CN120077051A

CN120077051A - KRAS inhibitors

Info

Publication number: CN120077051A
Application number: CN202380073715.7A
Authority: CN
Inventors: 李超; 陈建勇; 叶高洁; 黎流根; 胡文亮; 吴成喆
Original assignee: Yasheng Pharmaceutical Group Hong Kong Co ltd; Suzhou Yasheng Pharmaceutical Co ltd
Current assignee: Yasheng Pharmaceutical Group Hong Kong Co ltd; Suzhou Yasheng Pharmaceutical Co ltd
Priority date: 2022-10-21
Filing date: 2023-10-20
Publication date: 2025-05-30
Also published as: WO2024083246A1

Abstract

本公开涉及抑制KRAS的化合物。特别地，本公开涉及抑制KRAS G12D或KRAS G12V的活性的化合物、包含这些化合物的药物组合物及其使用方法。The present disclosure relates to compounds that inhibit KRAS. In particular, the present disclosure relates to compounds that inhibit the activity of KRAS G12D or KRAS G12V, pharmaceutical compositions containing these compounds, and methods of use thereof.

Description

KRAS inhibitors

Technical Field

The present disclosure relates to KRAS inhibiting compounds. In particular, the present disclosure relates to compounds that inhibit the activity of KRAS G12D or KRAS G12V, pharmaceutical compositions comprising these compounds, and methods of use thereof.

Background

RAS represents a group of monomeric globulins of 189 amino acids (21 kDa molecular mass) that are associated with the plasma membrane and bind to GDP or GTP. The RAS acts as a molecular switch. When the RAS contains bound GDP, it is in a resting or closed position and is "inactive". In response to exposure of the cells to certain growth-promoting stimuli, the RAS is induced to exchange its bound GDP for GTP. When bound to GTP, the RAS is "turned on" and is able to interact with and activate other proteins (its "downstream targets"). The inherent ability of the RAS protein itself to hydrolyze GTP back to GDP, turning itself into an off state, is very low. Turning off the RAS requires exogenous proteins called Gtpase Activating Proteins (GAPs), which interact with the RAS and greatly accelerate the conversion of GTP to GDP. Any mutation in the RAS that affects its ability to interact with GAP or convert GTP back to GDP will result in an extended activation time of the protein and thus an extended time for a signal to be transmitted to the cell that signals continued growth and division of the cell. Since these signals lead to cell growth and division, overactivated RAS signaling can ultimately lead to cancer. The most important members of the RAS are HRAS, KRAS and NRAS.

Structurally, RAS proteins contain a G domain responsible for the enzymatic activity of the RAS, i.e., guanine nucleotide binding and hydrolysis (gtpase reaction). It also contains a C-terminal extension called CAAX box, which can be post-translationally modified and is responsible for targeting proteins to the membrane. The G domain is about 21kDa to 25kDa in size and contains a phosphate binding ring (P-ring). The P-loop represents the pocket for nucleotide binding in the protein and this is a rigid part of the domain with conserved amino acid residues (glycine 12, threonine 26 and lysine 16) necessary for nucleotide binding and hydrolysis. The G domain also contains a switch I region (residues 30-40) and a switch II region (residues 60-76), and both regions are dynamic parts of the protein, often referred to as "spring-loaded" mechanisms, due to their ability to switch between a resting state and a loaded state. The key interactions are hydrogen bonds formed by threonine-35 and glycine-60 with the gamma-phosphate of GTP, which maintain the switch 1 and switch 2 regions, respectively, in the activated conformation. After GTP hydrolysis and phosphate release, the two regions relax into an unactivated GDP conformation.

Mutations in the KRAS gene are common events in human tumorigenesis. Indeed, mutations in KRAS are prevalent in some of the most fatal types of cancer, pancreatic cancer (95%), colorectal cancer (45%) and lung cancer (35%). The most common KRAS mutations are found at residues G12 and G13 and at residue Q61 in the P loop.

Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRAS primary amino acid sequence comprise about 40% of these KRAS-driven mutations in lung adenocarcinoma. KRAS G12D mutations are present in 25.0% of pancreatic ductal adenocarcinoma patients, 13.3% of colorectal cancer patients, 10.1% of rectal cancer patients, 4.1% of non-small cell lung cancer patients, and 1.7% of small cell lung cancer patients. (see, e.g., the AACR Project GENIE Consortium (2017), cancer Discovery, volume 7, 8: pages 818-831, dataset version 4).

Compounds that inhibit KRAS activity are still highly desirable and under investigation, including compounds that disrupt effectors such as guanine nucleotide exchange factors (see, e.g., sun et al (2012), AGNEW CHEM INT ED ENGL, volume 51, 25: pages 6140-6143, doi:10.1002/anie 201201358) and recent advances in covalently targeting the allosteric pocket of KRAS G12C (see, e.g., ostrem et al (2013), nature, volume 503, pages 548-551 and Fell et al (2018), ACS med. Chem., lett, volume 9, pages 1230-1234). Clearly, there is still a continuing need for attention and effort to develop inhibitors of KRAS, in particular inhibitors that activate KRAS mutants (especially KRAS G12D).

Thus, there is a need to develop new KRAS (especially KRAS G12D) inhibitors that exhibit sufficient efficacy for the treatment of KRAS G12D-mediated cancers.

Disclosure of Invention

In one aspect, the present disclosure provides compounds represented by any one of formulas I, II and III below, and pharmaceutically acceptable salts and solvates (e.g., hydrates) thereof, which are collectively referred to as "the presently disclosed compounds". The compounds of the present disclosure are KRAS (especially KRAS G12D) inhibitors and thus are useful in the treatment or prevention of diseases or disorders, such as KRAS G12D-associated cancers, wherein inhibition of KRAS G12D provides a beneficial effect.

In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

In another aspect, the present disclosure provides methods for inhibiting KRAS G12D or KRAS G12V activity in a cell, comprising contacting a cell in which inhibition of KRAS G12D or KRAS G12V activity is desired with an effective amount of a compound of the present disclosure or a pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure provides methods for treating KRAS G12D or G12V-related cancers comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition of the present disclosure. Preferably, the cancer is non-small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

In another aspect, the present disclosure provides a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with KRAS G12D or KRAS G12V mutation (e.g., KRAS G12D or G12V-associated cancer), and (b) administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure provides compounds of the present disclosure for inhibiting KRAS G12D or KRAS G12V activity in a cell.

In another aspect, the present disclosure provides compounds of the present disclosure for use in the treatment of KRAS G12D or G12V-related cancers.

In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for inhibiting KRAS G12D or KRAS G12V activity in a cell.

In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for the treatment of KRAS G12D or G12V-related cancer.

In another aspect, the present disclosure provides kits comprising a compound of the present disclosure and instructions for administering the compound of the present disclosure to a subject (e.g., patient) having a cancer (e.g., KRAS G12D or G12V-related cancer).

Additional embodiments and advantages of the disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

Detailed Description

Unless defined otherwise below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including those obvious alterations to techniques or equivalents thereof by those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present disclosure.

I. Definition of the definition

As used herein, the terms "comprising," "including," "having," "containing," or "containing" and other variations thereof are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

The term "KRAS" as used herein is collectively referred to as wild-type KRAS genes and proteins and mutant forms thereof. The most common mutations in the KRAS gene are mainly at codons 12, 13 or 61. KRAS mutations also occur at codons 63, 117, 119 and 146. Liu et al Acta Pharmaceutica Sinica B, volume 9, pages 871-879 (2019).

The term "KRAS inhibitor" as used herein refers to a compound that inhibits wild-type KRAS and/or mutant KRAS and includes electrophilic compounds that form irreversible covalent bonds with KRAS proteins.

As used herein, "KRAS G12D" refers to a mutant form of a mammalian KRAS protein that contains an amino acid substitution of aspartic acid for glycine at amino acid 12. The allocation of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Gly12Asp.

As used herein, "KRAS G12D inhibitor" refers to a compound of the present disclosure represented by the formula as described herein. These compounds are capable of down-regulating or inhibiting all or a portion of the enzymatic activity of KRAS G12D.

As used herein, "KRAS G12D-related disease or disorder" refers to a disease or disorder having or associated with or mediated by a KRAS G12D mutation. A non-limiting example of a KRAS G12D-related disease or disorder is KRAS G12D-related cancer.

As used herein, the terms "subject," "individual," or "patient" are used interchangeably to refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a KRAS G12D mutation. In some embodiments, the subject has a tumor positive for KRAS G12D mutation. The subject may be a subject suffering from a tumor positive for the KRAS G12D mutation. The subject may be a subject whose tumor has a KRAS G12D mutation. In some embodiments, the subject is suspected of having a KRAS G12D gene-related cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with a KRAS G12D mutation.

As used herein, the term "treating" refers to eliminating, alleviating or ameliorating a disease or condition and/or symptoms associated with the disease and/or condition. Although this is not precluded, the treatment of a disease or condition need not completely eliminate the disease, condition, or symptoms associated with the disease, condition. The term "treatment" and synonyms encompass the administration of a therapeutically effective amount of a compound of the present disclosure to a subject in need of such treatment. Treatment may be directed to symptoms, for example, to suppress symptoms. The treatment may be effective in a short period of time, for mid-term treatment, or may be a long-term treatment, for example in the context of maintenance therapy.

As used herein, the term "preventing" refers to a method of preventing the onset of a disease or condition and/or its attendant symptoms or preventing a subject from suffering from a disease. As used herein, "preventing" also includes delaying the onset of the disease and/or its accompanying symptoms and reducing the risk of the subject suffering from the disease. The term "preventing" may include "prophylactic treatment," which refers to reducing the likelihood of a subject not suffering from, but at risk of, or susceptible to, a disease or condition again or susceptible to recurrence of the disease or condition, or previously controlled disease recurrence.

As used herein, the term "therapeutically effective amount" or "effective dose" refers to an amount of an active ingredient that, when administered by the methods of the present disclosure, is sufficient to effectively deliver the active ingredient for treating a condition or disease of interest to a subject in need thereof. In the case of cancer or other proliferative disorders, a therapeutically effective amount of the agent may reduce (i.e., delay or terminate to some extent) undesired cell proliferation, reduce the number of cancer cells, reduce tumor size, inhibit (i.e., delay or terminate to some extent) infiltration of cancer cells into peripheral organs, inhibit (i.e., delay or terminate to some extent) tumor metastasis, inhibit to some extent tumor growth, and/or alleviate to some extent one or more symptoms associated with cancer. The administered compound or composition may be cytostatic and/or cytotoxic to the extent that it prevents the growth of and/or kills existing cancer cells.

The term "halo" or "halogen" as used herein, alone or as part of another group, refers to-Cl, -F, -Br or-I.

The term "cyano" when used herein alone or as part of another group refers to-CN.

The term "hydroxy" as used herein alone or as part of another group refers to-OH.

The term "alkyl" as used herein alone or as part of another group refers to a straight or branched chain aliphatic hydrocarbon containing one to twelve carbon atoms (i.e., a C ₁-C₁₂ alkyl group) or a straight or branched chain aliphatic hydrocarbon containing the specified number of carbon atoms (e.g., a C ₁ alkyl group such as methyl, a C ₂ alkyl group such as ethyl, etc.). In one embodiment, the alkyl is a C ₁-C₁₀ alkyl. In another embodiment, the alkyl is a C ₁-C₆ alkyl. In another embodiment, the alkyl is a C ₁-C₄ alkyl. In another embodiment, the alkyl is a C ₁-C₃ alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C ₁-C₁₂ alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl and decyl. In another embodiment, one or more of the hydrogen atoms of the alkyl group are replaced with deuterium atoms, i.e., the alkyl group is labeled with a deuterium isotope. A non-limiting exemplary deuterated alkyl is-CD ₃. In another embodiment, none of the hydrogen atoms of the alkyl group are replaced with deuterium atoms, i.e., the alkyl group is labeled with a deuterium isotope.

The term "alkylene" means a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. For example, the number of the cells to be processed, methylene (i.e., -CH ₂ -), ethylene (i.e., -CF ₂-CF₂ -or-CH (CH ₃) -) and propylene (i.e., -CH ₂-CH₂-CH₂-、-CH(-CH₂-CH₃) -or-CH ₂-CH(CH₃) -).

The term "haloalkyl" as used herein alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine and/or iodine atoms. In one embodiment, the alkyl group is substituted with one, two or three fluorine and/or chlorine atoms. In another embodiment, the alkyl group is substituted with one, two or three fluorine atoms. In another embodiment, the alkyl is a C ₁-C₆ alkyl. In another embodiment, the alkyl is a C ₁-C₄ alkyl. In another embodiment, the alkyl is a C ₁ or C ₂ or C ₃ alkyl. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1-difluoroethyl 2, 2-difluoroethyl, 2-trifluoroethyl, 3-trifluoropropyl 4, 4-trifluorobutyl and trichloromethyl.

As used herein, the term "hydroxyalkyl" or "(hydroxy) alkyl" alone or as part of another group refers to an alkyl group substituted with one, two or three hydroxy groups. In one embodiment, the alkyl is a C ₁-C₆ alkyl. In another embodiment, the alkyl is a C ₁-C₄ alkyl. In another embodiment, the alkyl is a C ₁ or C ₂ alkyl. In another embodiment, the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., is substituted with two hydroxyl groups. Non-limiting exemplary (hydroxy) alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl, such as 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyl, 2-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl and 1, 3-dihydroxyprop-2-yl.

The term "alkoxy" as used herein alone or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl is a C ₁-C₆ alkyl, and the resulting alkoxy is referred to as "C ₁-C₆ alkoxy". In another embodiment, the alkyl is a C ₁-C₄ alkyl, and the resulting alkoxy is referred to as a C ₁-C₄ alkoxy. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and t-butoxy.

The term "carbocycle" as used herein alone or as part of another group refers to saturated and partially unsaturated, for example, monocyclic, bicyclic or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms containing one or two double bonds, i.e., C _3-12 carbocycles. For example, a C ₅ carbocycle or a C ₆ carbocycle. When the aliphatic hydrocarbon is saturated, the carbocycle may also be referred to as cycloalkyl, e.g., C ₃ cycloalkyl such as cyclopropyl, C ₄ cycloalkyl such as cyclobutyl, and the like. In one embodiment, the carbocycle is cycloalkyl. In one embodiment, the cycloalkyl is bicyclic, i.e., it has two rings. In another embodiment, the cycloalkyl is monocyclic, i.e., it has one ring. In another embodiment, the cycloalkyl is a C _3-8 cycloalkyl. In another embodiment, cycloalkyl is C _3-6 cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, cycloalkyl is C ₅ cycloalkyl, i.e., cyclopentyl. In another embodiment, the cycloalkyl is a C ₆ cycloalkyl, i.e., cyclohexyl. Non-limiting exemplary C _3-12 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro [3.3] heptane.

The term "heterocyclyl" as used herein alone or as part of another group refers to saturated and partially unsaturated, e.g., a monocyclic, bicyclic or tricyclic group containing from three to fourteen ring members containing one or two double bonds, i.e., a 3-14 membered heterocyclyl containing one, two, three or four heteroatoms, e.g., 5-, 6-, 7-, 8-, 9-, 10-membered heterocyclyl. Each heteroatom is independently oxygen, sulfur or nitrogen. Each sulfur atom is independently oxidized to give a sulfoxide (i.e., S (=o)) or a sulfone (i.e., S (=o) ₂).

The term heterocyclyl includes groups in which one or more-CH ₂ -groups are replaced by one or more-C (=o) -groups, including cyclic ureido groups (such as imidazolidin-2-one), cyclic amide groups (such as pyrrolidin-2-one or piperidin-2-one) and cyclic carbamate groups (such as oxazolidin-2-one).

The term heterocyclyl also includes groups having a fused optionally substituted aryl or optionally substituted heteroaryl group such as indoline, indolin-2-one, 2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine, 2,3,4, 5-tetrahydro-1H-benzo [ d ] aza or 1,3,4, 5-tetrahydro-2H-benzo [ d ] aza-2-one.

In one embodiment, the heterocyclyl is a 4-8 membered cyclic group containing one ring and one or two oxygen atoms (e.g. tetrahydrofuran or tetrahydropyran), a 4-8 membered cyclic group containing one ring and one or two nitrogen atoms (e.g. pyrrolidine, piperidine or piperazine) or a 4-8 membered cyclic group containing one ring and one oxygen atom and one nitrogen atom (e.g. morpholine), and optionally one-CH ₂ -group is replaced by one-C (=o) -group, e.g. pyrrolidin-2-one or piperazin-2-one. In another embodiment, the heterocyclyl is a 5-8 membered cyclic group containing one ring and one or two nitrogen atoms, and optionally one-CH ₂ -group is replaced by one-C (=o) -group. In another embodiment, the heterocyclyl is a 5 or 6 membered cyclic group containing one ring and one or two nitrogen atoms, and optionally one-CH ₂ -group is replaced by one-C (=o) -group. In another embodiment, the heterocyclyl is an 8-12 membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclic ring may be attached to the remainder of the molecule via any available carbon or nitrogen atom. Non-limiting exemplary heterocyclic groups include:

The term "aryl" as used herein alone or as part of another group refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C ₆-C₁₄ aryl, C ₉-C₁₀ aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

The term "heteroaryl" as used herein alone or as part of another group refers to mono-and bi-cyclic aromatic ring systems having five to 14 fourteen ring members, i.e., 5-14 membered heteroaryl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, which contain one, two, three or four heteroatoms. Each heteroatom is independently oxygen, sulfur or nitrogen. In one embodiment, the heteroaryl group has three heteroatoms. In another embodiment, the heteroaryl group has two heteroatoms. In another embodiment, the heteroaryl group has one heteroatom. In another embodiment, the heteroaryl is a 5-10 membered heteroaryl. In another embodiment, the heteroaryl group has 5 ring atoms, such as thienyl, which is a 5 membered heteroaryl group having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl group has 6 ring atoms, such as pyridyl, which is a 6 membered heteroaryl group having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo [ b ] thienyl, naphtho [2,3-b ] thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuryl, benzoxazolyl, chromene, xanthenyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indazolyl, purinyl, isoquinolyl, quinolinyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4 aH-carbazolyl, β -carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl group is selected from thienyl (e.g., thiophen-2-yl and thiophen-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl and oxazolyl), isoxazolyl (e-4-oxazolyl) and isoxazolyl). The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is a pyridinyl N-oxide.

The term "(cycloalkyl) alkyl" as used herein alone or as part of another group refers to an alkyl group substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, the cycloalkyl is an optionally substituted C ₃-C₆ cycloalkyl. In another embodiment, the alkyl is a C ₁-C₆ alkyl. In another embodiment, the alkyl is a C ₁-C₄ alkyl. In another embodiment, the alkyl is a C ₁ or C ₂ alkyl. In another embodiment, the alkyl group is substituted with an optionally substituted cycloalkyl group. In another embodiment, the alkyl group is substituted with two optionally substituted cycloalkyl groups. Non-limiting exemplary (cycloalkyl) alkyl groups include:

The term "carboxy" when used alone or as part of another group refers to a group of formula-C (=o) OH.

