 (d, J=8.25 Hz, 1 H), 6.79 (d, J=2.13 Hz, 1 H), 6.64- 6.73 (m, 2 H), 2.45 (s, 3 H). MS-ESI (m/z) calc’d for C₂₄H₁₉N₄OS [M+H]⁺: 411.1. Found. 411.1. Compound 8

(Z)-5-(3-Methyl-2-oxoimidazolidin-1-yl)-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one tert-Butyl methyl(2-((2-oxoindolin-5-yl)amino)ethyl)carbamate. To a solution of 5- aminoindolin-2-one (2.85 g, 19.24 mmol) in DMF (6 mL) and MeOH (30 mL) were added tert-butyl A-methyl-A-(2-oxoethyl)carbamate (2.81 g, 16.20 mmol) and NaBH₃CN (848.29 mg, 13.50 mmol) at 20 °C. The mixture was then stirred at 20 °C for 12 h, diluted with H₂O, and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 0-52% EtOAc/petroleum ether gradient eluent to give the product (1.19 g, 20.3%) as a yellow solid. MS-ESI (m/z) calc’d for C₁₆H₂₄N₃O₃ [M+H]⁺: 306.1. Found. 306.2.

5-((2-(Methylamino)ethyl)amino)indolin-2-one. To a solution of tert-butyl methyl(2- ((2-oxoindolin-5-yl)amino)ethyl)carbamate (1.15 g, 3.77 mmol) in CH₂CI₂ (11 mL) was added TFA (3.48 g, 30.51 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 h and concentrated to give the product (1.2 g) as a yellow oil, TFA salt which was used without further purification. MS-ESI (m/z) calc’d for C₁₁H₁₆N₃O [M+H]⁺: 206.1. Found: 206.1.

5-(3-Methyl-2-oxoimidazolidin-l-yl)indolin-2-one. To a solution of 5-((2- (methylamino)ethyl)amino)indolin-2-one (1.2 g, 3.76 mmol, TFA salt) in CH₂CI₂ (20 mL) were added 1 , 1 '-carbonyldi imidazole (609.43 mg, 3.76 mmol) and triethylamine (2.24 g, 22.17 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h and then concentrated to give a residue. The residue was purified by preparative HPLC (Phenomenex luna C18; 100 x 40 mm, 3 um; 1-30% ACN/H₂O (0.1% TFA)) to give the product (235 mg, 31.8%) as a purple solid. MS-ESI (m/z) calc’d for C₁₂H₁₄N₃O₂ [M+H]⁺: 232.1. Found: 232.2.

(Z)-l-Acetyl-3-(methoxy(phenyl)methylene)-5-(3-methyl-2-oxoimidazolidin-l- yl)indolin-2-one. A mixture of 5-(3-methyl-2-oxoimidazolidin-1-yl)indolin-2-one (200 mg, 864.86 μmol), trimethoxymethylbenzene (236.39 mg, 1.30 mmol) in Ac₂O (1 mL) and toluene (3 mL) was degassed and purged with N₂ (3x) at 20 °C. The mixture was then stirred at 110 °C for 12 h under an N₂ atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the product (330 mg) as a brown solid which was used without further purification. MS-ESI (m/z) calc’d for C₂₂H₂₂N₃O₄ [M+H]⁺: 392.1. Found: 392.3.

(Z)-5-(3-Methyl-2-oxoimidazolidin-l-yl)-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one. To a solution of (Z)-1-acetyl-3- (methoxy(phenyl)methylene)-5-(3-methyl-2-oxoimidazolidin- 1 -yl)indolin-2-one (330 mg, 843.09 μmol) in toluene (4 mL) was added 2-methylpyridin-4-amine (182.34 mg, 1.69 mmol) at 20 °C. The mixture was then stirred at 100 °C for 12 h and concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 30-60% ACN/H₂O (10 mM NH₄HCO₃)) to give the product of insufficient purity. The material was then further purified by preparative HPLC (Phenomenex Luna Cl 8; 100 mm x 30 mm, 5 um; 10-40% ACN/H₂O (0.1% TFA)) to afford the product (2.7 mg, 0.6%) as an orange solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1 H), 10.88 (s, 1 H), 8.23 (d, J=6.50 Hz, 1 H), 7.66-7.76 (m, 3 H), 7.60-7.66 (m, 2 H), 7.44-7.48 (m, 1 H), 6.90 (br s, 1 H), 6.82 (d, .1 8.63 Hz, 1 H), 6.52-6.58 (m, 1 H), 6.06 (s, 1 H), 3.27 (br s, 4 H), 2.66 (s, 3 H), 2.40 (s, 3 H). MS-ESI (m/z) calc’d for C₂₅H₂₄N₅O₂ [M+H]⁺: 426.1. Found.

426.3.

Compound 9

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-(oxazol-4-yl)indolin-2-one

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-(oxazol-4-yl)indolin-2- one. A mixture of (Z)-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (30 mg, 66.18 μmol), 4-bromooxazole (11.75 mg, 79.41 μmol), KOAc (12.99 mg, 132.35 μmol), and Pd(amphos)Cl₂ (4.69 mg, 6.62 μmol) in EtOH (1 mL) and H₂O (0.1 mL) was degassed and purged with N₂ at 20 °C. The mixture was then stirred at 50 °C for 12 h under an N₂ atmosphere and concentrated to give a residue. The residue was purified by preparative HPLC (Phenomenex luna C18; 100 mm x 40 mm, 3 um; 35-55% ACN/H₂O (0.1% TFA)) to give the product (3.2 mg, 11 .7%) as a yellow solid, TFA salt. ¹ H NMR (400 MHz, MeOD) δ 8.53 (s, 1 H), 8.26 (s, 1 H), 8.11 (d, J=7.00 Hz, 1 H), 7.76-7.90 (m, 3 H), 7.65-7.72 (m, 2 H), 7.36 (dd, J=8.13, 1.63 Hz, 1 H), 6.98 (d, J=8.13 Hz, 1 H), 6.85 (d, J=2.13 Hz, 1 H), 6.73 (dd, J=6.94, 2.44 Hz, 1 H), 6.13 (d, J=1.38 Hz, 1 H), 2.47 (s, 3 H). MS-ESI (m/z) calc’d for C₂₄H₁₉N₄O₂ [M+H]⁺: 395.1. Found. 395.1

Compound 10

Ethyl (Z)-methyl(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)carbamate

Ethyl (Z)-methyl(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)carbamate. To a solution of (Z)-5-(methylamino)-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one (30 mg, 84.17 μmol) in CH₂CI₂ (1.5 mL) were added A, A-diisopropylethylamine (32.63 mg, 252.51 μmol) and ethyl chloroformate (10.96 mg, 101.00 μmol) at 0 °C. The mixture was then stirred at 20 °C for 1 h and concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 30-60% ACN/H₂O (10 mM NH₄HCO₃)) to afford the product (6.8 mg, 18.7%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1 H), 10.89 (s, 1 H), 8.03 (d, J=5.63 Hz, 1 H), 7.61-7.71 (m, 3 H), 7.55 (d, J=6.63 Hz, 2 H), 6.86-6.90 (m, 1 H), 6.80-6.84 (m, 1 H), 6.53 (d, J=1.75 Hz, 1 H), 6.26 (dd, J=5.57, 2.06 Hz, 1 H), 5.63 (d, J=1.75 Hz, 1 H), 3.91 (q, J=6.88 Hz, 2 H), 2.91 (s, 3 H), 2.24 (s, 3 H), 1.05 (br t, J=6.82 Hz, 3 H). MS-ESI (m/z) calc’d for C₂₅H₂₅N₄O₃ [M+H]⁺: 429.1. Found. 429.3. Compound 11

Cyclopropyl (Z)-methyl(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-

5-yl)carbamate

Cyclopropyl (Z)-methyl(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2- oxoindolin-5-yl)carbamate. To a solution of (Z)-5-(methylamino)-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one (10 mg, 28.06 μmol) in DCM (1.5 mL) were added A,A-diisopropylethylamine (10.88 mg, 84. 17 μmol) and cyclopropyl chloro formate (4.06 mg, 33.67 μmol) at 0 °C. The mixture was then stirred at 20 °C for 1 h and concentrated to give a residue that was purified by preparative HPLC (Phenomenex luna C18; 100 mm x 40 mm, 3 um; 15-45% ACN/H₂O (0.1% TFA)) to afford the product (2.3 mg, 14.5%) as a yellow solid, TFA salt. ¹ H NMR (400 MHz, CD₃CN) δ 12.35-12.49 (m, 1 H), 8.93 (br s, 1 H), 8.03 (d, J=6.88 Hz, 1 H), 7.66-7.77 (m, 3 H), 7.56 (br d, J=7.00 Hz, 2 H), 6.85-6.98 (m, 2

H), 6.66 (s, 1 H), 6.45-6.52 (m, 1 H), 5.80 (s, 1 H), 3.80-3.96 (m, 1 H), 2.95 (s, 3 H), 2.42 (s, 3 H), 0.55-0.65 (m, 2 H), 0.34-0.50 (m, 2 H). MS-ESI (m/z) calc’d for C₂₆H₂₅N₄O₃ [M+H]⁺: 441.1. Found. 441.3.

Compound 12

Isopropyl (Z)-methyl(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)carbamate

Isopropyl (Z)-methyl(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2- oxoindolin-5-yl)carbamate. To a solution of (Z)-5-(methylamino)-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one (20 mg, 56.11 μmol) in CH₂CI₂ (1.5 mL) were added N,N-diisopropylethylamine (21.76 mg, 168.34 μmol) and isopropyl chloroformate

(8.25 mg, 67.34 μmol) at 0 °C. The mixture was then stirred at 20 °C for 1 h. and concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 30-60% ACN/H₂O (10 mM NH₄HCO₃)) to afford the product (10 mg, 39.7%) as a yellow solid. ¹H NMR (400 MHz, CD₃CN) δ 12.03 (br s, 1 H), 8.64-8.80 (m, 1 H), 8.02 (d, J=5.75 Hz, 1 H), 7.57-7.70 (m, 3 H), 7.47-7.54 (m, 2 H), 6.87 (s, 2 H), 6.47 (d, J=1.88 Hz, 1 H), 6.26 (dd, J=5.63, 2.13 Hz, 1 H), 5.72 (s, 1 H), 4.73 (spt, J=6.30 Hz, 1 H), 2.94 (s, 3 H), 2.26 (s, 3 H), 1.08 (br d, J=5.88 Hz, 6 H). MS-ESI (m/z) calc’d for C₂₆H₂₇N₄O₃ [M+H]⁺: 443.2. Found. 443.3.

Compound 13

Methyl (Z)-methyl(2-oxo-3-(phenyl((2-(trifluoromethyl)pyridin-4- yl)amino)methylene)indolin-5-yl)carbamate

5-(Methylamino)indolin-2-one. To a solution of 5-aminoindolin-2-one (3 g, 20.25 mmol) in MeOH (50 mL) was added paraformaldehyde (600 mg, 20.25 mmol) at 0 °C. The mixture was stirred at 20 °C for 4 h. NaBH₃CN (3.18 g, 50.62 mmol) was added to the mixture at 20 °C. The mixture was stirred at 40 °C for 12 h. The mixture was concentrated to give a residue that was purified by reversed phase HPLC (800 g Agela C18; H₂O, 0-30% MeOH/H₂O (10 mM NH₄HCO₃)) to give the product (1.28 g, 19.5%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1 H), 6.58 (d, J=8.13 Hz, 1 H), 6.51 (s, 1 H), 6.34 (dd, J=8.25, 2.13 Hz, 1 H), 5.22 (br d, J=4.88 Hz, 1 H), 3.35 (s, 2 H), 2.62 (d, J=4.75 Hz, 3 H). MS-ESI (m/z) calc’d for C₉H11N₂O [M+H]⁺: 163.0. Found: 163.5.

Methyl methyl(2-oxoindolin-5-yl)carbamate. To a solution of 5- (methylamino)indolin-2-one (900 mg, 5.55 mmol) in DCM (10 mL) were added N,N- diisopropylethylamine (2.15 g, 16.65 mmol) and methyl chloroformate (629.25 mg, 6.66 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched by addition of saturated aqueous Na₂CO₃ and then diluted with H₂O and extracted with CH₂CI₂ (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was combined with material that was similarly prepared using 100 mg of 5-(methylamino)indolin-2-one and the combined material was purified by silica gel chromatography using a 0-40% EtOAc/petroleum ether gradient to give the product (380 mg, 28.0%) as a yellow solid. MS- ESI (m/z) calc’d for C₁₁H₁₃N₂O₃ [M+H]⁺: 221.0. Found: 221.1.

