4-(3, 8-diazabicyclo [3.2. 1] octane-3-yl)-7-naphthalene-pyrido [4, 3-d] pyrimidine derivatives as KRAS (G12d) mutant oncoprotein inhibitors for treatment of cancer

Abstract

The present application provides small molecule inhibitors of KRAS (G12D) mutant oncoprotein having the following structural formula (I): # imgabs0 #, and pharmaceutically acceptable salts and compositions thereof, which are useful in the treatment of cancer and related conditions.

Description

[0001] Related applications

[0002] This application claims the benefit of priority of international application No. PCT / CN2022 / 118115, filed on September 9, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] The Kirsten rat sarcoma viral homolog (KRAS) gene was discovered as a human cancer gene in the early 1980s. This gene encodes a small, monomeric 21kDa GTPase that has long been a difficult-to-study cancer drug target (Chang et al., PNAS, 1982, 79:4848-52; McCoy et al., Nature, 1983, 302:79-8). KRAS acts as a molecular switch that promotes cell growth by cycling between a GTP-bound state and a GDP-bound state. In the GTP-bound state, KRAS sends growth signals through the RAF-MAPK and PI3K-AKT-MTOR pathways. KRAS then hydrolyzes GTP to GDP with the help of GTPase-activating proteins (GAPs). This GDP-bound state switches KRAS growth-promoting signaling "off." KRAS can then be switched back “on” by exchanging GDP for GTP with the help of guanine nucleotide exchange factors such as SOS1 (Cox and Der, Small GTPases, 2010, 1: 2-27; Kerk et al., Nat Rev Cancer, 2021, 21: 510-525). Preventing this exchange by locking KRAS in the GDP-bound state is a practical approach to inhibiting its growth-promoting activity.

[0004] The human KRAS gene is encoded on chromosome 12p12.1 and is one of the most frequently mutated genes in human cancers (Pylayeva-Gupta et al., Nat Rev Cancer, 2011, 11: 761-774). Mutations that prevent GTP hydrolysis lock KRAS in an active GTP-bound state and reprogram cells to proliferate permanently. The glycine (G) mutation at the 12th codon of KRAS is converted to aspartic acid (D), resulting in a long-term active KRAS (G12D) oncoprotein, which was observed in 6.8% of cancer cases by next-generation sequencing analysis (Zhou et al., Pathol Oncol Res, 2020, 26: 2835-2837). In tumor type-specific studies, KRAS(G12D) was associated with adverse clinical outcomes and was observed in 17% of lung cancer, 14.3% of colorectal cancer, and 48% of pancreatic tumors (Aredo et al., Lung Cancer, 2019, 133:144-150; Olmedillas-López et al., World J Gastroenterol, 2017, 23(39):7087-709; Miglio et al., Pathol Res Pract, 2014, 210:307-11; Gou et al., Br J Cancer, 2020, 22:857-867), as well as in other cancers. Historically, oncogenic KRAS mutants were considered undruggable (McCormick F, Biochem J, 2019, 476: 356-74). However, the discovery of an allosteric pocket in GDP-bound KRAS has made it possible to find small molecule inhibitors (Ostrem et al., Nature, 2013, 503: 548-51). In addition, the G12D mutation also provides a unique chemical molecule binding space because the encoded acidic amino acid residue (D) replaces the small flexible amino acid residue (G) with only a hydrogen side chain. This change in the KRAS protein structure provides a unique space that can be used to specifically inhibit the oncogenic activity of KRAS (G12D) with small molecule drugs. Therefore, it is expected to design and develop small molecule drugs targeting KRAS (G12D) with sufficient bioavailability to treat diseases such as cancer. Summary of the Invention

[0005] Provided herein are small molecule inhibitors of KRAS (G12D) mutant oncoproteins. KRAS (G12D) inhibitors include those having the following structural formula I:

[0006]

[0007] and pharmaceutically acceptable salts and compositions comprising the same, wherein Y, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 9 As defined herein. The present application also discloses the use of these compounds, salts and compositions for treating diseases (such as cancer) that are responsive to inhibition of KRAS (G12D). In one aspect, the disclosed compounds show improved bioavailability. See, for example, Table 3. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 Tumor growth inhibition data for female NOD SCID mice treated with Compound 3 are shown.

[0009] Figure 2 The percent body weight change of female NOD SCID mice treated with Compound 3 is shown.

[0010] Figure 3 Tumor growth inhibition data for female NOD SCID mice treated with Compound 34 are shown.

[0011] Figure 4 Shown are the percent changes in body weight of female NOD SCID mice treated with Compound 34. DETAILED DESCRIPTION

[0012] 1. Compound Overview

[0013] As part of the first embodiment, the present application provides a compound of formula I:

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein

[0016] Y is hydrogen or -C(O)OCHR a OC(O)R b ;

[0017] X is CH or N;

[0018] R 1 is hydrogen, halogen, OH, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) hydroxyalkyl, -CHO, -C(O)OR b 、-C(O)ONR a R bor a 5- to 6-membered heteroaryl group optionally substituted by 1 to 3 groups selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and cyano;

[0019] R 2 is 1 to 3 selected from R c substituted 4 to 6 membered monocyclic heterocyclic group or optionally substituted by 1 to 3 groups selected from R d A 6- to 10-membered bicyclic heterocyclic group substituted with a group of

[0020] R 3 is selected from hydrogen, halogen, (C1-C4)alkyl, cyano and (C3-C6)cycloalkyl optionally substituted by 1 to 3 groups selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy and cyano;