The term "(heterocyclyl) alkyl" as used herein alone or as part of another group refers to an alkyl group substituted with one, two or three optionally substituted heterocyclyl groups. In one embodiment, the alkyl group is substituted with an optionally substituted 5-8 membered heterocyclyl. In another embodiment, the alkyl is a C ₁-C₆ alkyl. In another embodiment, the alkyl is a C ₁-C₄ alkyl. The heterocyclic group may be attached to the alkyl group through a carbon or nitrogen atom. Non-limiting exemplary (heterocyclic) alkyl groups include:

The term "(heteroaryl) alkyl" as used herein alone or as part of another group refers to an alkyl group substituted with one or two optionally substituted heteroaryl groups. In one embodiment, the alkyl group is substituted with an optionally substituted 5-14 membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-14 membered heteroaryl groups. In another embodiment, the alkyl group is substituted with an optionally substituted 5-9 membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-9 membered heteroaryl groups. In another embodiment, the alkyl group is substituted with an optionally substituted 5-or 6-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-or 6-membered heteroaryl groups. In one embodiment, the alkyl is a C ₁-C₆ alkyl. In another embodiment, the alkyl is a C ₁-C₄ alkyl. In another embodiment, the alkyl is a C ₁ or C ₂ alkyl. Non-limiting exemplary (heteroaryl) alkyl groups include:

The term "aralkyl" or "(aryl) alkyl" as used herein alone or as part of another group refers to an alkyl group substituted with one, two or three optionally substituted aryl groups. In one embodiment, the alkyl group is substituted with an optionally substituted aryl group. In another embodiment, the alkyl group is substituted with two optionally substituted aryl groups. In one embodiment, the aryl is optionally substituted phenyl or optionally substituted naphthyl. In another embodiment, the aryl group is an optionally substituted phenyl group. In one embodiment, the alkyl is a C ₁-C₆ alkyl. In another embodiment, the alkyl is a C ₁-C₄ alkyl. In another embodiment, the alkyl is a C ₁ or C ₂ alkyl. Non-limiting exemplary (aryl) alkyl groups include benzyl, phenethyl, -CHPh ₂, and-CH (4-F-Ph) ₂.

The term "amino" used alone or as part of another group refers to a group of formula-NR ^55aR^55b wherein R ^55a and R ^55b are independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy) alkyl, (alkoxy) alkyl, (amino) alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, (aryl) alkyl, (cycloalkyl) alkyl, (heterocyclyl) alkyl or (heteroaryl) alkyl.

In one embodiment, the amino group is-NH ₂.

The present disclosure encompasses any of the compounds of the present disclosure that are isotopically-labeled (i.e., radiolabeled) by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ² H (or deuterium (D))、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and ³⁶ Cl, e.g., ³H、¹¹ C and ¹⁴ C, respectively; in one embodiment, a compound is provided wherein substantially all atoms at a position within the compounds of the present disclosure are replaced with atoms having different atomic masses or mass numbers; in another embodiment, a compound is provided wherein substantially all atoms at a position within the compounds of the present disclosure are replaced with deuterium atoms, in another embodiment, a compound is provided wherein a portion of the atoms at a position within the compounds of the present disclosure are replaced, i.e., a position of the compounds of the present disclosure is enriched with atoms having a different atomic mass or mass number, there is provided a compound wherein none of the atoms of the compounds of the present disclosure are replaced with atoms having a different atomic mass or mass number.

The compounds of the present disclosure contain one or more asymmetric centers and thus can produce enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms, and mixtures thereof. In view of the present disclosure, individual enantiomers may be separated according to methods known in the art. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both geometric isomers of E and Z unless specified otherwise. All tautomers are also encompassed in the present disclosure.

As used herein, the term "stereoisomer" is a generic term for all isomers of a single molecule that differ only in the spatial orientation of their atoms. Stereoisomers include enantiomers and isomers (diastereomers) of compounds having more than one chiral center and which are not mirror images of each other.

The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

The terms "enantiomer" and "enantiomer" refer to a molecule that does not mirror and thus is optically active, wherein the enantiomer rotates the plane of polarized light in one direction and the mirror compound rotates the plane of polarized light in the opposite direction.

The term "racemate" refers to a mixture of equal parts of enantiomers, and the mixture is not optically active. In one embodiment, the compounds of the present disclosure are racemic.

The term "absolute configuration" refers to the spatial arrangement of atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

The stereochemical terms and conventions used in the specification are consistent with those described in Pure & appl. Chem, volume 68: page 2193 (1996), unless otherwise indicated.

The term "enantiomeric excess" or "ee" refers to a measure of the amount of one enantiomer present as compared to another. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |r-s| 100, where R and S are the corresponding mole fraction or weight fraction of the enantiomer in the mixture, such that r+s=1. In the case of knowing the optical rotation of a chiral material, the percent enantiomeric excess is defined as ([ α ] _obs/[α]_max) ×100, where [ α ] _obs is the optical rotation of the mixture of enantiomers and [ α ] _max is the optical rotation of the pure enantiomer. The enantiomeric excess can be determined using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or optical rotation determination.

As used herein, the term "about" includes the referenced number ± 10%. Thus, "about 10" means 9 to 11.

II compounds

In one aspect, the present disclosure provides a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof,

Wherein:

R ₁ represents C ₃-C₆ cycloalkyl or a 5-6 membered heterocyclyl or heteroaryl group containing 1,2 or 3N atoms, and R ₂ represents H, C ₁-C₆ alkyl or deuterated C ₁-C₆ alkyl, wherein C ₃-C₆ cycloalkyl or 5-6 membered heterocyclyl or heteroaryl group is optionally substituted by one or more of C ₁-C₄ alkyl, amino, halogen or OH, or

R ₁ and R ₂ together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring is optionally substituted with one or more of C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, amino, OH, CN, halogen or-C ₁-C₆ alkyl-CN;

l is selected from-O-, -S-and-N (R ₆) -, or L is a bond;

R ₆ is selected from hydrogen, C ₁-C₆ alkyl, and C ₁-C₆ haloalkyl;

A and Q are independently selected from = C (R ₇) -and = N-;

R ₇ is selected from hydrogen, CN, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl and C ₃-C₆ cycloalkyl;

R ₃ is- (CH ₂)_n) heterocycle, wherein the heterocycle is an optionally substituted 7-12 membered heterocycle comprising at least two rings bridged to each other, and n is 0, 1,2 or 3;

R ₄ is selected from the group consisting of C ₆-C₁₀ aryl, C ₆-C₁₀ heteroaryl, C ₆-C₁₀ heterocycle, and C ₃-C₆ cycloalkyl, wherein aryl, heteroaryl, heterocycle, and cycloalkyl are optionally substituted with one or more R ₈;

Wherein each R ₈, which may be the same or different, is independently selected from the group consisting of C ₁-C₆ alkyl, -S-C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, -C ₁-C₆ alkyl- (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl, and-N (C ₁-C₆ alkyl) ₂,

R ₅ is selected from the group consisting of C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, and halogen.

In one aspect, the present disclosure provides a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof,

Wherein:

R ₁ and R ₂ together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring is optionally substituted with one or more of C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, amino, OH, CN, halogen or-C ₁-C₆ alkylene-CN;

l is selected from-O-, -S-and-N (R ₆) -, or L is a bond;

R ₆ is selected from hydrogen, C ₁-C₆ alkyl, and C ₁-C₆ haloalkyl;

A and Q are independently selected from = C (R ₇) -and = N-;

Wherein each R ₈, which may be the same or different, is independently selected from the group consisting of C ₁-C₆ alkyl, -S-C ₁-C₆ alkyl, O-C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, -C ₁-C₆ alkyl- (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl, and-N (C ₁-C₆ alkyl) ₂,

In some embodiments, R ₁ and R ₂ together with the nitrogen atom to which they are attached form a 5-8 membered nitrogen containing heterocycle.

In some embodiments, R ₁ is cyclopropyl optionally substituted with one or more of C ₁-C₄ alkyl, amino, halogen, or OH.

In some embodiments, R ₁ and R ₂ together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle optionally substituted with one or more Rb groups as follows:

Wherein the method comprises the steps of Representing a single bond or a double bond, whenWhen a single bond is used, U represents O, NH or CH ₂, and whenIn the case of double bonds, U represents N or CH;

t is 0, 1, 2 or 3;

Each Rb may be the same or different and is independently selected from H, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, -C ₁-C₆ alkyl-CN, amino, OH, CN, halogen;

Or two R _b on the same carbon atom together with the carbon atom to which they are attached form c=ch ₂、C＝CH-C₁-C₆ alkyl, c= O, C ₃-C₆ haloalkyl or C ₃-C₆ heterocycle, wherein C ₃-C₆ haloalkyl or C ₃-C₆ heterocycle is optionally substituted with one or more of C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, amino, OH, CN and halogen;

Or two R _b on different carbon atoms are linked together to form a- (CH ₂)_s-(CH＝CH)_p -linker wherein s is 0, 1, 2 or 3;p is 0, 1, 2 or 3.

Wherein U represents O, NH or CH ₂;

t is 0, 1, 2 or 3;

In some embodiments, the nitrogen-containing heterocycle is

Wherein R ^2a、R^2b、R^2c and R ^2d independently represent H, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, -C ₁-C₆ alkylene-CN, amino, OH, CN, halogen, or any of R ^2a、R^2b、R^2c and R ^2d are joined together to form a- (CH ₂)_s-(CH＝CH)_p -linker wherein s is 0, 1,2 or 3;p is 0, 1,2 or 3.

In some embodiments, the nitrogen-containing heterocyclyl is selected from:

Represents a single bond or a double bond,

Wherein the nitrogen-containing heterocyclyl is optionally substituted with one or more of C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, amino, OH, CN, halogen or-C ₁-C₆ alkylene-CN.

In some embodiments, the nitrogen-containing heterocyclyl is selected from:

Represents a single bond or a double bond,

In some embodiments, the nitrogen-containing heterocyclyl is selected from:

Represents a single bond or a double bond,

In some embodiments, the nitrogen-containing heterocyclyl is selected from:

represents a single bond or a double bond.

Wherein the heterocyclyl is optionally substituted with one or more of C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, amino, OH, CN, halogen or-C ₁-C₆ alkylene-CN.

In some embodiments, the nitrogen-containing heterocyclyl is selected from:

represents a single bond or a double bond.

In some embodiments, R ₃ is selected from:

Wherein R ₃ is optionally substituted with one or more R _a, each R _a may be the same or different and is independently selected from C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, -C ₁-C₆ alkyl- (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl, -N (C ₁-C₆ alkyl) ₂、-CH₂O-CO-N(C₁-C₆ alkyl) ₂ and-CH ₂NH-CO-N(C₁-C₆ alkyl) ₂, or two R _a on the same carbon atom form C=CH ₂、C＝CH-C₁-C₆ alkyl or C=O.

In some embodiments, R ₃ is selected from:

Wherein each Ra, which may be the same or different, independently represents C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, -C ₁-C₆ alkyl- (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl, -N (C ₁-C₆ alkyl) ₂、-CH₂O-CO-N(C₁-C₆ alkyl) ₂ and-CH ₂NH-CO-N(C₁-C₆ alkyl) ₂, or two R _a on the same carbon atom form C=CH ₂、C＝CHF、C＝CF₂、C＝CH-C₁-C₆ alkyl, C=o, cyclopropyl or cyclobutyl, or two R _a on adjacent carbon atoms together with the carbon atom to which they are attached form a group optionally substituted by C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, cyclopropyl or cyclobutyl substituted by one or more of amino, OH, CN and halogen, and n is 0, 1, 2 or 3.

In some embodiments, R ₃ is selected from:

In some embodiments, R ₅ is F.

In some embodiments, both a and Q are =n-.

In some embodiments, the nitrogen-containing heterocycle is

Wherein R ^2a、R^2b、R^2c and R ^2d independently represent H, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, -C ₁-C₆ alkylene-CN, amino, OH, CN, halogen, or any of R ^2a、R^2b、R^2c and R ^2d are joined together to form a- (CH ₂)_S-(CH＝CH)_P -linker wherein s is 0,1,2 or 3;p is 0,1,2 or 3.

In some embodiments, the nitrogen-containing heterocyclyl is selected from:

Represents a single bond or a double bond,

In some embodiments, the nitrogen-containing heterocyclyl is selected from:

represents a single bond or a double bond.

In some embodiments, R ₃ is selected from:

Wherein each Ra, which may be the same or different, independently represents C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, -C ₁-C₆ alkyl- (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl, -N (C ₁-C₆ alkyl) ₂、-CH₂O-CO-N(C₁-C₆ alkyl) ₂ and-CH ₂NH-CO-N(C₁-C₆ alkyl) ₂, or two R _a on the same carbon atom form C=CH ₂、C＝CH-C₁-C₆ alkyl, C=o, cyclopropyl or cyclobutyl, or two R _a on adjacent carbon atoms together with the carbon atom to which they are attached form a group optionally substituted by C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, cyclopropyl or cyclobutyl substituted by one or more of amino, OH, CN and halogen, and n is 0, 1, 2 or 3.

In some embodiments, R ₃ is selected from:

Wherein R ₃ is optionally substituted with one or more R _a, each R _a may be the same or different and is independently selected from C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, -C ₁-C₆ alkyl- (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl, -N (C ₁-C₆ alkyl) ₂、-CH₂O-CO-N(C₁-C₆ alkyl) ₂ and-CH ₂NH-CO-N(C₁-C₆ alkyl) ₂, or two R _a on the same carbon atom form C=CH ₂、C＝CH-C₁-C₆ alkyl, C=O, cyclopropyl or cyclobutyl.

In some embodiments, R ₄ is selected from:

Wherein M is selected from the group consisting of = C (R ₇) -and = N-, and R ₇ is selected from the group consisting of hydrogen, CN, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, and C ₃-C₆ cycloalkyl;

Each R ₈ may be the same or different and is independently selected from C ₁-C₆ alkyl, -S-C ₁-C₆ alkyl, O-C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, Halogen, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, -C ₁-C₆ alkyl (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl and-N (C ₁-C₆ alkyl) ₂, or two R ₈ on adjacent carbon atoms together with the carbon atom to which they are attached form a moiety optionally substituted with C ₁-C₆ alkyl, A fused phenyl substituted with one or more of C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, amino, OH, CN, halogen, C ₂-C₆ alkenyl, and C ₂-C₆ alkynyl.

In another aspect, the present disclosure provides a compound of formula II:

or a pharmaceutically acceptable salt or solvate thereof,

Wherein:

l is selected from-O-, -S-and-N (R ₆) -, or L is a bond;

R ₆ is selected from hydrogen, C ₁-C₆ alkyl, and C ₁-C₆ haloalkyl;

A. Q and M are independently selected from = C (R ₇) -and = N-;

n is 0, 1, 2 or 3; Represents a single bond or a double bond,

Each R _a may be the same or different and independently represents C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, -C ₁-C₆ alkyl- (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl, -N (C ₁-C₆ alkyl) ₂、-CH₂O-CO-N(C₁-C₆ alkyl) ₂ and-CH ₂NH-CO-N(C₁-C₆ alkyl) ₂, or two R _a on the same carbon atom form C=CH ₂、C＝CH-C₁-C₆ alkyl, C=o, cyclopropyl or cyclobutyl, or two R _a on adjacent carbon atoms together with the carbon atom to which they are attached form a group optionally substituted by C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, Cyclopropyl or cyclobutyl substituted by one or more of amino, OH, CN and halogen;

R ₅ is selected from the group consisting of C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, and halogen;

Each R ₈ may be the same or different and is independently selected from C ₁-C₆ alkyl, -S-C ₁-C₆ alkyl, O-C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, Halogen, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, - (CO) -, -C ₁-C₆ alkyl- (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl and-N (C ₁-C₆ alkyl) ₂, or two R ₈ on adjacent carbon atoms together with the carbon atom to which they are attached form an optionally substituted C ₁-C₆ alkyl, A fused phenyl substituted with one or more of C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, amino, OH, CN, halogen, C ₂-C₆ alkenyl, and C ₂-C₆ alkynyl.

In another aspect, the present disclosure provides a compound of formula III:

Wherein each R ₉ may be the same or different and is independently selected from C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, C ₂-C₆ alkenyl, and C ₂-C₆ alkynyl, and the other substituents and parameters are as defined above.

In another aspect, the nitrogen-containing heterocyclyl is selected from:

In another aspect, the present disclosure provides a compound of formula IV:

or a pharmaceutically acceptable salt or solvate thereof,

Wherein:

l is selected from-O-, -S-and-N (R ₆) -, or L is a bond;

R ₆ is selected from hydrogen, C ₁-C₆ alkyl, and C ₁-C₆ haloalkyl;

A. Q and M are independently selected from = C (R ₇) -and = N-;

each n is independently 0, 1,2 or 3;

R ₈ is independently selected from the group consisting of C ₁-C₆ alkyl, -S-C ₁-C₆ alkyl, O-C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, - (CO) -, -C ₁-C₆ alkyl- (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl and-N (C ₁-C₆ alkyl) ₂, or two R ₈ on adjacent carbon atoms together with the carbon atom to which they are attached form an optionally substituted C ₁-C₆ alkyl, A fused phenyl substituted with one or more of C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, amino, OH, CN, halogen, C ₂-C₆ alkenyl, and C ₂-C₆ alkynyl;

Each R ₉, which may be the same or different, is independently selected from the group consisting of C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, C ₂-C₆ alkenyl, and C ₂-C₆ alkynyl;

each R ₁₀, which may be the same or different, may be on the same carbon atom or different carbon atoms, and is independently selected from C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, amino, OH, CN, halogen, and-C ₁-C₆ alkylene-CN.