Methyl (Z)-(l-acetyl-3-(methoxy(phenyl)methylene)-2-oxoindolin-5- yl)(methyl)carbamate. To a solution of methyl methyl(2-oxoindolin-5-yl)carbamate (80 mg, 363.27 μmol) in Ac₂O (0.5 mL) and toluene (1 mL) was added trimethoxymethylbenzene (99.29 mg, 544.90 μmol). The mixture was degassed and purged with N₂ at 20 °C and then stirred at 90 °C for 12 h under an N₂ atmosphere. The mixture was concentrated to give the product (130 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calc’d for C₂₁H₂₁N₂O₅ [M+H]⁺: 381.1. Found: 381.1.

Methyl (Z)-(l-acetyl-2-oxo-3-(phenyl((2-(trifluoromethyl)pyridin-4- yl)amino)methylene)indolin-5-yl)(methyl)carbamate. To a solution of methyl (Z)-(1-acetyl-3- (methoxy(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate (130 mg, 341.75 μmol) in DMF (2 mL) was added 2-(trifluoromethyl)pyridin-4-amine (166.21 mg, 1.03 mmol) at 20

°C. The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give the product (110 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calc’d for C₂₆H₂₂F₃N₄O₄ [M+H]⁺: 51 1.1. Found: 51 1.1.

Methyl (Z)-methyl(2-oxo-3-(phenyl((2-(trifluoromethyl)pyridin-4- yl)amino)methylene)indolin-5-yl)carbamate. To a solution of methyl (Z)-(1-acetyl-2-oxo-3- (phenyl((2-(trifluoromethyl)pyridin-4-yl)amino)methylene)indolin-5-yl)(methyl)carbamate (110 mg, 215.49 μmol) in MeOH (2 mL) was added K₂CO₃ (89.35 mg, 646.47 μmol) at 20

°C. The mixture was stirred at 20 °C for 2 h. The reaction was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 30-60% ACN/H₂O (10 mM NH₄HCO₃)) to give the product (3.1 mg, 2.8%) as a yellow solid. ¹H NMR (400 MHz, CD₃CN) δ 8.30 (d, J=5.52 Hz, 1 H), 7.60-7.71 (m, 3 H), 7.54 (d, J=7.53 Hz, 2 H), 6.86-6.94 (m, 2 H), 6.82 (d, J=2.13 Hz, 1 H), 6.76 (dd, J=5.58, 2.20 Hz, 1 H), 5.78 (s, 1 H), 3.51 (s, 3 H), 2.97 (s, 3 H). MS-ESI (m/z) calc’d for C₂₄H₂₀F₃N₄O₃ [M+H]⁺: 469.1. Found: 469.2.

Compound 14

Methyl (Z)-(3-(((2-cyclopropylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)(methyl)carbamate Methyl (Z)-(l-acetyl-3-(((2-cyclopropylpyridin-4-yl)amino)(phenyl)methylene)-2- oxoindolin-5-yl)(methyl)carbamate. To a solution of methyl (Z)-(1-acetyl-3- (methoxy(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate (90 mg, 236.60 μmol) in toluene (2 mL) was added 2-cyclopropylpyridin-4-amine (95.24 mg, 709.79 μmol) at 20 °C. The mixture was stirred at 100 °C for 12 h under an N₂ atmosphere and then concentrated to give the product (110 mg) as a yellow oil which was used without further purification. MS- ESI (m/z) calc’d for C₂₈H₂₇N₄O₄ [M+H]⁺: 483.2. Found. 483.3.

Methyl (Z)-(3-(((2-cyclopropylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)(methyl)carbamate. To a solution of methyl (Z)-(1-acetyl-3-(((2-cyclopropylpyridin-4- yl)amino)(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate (110 mg, 227.97 μmol) in MeOH (2 mL) was added K₂CO₃ (94.52 mg, 683.90 μmol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction was filtered, and the filtrate was concentrated under vacuum. The residue was was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 30-50% ACN/H₂O (10 mM NH₄HCO₃)) and further purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 1-45% ACN/H₂O (0.1% TFA)) to give the product (5.14 mg, 5.06%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, CD₃CN) δ 12.32 (s, 1 H), 8.94 (br s, 1 H), 8.10 (br d, J=6.63 Hz, 1 H), 7.64-7.77 (m, 3 H), 7.55 (d, J=6.88 Hz, 2 H), 6.85-7.00 (m, 2 H), 6.68 (br d, J=4.75 Hz, 1 H), 6.11 (d, J=2.13 Hz, 1 H), 5.83 (s, 1 H), 3.52 (s, 3 H), 2.97 (s, 3 H), 2.05-2.11 (m, 1 H), 1.04-1.16 (m, 2 H), 0.58-0.71 (m, 2 H) MS-ESI (m/z) calc’d for C₂₆H₂₅N₄O₃ [M+H]⁺: 441.1. Found. 441.3. Compound 15

Methyl (Z)-methyl(2-oxo-3-(phenyl(o-tolylamino)methylene)indolin-5-yl)carbamate

Methyl (Z)-methyl(2-oxo-3-(phenyl(o-tolylamino)methylene)indolin-5-yl)carbamate. 2-Methylaniline (92.96 mg, 867.52 μmol) was added to a solution of methyl (Z)-(1-acetyl-3- (methoxy(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate (110 mg, 289.17 μmol) in toluene at 20 °C. The mixture was then stirred at 90 °C for 12 h. The material was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 43-73% ACN/H₂O (10 mM NH₄HCO₃)) to give the product (9.7 mg, 7.4%) as a yellow solid. ¹H NMR (400 MHz, CD₃CN) δ 11.85 (br s, 1 H), 8.64 (br s, 1 H), 7.43-7.53 (m, 3 H), 7.37-7.43 (m, 2 H), 7.19 (d, J=7.38 Hz, 1 H), 6.97 (t, J=7.38 Hz, 1 H), 6.83-6.90 (m, 2 H), 6.76-6.82 (m, 1 H), 6.70 (d, J=7.88 Hz, 1 H), 5.61 (s, 1 H), 3.50 (s, 3 H), 2.95 (s, 3 H), 2.41 (s, 3 H) MS-ESI (m/z) calc’d for C₂₅H₂₄N₃O₃ [M+H]⁺: 414.1. Found. 414.3.

Compound 16

Methyl (Z)-(3-(((2-fluorophenyl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)(methyl)carbamate

Methyl (Z)-(l-acetyl-3-(((2-fluorophenyl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)(methyl)carbamate. To a solution of methyl (Z)-(1-acetyl-3-(methoxy(phenyl)methylene)- 2-oxoindolin-5-yl)(methyl)carbamate (130 mg, 341.75 μmol) in toluene (3 mL) was added 2- fluoroaniline (189.87 mg, 1.71 mmol) at 20 °C. The mixture was stirred at 100 °C for 12 h. The mixture was then concentrated to give the product (150 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calc’d for C₂₆H₂₃FN₃O₄ [M+H]⁺: 460.2. Found [M/2+H]⁺: 230.1

Methyl (Z)-(3-(((2-fluorophenyl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)(methyl)carbamate. To a solution of methyl (Z)-(1-acetyl-3-(((2- fluorophenyl)amino)(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate (150 mg, 326.46 μmol) in MeOH (3 mL) was added K₂CO₃ (310.75 mg, 2.25 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h, filtered, and the filtrate was concentrated under vacuum.

The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 36-66% ACN/H₂O (10 mM NH₄HCO₃)) to afford the product (5.8 mg, 4.2%) as a yellow solid. MS-ESI (m/z) calc’d for C₂₄H₂₁FN₃O₃ [M+H]⁺: 418.1. Found: 418.1. Compound 17

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-(piperidin-1-yl)indolin-2-one

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-(piperidin-l-yl)indolin-2- one. To a solution of (Z)-5-amino-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one (120 mg, 350.47 μmol) in DMF (4 mL) were added 1,5-dibromopentane (120.88 mg, 525.71 μmol) and Cs₂CO₃ (342.57 mg, 1.05 mmol) at

20 °C. The mixture was then stirred at 60 °C for 3 h. This reaction mixture was combined with a second reaction mixture that was similarly prepared using 30 mg of (Z)-5-amino-3- (((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2-one. The combined mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 10-40% ACN/H₂O (0.1% TFA)) to give the product (6.62 mg, 2.88%) as a yellow solid, TFA salt. ¹H

NMR (400 MHz, DMSO-d₆) δ 11.96-12.08 (m, 1 H) 10.88-11.08 (m, 1 H) 8.23-8.30 (m, 1 H) 7.68-7.79 (m, 3 H) 7.62-7.68 (m, 2 H) 6.81-7.06 (m, 3 H) 6.55-6.67 (m, 1 H) 5.69-6.03 (m, 1 H) 2.75-3.00 (m, 4 H) 2.41-2.45 (m, 3 H) 1.53-1.69 (m, 4 H) 1.47 (br s, 2 H). MS-ESI (m/z) calc’d for C₂₆H₂₇N₄O [M+H]⁺: 411.2. Found. 411.3. Compound 18

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-(pyrrolidin-1-yl)indolin-2-one

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-(pyrrolidin-l-yl)indolin-2- one. To a solution of (Z)-5-amino-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one (100 mg, 292.06 μmol) in DMF (3 mL) were added 1 ,4-dibromobutane (94.59 mg, 438.09 μmol) and Cs₂CO₃ (285.48 mg, 876.19 μmol) at 20 °C. The mixture was stirred at 60 °C for 3 h. This reaction mixture was combined with a second reaction mixture that was similarly prepared using 30 mg of (Z)-5-amino-3-(((2- methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2-one. The combined mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 100 mm x 30 mm, 3 um; 1-30% ACN/H₂O (0.1% TFA)) to give the product (10.4 mg, 5.37%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 12.19 (s, 1 H) 10.65 (s, 1 H) 8.24 (d, J=7.00 Hz, 1 H) 7.68-7.75 (m, 3 H) 7.62- 7.68 (m, 2 H) 6.93 (d, J=2.25 Hz, 1 H) 6.70 (d, J=8.38 Hz, 1 H) 6.57 (dd, J=7.00, 2.50 Hz, 1 H) 6.33 (dd, J=8.44, 2.06 Hz, 1 H) 5.31 (d, J=2.00 Hz, 1 H) 2.73-2.85 (m, 4 H) 2.42 (s, 3 H) 1.76-1.86 (m, 4 H). MS-ESI (m/z) calc’d for C₂₅H₂₅N₄O [M+H]⁺: 397.2. Found. 397.2. Compound 19

Methyl (Z)-N-methyl-N-(3-(((2-methylpyridin-4-yl)ainino)(phenyl)methylene)-2-oxoindolin- 5-yl)glycinate

(Z)-3-(Methoxy(phenyl)methylene)-5-nitroindolin-2-one. A mixture of 5 -nitroindo lin- 2-one (10 g, 56.13 mmol) and trimethoxymethylbenzene (30.69 g, 168.40 mmol) in Ac₂O (100 mL) was degassed and purged with N₂ (3x) at 20 °C. The mixture was then stirred at 90 °C for 12 h under an N₂ atmosphere. The reaction mixture was filtered and the solid was washed with H₂O (2x) and dried under vacuum to give the product (12.6 g) as a yellow solid which was used without further purification. MS-ESI (m/z) calc’d for C₁₆H₁₃N₂O₄ [M+H]⁺: 297.1. Found. 297.1.

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-nitroindolin-2-one. To a solution of (Z)-3-(methoxy(phenyl)methylene)-5 -nitroindo lin-2-one (12.6 g, 42.53 mmol) in DMF (150 mL) was added 2-methylpyridin-4-amine (4.83 g, 44.65 mmol) at 20 °C. The mixture was stirred at 100 °C for 12 h and concentrated under reduced pressure. The residue was dissolved in MeOH (50 mL) and K₂CO₃ (2.5 g) was added. The mixture was stirred at 20 °C for 2 h and was then concentrated under reduced pressure and poured into a solution of H₂O/iPrOH (10: 1). The mixture was then filtered, and the solid was washed with H₂O (2x) and dried under vacuum to give the product (44.6 g) as a purple solid which was used without further purification. MS-ESI (m/z) calc’d for C₂₁H₁₇N₄O₃ [M+H]⁺: 373.1. Found. 373.2.