In some embodiments, the piperidine ring is

In another aspect, the present disclosure provides a compound of formula V:

or a pharmaceutically acceptable salt or solvate thereof,

Wherein:

l is selected from-O-, -S-and-N (R ₆) -, or L is a bond;

R ₆ is selected from hydrogen, C ₁-C₆ alkyl, and C ₁-C₆ haloalkyl;

A. Q and M are independently selected from = C (R ₇) -and = N-;

each n is independently 0, 1,2 or 3;

each R _a may be the same or different and independently represents C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, -C ₁-C₆ alkyl- (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl, -N (C ₁-C₆ alkyl) ₂、-CH₂O-CO-N(C₁-C₆ alkyl) ₂ and-CH ₂NH-CO-N(C₁-C₆ alkyl) ₂, or two R _a on the same carbon atom form C=CH ₂、C＝CHF、C＝CF₂、C＝CH-C₁-C₆ alkyl, C=o, cyclopropyl or cyclobutyl, or two R _a on adjacent carbon atoms together with the carbon atom to which they are attached form a group optionally substituted by C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, Cyclopropyl or cyclobutyl substituted by one or more of amino, OH, CN and halogen;

u represents O, NH or CH ₂;

t is 0, 1, 2 or 3;

In another aspect, the present disclosure provides a compound of formula VI:

or a pharmaceutically acceptable salt or solvate thereof,

Wherein:

l is selected from-O-, -S-and-N (R ₆) -, or L is a bond;

R ₂ represents H, C ₁-C₆ alkyl or deuterated C ₁-C₆ alkyl;

R ₆ is selected from hydrogen, C ₁-C₆ alkyl, and C ₁-C₆ haloalkyl;

A. Q and M are independently selected from = C (R ₇) -and = N-;

each n is independently 0, 1,2 or 3;

j is 1, 2, 3 or 4;

r ₁₁ represents hydrogen, C ₁-C₄ alkyl, amino, halogen or OH.

In some embodiments, the compounds of the present disclosure are selected from:

Wherein a is selected from = C (R ₇) -and = N-;

R ₁ is selected from the group consisting of hydrogen, C ₁-C₆ alkyl, -S-C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, -C ₁-C₆ alkyl- (CO) -N (C ₁-C₆ alkyl) ₂、C₂-C₄ hydroxyalkynyl, and-N (C ₁-C₆ alkyl) ₂, and

X is selected from the group consisting of C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, NH ₂, OH, CN, halogen, C ₂-C₆ alkenyl, and C ₂-C₆ alkynyl,

Or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compounds of the present disclosure are selected from:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compounds of the present disclosure are selected from tables 1 to 9.

Compounds of table 1

Compounds of table 2

Compounds of table 3

Compounds of table 4

Compounds of table 5

Compounds of table 6

Compounds of table 7

Compounds of table 8

Compounds of table 9

Or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is selected from:

or a pharmaceutically acceptable salt or solvate thereof.

The present disclosure encompasses the preparation and use of salts of the compounds of the present disclosure. As used herein, the term "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of a compound of the present disclosure suitable for administration to a subject, e.g., a human. Salts of the compounds of the present disclosure may be prepared during the final isolation and purification of the compounds, or separately by reacting the compounds with a suitable acid. The pharmaceutically acceptable salts of the compounds of the present disclosure may be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Non-limiting examples of salts of compounds of the present disclosure include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphoric acid salt, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, and p-toluenesulfonate. In addition, the available amino groups present in the compounds of the present disclosure may be quaternized with methyl, ethyl, propyl and butyl chlorides, bromides and iodides, dimethyl, diethyl, dibutyl and dipentyl sulfates, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, and benzyl and phenethyl bromides. In light of the foregoing, any reference compounds of the present disclosure presented herein are intended to include compounds of the present disclosure, and pharmaceutically acceptable salts, hydrates, or solvates thereof.

The present disclosure encompasses the preparation and use of solvates of the compounds of the present disclosure. Solvates generally do not significantly alter the physiological activity or toxicity of the compound and therefore may act as pharmacological equivalents. As used herein, the term "solvate" is a combination, physical association, and/or solvated form of a compound of the present disclosure with a solvent molecule, such as a di-, mono-, or hemi-solvate, wherein the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1, or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate may be isolated. Thus, "solvate" encompasses both solution phases and separable solvates. The compounds of the present disclosure may exist in solvated forms with pharmaceutically acceptable solvents such as water, methanol, and ethanol, and the present disclosure is intended to include both solvated and unsolvated forms of the compounds of the present disclosure. One type of solvate is a hydrate. "hydrate" refers to a specific subset of solvates in which the solvent molecule is water. Solvates generally act as pharmacological equivalents. The preparation of solvates is known in the art. See, e.g., M.caira et al, J.Pharmiceut.Sci.93, volume 3, pages 601-611 (2004), which describe the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparations of solvates, hemi-solvates, hydrates, etc. are described by E.C. van Tonder et al, AAPS Pharm. Sci.Tech., vol.5, no. 1, article 12 (2004) and A.L. Bingham et al, chem. Commun. Pages 603-604 (2001). A typical non-limiting method of preparing a solvate involves dissolving a compound of the present disclosure in a desired solvent (organic solvent, water, or mixtures thereof) at a temperature of greater than 20 ℃ to about 25 ℃, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods (e.g., filtration). Analytical techniques such as infrared spectroscopy can be used to confirm the presence of solvates in the solvate crystals.

III composition

In one aspect, the present disclosure provides compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

Pharmaceutical compositions for use in accordance with the present disclosure are formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries which facilitate processing of the compounds of the present disclosure.

These pharmaceutical compositions may be prepared, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping or lyophilizing processes. The appropriate formulation depends on the route of administration selected. When a therapeutically effective amount of a compound of the present disclosure is administered orally, the composition is typically in the form of a tablet, capsule, powder, solution or elixir. When applied in tablet form, the composition may additionally contain a solid carrier, such as gelatin or an adjuvant. Tablets, capsules and powders contain from about 0.01% to about 95%, preferably from about 1% to about 50%, of the compounds of the present disclosure. When applied in liquid form, a liquid carrier, such as water, petroleum or an oil of animal or vegetable origin, may be added. The composition in liquid form may also contain physiological saline solution, dextrose or other saccharide solution or glycols. When applied in liquid form, the compositions contain from about 0.1% to about 90%, preferably from about 1% to about 50% by weight of the compounds of the present disclosure.

When a therapeutically effective amount of a compound of the present disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions is within the skill in the art, taking into account factors such as pH, isotonicity, stability, and the like, as appropriate. Preferred compositions for intravenous, cutaneous or subcutaneous injection typically contain isotonic solvents.

The compounds of the present disclosure may be readily combined with pharmaceutically acceptable carriers well known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, mack Publishing co., easton, PA, 19 th edition, 1995. Such carriers enable the active agent to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical formulations for oral use may be obtained by adding a compound of the present disclosure to a solid excipient, optionally grinding the resulting mixture after adding suitable adjuvants (if desired) and processing the particulate mixture to obtain a tablet or dragee core. Suitable excipients include, for example, fillers and cellulose preparations. If desired, a disintegrant may be added.

The compounds of the present disclosure may be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). The injectable preparation may be presented in unit dosage form, for example, with the addition of preservative ampoules or multi-dose containers. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agents in water-soluble form. In addition, suspensions of the compounds of the disclosure may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. The aqueous injection suspension may contain substances that increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, the compositions of the present disclosure may be in powder form for formulation with a suitable vehicle, such as sterile pyrogen-free water, prior to use.

The compounds of the present disclosure may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, the compounds of the present disclosure may also be formulated as depot formulations. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present disclosure may be formulated with suitable polymeric or hydrophobic materials (e.g., in the form of an emulsion in an acceptable oil) or ion exchange resins.

In particular, the compounds of the present disclosure may be administered orally, buccally or sublingually in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or ovules either alone or in combination with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid formulations may be prepared with pharmaceutically acceptable additives such as suspending agents. The compounds of the present disclosure may also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronary. For parenteral administration, the compounds of the present disclosure are typically used in the form of a sterile aqueous solution which may contain other substances, for example salts or monosaccharides (such as mannitol or glucose) to make the solution isotonic with blood.

IV method and use

In one aspect, the present disclosure provides a method for inhibiting KRAS G12D activity in a cell, comprising contacting a cell in which inhibition of KRAS G12D activity is desired with an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present disclosure.

In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

As used herein, the term "contacting" refers to bringing together designated parts in an in vitro system or in vivo system. For example, "contacting" KRAS G12D with a compound provided herein includes administering a compound provided herein to an individual or patient (such as a human) having KRAS G12D, and for example, introducing a compound provided herein into a sample containing cells or purified preparations comprising KRAS G12D.

By negatively modulating KRAS G12D activity, the methods described herein are designed to inhibit undesired cell proliferation due to enhanced intracellular KRAS G12D activity. Depending on the particular treatment regimen, the cells may be contacted in single or multiple doses to achieve the desired negative modulation of KRAS G12D. The ability of a compound to bind KRAS G12D can be monitored in vitro using well known methods. Furthermore, the inhibitory activity of exemplary compounds in cells can be monitored, for example, by measuring the inhibition of KRAS G12D activity by the amount of phosphorylated ERK.

In another aspect, the present disclosure provides a method for treating KRAS G12D-related cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure provides a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., KRAS G12D-associated cancer), and (b) administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present disclosure.

The compounds and compositions provided herein are useful for treating a variety of cancers (including tumors), such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, and the like. More specifically, cancers treatable by the compounds and compositions of the present disclosure include, but are not limited to, tumor types such as astrocyte, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid cancers, sarcomas, and the like. More specifically, these compounds are useful in the treatment of heart carcinoma such as sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibromas, lipomas and teratomas, lung carcinoma such as bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoid hamartoma, mesothelioma, gastrointestinal carcinoma such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon carcinoma, gastrinoma), Carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, smooth myoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, smooth myoma), genitourinary tract cancer, kidney (adenocarcinoma, wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, malignant teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor), Lipoma), liver cancer such as hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract cancer such as gallbladder carcinoma, ampulla carcinoma, cholangiocarcinoma, osteosarcoma such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticuloma), multiple myeloma, malignant giant cell tumor such as chordoma, osteochondral tumor (osteochondral exotose), benign chondrioma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor, and nervous system cancer such as skull (osteoma, hemangioma, granuloma, xanthoma, etc.), Malformed osteomyelitis), meninges (meningioma, glioma), brains (astrocytoma, medulloblastoma, glioma, ependymoma, germ cytoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma), gynaecological cancers, uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovaries (ovarian cancer (serous cystic adenocarcinoma, mucinous cystic adenocarcinoma, unclassified carcinoma), granulosa-follicular cytoma, sertoli-Leydig cell tumor, Anaplastic cell carcinoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), hematological carcinoma: blood (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma), skin carcinoma: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, dysplastic nevi, Lipoma, hemangioma, cutaneous fibroma, keloids, psoriasis, and adrenal cancer, neuroblastoma.

In certain embodiments, the cancer is non-small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer. In certain embodiments, the cancer is non-small cell lung cancer.

The therapeutically effective amount of a compound of the present disclosure required for use in therapy will vary with the nature of the condition being treated, the length of time activity is desired, and the age and condition of the subject, and is ultimately determined by the attending physician. The amount and interval of administration may be individually adjusted to provide a plasma level of a compound of the present disclosure sufficient to maintain the desired therapeutic effect. The desired dose may be administered in a single dose, or in multiple doses at appropriate intervals, for example one, two, three, four or more sub-doses per day. Multiple doses are typically required or desired. For example, compounds of the present disclosure may be administered four days apart, one dose per day, four doses total (q 4d 4), three days apart, one dose per day, four doses total (q 3d 4), five days apart, one dose per day (qd 5), one dose per week for three weeks (qwk 3), five doses per day, two days of rest, five doses per day (5/2/5), or any dosage regimen determined to be suitable for the situation.

The compounds of the present disclosure used in the methods of the present disclosure may be administered in an amount of about 0.005 mg to about 500 mg per dose, about 0.05 mg to about 250 mg per dose, or about 0.5 mg to about 100 mg per dose. For example, the compounds of the present disclosure may be administered in an amount of about 0.005 mg, about 0.05 mg, about 0.5 mg, about 5mg, about 10mg, about 20mg, about 30mg, about 40 mg, about 50mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg (including all doses between 0.005 mg and 500 mg) per dose.

The dosage of a composition containing a compound of the present disclosure or a composition containing the compound may be from about 1ng/kg to about 200mg/kg, from about 1 μg/kg to about 100mg/kg, or from about 1mg/kg to about 50mg/kg. The dosage of the composition may be any dosage including, but not limited to, about 1 μg/kg. The dosage of the composition may be any dosage, including, but not limited to, about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325 μg/kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about about 675 μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg/kg, about 975 μg/kg, about 1mg/kg, about 5mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/kg, about 100mg/kg, about 125mg/kg, about 150mg/kg, about, about 175mg/kg, about 200mg/kg or more. The above dosages are examples of general cases, but there may be individual cases where higher or lower dosages are required, and these cases are within the scope of the present disclosure. In practice, the physician determines the actual dosing regimen that best suits the individual subject, which may vary with the age, weight and response of the particular subject.

In certain embodiments, a therapeutically effective amount of the compound is between about 0.01mg/kg and 100mg/kg per day.

In another aspect, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting KRAS G12D activity in a cell.

In another aspect, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of KRAS G12D-related cancer.

In another aspect, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present disclosure, in the manufacture of a medicament for inhibiting KRAS G12D activity in a cell.

In another aspect, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present disclosure, in the manufacture of a medicament for the treatment of KRAS G12D-related cancer.

V. kit

In another embodiment, the present disclosure provides a kit comprising the compounds of the present disclosure (or compositions comprising the compounds of the present disclosure) packaged in a manner that facilitates their use in practicing the methods of the present disclosure. In one embodiment, the kit comprises a compound of the present disclosure (or a composition comprising a compound of the present disclosure), and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject having cancer. In one embodiment, the compound or composition is packaged in unit dosage form. The kit may further comprise a device suitable for administering the composition according to the intended route of administration.

Examples

In order to make the objects and technical solutions of the present disclosure more apparent, the present disclosure will be further described with reference to specific embodiments. It should be understood that these examples are not intended to limit the scope of the present disclosure. In addition, specific experimental methods not mentioned in the following examples were performed according to conventional experimental methods.

Example 1

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 1)

Step 1 (1R, 3S, 5R) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid 2- (tert-butyl) -3-methyl ester

To a solution of (1R, 3S, 5R) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid (1 g,4.40 mmol) in DMF (10 mL) under Ar were added K ₂CO₃ (1.216 g,8.80 mmol) and MeI (1.874 g,13.20 mmol) at 0 ℃. The mixture was then stirred at room temperature for 2 hours. The filtrate was concentrated under reduced pressure to give a residue, which was purified by a silica gel column and eluted with 0% to 30% EA/PE to give the title compound (1.03 g, 97%) as a colorless oil .¹H NMR(400MHz,CDCl₃):4.07-3.95(m,1H),3.73(s,3H),3.54-3.43(m,1H),2.37-2.18(m,2H),1.60-1.55(m,1H),1.43(s,9H),0.83-0.77(m,1H),0.48-0.44(m,1H).

Step 2 (1R, 3R, 5R) -3- (3-chloropropyl) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid 2- (tert-butyl) -3-methyl ester

Lithium bis (trimethylsilyl) amide (4.97 mmol) was added dropwise to a solution of 2- (tert-butyl) -3-methyl (1R, 3S, 5R) -3- (3-chloropropyl) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid 2- (tert-butyl) -3-methyl ester (410 mg,2.487 mmol) in THF (10 mL) under Ar at-70 ℃. After addition, the mixture was incubated at-70 ℃ for 1 hour. 1-chloro-3-iodopropane (559 mg,2.74 mmol) was then added at-70 ℃. Finally, the temperature was slowly raised to room temperature over one hour. Quench with saturated NH ₄ Cl solution (20 mL) and extract with ethyl acetate (20 mL. Times.3). The combined organic layers were washed with brine, dried over Na ₂SO₄ and concentrated in vacuo to give a residue which was purified by column on silica gel and eluted with 0% to 20% EA/PE to give the title compound (410 mg, 51.9%) as a colorless oil .¹H NMR(400MHz,CDCl₃):3.74-3.29(m,6H),2.34-2.15(m,3H),2.04-1.83(m,3H),1.49-1.40(m,10H),0.98-0.94(m,1H),0.81-0.67(m,1H).

Step 3 (1 aR,5aR,6 aR) -hexahydrocyclopropa [ b ] pyrrolizine-5 a (3H) -carboxylic acid methyl ester

A mixture of (1R, 3R, 5R) -3- (3-chloropropyl) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid-2- (tert-butyl) -3-methyl ester (410 mg,1.290 mmol) in DCM (3 mL) and HCl/dioxane (3.00 mL, 4N) was stirred at room temperature for 1 hour under Ar. LC-MS showed the reaction was complete and the volatiles were removed under reduced pressure to give a residue which was dissolved in ACN (5 mL) and K ₂CO₃ (891 mg,6.45 mmol) was added to the above mixture. The resulting mixture was stirred at room temperature for 1 hour. The filtrate was concentrated in vacuo to give a residue which was purified by column on silica and eluted with 0% to 5% MeOH in DCM to give the title compound (172 mg, 73.6%) as a colorless oil. MS 182.3 (M+H ⁺).

Step 4((1 aR,5aR,6 aR) -hexahydrocyclopropa [ b ] pyrrolizine-5 a (3H) -yl) methanol

To a mixture of methyl (1 Ar,5Ar,6 Ar) -hexahydrocyclopropa [ b ] pyrrolizine-5 a (3H) -carboxylate (165 mg,0.910 mmol) in THF was added LiAlH ₄ (69.1 mg, 1.8231 mmol) under Ar at 0 ℃ and the mixture was stirred at room temperature for 1 hour. Quench with sodium sulfate decahydrate and dilute with EA. The mixture was filtered and the filtrate concentrated in vacuo to give a residue which was purified by column on silica and eluted with 0% to 10% MeOH in DCM to give the title compound (101 mg, 72.4%) as a colourless oil. MS:154.25 (M+H ⁺).

Step 5 (1R, 5S) -3- (7-chloro-8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropa o [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a solution of ((1 Ar,5Ar,6 Ar) -hexahydrocyclopropa [ b ] pyrrolizin-5 a (3H) -yl) methanol (28.3 mg,0.185 mmol) was added sodium hydride (123 mg,3.08 mmol) under Ar at room temperature, and the mixture was stirred at room temperature for 0.5 hours. (1R, 5S) -3- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (75 mg,0.154 mmol) was added to the above mixture, and the mixture was stirred at room temperature for 2 hours. Quench with NH ₄ Cl solution, extract three times with EA, wash the combined organic layers with brine, dry over Na ₂SO₄, filter, concentrate the filtrate in vacuo to give a residue that is purified by column on silica eluting with 0% to 5% MeOH in DCM to give the title compound (75 mg, 89%) as a light brown solid. MS:372.4 (M+H ⁺).

Step 6 (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

A mixture of tripotassium phosphate (88 mg,0.413 mmol), (1R, 5S) -3- (7-chloro-8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (75 mg,0.138 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (70.5 mg,0.138 mmol), ruphos-Pd-G3 (115 mg,0.138 mmol) in water (1.5 mL) and THF (3 mL) was stirred under Ar for 1 hour at 60 ℃. After cooling to room temperature, EA was added and the resulting mixture was washed with water, brine, dried over Na ₂SO₄, filtered and concentrated in vacuo to give a residue which was purified by column on silica eluting with 0% to 2% MeOH in DCM to give the title compound (100 mg, 64.9%) as a brown solid. LCMS 896.7 (m+h ⁺).

Step 7:

4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 ar,5ar,6 ar) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

To a solution of tert-butyl (1 r,5 s) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((1 Ar,5Ar,6 Ar) -hexahydrocyclopropa o [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (100 mg,0.112 mmol) in DMF (5 mL) was added CsF (85 mg,0.559 mmol) under Ar, and the mixture was stirred at room temperature for 1 hour. LCMS showed the starting material disappeared. The solvent was removed under reduced pressure to give a residue, which was dissolved in HCl/DCM (10 ml,2 n), and the resulting mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure to give a residue which was purified by preparative HPLC to give the title compound (4.2 mg, 6.32%) as a pale yellow solid.

HNMR(DMSO-d6,400M):9.02(s,1H),7.97(dd,J＝9.1,5.9Hz,1H),7.46(t,J＝9.0Hz,1H),7.38(d,J＝2.4Hz,1H),7.17(d,J＝2.1Hz,1H),4.47(d,J＝12.2Hz,1H),4.30(d,J＝12.3Hz,1H),4.10-3.83(m,3H),3.69-3.49(m,4H),3.11-2.94(m,1H),2.84-2.70(m,1H),2.67-2.53(m,1H),2.00-1.72(m,10H),1.50-1.44(m,1H),0.54-0.48(m,1H),0.31-0.20(m,1H).MS:595.5(M+H⁺)

Example 2:

3- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol (Compound No. 2)

Step 1 (1R, 5S) -3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

A mixture of 2- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (105 mg, 0.356 mmol), (1R, 5S) -3- (7-chloro-8-fluoro-2- (((1 aR,5aR6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (120 mg,0.22 mmol), pd (dppf) Cl ₂ (16 mg,0.022 mmol) and Cs ₂CO₃ (359 mg,1.1 mmol) in dioxane (4 mL) and water (1 mL) was stirred under Ar for 8 hours at 100 ℃. After cooling to room temperature, water was added and extracted 3 times with EA. The combined organic layers were dried over anhydrous Na ₂SO₄ and concentrated in vacuo to give a residue, which was purified by column on silica gel and eluted with 0% to 5% MeOH in DCM to give the title compound (40 mg, 24.3%) as a brown oil. MS 749.6 (M+H ⁺)

Step 2 3- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol

A mixture of (1R, 5S) -3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropa [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (40 mg,0.053 mmol) in ACN (4 mL) and 4M HCl/dioxane (2 mL) was stirred at room temperature under Ar for 3 hours. Quench with aqueous NaHCO ₃ and extract 3 times with EA. The combined EA layers were dried over anhydrous Na ₂SO₄ and concentrated in vacuo to give a residue which was purified by preparative HPLC to give the title compound (5.5 mg, 17.0%) as a white solid.

¹H NMR(400MHz,DMSO)δ9.06(s,1H),7.19(d,J＝2.1Hz,1H),6.79(d,J＝2.2Hz,1H),4.46-4.40(m,2H),4.30-3.95(m,2H),3.80-3.60(m,5H),3.10-3.05(m,1H),2.90-2.80(m,1H),2.68-2.60(m,1H),2.05-1.89(m,3H),1.85-1.60(m,7H),1.55-1.45(m,1H),0.60-0.45(m,1H),0.38-0.28(m,1H).MS:605.3(M+H⁺).

Example 3

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,5aS,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 3)

The title compound was prepared following essentially the same procedure as described in example 1 substituting (1 r,3r,5 r) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid for (1 r,3s,5 r) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid to give (8.8 mg) as a white solid.

HNMR(400MHz,DMSO):10.1(s,1H),9.03(s,1H),8.05-7.90(m,1H),7.44(t,J＝8.8Hz,1H),7.39(s,1H),7.17(s,1H),4.48(d,J＝11.4Hz,1H),4.31(d,J＝11.2Hz,1H),4.15-3.84(m,3H),3.74-3.50(m,4H),3.07-3.02(m,1H),2.80-2.76(m,1H),2.67-2.57(m,2H),1.99-1.62(m,10H),1.47-1.42(m,1H),0.52-0.47(m,1H),0.28-0.24(m,1H).MS:595.5(M+H⁺).

Example 4

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,5aR,6 aS) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 4)

The title compound was prepared following essentially the same procedure as described in example 1 substituting (1 r,3s,5 r) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid with (1 s,3s,5 s) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid to give (7.1 mg) as a white solid.

HNMR(400MHz,DMSO):10.1(s,1H),9.03(s,1H),7.97(dd,J＝9.1,6.0Hz,1H),7.44(t,J＝9.0Hz,1H),7.39(s,1H),7.17(s,1H),4.48(d,J＝12.2Hz,1H),4.31(d,J＝12.2Hz,1H),4.15-3.84(m,3H),3.74-3.50(m,4H),3.07-3.02(m,1H),2.80-2.76(m,1H),2.67-2.54(m,2H),1.99-1.62(m,10H),1.47-1.42(m,1H),0.54-0.44(m,1H),0.29-0.24(m,1H).MS:595.5(M+H⁺).

Example 5

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,5aS,6 aS) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 5)

The title compound was prepared in essentially the same manner as described in example 1 substituting (1R, 3S, 5R) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid with (1S, 3R, 5S) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid to give (7.1 mg) as a white solid .HNMR(400MHz,DMSO):10.1(s,1H),9.03(s,1H),7.97(dd,J＝9.1,6.0Hz,1H),7.44(t,J＝9.0Hz,1H),7.39(s,1H),7.17(s,1H),4.48(d,J＝12.2Hz,1H),4.31(d,J＝12.2Hz,1H),4.15-3.84(m,3H),3.74-3.50(m,4H),3.07-3.02(m,1H),2.80-2.76(m,1H),2.67-2.54(m,2H),1.99-1.62(m,10H),1.47-1.42(m,1H),0.54-0.44(m,1H),0.29-0.24(m,1H).MS:595.5(M+H⁺).

Example 6

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,6 bR) -hexahydrocyclopropaneo [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 6)

Step 1 (1R, 2R, 5S) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid 3- (tert-butyl) -2-methyl ester

To a solution of (1 r,2r,5 s) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid (1.026 g,4.51 mmol) in DMF (20 mL) under Ar was added potassium carbonate (1.248 g,9.03 mmol) and Mel (1.92 g,13.54 mmol) at 0 ℃ and the resulting mixture was stirred at room temperature for 2 hours. The filtrate was concentrated under reduced pressure to give a residue, which was purified by a silica gel column and eluted with 0% to 30% EA/PE to give the title compound (1.05 g, 96%) as a colorless oil.

Step 2 (1R, 2S, 5S) -2- (3-chloropropyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid 3- (tert-butyl) -2-methyl ester

LiHMDS (520 mg,3.11 mmol) was added dropwise to a solution of (1R, 2R, 5S) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid-3- (tert-butyl) -2-methyl ester (500 mg,2.072 mmol) in THF (5 mL) under Ar at 70℃and the resulting mixture was incubated at-70℃for 1 hour. A solution of 1-chloro-3-iodopropane (635 mg,3.11 mmol) in THF was then added at-70 ℃. Finally, the temperature was slowly raised to room temperature over one hour. Quench with saturated NH ₄ Cl solution (50 mL) and extract with ethyl acetate (50 mL. Times.3). The combined organic layers were washed with brine, dried over Na ₂SO₄ and concentrated in vacuo to give a residue which was purified by column on silica gel and eluted with 0% to 20% EA/PE to give the title compound (370 mg, 56.2%) as a colorless oil.

Step 3 (1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -carboxylic acid methyl ester

A mixture of (1R, 2S, 5S) -2- (3-chloropropyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid-3- (tert-butyl) -2-methyl ester (370 mg,1.164 mmol) in DCM (3 mL) and HCl/dioxane (3.00 mL, 4N) was stirred at room temperature for 1 hour under Ar. The volatiles were removed under reduced pressure to give a residue which was dissolved in CAN (5 mL) and K ₂CO₃ (805 mg,5.82 mmol) was added to the above mixture. The resulting mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate concentrated in vacuo to give a residue which was purified by column on silica and eluted with 0% to 5% MeOH in DCM to give the title compound (160 mg, 76%) as a brown oil. MS 182.2 (M+H ⁺)

Step 4((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methanol

To a solution of methyl (1 as,6 br) -hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -carboxylate (160 mg,0.883 mmol) in THF (5 mL) under Ar was added LiAlH ₄ (67.0 mg,1.766 mmol) at 0 ℃ and the mixture was stirred at room temperature for 1 hour. Quenched with Na ₂SO₄·10H₂ O. The mixture was filtered and the filtrate concentrated in vacuo to give the title compound (129 mg, 95%) as a colourless oil, which was used directly in the next step. MS 154.3 (M+H ⁺).

Step 5 (1R, 5S) -3- (7-chloro-8-fluoro-2- (((1 aS,6 bR) -hexahydrocyclopropa o [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Sodium hydride (47.6 mg,1.191 mmol) was added to a mixture of ((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methanol (60.8 mg,0.397 mmol) in THF (5 mL) under Ar at room temperature, and the mixture was stirred at room temperature for 0.5 hours. (1R, 5S) -3- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (170 mg,0.397 mmol) was added to the above mixture, and the mixture was stirred at room temperature for 2 hours. Quench with NH ₄ Cl solution and extract the resulting mixture three times with EA. The combined organic layers were washed with brine, dried over Na ₂SO₄, filtered, and the filtrate concentrated in vacuo to give a residue which was purified by column on silica eluting with 0% to 5% MeOH in DCM to give the title compound (101 mg, 46.7%) as a yellow solid. MS 545.4 (M+H ⁺).

Step 6 (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((1 aS,6 bR) -hexahydrocyclopropaneo [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

A mixture of tripotassium phosphate (118 mg,0.556 mmol), (1R, 5S) -3- (7-chloro-8-fluoro-2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (101 mg,0.185 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (123 mg,0.241 mmol), ruphos-Pd-G3 (23.27 mg,0.028 mmol) in water (1.5 mL) and THF (3 mL) was stirred under Ar for 2 hours at 70 ℃. After cooling to room temperature, extraction with EA three times, the combined organic layers were washed with water, brine, dried over Na ₂SO₄, filtered, concentrated in vacuo to give a residue which was purified by column on silica gel and eluted with 0% to 2% MeOH in DCM to give the title compound (130 mg, 78%) as a brown solid. MS 895.7 (M+H ⁺)

Step 7 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,6 bR) -hexahydrocyclopropaneo [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

To a solution of tert-butyl (1 r,5 s) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((1 as,6 br) -hexahydrocyclopropa-o [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (130 mg,0.145 mmol) in DMF (5 mL) was added CsF (221 mg,1.452 mmol) under Ar, and the mixture was stirred at room temperature for 1 hour. LCMS showed the starting material disappeared. The solvent was removed under reduced pressure to give a residue, which was dissolved in HCl/DCM (10 ml,2 n), and the resulting mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure to give a residue which was purified by preparative HPLC to give the title compound (43.3 mg, 50.1%) as a pale yellow solid.

H NMR(400MHz,DMSO)10.16(s,1H),9.04(s,1H),7.97(dd,J＝9.2,6.0Hz,1H),7.46(t,J＝9.2Hz,1H),7.39(d,J＝2.4Hz,1H),7.17(d,J＝2.4Hz,1H),4.49(d,J＝11.1Hz,1H),4.40-4.26(m,1H),4.15(d,J＝10.2Hz,1H),4.03(d,J＝10.3Hz,1H),3.93(d,J＝5.5Hz,1H),3.66-3.56(m,4H),3.26-2.51(m,5H),1.99-1.62(m,9H),1.56-1.47(m,1H),0.63-0.55(m,1H),0.05-0.11(m,1H).MS:595.5(M+H⁺).

Example 7

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,6 bS) -hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 7)

The title compound was prepared following essentially the same procedure as described in example 6 substituting (1 r,2r,5 s) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid with (1 s, 2r,5 r) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid to give (4.5 mg) as a white solid.

Example 8

4- (4- (1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,6aR,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (compound No. 8A) and 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,6aS,6 bS) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (compound No. 8B)

The title compound was prepared as a mixture by substituting rel- (1 r,2s,5 s) -3-tert-butoxycarbonyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid for (1 r,2r,5 s) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid according to essentially the same procedure as described in example 6 to give (10.6 mg) as a white solid.

Example 9

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,5aS,6 aR) -4-methylenehexahydrocyclopropa [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 9)

Step 1 (1R, 3S, 5R) -3- (2- (chloromethyl) allyl) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid 2- (tert-butyl) -3-methyl ester

To a solution of (1R, 3S, 5R) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid-2- (tert-butyl) -3-methyl ester (1.0 g,4.14 mmol) in THF (10 mL) at-70℃under Ar was added LiHMDS (1.04 g,6.22 mmol) dropwise. The mixture was then stirred at-70 ℃ for 1 hour, and a solution of 3-chloro-2- (chloromethyl) prop-1-ene (0.777 g,6.22 mmol) in THF (5 mL) was added dropwise at-70 ℃. Finally, the temperature was slowly raised to room temperature overnight. Quench with saturated NH ₄ Cl solution and extract three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo to give a residue which was purified by column on silica gel and eluted with 0% to 20% EA/PE to give the title compound (1.03 g, 75%) as a colorless oil .HNMR(CDCl3,400M):5.39-5.37(m,1H),5.13-5.11(m,1H),4.10(s,2H),3.70(s,3H),3.34-3.15(m,2H),2.66-2.51(m,2H),2.18-2.11(m,1H),1.49-1.41(m,10H),1.04-1.00(m,1H),0.80-0.66(m,1H).

Step 2 (1 aR,5aS,6 aR) -4-methylenehexahydrocyclopropa [ b ] pyrrolizine-5 a (3H) -carboxylic acid methyl ester

A mixture of (1R, 3S, 5R) -3- (2- (chloromethyl) allyl) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid 2- (tert-butyl) -3-methyl ester (1.03 g,3.12 mmol) in DCM (3 mL) and HCl/dioxane (3 mL) was stirred at room temperature under Ar for 1 hour. Volatiles were removed under reduced pressure to give a residue which was redissolved in CAN (5 mL) and then K ₂CO₃ (2.158 g,15.61 mmol) was added to the above mixture and the resulting mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate concentrated in vacuo to give a residue which was purified by column on silica and eluted with 0% to 5% MeOH in DCM to give the title compound (587 mg, 97%) as a light brown oil. MS 194.31 (M+H ⁺)

Step 3((1 aR,5aS,6 aR) -4-methylenehexahydrocyclopropa [ b ] pyrrolizine-5 a (3H) -yl) methanol

LiAlH4 (39.3 mg,1.035 mmol) was added to a solution of methyl (1 aR,5aS,6 aR) -4-methylenehexahydrocyclopropa [ b ] pyrrolizine-5 a (3H) -carboxylate (100 mg,0.517 mmol) in THF (5 mL) under Ar, and the mixture was stirred at room temperature for 1 hour. Quench with Na ₂SO₄.10H₂ O, filter the resulting mixture, and concentrate the filtrate in vacuo to give the crude title compound (82 mg) as a colorless oil, which was used directly in the next step. MS 166.3 (M+H ⁺).

Step 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,5aS,6 aR) -4-methylenehexahydrocyclopropa [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared according to essentially the same protocol as described in example 1 to give 2.8mg as a pale yellow solid. MS:607.5 (M+H ⁺).

Example 10

3- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) aniline (Compound No. 10)

Step 12- (3-bromo-5-chloro-4- (trifluoromethyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan

1-Bromo-3-chloro-2- (trifluoromethyl) benzene (2.0 g,7.71 mmol), 4', 5', A mixture of 5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (3.92 g,15.42 mmol), 4 '-di-tert-butyl-2, 2' -bipyridine (210 mg,0.77 mmol) and [ Ir (OMe) (1, 5-cod) ]2 (250 mg,0.385 mmol) in anhydrous THF (60 mL) was stirred at 70℃for 3 hours. The volatiles were removed under reduced pressure to give a residue which was purified by column on silica gel and eluted with 0% to 10% EA/Hex to give the title compound (2.96 g, 100%) as a colorless oil.

Step 2 3-bromo-5-chloro-4- (trifluoromethyl) phenol

To a solution of (trifluoromethyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (2.96 g,7.71 mmol) in ACE (40 mL) and water (15 mL) was added potassium hydrogen persulfate (2.65 g,5.44 mmol) under ice water. The mixture was then stirred at room temperature for 1 hour. Dilute with water and extract 3 times with EA. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO₄ and concentrated in vacuo to give a residue which was purified by column on silica gel and eluted with 0% to 20% EA/Hex to give the title compound (1.5 g, 70.6%) as a colorless oil. ¹ H NMR (400 mhz, dmso) δ11.26 (s, 1H), 7.24 (d, j=2.0 hz, 1H), 7.07 (d, j=2.0 hz, 1H).

Step 3-3-bromo-5-chloro-4- (trifluoromethyl) phenyl triflate

To a solution of 3-bromo-5-chloro-4- (trifluoromethyl) phenol (1.5 g,5.45 mmol) and DIEA (2.1 g,16.34 mmol) in anhydrous DCM (40 mL) at 0 ℃ was added Tf ₂ O (2.61 g,9.26 mmol) under Ar. The reaction mixture was stirred at 0 ℃ for 1 hour. Dilute with DCM, wash with water, brine, dry over anhydrous Na ₂SO₄ and concentrate in vacuo. The residue was purified by flash chromatography eluting with Hex/ea=20:1 to give the title compound (1.5 g, 67.6%) as a colorless oil.

Step 4N- (3-bromo-5-chloro-4- (trifluoromethyl) phenyl) -1, 1-benzophenone imine

A mixture of trifluoro-methanesulfonic acid-3-bromo-5-chloro-4- (trifluoromethyl) phenyl ester (1.5 g,3.68 mmol), benzophenone imine (213 mg, 0.188 mmol), pd ₂(dba)₃ (170 mg,0.184 mmol), xanthos (1.5 g,5.45 mmol) and Cs ₂CO₃ (1.5 g,5.45 mmol) in toluene (40 mL) was stirred under Ar for 3 hours at 100 ℃. Filtration and concentration of the filtrate in vacuo gave a residue which was purified by column on silica gel and eluted with 0% to 5% EA/Hex to give the title compound (750 mg, 46.4%) as a yellow oil ms:438.2 (m+h ⁺).

Step 5N- (3-chloro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) phenyl) -1, 1-benzophenone imine

N- (3-bromo-5-chloro-4- (trifluoromethyl) phenyl) -1, 1-benzophenone imine (350 mg,0.798 mmol), 4', 5', A mixture of 5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (405 mg,1.596 mmol), pd (dppf) Cl ₂ (59 mg,0.08 mmol) and potassium acetate (390 mg,3.99 mmol) in toluene (15 mL) was stirred at 110℃for 3 hours. After cooling to room temperature, it was diluted with EA, washed with water and brine. Dried over anhydrous Na ₂SO₄ and concentrated in vacuo. The residue was purified by column on silica gel and eluted with 0% to 5% EA/Hex to give the title compound (60 mg, 15.5%) as a yellow oil. MS:486.6 (M+H ⁺).