(Z)-5-Amino-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2-one. To a solution of (Z)-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-5-nitroindolin-2-one (44.60 g, 52.70 mmol) in EtOH (250 mL) and H₂O (50 mL) were added Fe (14.71 g, 263.50 mmol) and NH₄CI (14.09 g, 263.50 mmol) at 20 °C. The mixture was stirred at 80 °C for 2 h and then filtered. The filtrate was concentrated under reduced pressure to remove EtOH and H₂O. The material was purified by reversed phase HPLC (Agela C18; 15-45% ACN/H₂O (0.075% TFA)) to give the product (5.9 g, 31%, 3 steps) as a yellow solid. MS-ESI (m/z) calc’d for C₂₁H₁₉N₄O [M+H]⁺: 343.2. Found. 343.2.

Methyl (Z)-(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)glycinate. To a solution of (Z)-5-amino-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one (300 mg, 876.19 μmol) in 1 ,2-dichloroethane (5 mL) and MeOH (5 mL) was added methyl 2-oxoacetate (200.61 mg, 1.14 mmol) and AcOH (5.26 mg, 87.62 μmol) at 20 °C. The mixture was stirred at 50 °C for 12 h. NaBH₃CN (110.12 mg, 1.75 mmol) was then added, and the mixture was stirred at 50 °C for an additional 12 h. This reaction mixture was combined with a second reaction mixture that was similarly prepared using 30 mg of (Z)-5-amino-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one. The combined mixture was filtered, and the filtrate was concentrated under reduced pressure to remove 1 ,2-dichloroethane and MeOH. The mixture was purified by preparative HPLC (Phenomenex Luna C18; 100 x 30 mm, 5 um; 5-35% ACN/H₂O (0.1% TFA)) to give the product (25 mg, 4.91%) as a brown solid, TFA salt. MS-ESI (m/z) calc’d for C₂₄H₂₃N₄O₃ [M+H]⁺: 415.2. Found. 415.2.

Methyl (Z)-N-methyl-N-(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2- oxoindolin-5-yl)glycinate. To a solution of methyl (Z)-(3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)-2-oxoindolin-5-yl)glycinate (25 mg, 60.32 μmol) in MeOH (3 mL) were added paraformaldehyde (10 mg) and NaBH₃CN (9.48 mg, 150.80 μmol) at 20 °C. The mixture was stirred at 40 °C for 12 h and then stirred at 60 °C for 8 h. Additional paraformaldehyde (20 mg) and AcOH (362.23 pg, 6.03 μmol) were added at 20 °C and the mixture was then stirred at 60 °C for 8 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The material was subjected to preparative HPLC (WePure Biotech XP tC 18; 150 mm x 40 mm; 7 um; 55-85% ACN/H₂O (10 mM NH₄HCO₃)) to give a product of insufficient purity. The material was then re-purified by preparative HPLC (WePure Biotech XP tC 18; 150 mm x 40 mm, 7 um; 30-60% ACN/H₂O (10 mM NH₄HCO₃)) to give the product (2.84 mg, 10.8%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1 H) 10.49 (s, 1 H) 8.01 (d, J=5.88 Hz, 1 H) 7.65 (br dd, J=4.94, 1.56 Hz, 3 H) 7.52-7.56 (m, 2 H) 6.67 (d, J=8.38 Hz, 1 H) 6.49 (d, J=1.63 Hz, 1 H) 6.34 (dd, J=8.38, 2.38 Hz, 1 H) 6.25 (dd, J=5.69, 1.81 Hz, 1 H) 5.22 (d, J=2.25 Hz, 1 H) 3.76 (s, 2 H) 3.56 (s, 3 H) 2.59 (s, 3 H) 2.23 (s, 3 H). MS-ESI (m/z) calc’d for C₂₅H₂₅N₄O₃ [M+H]⁺: 429.2. Found. 429.3. Compound 20

(Z)-A-Methyl-A-(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)acetamide

N-Methyl-N-(2-oxoindolin-5-yl)acetamide. To a solution of 5-(methylamino)indolin- 2-one (300.00 mg, 1.85 mmol) in CH₂CI₂ (4 mL) were added triethylamine (561.51 mg, 5.55 mmol) and acetyl chloride (159.72 mg, 2.03 mmol) at 0 °C. The mixture was then stirred at 0 °C for 1 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the product (300 mg) as a brown solid which was used without further purification. MS-ESI (m/z) calc’d for C₁₁H₁₃N₂O₂ [M+H]⁺: 205.0. Found. 205.1

(Z)-N-(l -Acetyl-3 -(methoxy (phenyl)methylene)-2-oxoindolin-5-yl)-N- methylacetamide. A mixture of A-methyl-A-(2-oxoindolin-5-yl)acetamide (300 mg, 1.47 mmol) and trimethoxymethylbenzene (535.34 mg, 2.94 mmol) in Ac₂O (2 mL) and toluene (4 mL) was degassed and purged with N₂ at 20 °C. The mixture was stirred at 90 °C for 12 h under an N₂ atmosphere. The reaction mixture was concentrated to give the product (400 mg) as a yellow solid which was used without further purification. MS-ESI (m/z) calc’d for C₂₁H₂₁N₂O₄ [M+H]⁺: 365.1. Found. 365.2

(Z)-N-(l-Acetyl-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)-N-methylacetamide. To a solution of (Z)-N-( I -acetyl-3-(methoxy(phenyl)methylene)-2- oxoindolin-5-yl)-N-methylacetamide (400.00 mg, 1.10 mmol) in DMF (5 mL) was added 2- methylpyridin-4-amine (124.64 mg, 1.15 mmol) at 20 °C. The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the product (200 mg) as a yellow solid which was used without further purification. MS-ESI (m/z) calc’d for C₂₆H₂₅N₄O₃ [M+H]⁺: 441.1. Found. 441.3.

(Z)-N-Methyl-N-(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)acetamide. To a solution of (Z)-A-(1-acetyl-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)-2-oxoindolin-5-yl)-A-methylacetamide (200 mg, 454.04 μmol) in MeOH (5 mL) was added K₂CO₃ (188.26 mg, 1.36 mmol) at 20 °C. The mixture was then stirred at 20 °C for 12 h, filtered, and the filtrate was concentrated under reduced pressure. The material was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 20-50% ACN/H₂O (10 mM NH₄HCO₃)) to give the product (6.81 mg, 3.66%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.85-12.06 (m, 1 H), 10.84- 11.08 (m, 1 H), 7.99-8.09 (m, 1 H), 7.62-7.76 (m, 3 H), 7.56 (br d, .1 6.88 Hz, 2 H), 6.78-6.99 (m, 2 H), 6.50-6.63 (m, 1 H), 6.21-6.34 (m, 1 H), 5.51 (s, 1 H), 2.88 (s, 3 H), 2.24 (s, 3 H), 1.56 (s, 3 H). MS-ESI (m/z) calc’d for C₂₄H₂₃N₄O₂ [M+H]⁺: 399.1. Found. 399.2 Compound 21

(Z)-5-(Isothiazol-4-yl)-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2-one

(Z)-l-Acetyl-5-iodo-3-(methoxy(phenyl)methylene)indolin-2-one. A mixture of 5- iodoindolin-2-one (2 g, 7.72 mmol) and trimethoxymethylbenzene (4.22 g, 23.16 mmol) in Ac₂O (20 mL) was degassed and purged with N₂ at 20 °C. The mixture was stirred at 90 °C for 12 h under an N₂ atmosphere. The reaction mixture was filtered and the solid was washed with H₂O (2x) and dried under vacuum to give the product (1.3 g) as a yellow solid which was used without further purification. MS-ESI (m/z) calc’d for C₁₈H₁₅INO₃ [M+H]⁺: 420.0. Found. 420.1.

(Z)-l-Acetyl-5-iodo-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2- one. To a solution of (Z)-1-acetyl-5-iodo-3-(methoxy(phenyl)methylene)indolin-2-one (1.3 g, 3.10 mmol) in DMF (10 mL) was added 2-methylpyridin-4-amine (352.12 mg, 3.26 mmol) at 20 °C. The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give a residue.

The residue was purified by silica gel chromatography using a 0-40% EtOAc/petroleum ether gradient eluent to give the product (400 mg, 26.0%) as a yellow solid. MS-ESI (m/z) calc’d for C₂₃H₁₉IN₃O₂ [M+H]⁺: 496.0. Found. 496.1.

(Z)-l-Acetyl-5-(isothiazol-4-yl)-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one. A mixture of (Z)-1-acetyl-5-iodo-3-(((2- methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2-one (150 mg, 302.84 μmol), 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isothiazole (76.71 mg, 363.41 μmol), Pd(amphos)Cl₂ (21.44 mg, 30.28 μmol), and KOAc (89.16 mg, 908.52 μmol) in EtOH (2 mL) and H₂O (0.2 mL) was degassed and purged with N₂ at 20 °C. The mixture was stirred at 90 °C for 3 h under an N₂ atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the product (130 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calc’d for C₂₆H₂₁N₄O₂S [M+H]⁺: 453.1. Found. 453.2.

(Z)-5-(Isothiazol-4-yl)-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)indolin-2- one. To a solution of (Z)-1-acetyl-5-(isothiazol-4-yl)-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one (130 mg, 287.28 μmol) in MeOH (3 mL) was added K₂CO₃ (119.11 mg, 861.83 μmol) at 20 °C. The mixture was stirred at 20 °C for 5 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 35-65% ACN/H₂O (10 mM NH₄HCO₃)) to give the product (9.6 mg, 8.05%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.76-12.20 (m, 1 H), 10.77-11.33 (m, 1 H), 8.66 (s, 1 H), 8.26-8.48 (m, 1 H), 7.96-8.14 (m, 1 H), 7.66- 7.80 (m, 3 H), 7.55-7.65 (m, 2 H), 7.32-7.43 (m, 1 H), 6.88-6.97 (m, 1 H), 6.53-6.63 (m, 1 H), 6.30-6.40 (m, 1 H), 5.92-6.11 (m, 1 H), 2.25 (s, 3 H). MS-ESI (m/z) calc’d for C₂₄H₁₉N₄OS [M+H]⁺: 411.1. Found. 411.2

Compound 22

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindoline-5-carbonitrile

(Z)-l-Acetyl-3-(methoxy(phenyl)methylene)-2-oxoindoline-5-carbonitrile. A mixture of 2-oxoindoline-5-carbonitrile (200 mg, 1.26 mmol) and trimethoxymethylbenzene (691.27 mg, 3.79 mmol) in Ac₂O (2 mL) was degassed and purged with N₂ (3x) at 20 °C, and then the mixture was stirred at 90 °C for 12 h under an N₂ atmosphere. The reaction mixture was filtered and the solid was washed with H₂O (2x) and dried under vacuum to give the title compound (170 mg) as a yellow solid which was used without further purification. MS-ESI (m/z) calc’d for C₁₉H₁₅N₂O₃ [M+H]⁺: 319.1. Found. 319.3. (Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindoline-5- carbonitrile. To a solution of (Z)-1-acetyl-3-(methoxy(phenyl)methylene)-2-oxoindoline-5- carbonitrile (150 mg, 471.22 μmol) in toluene (2.5 mL) was added 2-methylpyridin-4-amine (101.92 mg, 942.43 μmol) at 20 °C. The mixture was stirred at 100 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 30-60% ACN/H₂O (10 mM NH₄HCO₃)) to afford the title compound (43.6 mg, 26.0%) as a yellow solid. ¹H NMR (400 MHz, CD₃CN) δ 12.02 (br s, 1 H), 8.98-9.16 (m, 1 H), 8.06 (d, J=5.75 Hz, 1 H), 7.62-7.76 (m, 3 H), 7.51 (br d, J=7.00 Hz, 2 H), 7.33 (dd, J=8.19, 1.44 Hz, 1 H), 7.04 (d, J=8.13 Hz, 1 H), 6.53 (d, J=1.38 Hz, 1 H), 6.32 (br d, J=3.63 Hz, 1 H), 6.04 (s, 1 H), 2.28 (s, 3 H). MS-ESI (m/z) calc’d for C₂₂H₁₇N₄O [M+H]⁺: 353.1. Found. 353.1.

Compound 23

(Z)-A,WDimethyl-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxoindoline-5- carboxamide

N,N-Dimethyl-2-oxoindoline-5-carboxamide. To a solution of 2-oxoindoline-5- carboxylic acid (300 mg, 1.69 mmol) in CH₂CI₂ (10 mL) were added dimethylamine hydrochloride (276.18 mg, 3.39 mmol), Et₃N (514.07 mg, 5.08 mmol) and PyBOP (1.06 g, 2.03 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 h and concentrated under reduced pressure. The residue was passed through a column of silica gel using a 0-5% MeOH/CH₂Cl₂ gradient eluent to give the product (900 mg) as a red oil. MS-ESI (m/z) calc’d for C₁₁H₁₃N₂O₂ [M+H]⁺: 205.1. Found. 205.1.