Step 6 (1R, 5S) -3- (7- (3-chloro-5- ((diphenylmethylene) amino) -2- (trifluoromethyl) phenyl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

A mixture of N- (3-chloro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) phenyl) -1, 1-benzophenone imine (60 mg,0.124 mmol), (1R, 5S) -3- (7-chloro-8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (68 mg,0.124 mmol), pd (dppf) Cl ₂ (14 mg,0.02 mmol) and CS ₂CO₃ (201 mg,0.618 mmol) in dioxane (4 mL) and water (1 mL) was stirred under Ar for 8 hours at 100 ℃. After cooling to room temperature, it was diluted with water and extracted 3 times with EA. The combined organic layers were dried over anhydrous Na ₂SO₄ and concentrated in vacuo. The residue was purified by flash chromatography eluting with DCM/meoh=20:1-10:1 to give the title compound (50 mg, 46.6%) as a brown oil. MS 868.4 (M+H ⁺)

Step 7 3- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) aniline

A mixture of (1R, 5S) -3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropa [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (50 mg,0.124 mmol) in EA (4 mL) and 4M HCl/dioxane (2 mL) was stirred at room temperature under Ar for 3 hours. Quench with aqueous NaHCO ₃ and extract 3 times with EA. The combined organic layers were dried over anhydrous Na ₂SO₄ and concentrated in vacuo to give a residue which was purified by prep HPLC to give the title compound (8.0 mg, 28.8%) as a white solid .¹H NMR(400MHz,DMSO)δ9.09(s,1H),7.22(d,J＝2.0Hz,1H),6.82(d,J＝2.0Hz,1H),4.45(d,J＝12.4Hz,2H),4.10-3.99(m,2H),3.70-3.60(m,5H),3.10-3.00(m,1H),2.86-2.80(m,1H),2.68-2.60(m,1H),2.05-1.89(m,3H),1.85-1.60(m,7H),1.55-1.45(m,1H),0.6-0.5(m,1H),0.36-0.30(m,1H).MS:604.3(M+H⁺).

Example 11:

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 11)

To a solution of (1R, 2R, 5S) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid (5 g,22.0 mmol) in DMF (20 mL) was added potassium carbonate (6.08 g,44.0 mmol) under Ar at 0℃followed by methyl iodide (9.37 g,66.0 mmol). After stirring at room temperature for 2 hours, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by column on silica gel and eluted with 0% to 25% EA/PE to give the title product (5.2 g, 98%) as a colorless oil .HNMR(CDCl₃,400MHz):4.39-4.27(m,1H),3.74(s,3H),3.59-3.54(m,2H),1.61-1.39(m,11H),0.78-0.71(m,1H),0.35-0.30(m,1H).

Step 2 (1R, 2S, 5S) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid 3- (tert-butyl) -2-methyl ester and (1R, 2R, 5S) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid 3- (tert-butyl) -2-methyl ester

To a solution of (1 r,2r,5 s) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid-3- (tert-butyl) -2-methyl ester (5.2 g,21.55 mmol) in THF (15 mL) under Ar at-78 ℃ was added lithium bis (trimethylsilyl) amide (32.3 mmol), and the mixture was stirred at-78 ℃ for 1 hour. Finally, a solution of 3-chloro-2- (chloromethyl) prop-1-ene (4.04 g,32.3 mmol) in THF was added dropwise to the above mixture at-78 ℃, after which the mixture was gradually warmed to room temperature and stirred at room temperature overnight. Quench with saturated aqueous NH ₄ Cl and extract the resulting mixture with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which was purified by column on silica gel and eluted with 0% to 20% EA/PE to give the two eluted stereoisomers as a colorless oil. The stereochemistry of the asymmetric quaternary carbon atoms of these compounds has not been established.

The first eluting stereoisomer (3.23 g, 45.4%) was arbitrarily designated as (1 r,2s,5 s) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid-3- (tert-butyl) -2-methyl ester. MS:230.2 (M-100+H ⁺).

The second eluting stereoisomer (1.73 g, 24.34%) was arbitrarily designated as (1 r,2r,5 s) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid-3- (tert-butyl) -2-methyl ester. MS:230.2 (M-100+H ⁺).

Step 3 (1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -carboxylic acid methyl ester

A mixture of (1R, 2S, 5S) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid-3- (tert-butyl) -2-methyl ester (310 mg,0.940 mmol) in DCM (3 mL) and HCl/dioxane (4N, 3.00 mL) was stirred at room temperature for 1 hour under Ar. LC-MS showed the disappearance of starting material and removal of volatiles under reduced pressure gave a residue which was redissolved in a suspension of K ₂CO₃ (649 mg,4.70 mmol) in ACN (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The filtrate was concentrated in vacuo to give a residue which was purified by column on silica and eluted with 0% to 5% MeOH/DCM to give the title compound (160 mg, 88%) as a light brown oil .HNMR(CDCl₃,400MHz):4.91-4.82(m,2H),3.90-3.80(m,1H),3.75(s,3H),3.54-3,40(m,1H),3.31-3.22(m,1H),3.06-2.77(m,3H),1.91-1.85(m,1H),1.6-1.53(m,1H),0.64-0.50(m,1H),0.24-0.13(m,1H).MS:194.2(M+H⁺).

Step 4((1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methanol

To a mixture of methyl (1 as,6 br) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -carboxylate (160 mg, 0.8238 mmol) in THF (5 mL) was added LiAlH4 (62.8 mg,1.656 mmol) under Ar at 0 ℃ and the mixture was stirred at room temperature for 1 hour. Quenched with Na ₂SO₄.10H₂ O and the filtrate concentrated in vacuo to give the title compound (120 mg, 88%) as a colorless oil, which was used directly in the next step. MS 166.2 (M+H ⁺).

Step 5 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared following essentially the same protocol as described in example 6 substituting ((1 as,6 br) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methanol for ((1 as,6 br) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methanol to give 4.1mg as a pale yellow solid.

HNMR(DMSO,400MHz):10.15(s,1H),9.04(s,1H),8.01(dd,J＝8.5,5.9Hz,1H),7.49-7.46(m,1H),7.39(d,J＝2.4Hz,1H),7.23-7.18(m,1H),4.90(s,1H),4.86(s,1H),4.64-4.53(m,1H),4.46-4.37(m,1H),4.13-3.24(m,10H),2.88-2.77(m,1H),2.67-2.33(m,3H),1.90-1.74(m,5H),1.59-1.47(m,1H),0.67-0.56(m,1H),0.20-0.11(m,1H).MS:607.4(M+H⁺).

Example 12:

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,6aR,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 12)

Step 1 (1 aS,6aR,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -carboxylic acid methyl ester

A mixture of (1R, 2R, 5S) -2- (2- (chloromethyl) allyl) -3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid-3- (tert-butyl) -2-methyl ester (1.73 g,5.25mmol; from example 11-step 2) in DCM (3.0 mL) and HCl/dioxane (3.0 mL) was stirred at room temperature under Ar for 1 hour. LC-MS showed the disappearance of starting material and removal of volatiles under reduced pressure gave a residue which was redissolved in a suspension of K ₂CO₃ (3.62 g,26.2 mmol) in ACN (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The filtrate was concentrated in vacuo to give a residue which was purified by column on silica and eluted with 0% to 5% MeOH/DCM to give the title compound (972 mg, 96%) as a light brown oil .HNMR(CDCl₃,400MHz):5.00(s,1H),4.91(s,1H),3.74(s,3H),3.66-3.53(m,1H),3.40-3.20(m,2H),3.05-2.93(m,1H),2.76-2.68(m,1H),2.60-2.50(m,1H),1.84-1.70(m,1H),1.56-1.48(m,1H),0.96-0.85(m,1H),0.61-0.49(m,1H).MS:194.2(M+H⁺).

Step 2((1 aS,6aR,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methanol

To a mixture of methyl (1 as,6Ar,6 br) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -carboxylate (200 mg,1.035 mmol) in THF (5 mL) was added LiAlH ₄ (79 mg,2.070 mmol) under Ar, and the mixture was stirred at room temperature for 1 hour. Quenched with Na ₂SO₄·10H₂ O. The filtrate was concentrated in vacuo to give the title compound (160 mg, 94%) as a colorless oil, which was used directly in the next step. MS 166.2 (M+H ⁺).

Step 3 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,6aR,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared as a pale yellow solid by replacing ((1 as,6 br) -hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methanol with ((1 as,6ar,6 br) -5-methylene hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methanol according to essentially the same protocol as described in example 6.

HNMR(DMSO,400MHz):10.16(s,1H),9.04(s,1H),8.06-7.96(m,1H),7.53-7.46(m,1H),7.39(d,J＝2.4Hz,1H),7.17(d,J＝2.4Hz,1H),5.03(s,1H),4.94(s,1H),4.56-4.46(m,1H),4.38-4.28(m,1H),4.19-3.03(m,11H),,2.72-2.33(m,3H),1.73-1.66(m,5H),1.56-1.51(m,1H),0.71-0.60(m,1H),0.50-0.42(m,1H).MS:607.4(M+H⁺).

Example 13:

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,6 bR) -5-methylhexahydrocyclopropa-o [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 13)

Step 1((1 aS,6 bR) -5-methyl hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methanol

A mixture of ((1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methanol (60 mg, 0.803 mmol; example 11, step 4) and Pd/C (38.6 mg, 10%) in MeOH (5 mL) was stirred at room temperature for 18 hours under H ₂. After the reaction, the filtrate was concentrated in vacuo to give the title product (60 mg, 99%) as a colorless oil, which was used directly in the next step. MS 168.4 (M+H ⁺).

Step 2 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,6 bR) -5-methylhexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared in essentially the same manner as described in example 6 substituting ((1 aS,6 bR) -5-methylhexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methanol for ((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methanol to give 3.1mg as a pale yellow solid .HNMR(DMSO,400MHz):10.16(s,1H),9.04(s,1H),7.99-7,96(m,1H),7.49-7.44(m,1H),7.39(s,1H),7.17(s,1H),4.51-4.34(m,2H),4.19-3.93(m,3H),3.67-3.59(m,4H),3.20-3.17(m,1H),2.97-2.94(m,1H),2.72-2.67(m,2H),2.32-2.04(m,3H),1.72-1.67(m,5H),1.55-1.50(m,1H),1.37-1.31(m,1H),0.95(d,J＝6.4Hz,3H),0.65-0.61(m,1H),0.09-0.06(m,1H).MS:609.4(M+H⁺).

Example 14:

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 a 'S,6b' R) -tetrahydro-4'H-spiro [ cyclopropa-1, 5' -cyclopropaneo [ a ] pyrrolizine ] -6a '(6'H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (compound No. 14)

Step 1 (1 a 'S,6b' R) -tetrahydro-4'H-spiro [ cyclopropa-1, 5' -cyclopropa [ a ] pyrrolizine ] -6a '(6'H) -carboxylic acid methyl ester

To a mixture of methyl (1 as,6 br) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -carboxylate (500 mg,2.59mmol, example 11, step 3) and CH ₂I₂ (6.93 g,25.9 mmol) in anhydrous toluene (20 mL) was added diethyl zinc (28.5 mmol) under Ar at 0 ℃. The reaction mixture was stirred at 0 ℃ to room temperature for 16 hours. Quench with aqueous NH ₄ Cl and extract 3 times with EA. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO₄ and concentrated in vacuo to give the desired compound (500 mg, crude) as a pale yellow oil which was used directly in the next step without purification. MS:208.5 (M+H ⁺).

Step 2((1 a 'S,6b' R) -tetrahydro-4'H-spiro [ cyclopropa-1, 5' -cyclopropa [ a ] pyrrolizine ] -6a '(6'H) -yl) methanol

To a solution of (1 a's,6a ' r,6b ' r) -tetrahydro-4'H-spiro [ cyclopropa-1, 5' -cyclopropa [ a ] pyrrolizine ] -6a ' (6'H) -carboxylic acid methyl ester (500 mg, crude) in anhydrous THF (20 mL) was added LiAlH ₄ (458 mg,12.05 mmol) in portions under Ar at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour. Quench with Na ₂SO₄.10H₂ O and stir at room temperature for 30 minutes. Filtration and concentration of the filtrate in vacuo gave the title compound (300 mg, crude) as a colorless oil, which was used directly in the next step without purification.

MS:180.4(M+H⁺)

Step 3:

4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 a's,6b' r) -tetrahydro-4'H-spiro [ cyclopropa-1, 5' -cyclopropaneo [ a ] pyrrolizine ] -6a '(6'H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared in essentially the same manner as described in example 6 substituting ((1 as,6 br) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methanol with ((1 a's,6b' r) -tetrahydro-4'H-spiro [ cyclopropan-1, 5' -cyclopropa [ a ] pyrrolizin ] -6a '(6'H) -yl) methanol to give 38mg as a pale yellow solid .¹HNMR(400MHz,DMSO)δ10.15(s,1H),9.04(s,1H),8.00-7.95(m,1H),7.49-7.44(m,1H),7.39(d,J＝2.4Hz,1H),7.17(d,J＝2.4Hz,1H),4.55-4.42(m,1H),4.40-4.28(m,2H),4.09(d,J＝10.4Hz,1H),3.94(d,J＝9.2Hz,1H),3.70-3.55(m,4H),3.27-2.45(m,5H),2.10-2.02(m,1H),1.78-1.65(m,5H),1.60-1.50(m,2H),0.70-0.60(m,1H),0.55-0.40(m,4H),0.22-0.15(m,1H).MS:621.4(M+H⁺)

Example 15:

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 a ' S,6a ' R,6b ' R) -tetrahydro-4'H-spiro [ cyclopropa-1, 5' -cyclopropaneo [ a ] pyrrolizine ] -6a ' (6'H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (compound number 15)

The title compound was prepared in essentially the same manner as described in example 14 substituting methyl (1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -carboxylate methanol for methyl (1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -carboxylate to give 3.8mg as a pale yellow solid .¹H NMR(400MHz,DMSO)δ10.18(s,1H),9.06(s,1H),8.00-7.96(m,1H),7.50-7.44(m,1H),7.39(d,J＝2.4Hz,1H),7.18(d,J＝2.4Hz,1H),4.56-4.52(d,J＝12.8Hz,1H),4.40-4.34(m,2H),4.20-4.10(m,1H),3.96(d,J＝2.0Hz,1H),3.75-3.60(m,5H),3.14-3.11(d,J＝8.8Hz,1H),2.99-2.88(m,2H),1.99-1.86(m,2H),1.80-1.55(m,7H),0.65-0.46(m,4H),0.44-0.32(m,2H).MS:621.4(M+H⁺)

Example 16:

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-amine (Compound No. 16)

Step 1 (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

A mixture of (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (170 mg,0.19 mmol) in HCl/dioxane (2 mL) and ACN (4 mL) was stirred at room temperature under Ar for 2 hours. The volatiles were removed under reduced pressure to give the crude intermediate which was redissolved in a solution of DIEA (123 mg,0.95 mmol) and DCM (8 mL) and Boc ₂ O (62 mg, 0.284 mmol) was added under ice water. The reaction mixture was stirred at room temperature for 1 hour. Water was added and neutralized with 1N aqueous HCl. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO₄ and concentrated in vacuo to give a residue which was purified by column on silica and eluted with 0% to 5% MeOH in DCM to give the title compound (140 mg, 87%) as a pale yellow oil.

MS:851.7(M+H⁺)。

Step 2 (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (((trifluoromethyl) sulfonyl) oxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a solution of DIEA (106 mg,0.82 mmol) and tert-butyl (1 r,5 s) -3- (8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((1 Ar,5Ar,6 Ar) -hexahydrocycloprop-O [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (140 mg,0.164 mmol) in anhydrous DCM (4 mL) under Ar was added Tf ₂ O (70 mg,0.247 mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour. Dilute with DCM, wash with water, brine, dry over anhydrous Na ₂SO₄ and concentrate in vacuo to give a residue which is purified by column on silica and eluted with 0% to 5% MeOH in DCM to give the desired product (100 mg, 61.8%) as a yellow oil. MS:983.4 (M+H ⁺).

Step 3 (1R, 5S) -3- (7- (3- ((diphenylmethylene) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

A mixture of (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (((trifluoromethyl) sulfonyl) oxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (100 mg,0.102 mmol), benzophenone imine (37 mg,0.204 mmol), pd ₂(dba)₃ (9.3 mg,0.01 mmol), xanthos (11.8 mg,0.02 mmol) and Cs ₂CO₃ (166 mg,0.51 mmol) in anhydrous toluene (4 mL) was stirred under Ar for 8 hours at 100 ℃. Filtration and concentration of the filtrate in vacuo gave a residue which was purified by column on silica and eluted with 0% to 5% MeOH in DCM to give the title compound (45 mg, 43.6%) as a brown oil. MS:1014.7 (M+H ⁺).

Step 4 (1R, 5S) -3- (7- (3- ((diphenylmethylene) amino) -8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropa [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

A mixture of (1R, 5S) -3- (7- (3- ((diphenylmethylene) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (40 mg,0.039 mmol) and CsF (60 mg,0.39 mmol) in anhydrous DMF (1 mL) was stirred under Ar for 1 hour at room temperature. Dilution with EA, washing with water, brine, drying over anhydrous Na ₂SO₄ and concentration in vacuo afforded the title compound (34 mg, crude) as a brown oil, which was used directly in the next step without further purification. MS:858.6 (M+H ⁺).

Step 5:

4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 ar,5ar,6 ar) -hexahydrocyclopropaneo [ b ] pyrrolizine-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-amine

A mixture of (1R, 5S) -3- (7- (3- ((diphenylmethylene) amino) -8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- (((1 aR,5aR,6 aR) -hexahydrocyclopropaneo [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (34 mg, crude) in EA (2 mL) and 4N HCl/dioxane (1 mL) was stirred at room temperature under Ar for 3 hours. Quench with aqueous NaHCO ₃ and extract 3 times with EA. The combined organic layers were concentrated in vacuo and purified by prep HPLC to give the title compound (2.6 mg, 11.1%) as a white solid.