(Z)-l-Acetyl-3-(methoxy(phenyl)methylene)-N,N-dimethyl-2-oxoindoline-5- carboxamide. To a solution of A,A-dimethyl-2-oxoindoline-5-carboxamide (700 mg, 1.03 mmol) in toluene (7 mL) and Ac₂O (2 mL) was added trimethoxymethylbenzene (374.74 mg, 2.06 mmol) at 20 °C. The mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove toluene. The material was passed through a column of silica gel using a 0-8% MeOH/CH₂Cl₂ gradient eluent to give the product (390 mg) as a dark red oil. MS-ESI (m/z) calc’d for C₂₁H₂₁N₂O₄ [M+H]⁺: 365.1. Found. 365.2.

(Z)-N,N-Dimethyl-3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2- oxoindoline-5-carboxamide. To a solution of (Z)-1-acetyl-3-(methoxy(phenyl)methylene)- A,A-dimethyl-2-oxoindoline-5-carboxamide (390 mg, 642.16 μmol) in DMF (4 mL) was added 2-methylpyridin-4-amine (72.92 mg, 674.27 μmol) at 20 °C. The mixture was then stirred at 100 °C for 12 h and concentrated under reduced pressure to remove DMF. The residue was dissolved in MeOH (2 mL) and K₂CO₃ (100 mg) was added. This mixture was stirred at 20 °C for 2 h, filtered, and the filtrate was concentrated under reduced pressure to remove MeOH. The residue was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 5-35% H₂O (0.1% TFA)/ACN) to afford insufficiently pure material. This material was combined with 5 mg of additional material that was similarly prepared and a second purification by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 15-45% ACN/H₂O (10 mM NH₄HCO₃)) gave the product (8.66 mg, 1.26%) as a yellow solid. ¹ H NMR (400 MHz, CD₃CN) δ 12.00-12.05 (br s, 1 H) 8.77-8.88 (br s, 1 H) 8.03 (d, J=5.75 Hz, 1 H) 7.60-7.70 (m, 3 H) 7.49-7.53 (m, 2 H) 7.08 (dd, J=8.07, 1.56 Hz, 1 H) 6.94 (d, J=8.00 Hz, 1 H) 6.47 (d, J=2.00 Hz, 1 H) 6.26 (d, J=5.52 Hz, 1 H) 5.97 (d, J=1.50 Hz, 1 H) 2.69-2.92 (br s, 6 H) 2.26 (s, 3 H). MS-ESI (m/z) calc’d for C₂₄H₂₃N₄O₂ [M+H]⁺:

399.2. Found. 399.2.

Compound 24

(Z)-5-(3-Methyl-2-oxo-2,3-dihydro- 1 H-imidazol- 1 -yl)-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one l-(2,2-Dimethoxyethyl)-l-methyl-3-(2-oxoindolin-5-yl)urea. To a solution of 5- aminoindolin-2-one (1 g, 6.75 mmol) in THF (10 mL) were added N,N- diisopropylethylamine (1.31 g, 10.12 mmol) and CDI (1.09 g, 6.75 mmol) at 0 °C and the mixture was stirred at 0 °C for 0.5 h. 2, 2-Di methoxy-N-methylethan- 1 -amine (965.12 mg, 8.10 mmol) was added at 0 °C and the mixture was then stirred at 20 °C for 12 h. The yellow reaction solution was taken and used directly in the next step. MS-ESI (m/z) calc’d for C₁₄H₂₀N₃O₄ [M+H]⁺: 294.1. Found. 294.1.

5-(3-Methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)indolin-2-one. To the solution of 1- (2,2-dimethoxyethyl)-1-methyl-3-(2-oxoindolin-5-yl)urea in 10 mL of THF (obtained from previous step) was added N,N-diisopropylethylamine (991.40 mg, 7.67 mmol) and TFA (3.50 g, 30.68 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was added to a solution of saturated aqueous Na₂CO₃ (20 ml) and then diluted with H₂O and extracted with CH₂CI₂ (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 0-10% CH₂Cl₂/MeOH gradient eluent to give the product (800 mg, 51.70%, 2, steps) as a white solid. MS-ESI (m/z) calc’d for C₁₂H₁₂N₃O₂ [M+H]⁺: 230.0. Found. 230.1.

(Z)-l-Acetyl-3-(methoxy(phenyl)methylene)-5-(3-methyl-2-oxo-2,3-dihydro-1H- imidazol-l-yl)indolin-2-one. A mixture of 5-(3-methyl-2-oxo-2,3-dihydro- 1H-iinidazol- 1 - yl)indolin-2-one (120 mg, 523.48 μmol) and trimethoxymethylbenzene (190.77 mg, 1.05 mmol) in Ac₂O (1 mL) and toluene (2 mL) was degassed and purged with N₂ (3x) at 20 °C The mixture was then stirred at 90 °C for 12 h under an N₂ atmosphere. The mixture was concentrated to give the product (200 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calc’d for C₂₂H₂₀N₃O₄ [M+H]⁺: 390.1. Found. 390.2.

(Z)-5-(3-Methyl-2-oxo-2,3-dihydro-1H-imidazol-l-yl)-3-(((2-methylpyridin-4- yl)amino)(phenyl)methylene)indolin-2-one. To a solution of (Z)-1-acetyl-3- (methoxy(phenyl)methylene)-5-(3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)indolin-2- one (120 mg, 308.16 μmol) and 2-methylpyridin-4-amine (33.33 mg, 308.16 μmol) in DMF (2 mL) was added K₂CO₃ (42.59 mg, 308.16 μmol) at 20 °C. The mixture was stirred at 20 °C for 12 h and then concentrated to give a residue. The residue was purified by preparative HPLC (WePure Biotech XPt C18; 150 mm x 40 mm, 7 um; 20-50% ACN/H₂O (10 mM NH₄HCO₃)) to give the product (1.6 mg, 1.2%) as a white solid. ¹H NMR (400 MHz, CD₃CN) δ 11.90-12.19 (m, 1 H), 8.74-8.84 (m, 1 H), 8.03 (d, .1 5.63 Hz, 1 H), 7.59-7.65 (m, 3 H), 7.52 (dd, J=7.88, 1.63 Hz, 2 H), 7.27 (dd, J=8.38, 2.13 Hz, 1 H), 6.94 (d, J=8.38 Hz, 1 H), 6.49 (d, J=2.25 Hz, 1 H), 6.25-6.36 (m, 2 H), 6.15 (d, J=3.00 Hz, 1 H), 5.94 (d, J=2.00 Hz, 1 H), 3.13 (s, 3 H), 2.26 (s, 3 H). MS-ESI (m/z) calc’d for C₂₅H₂₂N₅O₂ [M+H]⁺: 424.1.

Found. 424.1.

Compound 25

(Z)-3-(Phenyl((4-(piperidin-1-ylmethyl)phenyl)amino)methylene)-5-(thiazol-4-yl)indolin-2- one

(Z)-l-Acetyl-5-iodo-3-(phenyl((4-(piperidin-l- ylmethyl)phenyl)amino)methylene)indolin-2-one. To a solution of (Z)-1-acetyl-5-iodo-3- (methoxy(phenyl)methylene)indolin-2-one (600 mg, 1.43 mmol) in DMF (10 mL) was added 4-(1-piperidylmethyl)aniline (299.58 mg, 1.57 mmol) at 20 °C. The mixture was then stirred at 100 °C for 12 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 0-30% EtOAc/petroleum ether gradient eluent to give the product (400 mg, 48.4%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1 H), 7.94 (d, J=8.50 Hz, 1 H), 7.55-7.63 (m, 3 H), 7.46 (dd, J=7.88, 1.38 Hz, 2 H), 7.33 (dd, J=8.50, 1.75 Hz, 1 H), 7.10 (d, J=8.38 Hz, 2 H), 6.92 (d, J=8.38 Hz, 2 H), 5.87 (d, J=1.75 Hz, 1 H), 3.31 (br s, 2 H), 2.73 (s, 3 H), 2.23 (br s, 4 H), 1.41-1.48 (m, 4 H), 1.31-1.40 (m, 2 H) MS-ESI (m/z) calc’d for C₂₉H₂₉IN₃O₂ [M+H]⁺: 578.1. Found: 578.2. (Z)-l-Acetyl-3-(phenyl((4-(piperidin-l-ylmethyl)phenyl)amino)methylene)-5-(thiazol-

4-yl)indolin-2-one. A mixture of (Z)-1-acetyl-5-iodo-3-(phenyl((4-(piperidin-1- ylmethyl)phenyl)amino)methylene)indolin-2-one (150 mg, 259.76 μmol), tributyl(thiazol-4- yl)stannane (145.79 mg, 389.64 μmol) and XPhos Pd G4 (22.35 mg, 25.98 μmol) in dioxane (3 mL) was degassed and purged with N₂ at 20 °C. The mixture was then stirred at 80 °C for 12 h under an N₂ atmosphere. The reaction mixture was diluted with H₂O and extracted with

EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give the product (140 mg) as a white solid which was used without further purification. MS-ESI (m/z) calc’d for C₃₂H₃₁N₄O₂S [M+H]⁺: 535.2. Found: 535.3.

(Z)-3-(Phenyl((4-(piperidin-l-ylmethyl)phenyl)amino)methylene)-5-(thiazol-4- yl)indolin-2-one. To a solution of (Z)-1-acetyl-3-(phenyl((4-(piperidin-1- yl methyl)phenyl )am i no )methylene)-5-( th iazol-4-yl )i ndol i n-2-one (140 mg, 261.84 μmol) in MeOH (3 mL) was added K₂CO₃ (72.38 mg, 523.69 μmol) at 20 °C and the mixture was stirred for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The material was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 15-45% ACN/H₂O (0.1% TFA)) to give the product (68.4 mg, 42.7%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1 H), 10.89 (s, 1 H), 9.07-9.17 (m, 1 H), 9.02 (d, J=1.88 Hz, 1 H), 7.61-7.70 (m, 3 H), 7.57 (ddd, J=9.41, 8.10, 1.63 Hz, 3 H), 7.19-7.32 (m, 3 H), 6.90 (dd, J=12.51, 8.38 Hz, 3 H), 6.40 (d, J=1.38 Hz, 1 H), 4.14 (d, J=5.13 Hz, 2 H), 3.23 (br d, J=12.26 Hz, 2 H), 2.74-2.84 (m, 2 H), 1.73-1.84 (m, 2 H), 1.29-1.69 (m, 4 H). MS-ESI (m/z) calc’d for C₃₀H₂₉N₄OS [M+H]⁺: 493.2. Found: 493.2.

Compound 26

Methyl (Z)-methyl(3-(((6-methylpyridin-3-yl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)carbamate

Methyl (Z)-methyl(3-(((6-methylpyridin-3-yl)amino)(phenyl)methylene)-2-oxoindolin- 5-yl)carbamate. To a solution of methyl (Z)-(1-acetyl-3-(methoxy(phenyl)methylene)-2- oxoindolin-5-yl)(methyl)carbamate (150 mg, 394.33 μmol) in toluene (2 mL) was added 6- methylpyridin-3 -amine (85.29 mg, 788.66 μmol) at 20 °C. The mixture was then stirred at 100 °C for 12 h and concentrated to give a residue. The residue was purified by preparative HPLC (WePure Biotech XPt C18; 150 mm x 40 mm, 7 um; 25-55% ACN/H₂O (10 mM NH₄HCO₃)) to afford the product (9.2 mg, 5.6%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1 H), 10.76 (s, 1 H), 8.03 (d, J=2.38 Hz, 1 H), 7.51-7.58 (m, 3 H), 7.44-7.48 (m, 2 H), 7.14 (dd, J=8.32, 2.69 Hz, 1 H), 7.03 (d, J=8.38 Hz, 1 H), 6.81 (s, 2 H), 5.53 (s, 1 H), 3.46 (s, 3 H), 2.91 (s, 3 H), 2.33 (s, 3 H) MS-ESI (m/z) calc’d for C₂₄H₂₃N₄O₃ [M+H]⁺: 415.1. Found. 415.2

Compound 27

Methyl (Z)-(3-(((3,5-dichlorophenyl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)(methyl)carbamate

Methyl (Z)-(3-(((3,5-dichlorophenyl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)(methyl)carbamate. To a solution of methyl (Z)-(1-acetyl-3-(methoxy(phenyl)methylene)- 2-oxoindolin-5-yl)(methyl)carbamate (150 mg, 394.33 μmol) in toluene (2 mL) was added 3,5-dichloroaniline (127.78 mg, 788.66 μmol) at 20 °C. The mixture was then stirred at 100 °C for 12 h and concentrated to give a residue. The residue was purified by preparative HPLC (WePure Biotech XPt C 18; 150 mm x 40 mm, 7 um; 55-85% ACN/H₂O (10 mM NH₄HCO₃)) to afford the product (7.97 mg, 4.30%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (br s, 1 H), 10.83 (s, 1 H), 7.57-7.65 (m, 3 H), 7.49-7.55 (m, 2 H), 7.19 (s, 1 H), 6.80- 6.87 (m, 4 H), 5.62 (s, 1 H), 3.46 (s, 3 H), 2.92 (s, 3 H). MS-ESI (m/z) calc’d for C₂₄H₂₀CI₂N₃O₃ [M+H]⁺: 468.0/470.0. Found. 468.1/470.1. Compound 28

Methyl (Z)-(3-(((4-((dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-

5-yl)(methyl)carbamate

Methyl (Z)-(3-(((4-((dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-2- oxoindolin-5-yl)(methyl)carbamate. To a solution of methyl (Z)-(1-acetyl-3- (methoxy(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate (150 mg, 394.33 μmol) in toluene (2 mL) was added 4- [(dimethylamino)methyl] aniline (118.47 mg, 788.66 μmol) at 20 °C. The mixture was then stirred at 100 °C for 12 h and concentrated to give a residue. The residue was purified by preparative HPLC (WePure Biotech XP tC 18; 150 mm x 40 mm, 7um; 30-60% ACN/H₂O (10 mM NH₄HCO₃)) to afford the product (13.3 mg, 7.15%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, 1 H), 10.73 (s, 1 H), 7.52-7.59 (m, 3 H), 7.43-7.48 (m, 2 H), 7.05 (d, J=8.38 Hz, 2 H), 6.74-6.82 (m, 4 H), 5.51 (s, 1 H), 3.46 (s, 3

H), 3.24 (s, 2 H), 2.91 (s, 3 H), 2.05 (s, 6 H). MS-ESI (m/z) calc’d for C₂₇H₂₉N₄O₃ [M+H]⁺: 457.2. Found. 457.3. Compound 29

Methyl (Z)-methyl(2-oxo-3-(phenyl((4-(piperidin- 1 - ylmethyl)phenyl)amino)methylene)indolin-5-yl)carbamate

Methyl (Z)-methyl(2-oxo-3-(phenyl((4-(piperidin- 1 - ylmethyl)phenyl)amino)methylene)indolin-5-yl)carbamate. To a solution of methyl (Z)-( 1 - acetyl-3-(methoxy(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate (150 mg, 394.33 μmol) in toluene (2 mL) was added 4-(l -piperidylmethyl) aniline (150.07 mg, 788.66 μmol) at 20 °C. The mixture was then stirred at 100 °C for 12 h and concentrated to give a residue. The residue was purified by preparative HPLC (WePure Biotech XPt C18; 150 mm x 40 mm, 7 um; 40-70% ACN/H₂O (10 mM NH₄HCO₃)) to give material of insufficient purity. The material was purified a second time by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 1-45% ACN/H₂O (0.1% TFA)) to afford the product (8.6 mg, 4.4%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 1 H), 10.79 (s, 1 H), 9.14 (br d, .1 3.63 Hz, 1 H), 7.56-7.66 (m, 3 H), 7.47-7.54 (m, 2 H), 7.25 (d, J=8.38 Hz, 2 H), 6.79-6.90 (m, 4 H), 5.53 (s, 1 H), 4.13 (br d, J=5.00 Hz, 2 H), 3.46 (s, 3 H), 3.23 (br d, J=11.63 Hz, 2 H), 2.91 (s, 3 H), 2.72-2.84 (m, 2 H), 1.78 (br d, J=13.26 Hz, 2 H), 1.50-1.69 (m, 3 H), 1.25-1.38 (m, 1 H). MS-ESI (m/z) calc’d for C₃₀H₃₃N₄O₃ [M+H]⁺: 497.2. Found. 497.3. Compound 30

(Z)- 1 ,3-Dimethyl- 1 -(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxo-2,3- dihydro- 1 H-pyrrolo [2,3 -c]pyridin-5 -yl)urea

Diethyl 2-(2-chloro-5-nitropyridin-4-yl)malonate. To a solution of diethyl malonate (24.90 g, 155.45 mmol) in THF (370 mL) was added NaH (6.22 g, 155.45 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h under an N₂ atmosphere. 2, 4-Dichloro-5 -nitropyridine (25 g, 129.54 mmol) was then added at 25 °C, and the mixture was stirred at 70 °C for 12 h. The reaction mixture was poured into ice water (1 L) and extracted with EtOAc (3x). The organic layers were combined and dried over anhydrous Na₂SO₄. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove EtOAc. The residue was purified by silica gel column chromatography using 0- 10% EtOAc/petroleum ether gradient eluent to give the product (34.22 g, 83.41%) as a yellow oil. MS-ESI (m/z) calc’d for C₁₂H₁₄CIN₂O₆ [M+H]⁺: 317.1/319.0. Found. 317.1/319.1.

Ethyl 2-(2-chloro-5-nitropyridin-4-yl)acetate. To a solution of diethyl 2-(2-chloro-5- nitropyridin-4-yl)malonate (34.22 g, 108.05 mmol) in DMSO (400 mL) were added LiCI (9.16 g, 216.11 mmol) and H₂O (1.95 g, 108.05 mmol) at 25 °C. The mixture was then stirred at 100 °C for 3 h, diluted with EtOAc (1 L), and washed with H₂O (2x). The organic layer was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the product (33.3 g) as a yellow oil which was used without further purification. MS-ESI (m/z) calc’d for C₉H₁₀N₂O₄ [M+H]⁺: 245.0/247.0. Found. 245.0/247.0.

Ethyl 2-(2-(methylamino)-5-nitropyridin-4-yl)acetate. To a solution of ethyl 2-(2- chloro-5-nitropyridin-4-yl)acetate (33.3 g, 107.54 mmol) in dioxane (450 mL) were added methylamine hydrochloride (14.52 g, 215.07 mmol) and N,N-diisopropylethylainine (41.70 g, 322.61 mmol) at 25 °C. The mixture was then stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove dioxane. The material was extracted with EtOAc and H₂O. The organic layer was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 20-50% EtOAc/petroleum ether gradient eluent to give the product (7.05 g, 27.4%) as a yellow solid. MS-ESI (m/z) calc’d for C₁₀H₁₄N₃O₄ [M+H]⁺: 240.1. Found. 240.1.

Ethyl 2-(2-(l,3-dimethylureido)-5-nitropyridin-4-yl)acetate. To a solution of ethyl 2- (2-(methylamino)-5-nitropyridin-4-yl)acetate (7.05 g, 29.47 mmol) in THF (200 mL) was added bis(trichloromethyl) carbonate (2.69 g, 9.06 mmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. A solution of methylamine in THF (2 M, 37.8 mL) was added to mixture and the mixture was stirred at 40 °C for 11.5 h. The mixture was diluted with saturated, aqueous NaHCO₃ (100 mL) and H₂O (200 mL) and extracted with EtOAc (2x). The organic layers were combined and dried over anhydrous Na₂SO₄. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove EtOAc. The material was purified by reversed phase HPLC (Agela C18; 30-60% ACN/H₂O). At this point, the purity of the product was insufficient. The material was subjected to a second purification by preparative HPLC (Welch Xtimate C18; 180 mm x 70 mm, 10 um; 10-40% ACN/H₂O (10 mM NH₄HCO₃)) to give the product (970 mg, 11.1%) as a yellow solid. MS-ESI (m/z) calc’d for C₁₂H₁₇N₄O₅ [M+H]⁺: 297.1. Found. 297.1.

Ethyl 2-(5-amino-2-(l,3-dimethylureido)pyridin-4-yl)acetate. To a solution of ethyl 2- (2-(l,3-dimethylureido)-5-nitropyridin-4-yl)acetate (200 mg, 675.04 μmol) in EtOH (4 mL) and H₂O (1 mL) were added Fe (113.09 mg, 2.03 mmol) and NH₄CI (108.33 mg, 2.03 mmol) at 25 °C. The mixture was stirred at 80 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove EtOH and H₂O. The residue was diluted with EtOH (10 mL), filtered again, and the filtrate was concentrated under reduced pressure to give the product (233 mg) as a brown solid which was used without further purification. MS-ESI (m/z) calc’d for C₁₂H₁₉N₄O₃ [M+H]⁺: 267.1. Found. 267.2. l,3-Dimethyl-l-(2-oxo-2,3-dihydro-lH-pyrrolo[2,3-c]pyridin-5-yl)urea. To a solution of ethyl 2-(5-amino-2-(l,3-dimethylureido)pyridin-4-yl)acetate (213 mg, 799.86 ginol) in toluene (6 mL) was added Al Me i (2 M, 1.20 mL) at 0 °C under an N₂ atmosphere and the mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to 0 °C and MeOH (1 mL) was added dropwise. H₂O (3 mL) was then added, and the mixture was extracted with EtOAc (3x). The organic layers were combined and dried over anhydrous Na₂SO₄. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the product (194 mg) as a yellow solid which was used without further purification. MS-ESI (m/z) calc’d for C₁₀H₁₃N₄O₂ [M+H]⁺: 221.1. Found. 221.1.

(Z)-l-(l-acetyl-3-(methoxy(phenyl)methylene)-2-oxo-2, 3-dihydro-lH-pyrrolo[2, 3- c]pyridin-5-yl)-l,3-dimethylurea. A mixture of 1,3 -dimethyl- l-(2-oxo-2, 3 -dihydro- 1H- pyrrolo[2,3-c]pyridin-5-yl)urea (194 mg, 607.83 ginol) and trimethoxymethylbenzene (332.27 mg, 1.82 mmol) in toluene (2 mL) and Ac₂O (1 mL) was degassed and purged with N₂ (3x) at 25 °C, and then the mixture was stirred at 90 °C for 12 h under an N₂ atmosphere. The mixture was concentrated under reduced pressure to remove toluene and Ac₂O to give the product (220 mg) as a red solid which was used without purification. MS-ESI (m/z) calc’d for C₂₀H₂₁N₄O₄ [M+H]⁺: 381.2. Found. 381.2.

(Z)-l, 3-dimethyl-l-(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxo-2, 3- dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)urea. To a solution of (Z)-1-(1-acetyl-3- (methoxy(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-l,3- dimethylurea (220 mg, 578.34 μmol) in DMF (5 mL) was added 2-methylpyridin-4-amine (187.63 mg, 1.74 mmol) at 25 °C. The mixture was then stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was dissolved in MeOH (3 mL) and K₂CO₃ (150 mg) was added. The mixture was stirred at 25 °C for 2 h. The mixture was then filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (WePure Biotech XP tC 18; 150 mm x 40 mm, 7 um; 6- 46% ACN/H₂O (10 mM NH₄HCO₃)) to give the product (17.7 mg, 7.27%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1 H) 10.99 (s, 1 H) 8.42 (br d, J=3.75 Hz, 1 H) 8.10 (d, J=5.63 Hz, 1 H) 7.85 (s, 1 H) 7.62-7.73 (m, 3 H) 7.54-7.61 (m, 2 H) 6.67 (s, 1 H) 6.41 (br d, J=4.63 Hz, 1 H) 5.46 (s, 1 H) 2.79 (s, 3 H) 2.61 (d, J=4.50 Hz, 3 H) 2.27 (s, 3 H). MS-ESI (m/z) calc’d for C₂₃H₂₃N₆O₂ [M+H]⁺: 415.2. Found. 415.2.

Compound 31 Methyl (Z)-methyl(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate

Diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonate. To a solution of diethyl malonate (24.90 g, 155.45 mmol) in 1 ,2-dimethoxyethane (300 mL) was added NaH (6.22 g, 155.45 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h under an N₂ atmosphere, and then 2,6-dichloro-3-nitro-pyridine (25 g, 129.54 mmol) was added to the mixture at 20 °C. The mixture was stirred at 20 °C for 12 h under an N₂ atmosphere. The reaction mixture was quenched by addition of saturated aqueous NH₄CI (400 ml) and then diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The material was purified by silica gel chromatography using a 0-7% EtOAc/petroleum ether gradient eluent to give the product (26 g, 63.4%) as a yellow oil. MS-ESI (m/z) calc’d for C₁₂H₁₄CIN₂O₆ [M+H]⁺: 317.0/319.0. Found: 317.0/319.0.