MS:594.5(M+H⁺)。

Example 17:

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,6aR,6 bR) -hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-amine (Compound No. 17A)

And

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aR,6aS,6 bS) -hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-amine (Compound No. 17B)

The title compound was prepared as a pale yellow solid by following essentially the same procedure as described in example 16 substituting tert-butyl (1 r,5 s) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((1 as,6ar,6 br) -hexahydrocyclopropaneo [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate for tert-butyl (1 r,5 s) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((1 ar,5ar,6 ar) -hexahydrocyclopropaneo [ b ] pyrrolizin-5 a (3H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate to give a pale yellow solid, 20mg of the title compound .¹H NMR(400MHz,DMSO)δ9.04(s,1H),7.79-7.75(m,1H),7.35-7.30(m,1H),7.05-7.00(m,2H),5.65-5.60(m,2H),4.60-4.50(m,1H),4.43-4.25(m,1H),4.18-4.02(m,2H),3.86(d,J＝5.6Hz,1H),3.85-3.60(m,4H),3.34 -2.51(m,5H),2.00-1.62(m,9H),1.56-1.50(m,1H),0.65-0.55(m,1H),0.13-0.07(m,1H).MS:594.5(M+H⁺).

Example 18:

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((1 aS,6 bR) -hexahydrocyclopropaneo [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-amine (Compound No. 18)

The title compound was prepared according to the essentially same protocol as that described in example 16 to give the title compound (90 mg) as a pale yellow solid .¹H NMR(400MHz,DMSO)δ9.05(s,1H),7.82-7.77(m,1H),7.39-7.33(m,1H),7.08-7.00(m,2H),5.67(s,2H),4.55-4.45(m,1H),4.38-4.30(m,1H),4.20-4.03(m,2H),3.89(d,J＝5.6Hz,1H),3.70-3.50(m,4H),3.33-2.55(m,5H),2.00-1.60(m,9H),1.60-1.50(m,1H),0.68-0.60(m,1H),0.13-0.08(m,1H).MS:594.5(M+H⁺).

Example 19:

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((1 aS,6 bR) -hexahydrocyclopropaneo [ a ] pyrrolizine-6 a (4H) -yl) methoxy) -8-methoxypyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 19)

Step 1:

(1R, 5S) -3- (7-chloro-2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) -8-methoxypyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a suspension of methanol (32 mg,1.10 mmol) and NaH (80 mg,2.20 mmol) in anhydrous THF (5 mL) was added under Ar (1 r,5 s) -3- (7-chloro-8-fluoro-2- (((1 as,6 br) -hexahydrocycloprop-o [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (200 mg,0.367 mmol) at 40 ℃. The reaction mixture was stirred at 40 ℃ for 4 hours. Quench with aqueous NH ₄ Cl under ice water and extract 3 times with EA. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO₄ and concentrated in vacuo to give a residue which was purified by column on silica and eluted with 0% to 5% MeOH in DCM to give the title compound (150 mg, 77%) as a yellow solid. MS 557.4 (M+H ⁺)

Step 2:

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) -8-methoxypyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

The title compound was prepared according to the essentially same protocol as that described in example 6 to give the title compound (38 mg) as a pale yellow solid .¹H NMR(400MHz,DMSO)δ10.07(s,1H),8.92(s,1H),7.98-7.92(m,1H),7.48-7.40(m,1H),7.34(d,J＝2.4Hz,1H),7.09(d,J＝2.4Hz,1H),4.51(d,J＝12.0Hz,1H),4.25(d,J＝12.0Hz,1H),4.20-4.06(m,2H),3.90(s,1H),3.85(s,3H),3.68-3.63(m,1H),3.57-3.50(m,3H),3.38-3.35(m,1H),3.30-3.23(m,1H),2.98-2.92(m,1H),2.76(d,J＝11.2Hz,1H),2.60-2.55(m,1H),1.99-1.80(m,3H),1.80-1.65(m,6H),1.60-1.50(m,1H),0.68-0.60(m,1H),0.13-0.07(m,1H).MS:607.4(M+H⁺).

Example 20:

4- (4- (azepan-1-yl) -8-fluoro-2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (compound number 20)

Step 14- (azepan-1-yl) -2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidine

N-ethyl-N-isopropyl-2-amine (3.07 g,23.77 mmol) and 2,4, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidine (2 g,7.92 mmol) were added to a solution of azepane (0.864 g,8.71 mmol) in DCM (20 mL) under Ar at 0℃and the mixture was stirred at room temperature for 0.5 h. Water was added and the resulting mixture was partitioned between DCM/H ₂ O and the separated organic layer was washed with brine, dried over Na ₂SO₄, filtered and concentrated under reduced pressure to give a residue which was purified by column over silica gel to give the title compound (1.8 g, 72.1%) as a yellow solid. MS 315.2 (M+H ⁺).

Step 2:

(1 aS,6 bR) -6a- (((4- (azepan-1-yl) -7-chloro-8-fluoropyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl) octahydrocyclopropaneo [ a ] pyrrolizine

To a mixture of ((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methanol (0.25 g,1.632mmol; example 6, step 4) in THF (5 mL) was added sodium hydride (0.117 g,4.89 mmol) under Ar and the mixture was stirred at room temperature for 0.5H. 4- (azepan-1-yl) -2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidine (0.514 g, 1.630 mmol) was added to the above mixture at room temperature, and the mixture was stirred at room temperature for 4 hours. The extraction was quenched with NH ₄ Cl solution, extracted three times with EA, the combined organic layers were washed with brine, dried over Na ₂SO₄, filtered, and the filtrate concentrated in vacuo to give a residue which was purified by column on silica eluting with 0% to 5% MeOH in DCM to give the title compound (520 mg, 73.8%) as a yellow solid. MS 432.3 (M+H ⁺).

Step 3 (1 aS,6 bR) -6a- (((4- (azepan-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl) octahydrocyclopropa [ a ] pyrrolizine

A mixture of (1 aS,6 bR) -6a- (((4- (azepan-1-yl) -7-chloro-8-fluoropyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl) octahydrocyclopropa [ a ] pyrrolizine (170 mg, 0.390 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (242 mg,0.472 mmol), cs ₂CO₃(385mg,1.181mmol)、Pd(dppf)Cl₂ (28.8 mg,0.039 mmol) in water (2 mL) and 1, 4-dioxane (16 mL) was stirred under Ar for 16 h at 100 ℃. After cooling to room temperature, EA was added, the separated organic layer was washed with brine, dried over Na ₂SO₄, filtered, concentrated in vacuo to give a residue which was purified by column on silica gel and eluted with 0% to 2% MeOH in DCM to give the title compound (115 mg, 37.4%) as a brown solid. MS:782.6 (M+H ⁺).

Step 4:

4- (4- (azepan-1-yl) -8-fluoro-2- (((1 as,6 br) -hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

A mixture of (1 aS,6 bR) -6a- (((4- (azepan-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl) octahydrocyclopropaneo [ a ] pyrrolizine (105 mg,0.134 mmol) and CsF in anhydrous DMF (1 mL) was stirred at room temperature under Ar for 2 hours. EA was added and the separated organic layer was washed with brine and concentrated in vacuo to give a residue. It was redissolved in 4N HCl/dioxane solution and stirred at room temperature for 2 hours. Quench with NH ₃/MeOH, concentrate the resulting mixture under reduced pressure to give a residue, which was purified by preparative HPLC to give the title compound (12 mg, 15.37%) as a yellow solid .¹H NMR(400MHz,DMSO-d₆)δ10.24(s,1H),δ9.08(s,1H),8.05-7.91(m,1H),7.51-7.33(m,2H),7.18(d,J＝2.5Hz,1H),4.13-1.54(m,25H)0.67-0.55(m,1H),0.18-0.01(m,1H).MS:582.4(M+H⁺)

Example 21:

(R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((laS, 6aS,6 bR) -hexahydrocyclopropaneo [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperidin-3-ol (compound No. 21)

The title compound was prepared following essentially the same protocol as described in example 20 substituting (R) -3-methylpiperidin-3-ol for azepane to give (2.2 mg) as a brown solid. MS:598.4 (M+H ⁺).

Example 22:

5-ethynyl-6-fluoro-4- (8-fluoro-2- (((1 aS,6 bR) -hexahydrocyclopropa-o [ a ] pyrrolizine-6 a (4H) -yl) methoxy) -4- (1, 4-oxaazepan-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 22)

Step 1 4- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -1, 4-oxaazepane

To a solution of 2,4, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidine (2.5 g,9.9 mmol) and DIPEA (3.84 g,29.7 mmol) in anhydrous THF (50 mL) was added 1, 4-oxaazepane (1.0 g,9.9 mmol) under Ar at 0 ℃. The mixture was then stirred at 0 ℃ for 1 hour. Water was added and the resulting mixture was extracted 3 times with EA. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO₄ and concentrated in vacuo to give a residue which was purified by column on silica gel and eluted with 0% to 20% EA/Hex to give the title compound (2.5 g, 80%) as a yellow solid. MS 317.2 (M+H+).

Step 2 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((1 aS,6 bR) -hexahydrocyclopropa-o [ a ] pyrrolizin-6 a (4H) -yl) methoxy) -4- (1, 4-oxaazepan-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol

Following a procedure substantially similar to that described in example 20, substituting 4- (azepan-1-yl) -2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidine-4-yl) -1, 4-oxaazepan with 4- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidine (step 1), gave (36 mg) as a brown solid .¹H NMR(400MHz,DMSO)δ10.19(s,1H),9.14(s,1H),8.04-7.98(m,1H),7.53-7.48(m,1H),7.30(d,J＝2.4Hz,1H),7.22(d,J＝2.4Hz,1H),4.22-3.96(m,9H),3.83-3.76(m,2H),3.28-3.22(m,1H),2.98-2.91(m,1H),2.80-2.74(m,1H),2.60-2.55(m,1H),2.18-2.11(m,2H),2.00-1.70(m,5H),1.58-1.52(m,1H),0.68-0.60(m,1H),0.16-0.10(m,1H).MS:584.5(M+H⁺).

Example 23:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) -2- (((1 aS,6 bR) -hexahydrocyclopropaneo [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (Compound No. 23)

Step1 5-fluoro-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester and 3, 3-difluoropiperidine-1-carboxylic acid tert-butyl ester

DAST (19.42 g,120 mmol) was added to a solution of tert-butyl 3-oxopiperidine-1-carboxylate (8.0 g,40.2 mmol) in THF (100 mL) under Ar at 0deg.C, and the mixture was stirred at 60deg.C for 6 hr. TLC showed the reaction was complete. Ice water was added, the resulting mixture was partitioned between EA/H ₂ O, and the organic layer was washed with brine, dried over Na ₂SO₄, filtered, concentrated and purified on flash chromatography to give the title mixture (8.90 g).

Step 2 5-fluoro-1, 2,3, 6-tetrahydropyridine and 3, 3-difluoropiperidine

To a mixture of tert-butyl 5-fluoro-3, 6-dihydropyridine-1 (2H) -carboxylate and tert-butyl 3, 3-difluoropiperidine-1-carboxylate (8.9 g) in DCM (100 mL) was added TFA (30 mL) at room temperature under Ar. After stirring at room temperature for 1 hour, the volatiles were removed under reduced pressure to give the title crude mixture which was used directly in the next step without further purification.

Step 3:

2, 7-dichloro-8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) pyrido [4,3-d ] pyrimidine and 2, 7-dichloro-4- (3, 3-difluoropiperidin-1-yl) -8-fluoropyrido [4,3-d ] pyrimidine

A mixture of 5-fluoro-1, 2,3, 6-tetrahydropyridine and 3, 3-difluoropiperidine (0.9 g) and 2,4, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidine (1.5 g,5.94 mmol) and DIPEA (1.536 g,11.88 mmol) in THF (20 mL) was stirred at room temperature under Ar for 2 hours. After the reaction, the mixture was partitioned between EA/water, the separated organic layer was washed with brine, dried over Na ₂SO₄, concentrated under reduced pressure to give a residue which was purified by column on silica gel to give 2, 7-dichloro-4- (3, 3-difluoropiperidin-1-yl) -8-fluoropyrido [4,3-d ] pyrimidine (650 mg) as a yellow solid. MS:337.2 (M+H ⁺). And 2, 7-dichloro-8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) pyrido [4,3-d ] pyrimidine (1.0 g) as a yellow solid. MS 317.2 (M+H ⁺).

Step 3 5-ethynyl-6-fluoro-4- (8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) -2- (((1 aS,6 bR) -hexahydrocyclopropaneo [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol

Following a procedure substantially the same as described in example 20, substituting 2, 7-dichloro-8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) pyrido [4,3-d ] pyrimidine for 4- (azepan-1-yl) -2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidine to give (14 mg) as a yellow solid .¹H NMR(400MHz,DMSO-d₆)δ10.17(s,1H),9.05(s,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.46(t,J＝9.0Hz,1H),7.40(d,J＝2.6Hz,1H),7.20(d,J＝2.6Hz,1H),5.64(d,J＝16.4Hz,1H),4.55-4.41(m,2H),4.24-4.15(m,1H),4.14-4.06(m,2H),4.02(dd,J＝4.8,1.0Hz,1H),3.92-3.81(m,1H),3.25-1.48(m,12H),0.68-0.52(m,1H),0.13-0.06(m,1H).MS:584.5(M+H⁺).

Example 24:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1R, 2R) -2-fluorocyclopropyl) (methyl) amino) -2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 24A) and 5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1S, 2S) -2-fluorocyclopropyl) (methyl) amino) -2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 24B)

Step 12, 7-dichloro-8-fluoro-N- ((1R, 2R) -2-fluorocyclopropyl) pyrido [4,3-d ] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ((1S, 2S) -2-fluorocyclopropyl) pyrido [4,3-d ] pyrimidin-4-amine

To a mixture of trans-2-fluorocyclopropane-1-amine hydrochloride (750 mg,6.72 mmol), DIPEA (4345 mg,33.6 mmol) in DCM (10 mL) was added 2,4, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidine (1697 mg,6.72 mmol) under Ar at-40 ℃ and the mixture was stirred at room temperature for 2 hours. Water was added and extracted three times with DCM, the combined organic layers were washed with brine, dried over Na ₂SO₄, filtered, concentrated in vacuo to give a residue which was purified by column on silica gel and eluted with PE/dcm=1:1 to give the title compound (1.75 g, 89%) as a yellow solid. MS:291.1,293.1 (M+H ⁺).

Step 2:

2, 7-dichloro-8-fluoro-N- ((1R, 2R) -2-fluorocyclopropyl) -N-methylpyrido [4,3-d ] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ((1S, 2S) -2-fluorocyclopropyl) -N-methylpyrido [4,3-d ] pyrimidin-4-amine

To a mixture of 2, 7-dichloro-8-fluoro-N- ((1 r,2 r) -2-fluorocyclopropyl) pyrido [4,3-d ] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ((1 s,2 s) -2-fluorocyclopropyl) pyrido [4,3-d ] pyrimidin-4-amine (650 mg,2.233 mmol) in anhydrous THF (10 mL) was added NaH (719 mg,4.47 mmol) under Ar at 0 ℃, after stirring at room temperature for 30min, meI (1268 mg,8.93 mmol) was added under ice water, and the mixture was stirred at room temperature for 2 hours. Quenched with water, extracted three times with EA, the combined organic layers were washed with brine, dried over Na ₂SO₄, filtered, concentrated in vacuo to give a residue which was purified by column on silica gel and eluted with PE/dcm=3:1 to give the title compound (110 mg, 16.15%) as a white solid. MS 305.2 (M+H ⁺).

Step 3 5-Ethynyl-6-fluoro-4- (8-fluoro-4- (((1R, 2R) -2-fluorocyclopropyl) (methyl) amino) -2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol and 5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1S, 2S) -2-fluorocyclopropyl) (methyl) amino) -2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol

The title compound was prepared according to essentially the same protocols as described in example 20 to give (11 mg) as a yellow solid .¹H-NMR(DMSO-d₆,400M):10.14(s,1H),9.48(d,J＝15.6Hz,1H),8.00-7.96(m,1H),7.47(t,J＝8.8Hz,1H),7.39(d,J＝2.4Hz,1H),7.20(d,J＝2.4Hz,1H),5.09-4.83(m,1H),4.17-3.97(m,4H),3.34-2.52(m,7H),1.93-1.22(m,8H),0.63-0.57(m,1H),0.10-0.06(m,1H).MS:572.6(M+H⁺).

Example 25:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1R, 2R) -2-fluorocyclopropyl) (methyl-d 3) amino) -2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 25A) and 5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1S, 2S) -2-fluorocyclopropyl) (methyl-d 3) amino) -2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 25B)

Step 12, 7-dichloro-8-fluoro-N- ((1R, 2R) -2-fluorocyclopropyl) -N- (methyl-d 3) pyrido [4,3-d ] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ((1S, 2S) -2-fluorocyclopropyl) -N- (methyl-d 3) pyrido [4,3-d ] pyrimidin-4-amine

Sodium hydride (0.3831 g,15.87 mmol) was added to a mixture of 2, 7-dichloro-8-fluoro-N- ((1 r,2 r) -2-fluorocyclopropyl) pyrido [4,3-d ] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ((1 s,2 s) -2-fluorocyclopropyl) pyrido [4,3-d ] pyrimidin-4-amine (2.31 g,7.94mmol, example 24, step 1) in anhydrous DMF (20 mL) under Ar, and the mixture was stirred at room temperature for 30 min. Methyl iodide-d ₃ (4.60 g,31.7 mmol) was added at room temperature and the resulting mixture was stirred at room temperature for 2 hours. Quenched with water and extracted three times with EA. The combined organic layers were washed with brine, dried over Na ₂SO₄, concentrated under reduced pressure to give a residue which was purified by column over silica gel to give the title compound (780 mg, 31.9%) as a yellow solid. MS:308.2 (M+H ⁺).

Step 2 5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1R, 2R) -2-fluorocyclopropyl) (methyl-d 3) amino) -2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol and 5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1S, 2S) -2-fluorocyclopropyl) (methyl-d 3) amino) -2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol

The title compound was prepared according to essentially the same protocols as described in example 20 to give (40 mg) as a yellow solid .¹H NMR(400MHz,DMSO-d₆)δ10.15(s,1H),9.55-9.37(m,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.46(t,J＝9.0Hz,1H),7.40(d,J＝2.5Hz,1H),7.20(d,J＝2.5Hz,1H),5.14-4.80(m,1H),4.21-3.91(m,4H),3.22(dd,J＝11.4,4.1Hz,1H),2.95-2.88(m,1H),2.73(d,J＝11.3Hz,1H),2.54-1.17(m,9H),0.63-0.56(m,1H),0.11-0.05(m,1H).MS:575.6(M+H⁺).

Example 26:

4- (4- (5-oxa-2-azabicyclo [5.1.0] oct-2-yl) -8-fluoro-2- (((1 aS,6 bR) -hexahydrocyclopropaneo [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound No. 26)

Step 1 5-oxo-1, 4-oxaazepane-4-carboxylic acid benzyl ester

To a solution of 1, 4-oxaazepan-5-one (5 g,43.4 mmol) in THF (130 mL) under Ar at-78℃was added dropwise butyllithium (2.79 g,43.5 mmol). After the addition, the mixture was stirred at-78℃for 30 minutes, and a solution of benzyl chloroformate (7.42 g,43.5 mmol) in THF (50 mL) was added dropwise at-78 ℃. After 4 hours, the mixture was quenched with saturated NH ₄ Cl, the resulting mixture was extracted three times with EA, and the combined organic layers were washed with brine, dried over MgSO ₄, concentrated in vacuo to give a residue which was purified by a silica gel column to give the title compound (7.4 g, 68.4%) as a colorless oil.