Ethyl 2-(6-chloro-3-nitropyridin-2-yl)acetate. To a solution of diethyl 2-(6-chloro-3- nitropyridin-2-yl)malonate (26 g, 82.10 mmol) in DMSO (200 mL) was added LiCI (6.96 g, 164.20 mmol) and H₂O (1.48 g, 82. 10 mmol) at 20 °C. The mixture was then stirred at 100 °C for 6 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The material was purified by silica gel chromatography using a 0-7% EtOAc/petroleum ether gradient eluent to give the product (9.2 g, 45.8%) as a yellow oil. MS-ESI (m/z) calc’d for C₉H₁₀CIN₂O₄ [M+H]⁺: 245.0/247.0. Found: 245.1/246.9. Ethyl 2-(6-(methylamino)-3-nitropyridin-2-yl)acetate. To a solution of ethyl 2-(6- chloro-3-nitropyridin-2-yl)acetate (9.2 g, 37.61 mmol) in DMA (150 mL) were added N,N- diisopropylethylamine (14.58 g, 112.82 mmol) and methylamine hydrochloride (5.08 g, 75.22 mmol) at 20 °C. The mixture was then stirred at 130 °C for 3 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 0-30% EtOAc/petroleum ether gradient eluent to give the product (7.2 g, 80.0%) as a yellow oil. MS-ESI (m/z) calc’d for C₁₀H₁₄N₃O₄ [M+H]⁺: 240.0. Found: 240.1.

Ethyl 2-(6-((methoxycarbonyl)(methyl)amino)-3-nitropyridin-2-yl)acetate. To a solution of ethyl 2-(6-(methylamino)-3-nitropyridin-2-yl)acetate (3 g, 12.54 mmol) in THF (80 mL) at 20 °C was added bis(trichloromethyl) carbonate (2.27 g, 7.65 mmol). The mixture was stirred for 0.5 h and then MeOH (5.54 g, 172.98 mmol) was added followed by stirring at 60 °C for 12 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 0-30% EtOAc/petroleum ether gradient eluent to give material of insufficient purity. The residue was further purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5um; 30-60% ACN/H₂O (0.1% TFA)) to give the product (1.2 g, 32.2%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (d, J=9.26 Hz, 1 H), 8.07 (d, J=9.25 Hz, 1 H), 4.21 (s, 2 H), 4.11 (q, J=7.05 Hz, 2 H), 3.81 (s, 3 H), 3.45 (s, 3 H), 1.18 (t, J=7.13 Hz, 3 H). MS-ESI (m/z) calc’d for C₁₂H₁₆N₃O₆ [M+H] ⁺: 298.1. Found: 298.2.

Ethyl 2-(3-amino-6-((methoxycarbonyl)(methyl)amino)pyridin-2-yl)acetate. To a solution of ethyl 2-(6-((methoxycarbonyl)(methyl)amino)-3-nitropyridin-2-yl)acetate (150 mg, 504.60 μmol) in EtOH (2 mL) and H₂O (0.5 mL) were added Fe (84.54 mg, 1.51 mmol) and NH₄Cl (80.98 mg, 1.51 mmol) at 20 °C. The mixture was then stirred at 80 °C for 2 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give the product (130 mg) as a yellow solid which was used without further purification. MS-ESI (m/z) calc’d for C₁₂H₁₈N₃O₄ [M+H]⁺: 268.1. Found: 268.1.

Methyl methyl(2-oxo-2,3-dihydro-lH-pyrrolo[3,2-b]pyridin-5-yl)carbamate. To a solution of ethyl 2-(3-amino-6-((methoxycarbonyl)(methyl)amino)pyridin-2-yl)acetate (130 mg, 486.38 μmol) in toluene (2 mL) was added AlMe₃ (2 M, 729.57 μL) at 0 °C under an N₂ atmosphere. The mixture was then stirred at 60 °C for 1 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the product (70 mg) as a yellow solid which was used without further purification. MS-ESI (m/z) calc’d for C₁₀H₁₂N₃O₃ [M+H]⁺: 222.0. Found: 222.1.

Methyl (Z)-(l -acetyl-3-(methoxy(phenyl)methylene)-2-oxo-2, 3-dihydro-lH- pyrrolo[3,2-b]pyridin-5-yl)(methyl)carbamate. A mixture of methyl methyl(2-oxo-2,3- dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (50 mg, 226.03 μmol) and trimethoxymethylbenzene (82.37 mg, 452.05 μmol) in toluene (1 mL) and Ac₂O (0.5 mL) was degassed and purged with N₂ (3x) at 20 °C. The mixture was then stirred at 90 °C for 12 h under an N₂ atmosphere. The mixture was concentrated under reduced pressure to give the product (50 mg) as a yellow oil which was used without further purification. MS-ESI (m/z) calc’d for C₂₀H₂₀N₃O₅ [M+H]⁺: 382.1. Found: 382.0.

Methyl (Z)-methyl(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2-oxo-2,3- dihydro-lH-pyrrolo[3,2-b]pyridin-5-yl)carbamate. To a solution of methyl (Z)-(1-acetyl-3- (methoxy(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5- yl)(methyl)carbamate (50 mg, 131.10 μmol ) in toluene (2 mL) was added 2-methylpyridin-4- amine (42.53 mg, 393.31 μmol) at 20 °C. The mixture was then stirred at 90 °C for 12 h. The mixture was concentrated to give a residue that was purified by preparative HPLC (WePure Biotech XPt C18; 150 mm x 40 mm, 7um; 23-63% ACN/H₂O (10 mM NH₄HCO₃)) to give the product (6.1 mg, 11.2%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.37-12.09 (m, 1 H), 10.23-10.95 (m, 1 H), 8.01-8.13 (m, 1 H), 7.42-7.60 (m, 5 H), 7.11-7.25 (m, 2 H),

6.43-6.65 (m, 1 H), 6.24-6.37 (m, 1 H), 3.58-3.70 (m, 3 H), 2.65-2.84 (m, 3 H), 2.15-2.30 (m, 3 H). MS-ESI (m/z) calc’d for C₂₃H₂₂N₅O₃ [M+H]⁺: 416.1. Found: 416.2.

Compound 32

Methyl (Z)-methyl(3-(((3-methyl-4-morpholinophenyl)amino)(phenyl)methylene)-2- oxoindolin-5-yl)carbamate

Methyl (Z)-methyl(3-(((3-methyl-4-morpholinophenyl)amino)(phenyl)methylene)-2- oxoindolin-5-yl)carbamate. To a solution of methyl (Z)-(1-acetyl-3- (methoxy(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate in toluene (3 mL) was added 3-methyl-4-morpholinoaniline (101.08 mg, 525.77 μmol) at 20 °C. The mixture was then stirred at 100 °C for 12 h under an N₂ atmosphere. The mixture was concentrated to give a residue that was purified by preparative HPLC (Phenomenex Luna C 18 100 mm x 30 mm; 5 um; 30-60% CH₃CN/H₂O (0.1% TFA)) to give the product (18.25 mg, 11.30%) as a yellow solid, TFA salt. ¹ H NMR(400 MHz, DMSO-d₆) δ 11.96 (s, 1 H), 10.71 (s, 1 H), 7.52-7.63 (m, 3 H), 7.42-7.50 (m, 2 H), 6.75-6.82 (m, 3 H), 6.72 (d, J=2.38 Hz, 1 H), 6.56 (dd, J=8.63, 2.50

Hz, 1 H), 5.47 (s, 1 H), 3.63-3.70 (m, 4 H), 3.46 (s, 3 H), 2.91 (s, 3 H), 2.69-2.75 (m, 4 H), 2.08 (s, 3 H). MS-ESI (m/z) calc’d for C₂₉H₃₁N₄O₄ [M+H]⁺: 499.2 Found. 499.2.

Compound 33

Methyl (Z)-methyl(3-(((3-methyl-4-(piperidin-1-ylmethyl)phenyl)amino)(phenyl)methylene)-

2-oxoindolin-5-yl)carbamate l-(2-Methyl-4-nitrobenzyl)piperidine. To a solution of 1 -(bromomethyl)-2-methyl-4- nitrobenzene (500 mg, 2.17 mmol) in CH₃CN (15 mL) were added K₂CO₃ (901.14 mg, 6.52 mmol), KI (36.08 mg, 217.34 μmol), and piperidine (185.06 mg, 2.17 mmol) at 20 °C. The mixture was then stirred at 20 °C for 12 h. The mixture was concentrated to give a residue that was diluted with H₂O (10 mL) and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated to give the product (500 mg) as a yellow oil that was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.96-8.13 (m, 2 H), 7.54 (d, J=8.38 Hz, 1 H), 3.48 (s, 2 H), 2.41 (s, 3 H), 2.35 (br s, 4 H), 1.50 (quin, J=5.38 Hz, 4 H), 1.40 (br d, J=4.88 Hz, 2 H). MS-ESI (m/z) calc’d for C₁₃H₁₉N₂O₂ [M+H]⁺: 235.3. Found. 235.2.

3-Methyl-4-(piperidin-l-ylmethyl)aniline. To a solution of 1 -(2-methyl-4- nitrobenzyl)piperidine (500 mg, 2.13 mmol) in EtOH (4 mL) and H₂O (2 mL) was added Fe (595.89 mg, 10.67 mmol) and NH₄Cl (570.77 mg, 10.67 mmol) at 20 °C. The mixture was then stirred at 50 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated to give a residue that was purified by preparative HPLC (WePure Biotech XP tC18; 150 mm x 40 mm; 7 um; 1-30% CH₃CN/H₂O (10 mM NH₄HCO₃)) to give the product (294 mg, 66.3%, 2 steps) as a yellow oil. MS-ESI (m/z) calc’d for C₁₃H₂₁N₂ [M+H]⁺: 205.3. Found. 205.2.

Methyl (Z)-methyl(3-(((3-methyl-4-(piperidin-l- ylmethyl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-5-yl)carbamate. To a solution of methyl (Z)-(1-acetyl-3-(methoxy(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate (230 mg, 604.64 μmol) in toluene (7 mL) was added 3-methyl-4-(piperidin-1-ylmethyl)aniline (247.07 mg, 1.21 mmol). The mixture was then stirred at 100 °C for 12 h. The reaction mixture was concentrated to give a residue that was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30mm; 5 um; 15-45% CH₃CN/H₂O (0.1% TFA)) to give the product (72.7 mg, 23.5%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, CD₃CN) δ 12.06 (s, 1 H), 9.29 (br s,

1 H), 7.52-7.64 (m, 3 H), 7.44-7.49 (m, 2 H), 7.18 (d, J=8.38 Hz, 1 H), 6.79-6.89 (m, 2 H), 6.74 (d, J=2.25 Hz, 1 H), 6.57 (dd, J=8.44, 2.19 Hz, 1 H), 5.63 (d, J=1.50 Hz, 1 H), 4.05 (br s,

2 H), 3.50 (s, 3 H), 3.29 (br d, J=12.76 Hz, 2 H), 2.95 (s, 3 H), 2.78 (br s, 2 H), 2.20 (s, 3 H), 1.69-1.79 (m, 5 H), 1.31-1.47 (m, 1 H). MS-ESI (m/z) calc’d for C₃₁H₃₅N₄O₃ [M+H]⁺: 511.6.

Found. 511.3.

Compound 34

Methyl (Z)-(3-(((3,5-dimethyl-4-(piperidin- 1 -ylmethyl)phenyl)amino)(phenyl)methylene)-2- oxoindolin-5-yl)(methyl)carbamate l-(4-Bromo-2,6-dimethylbenzyl)piperidine. To a solution of 4-bromo-2,6-dimethyl- benzaldehyde (1.0 g, 4.69 mmol) in CH₂CI₂ (15 mL) were added piperidine (479.54 mg, 5.63 mmol) and triethylamine (2.85 g, 28.16 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. NaBH(OAc)₃ (5.97 g, 28.16 mmol) was then added, and the mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H₂O (40 mL) and extracted with CH₂CI₂ (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0- 40% EtOAc/petroleum ether gradient eluent to give the product (720 mg, 54.4%) as a yellow oil. MS-ESI (m/z) calc’d for C₁₄H₂₁BrN [M+H]⁺: 282.0/282.2 Found. 3282.0/284.1. tert-Butyl (3 ,5-dimethyl-4-(piperidin-l -ylmethyl)phenyl)carbamate. A mixture of l-(4- bromo-2,6-dimethylbenzyl)piperidine (270 mg, 956.71 μmol), tert-butyl carbamate (134.49 mg, 1.15 mmol), Cs₂CO₃ (467.57 mg, 1.44 mmol), XPhos (45.61 mg, 95.67 μmol) and Pd(OAc)₂ (21.48 mg, 95.67 μmol) in dioxane (10 mL) was degassed and purged with N₂ (3x) at 20 °C and then stirred at 100 °C for 12 h under an N₂ atmosphere. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography using a 0-30% EtOAc/petroleum ether gradient eluent to give the product (240 mg, 78.8%) as a yellow solid. MS-ESI (m/z) calc’d for C₁₉H₃₁N₂O₂ [M+H]⁺: 319.2 Found. 319.3.