Step 2, 3-dihydro-1, 4-oxaazepane-4 (7H) -carboxylic acid benzyl ester

To a solution of benzyl 5-oxo-1, 4-oxaazepane-4-carboxylate (3.2 g,12.84 mmol) in toluene (30 mL) under Ar was added lithium triethylborohydride (1.630 g,15.41 mmol) at-78℃and the mixture was stirred at that temperature for 2 hours. DIPEA (8.30 g,64.2 mmol), DMAP (0.157 g,1.284 mmol) and TFAA (3.24 g,15.41 mmol) were added at-78 ℃. The resulting mixture was then stirred at room temperature for 12 hours. Quench with saturated NH4C1 solution, extract the resulting mixture three times with EA, wash the combined organic layers with brine, dry over MgSO4, concentrate in vacuo to give a residue which is purified by column on silica gel to give the title compound (1.7 g, 56.8%) as an oil .1H NMR(400MHz,CDC13)δ7.40-7.33(m,5H),6.74(s,1H),5.19(s,2H),4.94(d,J＝9.0Hz,1H),4.22(dd,J＝4.4,1.5Hz,2H),3.85(d,J＝30.0Hz,4H).

Step 3 5-oxa-2-azabicyclo [5.1.0] octane-2-carboxylic acid benzyl ester

To a solution of benzyl 2, 3-dihydro-1, 4-oxaazepane-4 (7H) -carboxylate (1.7 g,7.29 mmol) in DCM (10 mL) under Ar was added ZnEt ₂ (22 mmol) and the mixture was stirred at room temperature for 30min. CH ₂I₂ (9.6 g,36 mmol) was added to the above mixture at 0 ℃. Finally the mixture was stirred at room temperature for 16 hours. Quench with aqueous NH ₄ Cl, extract the resulting mixture three times with EA, wash the combined organic layers with brine, dry over MgSO4, concentrate in vacuo to give a residue which is purified by column on silica gel to give the title compound (1.55 g, 86%). MS 248.3 (M+H ⁺)

Step 4 5-oxa-2-azabicyclo [5.1.0] octane

A mixture of benzyl 5-oxa-2-azabicyclo [5.1.0] octane-2-carboxylate (1.3 g,5.26 mmol) and Pd-C (90 mg) in MeOH (20 mL) was stirred under hydrogen at room temperature for 48 hours. The filtrate was concentrated in vacuo to give the title compound (0.4 g, 67.2%) as a colourless oil.

MS:114.2(M+H⁺)

Step 5 4- (4- (5-oxa-2-azabicyclo [5.1.0] oct-2-yl) -8-fluoro-2- (((1 aS,6 bR) -hexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

Following a procedure substantially the same as described in example 20, substituting 5-oxa-2-azabicyclo [5.1.0] octane for 4- (azepan-1-yl) -2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidine (step 1) to give (19 mg) as a yellow solid .¹H NMR(400MHz,DMSO-d₆)δ10.20-6.91(m,7H),5.50-1.35(m,20H),0.91--0.25(m,4H).MS:596.4(M+H⁺).

Example 27:

4- (4- (3-azabicyclo [4.1.0] heptan-3-yl) -8-fluoro-2- (((1 aS,6 bR) -hexahydrocyclopropaneo [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (compound No. 27)

The title compound was prepared following essentially the same protocol as described in example 20 substituting 3-azabicyclo [4.1.0] heptane for azepane to give (40 mg) as a brown solid. MS:580.4 (M+H ⁺).

Example 28:

4- (4- (cyclopropyl (methyl) amino) -8-fluoro-2- (((1 as,6 br) -hexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (compound No. 28)

The title compound was prepared following essentially the same protocol as described in example 20 substituting 3-azabicyclo [4.1.0] heptane for azepane to give (2 mg) as a brown solid. MS:554.4 (M+H ⁺).

Example 29:

5-ethynyl-6-fluoro-4- (8-fluoro-2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa o [ a ] pyrrolizine-6 a (4H) -yl) methoxy) -4- (1, 4-oxaazepan-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (Compound No. 29)

Step 1 4- (7-chloro-8-fluoro-2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa o [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -1, 4-oxaazepan

To a solution of ((1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methanol (0.157 g,0.952mmol; example 11, step 4) in THF (5 mL) was added NaH (0.114 g,2.86 mmol) under Ar at room temperature. After stirring for 10 minutes, 4- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -1, 4-oxaazepane (0.3 g) was added, and the mixture was stirred at room temperature overnight. Quench with NH ₄ Cl solution, extract the resulting mixture three times with EA, wash the combined organic layers with brine, dry over Na ₂SO₄, concentrate in vacuo to give a residue that is purified by column over silica and eluted with 0% to 5% MeOH in DCM to give the title compound (0.105 g) as a yellow solid. MS 446.4 (M+H ⁺).

Step 2 5-ethynyl-6-fluoro-4- (8-fluoro-2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) -4- (1, 4-oxaazepan-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol

The title compound was prepared as a yellow solid by substituting 4- (7-chloro-8-fluoro-2- (((1 as,6 br) -5-methylenehexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -1, 4-oxaazepan for (1 as,6 br) -6a- (((4- (azepan-1-yl) -7-chloro-8-fluoropyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl) octahydrocyclopropa-pyrrolizine (example 20, step 2) according to essentially the same protocol as described in example 20 .¹H NMR(400MHz,DMSO)δ10.21(s,1H),9.13(s,1H),8.00(dd,J＝9.1,6.0Hz,1H),7.49(t,J＝9.0Hz,1H),7.42(d,J＝2.0Hz,1H),7.21(d,J＝1.9Hz,1H),4.88(d,J＝18.3Hz,2H),4.28-2.54(m,15H),2.19-1.19(m,6H),0.68-0.55(m,1H),0.22-0.06(m,1H).MS:596.4(M+H⁺).

Example 30:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) -2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 30)

The title compound was prepared following essentially the same protocol as described in example 29 substituting 5-fluoro-1, 2,3, 6-tetrahydropyridine for 1, 4-oxaazepane to give 13mg as a yellow solid. MS:596.4 (M+H ⁺).

¹H NMR(400MHz,DMSO-J&)8 10.17(s,1H),9.05(s,1H),7.98(dd,J＝9.2,6.0Hz,1H),7.55-7.37(m,2H),7.21(dd,J＝5.1,2.6Hz,1H),5.64(d,J＝16.5Hz,1H),4.85(d,J＝18.6Hz,2H),4.52-3.30(m,11H),2.86-1.43(m,6H),0.63-0.55(m,1H),0.17-0.10(m,1H).

Example 31:

4- (4- (3, 3-difluoropiperidin-1-yl) -8-fluoro-2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa-o [ a ] pyrrolizine-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (compound number 31)

The title compound was prepared according to essentially the same protocol as described in example 29 to give 4mg as a yellow solid. MS:616.5 (M+H ⁺).

Example 32:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1R, 2R) -2-fluorocyclopropyl) (methyl-d 3) amino) -2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 32A) and 5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1S, 2S) -2-fluorocyclopropyl) (methyl-d 3) amino) -2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 32B)

The title compound was prepared in essentially the same manner as described in example 29 using 2, 7-dichloro-8-fluoro-N- ((1 r,2 r) -2-fluorocyclopropyl) -N- (methyl-d 3) pyrido [4,3-d ] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ((1 s,2 s) -2-fluorocyclopropyl) -N- (methyl-d 3) pyrido [4,3-d ] pyrimidin-4-amine (example 25, step 1) instead of 4- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -1, 4-oxaazepane to give 18mg as a yellow solid .MS:587.5(M+H⁺).¹H NMR(400MHz,DMSO-d₆)δ10.15(s,1H),9.48(d,J＝14.9Hz,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.47(t,J＝9.0Hz,1H),7.40(d,J＝2.6Hz,1H),7.20(d,J＝2.5Hz,1H),5.1-4.9(m,1H),4.85(d,J＝17.7Hz,2H),4.18-3.92(m,5H),3.56(d,J＝13.1Hz,1H),3.23(s,2H),2.78(d,J＝11.4Hz,1H),2.68-2.54(m,2H),1.81-1.57(m,3H),1.53-1.47(m,1H),1.35-1.26(m,1H),0.59(q,J＝7.1Hz,1H),0.18-0.09(m,1H).

Example 33:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1R, 2R) -2-fluorocyclopropyl) (methyl) amino) -2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 33A) and 5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1S, 2S) -2-fluorocyclopropyl) (methyl) amino) -2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 33B)

The title compound was prepared following essentially the same procedure as described in example 29 substituting 2, 7-dichloro-8-fluoro-N- ((1 r,2 r) -2-fluorocyclopropyl) -N-methylpyrido [4,3-d ] pyrimidin-4-amine and 2, 7-dichloro-8-fluoro-N- ((1 s,2 s) -2-fluorocyclopropyl) -N-methylpyrido [4,3-d ] pyrimidin-4-amine (example 24, step 2) for 4- (2, 7-dichloro-8-fluorocyclo [4,3-d ] pyrimidin-4-yl) -1, 4-oxaazepane to give 18mg as a yellow solid. MS:584.5 (M+H ⁺).

Example 34:

(R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((1 aS,6 bR) -5-methylenehexahydrocyclopropa [ a ] pyrrolizin-6 a (4H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperidin-3-ol (Compound No. 34)

The title compound was prepared according to essentially the same protocol as described in example 29 to give 10mg as a yellow solid. MS:610.4 (M+H ⁺).

Example 35:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (1, 4-oxaazepan-4-yl) -2- (((1 a 'S,6b' R) -tetrahydro-4'H-spiro [ cyclopropa-1, 5' -cyclopropaneo [ a ] pyrrolizine ] -6a '(6'H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound number 35)

The title compound was prepared following essentially the same protocol as described in example 29 substituting ((1 a s,6as,6 br) -5-methylenehexahydrocyclopropa [ a ] pyrrolizine-6 a (4H) -yl) methanol (example 14, step 2) with ((1 a's,6b' r) -tetrahydro-4'H-spiro [ cyclopropane-1, 5' -cyclopropaneo [ a ] pyrrolizine ] -6a '(6'H) -yl) methanol to give 17mg as a yellow solid. MS:610.4 (M+H ⁺).

Example 36:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (5-fluoro-3, 6-dihydropyridin-1 (2H) -yl) -2- (((la 'S,6a' S,6 bR) -tetrahydro-4'H-spiro [ cyclopropa-1, 5' -cyclopropaneo [ a ] pyrrolizine ] -6a '(6'H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound number 36)

The title compound was prepared according to essentially the same protocol as described in example 29 to give 30mg as a yellow solid. MS:610.4 (M+H ⁺).

Example 37:

5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1 r,2 r) -2-fluorocyclopropyl) (methyl-d 3) amino) -2- (((1 a's,6 br) -tetrahydro-4'H-spiro [ cyclopropa-1, 5' -cyclopropaneo [ a ] pyrrolizine ] -6a ' (6'H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 37A) and 5-ethynyl-6-fluoro-4- (8-fluoro-4- (((1 s,2 s) -2-fluorocyclopropyl) (methyl-d 3) amino) -2- (((1 a's,6B ' r) -tetrahydro-4'H-spiro [ cyclopropa-1, 5' -cyclopropaneo [ a ] pyrrolizine ] -6a ' (6'H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol (compound No. 37B)

The title compound was prepared according to essentially the same protocols as described in example 29 to give 24mg.¹HNMR(400MHz,DMSO)δ10.17(s,1H),9.57-9.41(m,1H),8.01(dd,J＝9.2,5.9Hz,1H),7.49(t,J＝9.0Hz,1H),7.43(d,J＝2.5Hz,1H),7.23(d,J＝2.4Hz,1H),5.16-4.80(m,1H),4.48-4.28(m,1H),4.23-3.95(m,3H),2.98-2.66(m,2H),2.20-2.04(m,1H),1.84-1.52(m,4H),1.40-1.12(m,3H),0.67(dd,J＝12.9,7.9Hz,1H),0.58-0.39(m,4H),0.21(d,J＝3.7Hz,1H).MS:601.4(M+H+).

Cell proliferation assay

Cell proliferation assay in GP2D cells (KRAS G12D)

UsingLuminescent cell viability assay (Promega), inhibition of cell proliferation by test compounds was determined according to the manufacturer's instructions.

GP2d cells (ECACC# 95090715) were cultured in DMEM medium supplemented with 10% fetal bovine serum, 10U/mL penicillin and 10. Mu.g/mL streptomycin. Cells were seeded at a density of 2000 cells/well in 96-well plates and allowed to attach for 120-124 hours. The cells were then treated with various concentrations of the test compound for 72 hours. CellTiter-Reagents were added to the wells and incubated for 10 minutes at room temperature. At the position ofThe plates are read on a 96 microplate photometer or compatible microplate reader. The percent cell viability was calculated as follows:

Cell viability = (average RLU sample-average RLU blank)/(RLU cell control-RLU blank) ×100.IC ₅₀ values were calculated using GRAPHPAD PRISM (San Diego, CA). The measurement was performed in three times.

Cell proliferation assay in SW620 cells (KRAS G12V):

1. Cell culture

Cancer cell line SW620 was cultured in culture conditions (L-15 medium containing 10% FBS) at 37℃in a 5% CO2 atmosphere in air. Tumor cells are routinely subcultured. Cells grown in exponential growth phase were harvested and counted for inoculation.

2. Cell seeding

(1) Counting the cells by means of a cell counter.

(2) The cell concentration was adjusted to 1X 10 ⁴ cells/mL.

(3) Mu.L of the cell suspension (about 1X 10 ³ cells/well) was inoculated into the assay plate according to the plate diagram. mu.L of assay medium was added to the blank wells.

(4) Plates were incubated for 4 hours at 37 ℃, 5% CO ₂, 95% air and 100% relative humidity.

3. Preparation of compound storage plates

Preparation of compound stock plates (400-fold stock plates) stock solutions were serially diluted in DMSO from highest concentration to lowest concentration according to the plate map (table 1).

4. Compound plate (20-fold) preparation and compound treatment

(1) 20-Fold concentrated compound plates were prepared by adding 95. Mu.L of assay medium to each well of the V-shaped bottom plate, and then transferring 5. Mu.L of each concentration of stock compound solution from the stock plate (400-fold stock plate). Mu LDMSO was added to the blank and control wells. Pipette up and down to mix well. The V-shaped plate is called a 20-fold concentrated compound plate.

(2) Compound treatment 5 μl of compound-medium from each well of a 20-fold concentrated compound plate was added to cells in a 96-well assay plate according to the plate map. mu.L of DMSO-medium was added to the blank wells and control wells. The final DMSO concentration was 0.25%.

(3) The assay plates were returned to the incubator and incubated for 3 days

Ctg cell viability assay

(1) Add 30. Mu.L CTG reagent to each well.

(2) The contents were mixed for 2 minutes with an orbital shaker. The assay plates were incubated for 15 minutes at room temperature to stabilize the signal.

(3) RLU was recorded with a Biotek microplate reader.

6. Data analysis

The cell viability of the test compounds was determined by the following formula:

(RLU_{Compounds of formula (I)}-RLU_{Blank space})/(RLU_Control_RLU_{Blank space})*100%

All cell viability for the different doses of compound was calculated in Excel file and then used to plot curves and evaluate relevant parameters such as Min, max and IC50. The data is interpreted by GRAPHPAD PRISM. The results are provided in table 1.

TABLE 1

Na is inapplicable to

P-ERK assay

Expression of p-ERK was detected in this assay. First, AGS cells (40000 cells/well) were seeded overnight in 96-well culture plates and treated with KRAS-G12D compound inhibitor at a concentration of 1 μm, 0.33 μm, 0.11 μm, 0.03 μm, 0.01 μm, 0.004 μm, 0.001 μm, 0.0004 μm, 0.0001 μm for 3 hours at 37 ℃. Then, an equal volume (100. Mu.L) of 8% paraformaldehyde solution was added to fix the cells and crosslink the cells onto the microplate for 15 minutes. mu.L of 1-fold membrane-rupture fluid was added to the wells for 30 minutes, and 100. Mu.L of 1-fold blocking fluid was added thereto for 2 hours. After each reaction, the reaction mixture was washed 3 times with PBS. Finally, incubation was performed with primary mab (anti-mouse β -actin and anti-rabbit p-ERK) and secondary mab (goat anti-mouse IgG H & L IRDye800CW and goat anti-rabbit IgG H & L IRDye 680 RW) for 2 hours. Optionally, the microplate is imaged with an IR scanner or HRP-labeled microplate is developed and read with a spectrophotometer. Fluorescence signals were monitored using a microplate reader (Azure biosystems, saphire biomolecular imager) using excitation and emission wavelengths of 680nm and 800nm, respectively. Data is exported. The dose-response curve of the inhibitor was analyzed using a normalized IC ₅₀ regression curve fitted to a control-based normalization method.

TABLE 2

Pharmacokinetic studies in mice

Representative compounds of the present disclosure are characterized by Pharmacokinetic (PK) profile following single i.v. and p.o. administration in ICR (CD 1, male) mice. The results are provided in table 6.

All procedures performed on animals will be reviewed and approved by a separate ethical review board according to established guidelines. The study design is summarized in table 4.

TABLE 4 animal treatment protocol

Animals were weighed prior to dosing and the dose volume for each animal was calculated using the formula:

dose volume (mL) = [ nominal dose (mg/kg)/dose concentration (mg/mL) ]xanimal body weight (kg)

The actual body weight and dosing volume were recorded accordingly.

TABLE 5 sample collection information

Group of	Sample of	Anticoagulant agent	Sampling time
				A1、A2、A3	Plasma of blood	EDTA-K2	0.083h、1h、8h
A4、A5、A6	Plasma of blood	EDTA-K2	0.25h、2h、10h
				A7、A8、A9	Plasma of blood	EDTA-K2	0.5h、4h、24h
B1、B2、B3	Plasma of blood	EDTA-K2	Before administration, 1h, 8h
				B4、B5、B6	Plasma of blood	EDTA-K2	0.25h、2h、10h
B7、B8、B9	Plasma of blood	EDTA-K2	0.5h、4h、24h

Blood samples (about 100. Mu.L) were collected into anticoagulants (coated with EDTA-K ₂) at different time points. The blood sampling time is recorded accordingly. The tube was gently inverted several times to ensure mixing. Whole blood was centrifuged at 1500g-1600g for 10 minutes. Plasma samples were collected and kept below-90 to-60 ℃ prior to analysis. Recording blood sampling times accordingly

IV administration T1/2 (terminal half-life), CO, AUClast, AUCinf, MRTinf, cl, vss, regression points.