3,5-Dimethyl-4-(piperidin-l-ylmethyl)aniline. A solution of tert-butyl (3,5-dimethyl-4- (piperidin- 1 -ylmethyl)phenyl)carbamate (200 mg, 628.04 μmol) in HCl/EtOAc (4 M, 6.67 mL) was stirred at 20 °C for 2 h. The mixture was concentrated to give 3,5-dimethyl-4-(piperidin- 1 -ylmethyl)aniline (120 mg) as a white solid that was used without further purification. MS- ESI (m/z) calc’d for C₁₄H₂₃N₂ [M+H]⁺: 219.1 Found. 219.2.

Methyl (Z)-(3-(((3,5-dimethyl-4-(piperidin-l- ylmethyl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate. To a solution of methyl (Z)-(1-acetyl-3-(methoxy(phenyl)methylene)-2-oxoindolin-5- yl)(methyl)carbamate (400 mg, 1.05 mmol) and KOH (59.00 mg, 1.05 mmol) in MeOH (5 mL) was added 3,5-dimethyl-4-(piperidin-1-ylmethyl)aniline (120 mg, 549.61 μmol, 0.5 eq) at 20 °C. The mixture was then stirred at 60 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (WePure Biotech XP tC 18; 150 mm x 40 mm; 7 um; 35-98% CH₃CN/H₂O (10 mM NH₄HCO₃)) to give the product (1.56 mg, 0.5%, 2 steps) as a yellow solid. ¹H NMR(400 MHz, CD₃CN) δ 11.84-12.00 (m, 1 H), 8.63 (br s, 1 H), 7.51-7.58 (m, 3 H), 7.42-7.47 (m, 2 H), 6.84-6.89 (m, 1 H), 6.77-6.83 (m, 1 H), 6.47 (s, 2 H), 5.59 (s, 1 H), 3.50 (s, 3 H), 3.29 (br d, J=1.00 Hz, 2 H), 2.95 (s, 3 H), 2.29- 2.43 (m, 4 H), 2.12 (br d, J=2.38 Hz, 6 H), 1.44 (br d, J=5.75 Hz, 6 H). MS-ESI (m/z) calc’d for C₃₂H₃₇N₄O₃ [M+H]⁺: 525.2 Found. 525.3. Compound 35

Methyl (Z)-methyl(2-oxo-3-(phenyl((4-( 1 -(piperidin- 1 - yl)ethyl)phenyl)amino)methylene)indolin-5-yl)carbamate l-(l-(4-Nitrophenyl)ethyl)piperidine. To a solution of l-(1-bromoethyl)-4- nitrobenzene (500 mg, 2.17 mmol) in CH₃CN (10 mL) were added K₂CO₃ (600.74 mg, 4.35 mmol), KI (36.08 mg, 217.34 μmol), and piperidine (203.56 mg, 2.39 mmol) at 20 °C. The mixture was then stirred at 20 °C for 2 h. The mixture was concentrated to give a residue that was diluted with H₂O (10 mL) and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated to give the product (497 mg) as a yellow oil that was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J=8.78 Hz, 2 H), 7.51 (br d, J=8.41 Hz, 2 H), 3.49 (q, J=6.36 Hz, 1 H), 2.27-2.47 (m, 4 H), 1.53-1.59 (m, 4 H), 1.39-1.46 (m, 2 H), 1.36 (br d, J=6.65 Hz, 3 H). MS-

ESI (m/z) calc’d for C₁₃H₁₉N₂O₂ [M+H]⁺: 235.3. Found. 235.4. 4-(l -(Piperidin-1 -yl)ethyl)aniline. To a solution of 10% Pd/C (90.84 mg, 85.36 umol) in MeOH (3 mL) was added l-(1-(4-nitrophenyl)ethyl)piperidine (200 mg, 853.63 umol) at 20 °C. The mixture was then stirred at 20 °C for 1.5 h under an H₂ atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated to give a residue that was purified by preparative HPLC (WePure Biotech XP tC18; 150 mm x 40 mm; 7 um; 1-25% CH₃CN/H₂O (10 mM NH₄HCO₃)) to give the product (80 mg, 44.5%, 2 steps) as a yellow oil. MS-ESI (m/z) calc’d for C₁₃H₂₁N₂ [M+H]⁺: 205.3. Found. 205.3.

Methyl (Z)-methyl(2-oxo-3-(phenyl((4-(l-(piperidin-l- yl)ethyl)phenyl)amino)methylene)indolin-5-yl)carbamate. To a solution of methyl (Z)-(l- acetyl-3-(methoxy(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate (65 mg, 170.88 μmol) in toluene (2 mL) was added 4-(l -(piperidin-1 -yl)ethyl)aniline (69.82 mg, 341.75 ginol) at 20 °C. The mixture was then stirred at 100 °C for 12 h and concentrated to give a residue. The residue was diluted with MeOH (1 mL), and K₂CO₃ (20 mg) was added to the mixture. The mixture was then stirred at 20 °C for 1 h. The mixture was concentrated to give a second residue that was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm; 5 um; 15-45% CH₃CN/H₂O (0.1% TFA)) to give the product (8.86 mg, 7.65%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, CD₃CN) δ 12.08 (s, 1 H), 9.73-9.95 (m, 1 H), 8.71 (br s, 1 H),

7.53-7.63 (m, 3 H), 7.45-7.49 (m, 2 H), 7.23 (d, J=8.63 Hz, 2 H), 6.80-6.90 (m, 4 H), 5.64 (s,

1 H), 4.16-4.27 (m, 1 H), 3.51 (s, 3 H), 3.11-3.21 (m, 1 H), 2.96 (s, 3 H), 2.38-2.66 (m, 3 H), 1.66-1.81 (m, 6 H), 1.60 (d, J=7.00 Hz, 3 H). MS-ESI (m/z) calc’d for C₃₁H₃₅N₄O₃ [M+H]⁺: 511.6. Found. 511.2. Compound 36

Methyl (Z)-methyl(2-oxo-3-(phenyl((4-(piperidin-1-yl)phenyl)amino)methylene)indolin-5- yl)carbamate

Methyl (Z)-methyl(2-oxo-3-(phenyl((4-(piperidin-l- yl)phenyl)amino)methylene)indolin-5-yl)carbamate. To a solution of methyl (Z)-(1-acetyl-3- (methoxy(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate (100 mg, 262.89 μmol) in toluene (3 mL) was added 4-(1-piperidyl)aniline (92.67 mg, 525.77 μmol) at 20 °C. The mixture was then stirred at 100 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated to give a residue that was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm; 5 um; CH₃CN/H₂O (0.1% TFA)) to give the product (16.8 mg, 10.3 %) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (s, 1 H), 10.71 (s, 1 H), 7.53-7.61 (m, 3 H), 7.43-7.49 (m, 2 H), 6.72-7.04 (m, 6 H), 5.48 (s, 1 H), 3.47 (s, 3 H),

3.15 (br s, 4 H), 2.92 (s, 3 H), 1.63 (br d, J=1.13 Hz, 4 H), 1.53 (br d, J=3.38 Hz, 2 H). MS-ESI (m/z) calc’d for C₂₉H₃₁N₄O₃ [M+H]⁺: 483.2. Found. 483.2. Compound 37

Methyl (Z)-methyl(3-(((4-morpholinophenyl)amino)(phenyl)methylene)-2-oxoindolin-5- yl)carbamate

Methyl (Z)-methyl(3-(((4-morpholinophenyl)amino)(phenyl)methylene)-2-oxoindolin- 5-yl)carbamate. To a solution of methyl (Z)-(1-acetyl-3-(methoxy(phenyl)methylene)-2- oxoindolin-5-yl)(methyl)carbamate (100.00 mg, 262.89 μmol) in toluene (3 mL) was added 4- morpholinoaniline (93.71 mg, 525.77 μmol) at 20 °C. The mixture was stirred at 100 °C for 12 h. The reaction was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm; 5 um; 20-55% CH₃CN/H₂O (0.1% TFA)) to give the product (21.72 mg, 12.95%) as a yellow solid, TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1 H), 10.67 (s, 1 H), 7.50-7.59 (m, 3 H), 7.40-7.47 (m, 2 H), 6.72-6.82 (m, 6 H), 5.46 (s, 1 H), 3.68 (br s, 4 H), 3.46 (s, 3 H), 2.98-3.04 (m, 4 H),

2.91 (s, 3 H). MS-ESI (m/z) calc’d for C₂₈H₂₉N₄O₄ [M+H]⁺: 485.2. Found. 485.2. Compound 38

Methyl (Z)-(3-(((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)amino)(phenyl)methylene)-2- oxoindolin-5-yl)(methyl)carbamate

6-(4-Nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane. To a solution of l-fluoro-4- nitrobenzene (500 mg, 3.54 mmol) in CH₃CN (10 mL) were added DIEA (1.10 g, 8.50 mmol) and 2-oxa-6-azaspiro[3.3]heptane (351.28 mg, 3.54 mmol) at 20 °C. The mixture was then stirred at 80 °C for 12 h and a solid formed. The reaction mixture was filtered and the solid was washed with H₂O (2x) and dried to give the product (500 mg) as a yellow solid that was used without further purification. MS-ESI (m/z) calc’d for C₁₁H₁₃N₂O₃ [M+H]⁺: 221.0 Found. 221.1.

4-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)aniline. To a solution of 6-(4-nitrophenyl)-2- oxa-6-azaspiro[3.3]heptane (100 mg, 454.08 μmol) in THF (1 mL), EtOH (1 mL) and H₂O (0.3 mL) were added Fe (126.79 mg, 2.27 mmol) and NH₄CI (48.58 mg, 908.17 μmol) at 20 °C. The mixture was then stirred at 80 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the product (70 mg) as a yellow solid that was used without further purification. MS-ESI (m/z) calc’d for C₁₁H₁₅N₂O [M+H]⁺: 191.1 Found. 191.2.

Methyl (Z)-(3-(((4-(2-oxa-6-azaspiro[3.3]heptan-6- yl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate. To a solution of methyl (Z)-(1-acetyl-3-(methoxy(phenyl)methylene)-2-oxoindolin-5-yl)(methyl)carbamate (60 mg, 157.73 μmol) in toluene (1 mL) was added 4-(2-oxa-6-azaspiro[3.3]heptan-6- yl)aniline (60.01 mg, 315.46 μmol) at 20 °C. The mixture was then stirred at 90 °C for 12 h under an N₂ atmosphere. The reaction mixture was concentrated to give a residue that was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm; 5 um; 20-55% CH₃CN/H₂O (0.1 % TFA)) to give the product (4.04 mg, 2.68%, 3 steps) as a yellow solid, TFA salt. ¹ H NMR(400 MHz, DMSO-d₆) δ 11.84 (s, 1 H), 10.65 (s, 1 H), 7.46-7.57 (m, 3 H), 7.36- 7.43 (m, 2 H), 6.71-6.81 (m, 4 H), 6.22 (d, J=8.76 Hz, 2 H), 5.43 (s, 1 H), 4.66 (s, 4 H), 3.87 (s, 4 H), 3.48-3.49 (m, 3 H), 2.90 (s, 3 H). MS-ESI (m/z) calc’d for C₂₉H₂₉N₄O₄ [M+H]⁺: 497.2 Found. 497.2.

The following compounds were prepared according to procedures analogous to those disclosed above for Compounds 1-38, using appropriate starting materials. Compound 39

Methyl (Z)-methyl(3-(((2-methyl-4-morpholinophenyl)amino)(phenyl)methylene)-2- oxoindolin-5-yl)carbamate. ¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1 H), 10.64 (s, 1 H), 7.43-7.54 (m, 3 H), 7.30-7.43 (m, 2 H), 6.71-6.84 (m, 3 H), 6.61 (d, J=8.88 Hz, 1 H), 6.47

(dd, J=8.82, 2.69 Hz, 1 H), 5.45 (d, J=1.38 Hz, 1 H), 3.60-3.72 (m, 4 H), 3.45 (s, 3 H), 2.96- 3.08 (m, 4 H), 2.90 (s, 3 H), 2.24-2.33 (m, 3 H). MS-ESI (m/z) calc’d for C₂₉H₃₁N₄O₄ [M+H]⁺: 499.2. Found. 499.2. Compound 40

Methyl (Z)-methyl(2-oxo-3-(phenyl((4-(pyrro lidin- 1 - yl)phenyl)amino)methylene)indolin-5-yl)carbamate. ¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1 H), 10.63 (s, 1 H), 7.46-7.54 (m, 3 H), 7.36-7.43 (m, 2 H), 6.72-6.80 (m, 4 H), 6.31 (d, J=9.01 Hz, 2 H), 5.42 (d, J=1.38 Hz, 1 H), 3.45 (s, 3 H), 3.09-3.15 (m, 4 H), 2.90 (s, 3 H),

1.86-1.93 (m, 4 H). MS-ESI (m/z) calc’d for C₂₈H₂₉N₄O₃ [M+H]⁺: 469.2. Found. 469.3. Compound 41

(Z)-3-(((2-Methylpyridin-4-yl)amino)(phenyl)methylene)-5-(2-methylthiazol-5- yl)indolin-2-one. ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, 1 H), 11.15 (s, 1 H), 8.28 (d, J=6.88 Hz, 1 H), 7.79-7.85 (m, 1 H), 7.76 (t, J=7.38 Hz, 2 H), 7.65-7.71 (m, 2 H), 7.44 (s, 1 H), 7.36 (dd, J=8.00, 1.75 Hz, 1 H), 7.03 (d, J=2.00 Hz, 1 H), 6.93 (d, J=8.25 Hz, 1 H), 6.66 (dd, J=6.94, 2.44 Hz, 1 H), 6.04 (d, J=1.38 Hz, 1 H), 2.59 (s, 3 H), 2.44 (s, 3 H). MS-ESI (m/z) calc’d for C₂₅H₂₁N₄OS [M+H]⁺: 425.1. Found. 425.1.

Compound 42

(Z)-3-(((2-Chloropyridin-4-yl)amino)(phenyl)methylene)-5-(thiazol-5-yl)indolin-2- one. ¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1 H), 11.08 (s, 1 H), 8.91 (s, 1 H), 8.07 (d, J=5.75 Hz, 1 H), 7.71-7.82 (m, 4 H), 7.62-7.67 (m, 2 H), 7.37 (dd, J=8.07, 1.81 Hz, 1 H), 6.94 (d, J=8.13 Hz, 1 H), 6.71 (dd, J=5.69, 2.06 Hz, 1 H), 6.63 (d, J=2.00 Hz, 1 H), 6.00 (d, J=1.75 Hz, 1 H). MS-ESI (m/z) calc’d for C₂₃H₁₆CIN₄OS [M+H]⁺: 431.1. Found. 431.0.

Compound 43

Methyl (Z)-methyl(3-(((4-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3- yl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-5-yl)carbamate. ¹H NMR (400 MHz, DMSO-d₆) δ 11.78-11.97 (m, 1 H), 10.40 (s, 1 H), 7.53 (br s, 3 H), 7.44 (br d, J=3.34 Hz, 2 H), 6.88 (d, J=8.94 Hz, 2 H), 6.79-6.83 (m, 1 H), 6.73-6.78 (m, 1 H), 6.60 (br d, J=8.82 Hz, 2 H), 5.45-5.61 (m, 1 H), 4.28-4.47 (m, 2 H), 3.62-3.76 (m, 4 H), 3.48 (s, 3 H), 3.03 (br d, J=2.15 Hz, 1 H), 2.92 (s, 3 H), 2.47 (br s, 3 H), 1.95 (br d, J=10.61 Hz, 1 H). MS-ESI (m/z) calc’d for C₃₁H₃₂N₅O₃ [M+H]⁺: 510.3. Found. 510.1.

Compound 44

(Z)-5-(2-Oxopyrrolidin- 1 -yl)-3-(phenyl((4-(piperidin- 1 - ylmethyl)phenyl)amino)methylene)indolin-2-one. ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1 H) 10.75 (s, 1 H) 9.18 (br s, 1 H) 7.56-7.64 (m, 3 H) 7.48-7.54 (m, 2 H) 7.37 (dd, J=8.44, 2.06 Hz, 1 H) 7.25 (d, J=8.50 Hz, 2 H) 6.80-6.89 (m, 3 H) 5.89 (d, J=1.88 Hz, 1 H) 4.13 (br d, J=5.00 Hz, 2 H) 3.31 (t, J=7.00 Hz, 2 H) 3.23 (br d, J=11.88 Hz, 2 H) 2.72-2.84 (m, 2 H) 2.30-2.36 (m, 2 H) 1.91 (quin, J=7.50 Hz, 2 H) 1.78 (br d, J=14.01 Hz, 2 H) 1.50-1.69 (m, 3 H) 1.25-1.39 (m, 1 H). MS-ESI (m/z) calc’d for C₃₁H₃₃N₄O₂ [M+H]⁺: 493.3. Found. 493.2.

Compound 45

O-Methyl (Z)-methyl(3-(((2-methylpyridin-4-yl)amino)(phenyl)methylene)-2- oxoindolin-5-yl)carbamothioate. ¹H NMR (400 MHz, CD₃CN) δ 12.37 (br s, 1 H), 8.96 (br s, 1 H), 8.04 (d, J=6.75 Hz, 1 H), 7.63-7.78 (m, 3 H), 7.51-7.60 (m, 2 H), 6.87-7.01 (m, 2 H), 6.66 (d, J=1.88 Hz, 1 H), 6.48 (dd, J=6.82, 2.19 Hz, 1 H), 5.63-5.87 (m, 1 H), 3.55-4.13 (m, 3 H), 3.04-3.51 (m, 3 H), 2.42 (s, 3 H). MS-ESI (m/z) calc’d for C₂₄H₂₃N₄O₂S [M+H]⁺: 431.2. Found. 431.2. Example 2 Kinase Activity Assay

LRRK2 kinase activity was measured using a LanthaScreen™ Kinase Activity Assay from ThermoFisher Scientific. Recombinant wild type or G2019S-LRRK2 protein (Life Technologies, PR8604B or PV4881, respectively), was incubated with a fluorescein-labeled peptide substrate called LRRKtide that is based upon ezrin/radixin/moesin (ERM) (Life Technologies, PV4901) in the presence of ATP and serially diluted compound. After an incubation period of 1 h, the phosphotransferase activity was stopped and a terbium-labelled anti-pERM antibody (Life Technologies, PV4899) was added to detect the phosphorylation of LRRKtide by measuring the time resolved-Forster resonant energy transfer (TR-FRET) signal from the terbium label on the antibody to the fluorescein tag on LRRKtide, expressed as the 520nm/495nm emission ratio. Compound-dependent inhibition of the TR-FRET signal was used to generate a concentration-response curve for IC50 determination.

The assay was carried out under the following protocol conditions: 1 mM compound in DMSO was serially diluted 1 :3, 11 points in DMSO with a Biomek FX and 0.1 pL of the diluted compound was subsequently stamped into the assay plate (384-well format Lumitrac 200, Greiner, 781075) with an Echo Labcyte such that the final compound concentration in the assay was 10 pM to 169 pM. Subsequently, 5 pL of 2x kinase solution (2.9 nM final concentration) was added to the assay plate in assay buffer composed of 50 mM Tris pH 8.5 (Sigma, T6791), 5 mM MgCl₂ (Fluka, 63020), 1 mM EGTA (Sigma, E3889), 0.01% BRIJ-35 (Sigma, PI 254) and 2 mM DTT. The reaction was started by addition of 2x ATP/LRRKtide solution in assay buffer such that the final concentration was 400 nM LRRKtide and 25 pM ATP. After 60 min incubation at room temperature, the reaction was stopped by addition of 10 pL of 2x stop solution containing a final concentation of 2 nM anti-pERM antibody and 10 mM EDTA. After a 30 min incubation at RT, the TR-FRET signal was measured on a Wallac 2104 EnVision® multilabel reader at an excitation wavelength of 340 nm and reading emission at 520 nm and 495 nm. The ratio of the 520 nm and 495 nm emission was used to analyze the data.

The results of the LRRK2 kinase activity assay are shown below:

Claims

1. A compound of formula (I) : or a pharmaceutically acceptable salt thereof, wherein:

R^a1 R^{b 1} R^{c 1} R^d1 R^e1 R^f1 R^g1 R^h1 Rⁱ¹ R^j1 R^k1 R^l1 R^m1 R^a2 R^b2 R^C2 R^d2 R^e2 R^f2 R^g2, R^h2, Rⁱ², R^j2, R^k2, R^l2, R^m2, R^a3, R^b3, R^c3, R^d3, R^e3, R^f3, R^g3, R^h3, Rⁱ³, R^j3, and R^k3 are each independently selected from H, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 haloalkyl, aryl, and C_3-6 cycloalkyl; X¹ is CR^4a or N;

X² is CR^4b or N;

X³ is CR^4C or N; and

R^4a, R^4b, and R^4c are each independently selected from H, D, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, halo, C_1-4 haloalkyl, C_1-4 alkoxy, and C _1-4 haloalkoxy; wherein no more than two of X¹, X², and X³ are simultaneously N.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from phenyl and pyridinyl, which is substituted with 1 , 2, or 3 substituents independently selected from C_1-4 alkyl, halo, C_1-4 haloalkyl, and -(CR^aR^b)_m-G¹, wherein m is 0 or 1, R^a and R^b are each independently hydrogen or methyl, and G¹ is a C_3-6 cycloalkyl, a 5- or 6-membered monocyclic heterocyclyl having one or two heteroatoms independently selected from N and O, a 7-membered bicyclic heterocyclyl having one or two heteroatoms independently selected from N and O, or dialkylamino, wherein G¹ is unsubstituted or substituted with 1 substituent selected from C_1-4 alkyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from phenyl and pyridinyl, which is substituted with 1 or 2 substituents independently selected from C_1-4 alkyl, halo, C_1-4 haloalkyl, and -(CR^aR^b)_m-G¹, wherein m is 1, R^a and R^b are each hydrogen, and G¹ is a C_3-6 cycloalkyl, a 6-membered monocyclic heterocyclyl having one N atom, or dialkylamino.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from:

5. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R² is aryl.

6. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R² is unsubstituted phenyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from: 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, S, and O; 5-membered monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, S, and O; -O-(C_3-6 cycloalkyl); -NR^a3C(Q)OR^b3; -NR^c3C(O)N(R^d3)(R^e3), -C(O)N(R^f3)(R^g3), -NR^h3CH₂C(O)ORⁱ³, - NR^j3C(O)R^k3, and cyano, wherein Q is O or S, and wherein the heterocyclyl and cycloalkyl are unsubstituted or substituted with 1 or 2 substituents independently selected from methyl and oxo, and wherein R^a3, R^b3, R^c3, R^d3, R^e3, R^f3, R^g3, R^h3, Rⁱ³, R^j3, and R^k3 are each independently selected from hydrogen, C _1-4 alkyl, and C_3-6 cycloalkyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R³ is -NR^a3C(O)OR^b3, wherein R^a3 and R^b3 are each independently C_1-4 alkyl (e.g., methyl, ethyl, isopropyl) or C_3-6 cycloalkyl.

9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from:

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein: X¹ is CR^4a; X² is CR^4b; X³ is CR^4c; and R^4a, R^4b, and R^4c are each H.

11. The compound of claim 1, wherein the compound is selected from:

and pharmaceutically acceptable salts thereof.

12. A pharmaceutical composition comprising a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. A method of inhibiting LRRK2 in a sample, comprising contacting the sample with an effective amount of a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof.

14. A method of treating Parkinson's disease, cancer, leprosy, Crohn's disease, Alzheimer’s disease, other neurodegenerative diseases, or an immune-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof.

15. The method of claim 16, wherein the disorder is Parkinson's disease.

16. A compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, for use as a medicament.

17. A compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, for use in treatment of Parkinson's disease, cancer, leprosy, Crohn's disease, Alzheimer’s disease, other neurodegenerative diseases, or an immune-mediated disorder.

18. The compound for use of claim 17, wherein the disorder is Parkinson’s disease.