PO administration T1/2 (terminal half-life), cmax, tmax, MRTinf, AUCinf, AUClast, F%, regression points. Pharmacokinetic data are described using descriptive statistics such as mean, standard deviation.

Table 6:

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof,

in:

_R1 represents _C3 - _C6 cycloalkyl or a 5-6-membered heterocyclyl or heteroaryl containing 1, 2 or 3 N atoms, and _R2 represents H, _C1 - _C6 alkyl or deuterated _C1 - _C6 alkyl, wherein the _C3 - _C6 cycloalkyl or the 5-6-membered heterocyclyl or heteroaryl is optionally substituted by one or more _of C1- _C4 alkyl, amino, halogen or OH; or _R1 and _R2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle, wherein the nitrogen-containing heterocycle is optionally substituted by one or more of _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, amino, OH, CN, halogen or -C1 _- _C6 alkyl-CN;

L is selected from -O-, -S- and -N(R ₆ )-; or L is a bond;

R ₆ is selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;

A and Q are independently selected from =C(R ₇ )- and =N-;

R ₇ is selected from hydrogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₆ cycloalkyl;

R ₃ is -(CH ₂ ) _n heterocycle, wherein the heterocycle is an optionally substituted 7-12 membered heterocycle comprising at least two rings bridged to each other; and n is 0, 1, 2 or 3;

R ₄ is selected from C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ heteroaryl, C ₆ -C ₁₀ heterocycle and C ₃ -C ₆ cycloalkyl, wherein the aryl, heteroaryl, heterocycle and cycloalkyl are optionally substituted with one or more R ₈ ;

wherein each R ₈ may be the same or different and is independently selected from C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl, -C ₁ -C ₆ alkyl-(CO)-N(C ₁ -C ₆ alkyl) ₂ , C ₂ -C ₄ hydroxyalkynyl and -N(C ₁ -C ₆ alkyl) ₂ , and R ₅ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN and halogen.

2. A compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof,

in:

_R1 and _R2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring is optionally substituted with one or more of _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, amino, OH, CN, halogen, or -C1 _-C6 _alkylene -CN;

L is selected from -O-, -S- and -N(R ₆ )-; or L is a bond;

R ₆ is selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;

A and Q are independently selected from =C(R ₇ )- and =N-;

wherein each R ₈ may be the same or different and is independently selected from C ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl, -C ₁ -C ₆ alkyl-(CO)-N(C ₁ -C ₆ alkyl) ₂ , C ₂ -C ₄ hydroxyalkynyl and -N(C ₁ -C ₆ alkyl) ₂ , and R ₅ is selected from -C ₁ -C ₆ alkyl, -C ₁ -C ₆ hydroxyalkyl, -C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ alkoxy, NH ₂ , OH, CN and halogen.

3. The compound according to claim 1 or 2, wherein _R1 and _R2 together with the nitrogen atom to which they are attached form a 5-8 membered nitrogen-containing heterocyclic ring.

The compound according to claim 1 , wherein R ₁ is cyclopropyl optionally substituted with one or more of C ₁ -C ₄ alkyl, amino, halogen or OH.

5. A compound according to any one of claims 1 to 3, wherein R ₁ and R ₂ together with the nitrogen atom to which they are attached form the following nitrogen-containing heterocycle optionally substituted by one or more R b groups:

in represents a single bond or a double bond; when When is a single bond, U represents O, NH or CH ₂ ; and when When it is a double bond, U represents N or CH;

t is 0, 1, 2, or 3;

Each Rb may be the same or different and is independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkyl-CN, amino, OH, CN, halogen;

or two R _b on the same carbon atom together with the carbon atom to which they are attached form C═CH ₂ , C═CH-C ₁ -C ₆ alkyl, C═O, C ₃ -C ₆ haloalkyl or C ₃ -C ₆ heterocycle; wherein the C ₃ -C ₆ haloalkyl or C ₃ -C ₆ heterocycle is optionally substituted with one or more of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, amino, OH, CN and halogen;

or two R _b on different carbon atoms are linked together to form a —(CH ₂ ) _s —(CH═CH) _p —linker, wherein s is 0, 1, 2, or 3; and p is 0, 1, 2, or 3.

6. A compound according to any one of claims 1 to 3, wherein R ₁ and R ₂ together with the nitrogen atom to which they are attached form the following nitrogen-containing heterocycle optionally substituted by one or more R b groups:

wherein U represents O, NH or CH ₂ ;

t is 0, 1, 2, or 3;

7. The compound according to any one of claims 1 to 3, wherein the nitrogen-containing heterocycle is:

wherein R ^2a , R ^2b , R ^2c and R ^2d independently represent H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, -C ₁ -C ₆ alkylene-CN, amino, OH, CN, halogen; or any one of R ^2a , R ^2b , R ^2c and R ^2d are linked together to form a -(CH ₂ ) _S -(CH＝CH) _P - linker, wherein s is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

8. The compound according to any one of claims 1 to 3, wherein the nitrogen-containing heterocyclic group is selected from:

represents a single bond or a double bond,

The nitrogen-containing heterocyclic group is optionally substituted by one or more of a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, an amino group, OH, CN, a halogen group, or a -C ₁ -C ₆ alkylene group-CN.

9. The compound according to any one of claims 1 to 3, wherein the nitrogen-containing heterocyclic group is selected from:

represents a single bond or a double bond,

10. The compound according to any one of claims 1 to 3, wherein the nitrogen-containing heterocyclic group is selected from:

represents a single bond or a double bond,

11. The compound according to any one of claims 1 to 3, wherein the nitrogen-containing heterocyclic group is selected from:

represents a single bond or a double bond,

wherein the heterocyclic group is optionally substituted by one or more of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, amino, OH, CN, halogen, or -C ₁ -C ₆ alkylene-CN.

12. The compound according to any one of claims 1 to 3, wherein the nitrogen-containing heterocyclic group is selected from:

represents a single bond or a double bond,

13. A compound according to any one of claims 1 to 12, wherein R ₃ is selected from:

wherein said R ₃ is optionally substituted by one or more _Ra , each _Ra may be the same or different and is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, -C ₁ -C ₆ alkyl-(CO)-N(C ₁ -C ₆ alkyl) ₂ , C ₂ -C ₄ hydroxyalkynyl, -N(C ₁ -C ₆ alkyl) ₂ , -CH ₂ O-CO-N(C ₁ -C ₆ alkyl) ₂ and -CH ₂ NH-CO-N(C ₁ -C ₆ alkyl) ₂ ; or two _Ra on the same carbon atom form C=CH ₂ , C=CH-C ₁ -C ₆ alkyl or C=O.

14. A compound according to any one of claims 1 to 12, wherein R ₃ is selected from:

wherein each Ra may be the same or different and independently represents C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, -C ₁ -C ₆ alkyl-(CO)-N(C ₁ -C ₆ alkyl) ₂ , C ₂ -C ₄ hydroxyalkynyl, -N(C ₁ -C ₆ alkyl) ₂ , -CH ₂ O-CO-N(C ₁ -C ₆ alkyl) ₂ and -CH ₂ NH-CO-N(C ₁ -C ₆ alkyl) ₂ ; or two _Ras on the same carbon atom form C═CH ₂ , C═CHF, C═CF ₂ , C═CH-C ₁ -C ₆ alkyl, C═O, cyclopropyl or cyclobutyl; or two _Ras on adjacent carbon atoms together with the carbon atoms to which they are attached form a C 1 -C 6 alkyl radical optionally replaced by a C ₁ -C 6 alkyl radical; The invention further comprises a cyclopropyl or cyclobutyl group substituted with one or more of C 1 -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, amino, OH, CN and halogen; and n is 0, 1, 2 or 3.

15. A compound according to any one of claims 1 to 12, wherein R ₃ is selected from:

wherein each Ra may be the same or different and independently represents C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, -C ₁ -C ₆ alkyl-(CO)-N(C ₁ -C ₆ alkyl) ₂ , C ₂ -C ₄ hydroxyalkynyl, -N(C ₁ -C ₆ alkyl) ₂ , -CH ₂ O-CO-N(C ₁ -C ₆ alkyl) ₂ and -CH ₂ NH-CO-N(C ₁ -C ₆ alkyl) ₂ ; or two _Ras on the same carbon atom form C═CH ₂ , C═CH-C ₁ -C ₆ alkyl, C═O, cyclopropyl or cyclobutyl; or two _Ras on adjacent carbon atoms together with the carbon atoms to which they are attached form a radical optionally replaced by C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C═O, cyclopropyl or cyclobutyl. cyclopropyl or cyclobutyl substituted with one or more of ₁ -C ₆ alkoxy, amino, OH, CN and halogen; and n is 0, 1, 2 or 3.

16. A compound according to any one of claims 1 to 12, wherein R ₃ is selected from:

wherein said R ₃ is optionally substituted by one or more _Ra , each _Ra may be the same or different and is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, -C ₁ -C ₆ alkyl-(CO)-N(C ₁ -C ₆ alkyl) ₂ , C ₂ -C ₄ hydroxyalkynyl, -N(C ₁ -C ₆ alkyl) ₂ , -CH ₂ O-CO-N(C ₁ -C ₆ alkyl) ₂ and -CH ₂ NH-CO-N(C ₁ -C ₆ alkyl) ₂ ; or two _Ra on the same carbon atom form C=CH ₂ , C=CH-C ₁ -C ₆ alkyl, C=O, cyclopropyl or cyclobutyl.

17. A compound according to any one of claims 1 to 12, wherein R ₃ is selected from:

18. A compound according to any one of claims 1-17, wherein R ₅ is F.

19. The compound of any one of claims 1-18, wherein A and Q are both =N-.

20. A compound according to any one of claims 1-19, wherein R ₄ is selected from:

wherein M is selected from =C(R ₇ )- and =N-; and R ₇ is selected from hydrogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₆ cycloalkyl;

Each R ₈ may be the same or different and is independently selected from C ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl, -C ₁ -C ₆ alkyl-(CO)-N(C ₁ -C ₆ alkyl) ₂ , C ₂ -C ₄ hydroxyalkynyl and -N(C ₁ -C ₆ alkyl) ₂ ; or two R ₈ on adjacent carbon atoms together with the carbon atoms to which they are attached form a radical optionally substituted by C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, amino, OH, CN, halogen, C ₂ -C ₆ alkenyl and C ₂ -C ₆ A fused phenyl group substituted by one or more of alkynyl groups.

21. A compound of formula II according to any one of claims 1 to 19:

or a pharmaceutically acceptable salt or solvate thereof,

in:

L is selected from -O-, -S- and -N(R ₆ )-; or L is a bond;

R ₆ is selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;

A, Q and M are independently selected from =C(R ₇ )- and =N-; R ₇ is selected from hydrogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₆ cycloalkyl;

n is 0, 1, 2, or 3; represents a single bond or a double bond,

Each _Ra may be the same or different and independently represents _C1 - _C6 alkyl, C1- _C6 hydroxyalkyl, _C1 -C6 haloalkyl, _C1 _- _C6 alkoxy, _NH2 , OH, CN, halogen, -C1- _C6 alkyl-(CO)-N( _C1 _- _C6 alkyl) ₂ , _C2 - _C4 hydroxyalkynyl, -N(C1- _C6 alkyl) ₂ , _-CH2O -CO-N( _C1 - _C6 alkyl) ₂ and _-CH2NH -CO-N( _C1 - _C6 alkyl) ₂ ; or two _Ras on the same carbon atom form _{C=CH2, C=CH-C1-C6} _alkyl _, _C =O, cyclopropyl or cyclobutyl; or two _Ras on adjacent carbon atoms together with the carbon atoms to which they are attached form _a radical optionally replaced by _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, C=O, cyclopropyl or cyclobutyl. ₁ -C ₆ alkoxy, amino, OH, CN and halogen substituted cyclopropyl or cyclobutyl;

R ₅ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN and halogen;

Each R ₈ may be the same or different and is independently selected from C ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl, -(CO)-, -C ₁ -C ₆ alkyl-(CO)-N(C ₁ -C ₆ alkyl) ₂ , C ₂ -C ₄ hydroxyalkynyl and -N(C ₁ -C ₆ alkyl) ₂ ; or two R ₈ on adjacent carbon atoms together with the carbon atoms to which they are attached form a radical optionally substituted by C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, amino, OH, CN, halogen, C ₂ -C ₆ alkenyl and C ₂ -C ₆ A fused phenyl group substituted by one or more of alkynyl groups.

22. A compound of formula III according to claim 21:

wherein each R ₉ may be the same or different and is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, C ₂ -C ₆ alkenyl; and C ₂ -C ₆ alkynyl; and other substituents and parameters are as defined in claim 19.

23. A compound according to any one of claims 1-2, wherein the nitrogen-containing heterocyclic group is selected from:

24. A compound of formula IV according to claim 23:

or a pharmaceutically acceptable salt or solvate thereof,

in:

L is selected from -O-, -S- and -N(R ₆ )-; or L is a bond;

R ₆ is selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;

Each n is independently 0, 1, 2 or 3;

R ₈ is independently selected from C ₁ -C ₆ alkyl, -SC ₁ -C ₆ alkyl, OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl, -(CO)-, -C ₁ -C ₆ alkyl-(CO)-N(C ₁ -C ₆ alkyl) ₂ , C ₂ -C ₄ hydroxyalkynyl and -N(C ₁ -C ₆ alkyl) ₂ ; or two R ₈ on adjacent carbon atoms together with the carbon atoms to which they are attached form a radical optionally substituted by C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, amino, OH, CN, halogen, C ₂ -C ₆ alkenyl and C ₂ -C ₆ fused phenyl substituted by one or more alkynyl groups;

Each R ₉ may be the same or different and is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, C ₂ -C ₆ alkenyl; and C ₂ -C ₆ alkynyl;

Each R ₁₀ may be the same or different, may be on the same carbon atom or different carbon atoms, and is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, amino, OH, CN, halogen, and -C ₁ -C ₆ alkylene-CN.

25. The compound according to claim 23 or 24, wherein the piperidine ring is

26. The compound of formula V according to claim 1:

or a pharmaceutically acceptable salt or solvate thereof,

in:

L is selected from -O-, -S- and -N(R ₆ )-; or L is a bond;

R ₆ is selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;

Each n is independently 0, 1, 2 or 3;

Each _Ra may be the same or different and independently represents _C1 - _C6 alkyl, C1- _C6 hydroxyalkyl, _C1 -C6 haloalkyl, _C1 _- _C6 alkoxy, _NH2 , OH, CN, halogen, -C1- _C6 alkyl-(CO)-N( _C1 _- _C6 alkyl) ₂ , _C2 - _C4 hydroxyalkynyl, -N(C1- _C6 alkyl) ₂ , _-CH2O -CO-N( _C1 - _C6 alkyl) ₂ and _-CH2NH -CO-N( _C1 - _C6 alkyl) ₂ ; or two _Ras on the same carbon atom form C= _CH2 , C= _CHF , C ₌ _CF2 , C=CH-C1- _C6 alkyl, C=O, cyclopropyl or cyclobutyl; or two _Ras on adjacent carbon atoms together with the carbon atoms to which they are attached form _a C1-C6 alkyl radical optionally replaced by _C1 -C6 alkyl. cyclopropyl or cyclobutyl substituted with one or more of C 1 -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, amino, OH, CN and halogen;

U represents O, NH or CH ₂ ;

t is 0, 1, 2, or 3;

or two R _b on different carbon atoms are linked together to form a —(CH ₂ ) _s —(CH═CH) p —linker, wherein s is 0, 1, 2, or 3; and p is 0, 1, 2, or 3.

27. The compound of formula VI according to claim 1:

or a pharmaceutically acceptable salt or solvate thereof,

in:

L is selected from -O-, -S- and -N(R ₆ )-; or L is a bond;

R ₂ represents H, C ₁ -C ₆ alkyl or deuterated C ₁ -C ₆ alkyl;

R ₆ is selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;

A, Q and M are independently selected from =C(R ₇ )- and =N-;

Each n is independently 0, 1, 2 or 3;

j is 1, 2, 3, or 4;

R ₁₁ represents hydrogen, C ₁ -C ₄ alkyl, amino, halogen or OH.

28. A compound selected from:

wherein A is selected from ＝C(R ₇ )- and ＝N-;

R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl, -C ₁ -C ₆ alkyl-(CO)-N(C ₁ -C ₆ alkyl) ₂ , C ₂ -C ₄ hydroxyalkynyl and -N(C ₁ -C ₆ alkyl) ₂ ; and

X is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, NH ₂ , OH, CN, halogen, C ₂ -C ₆ alkenyl; and C ₂ -C ₆ alkynyl, or a pharmaceutically acceptable salt or solvate thereof.

29. A compound selected from:

wherein A is selected from ＝C(R ₇ )- and ＝N-;

30. A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

31. A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

32. A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

33. A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

34. A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

36. A method for inhibiting KRAS G12D or KRAS G12V activity in a cell, the method comprising contacting the cell in which inhibition of KRAS G12D or KRAS G12V activity is required with an effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition according to claim 35.

37. A method for treating KRAS G12D or G12V-related cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition according to claim 35.

38. The method of claim 37, wherein the therapeutically effective amount of the compound is between about 0.01 mg/kg and 100 mg/kg per day.

39. The method of claim 37 or 38, wherein the KRAS G12D or G12V-associated cancer is selected from the group consisting of cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal cancer: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma Tumor), colorectal (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract cancer: kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, malignant teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver cancer: hepatoma (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract cancer: gallbladder cancer, ampullary carcinoma, bile duct cancer; bone cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell Cancers of the nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecological cancers: uterus (endometrial cancer (serous cystadenocarcinomas, mucinous cystadenocarcinomas, unclassified carcinomas), granulosa-theca cell =Cancer: Hematologic cancers: Hematologic cancers (myeloid leukemias (acute and chronic), acute lymphoblastic leukemias, chronic lymphoblastic leukemias, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphomas (malignant lymphomas); Skin cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland cancers: neuroblastoma.

40. The method of claim 39, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

41. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS G12D or G12V mutation (e.g., a KRAS G12D or G12V-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition according to claim 35.

42. A compound according to any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting KRAS G12D or G12V activity in a cell.

43. A compound according to any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, for use in treating KRAS G12D or G12V related cancers.

44. Use of a compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 35 in the preparation of a medicament for inhibiting KRAS G12D or KRAS G12V activity in a cell.

45. Use of a compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 35 in the preparation of a medicament for treating KRAS G12D or G12V-related cancer.

46. A kit comprising a compound according to any one of claims 1-34, or a pharmaceutical composition according to claim 35, and instructions for administering the compound or a pharmaceutically acceptable salt or solvate thereof to a subject suffering from cancer.