[0021] R 4 selected from hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, deuterated (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) alkynyl, (C1-C4) alkenyl, halogen, (C3-C6) cycloalkyl, -O(C3-C6) cycloalkyl, cyano, NH2, -NH(C1-C4) alkyl, -N[(C1-C4) alkoxy] -C4)alkyl]2, -P(O)[(C1-C4)alkyl]2 and -S(C1-C4)alkyl, wherein the (C3-C6)cycloalkyl and the (C3-C6)cycloalkyl of -O(C3-C6)cycloalkyl are optionally substituted with 1 to 3 groups selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy and cyano;

[0022] R 5 is (C2-C4)alkynyl;

[0023] R 6 is hydrogen or a halogen;

[0024] R 7 is hydrogen or OH;

[0025] R 8 and R 9 Together they form =CH or cyclopropyl;

[0026] R a and R b are each independently selected from hydrogen and (C1-C4)alkyl; and

[0027] R c and R dare each independently selected from halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, cyano, OH, oxo, -C(O)OR a 、-C(O)R a 、-SO2R a 、-S(O)R a 、-SO2NR a R b 、-NR a C(O)R b 、-NR a SO2R b 、-NR a R b and NO2;

[0028] The condition is that when R 4 When it is (C3) alkyl, R 2 Not (C1-C4) alkyl, -C(O)OR a or -C(O)R a Substituted piperazinyl.

[0029] 2. Definition

[0030] As used herein, the articles "a" and "an" refer to one or more than one of the grammatical object of the article, for example, to at least one of the grammatical object of the article. When used in conjunction with the term "comprising" herein, the use of the word "a" or "an" can mean "one", but is also consistent with the meaning of "one or more", "at least one" and "one or more than one".

[0031] As used herein, the terms "comprising" or "including" are used to refer to compositions, methods, and their respective components, which are present in a given embodiment, but are also open to including unspecified elements.

[0032] As used herein, unless otherwise indicated, the term "alkyl" means a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms, such as (C1-C6) alkyl or (C1-C4) alkyl. Representative straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl; while saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl. , 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, etc.

[0033] As used herein, unless otherwise indicated, the term "alkynyl" means a saturated straight or branched non-cyclic hydrocarbon having 2 to 10 carbon atoms (e.g., (C2-C6) alkynyl or (C2-C4) alkynyl) and having at least one carbon-carbon triple bond. Representative straight and branched alkynyl groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, etc.

[0034] As used herein, the term "cycloalkyl" means a saturated monocyclic alkyl group having, for example, 3 to 10 carbon atoms (e.g., 3 to 6 carbon atoms). Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0035] The term "oxo" refers to the group =0.

[0036] As used herein, the term "haloalkyl" means that one or more (including all) hydrogen atoms in an alkyl group are replaced by a halo group, wherein each halo group is independently selected from -F, -Cl, -Br, and -I. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.

[0037] "Alkoxy" means an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0038] "Deuterated alkoxy" refers to an alkoxy group in which one or more hydrogens (eg, one or two hydrogens) have been replaced with deuterium.

[0039] "Haloalkoxy" is a haloalkyl group attached to another moiety through an oxygen atom, such as, for example, -OCHF2 or -OCF3.

[0040] As used herein, the term "halogen" or "halo" means F, Cl, Br, or I.

[0041] As used herein, the term "heterocyclyl" means a 4 to 12 membered monocyclic or polycyclic (e.g., bridged bicyclic, fused bicyclic, or spirobicyclic) saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O, and S. Where valence permits, the heterocycle may be attached by any heteroatom or carbon atom. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidonyl, pyrrolidinyl, piperidinyl, piperazinyl, glycidyl, dioxanyl, oxetanyl, dihydrofuranyl, dihydropyranyl, isoindolyl, dihydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, diazabicyclooctyl, hexahydropyrrolidinyl, 2-azaspiro[3.3]heptynyl, 2,7-diazaspiro[3.5]nonyl, [3.5]decyl, 1,4-dioxa-8-azaspiro[4.5]decyl, or 1,2,3,6-tetrahydropyridinyl. Optional substituents on the heterocyclic group may be present at any substitutable position and, for example, include positions at which the heterocyclic group is attached where valence permits.

[0042] The term "spiro" refers to two rings that share one ring atom (eg, carbon).

[0043] The term "fused" refers to two rings that share two adjacent ring atoms with each other.

[0044] The term "bridged" refers to two rings that share three ring atoms with each other.

[0045] As used herein, the term "heteroaryl" means a 5 to 12 membered aromatic group containing 1 to 4 heteroatoms selected from N, O, and S. Where valence permits, the heteroaryl group may be attached via any heteroatom or carbon atom. Representative heteroaryl groups include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolyl, indazolyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, benzothienyl, etc. Optional substituents on a heteroaryl group may be present at any substitutable position and, for example, include positions where the heteroaryl group is attached where valence permits.

[0046] When used to describe a chemical group that can have multiple points of attachment, a hyphen (-) indicates the point of attachment of the group to the variable defining it. For example, -(C1-C4)alkylaryl means that the point of attachment of the group occurs on the alkyl group.

[0047] like The wavy line in the represents the point of attachment of the described group to the defined variable.

[0048] The term "KRAS" refers to the protein product of the KRAS proto-oncogene, a GTPase gene.

[0049] The term "KRAS(G12D)" refers to the protein product of the KRAS gene carrying a mutation resulting in a substitution of glycine with aspartic acid at position 12 of KRAS.

[0050] “With KRAS G12D "Binding chemical entity" refers to a chemical entity that binds to KRAS G12D In some aspects, the KRAS G12D The chemical entity that binds is a small molecule. In some aspects, the KRAS G12D The chemical entity that is bound is a small molecule with a molecular weight of less than 2,000 g / mol. G12D The bound chemical entity induces KRAS G12D conformational changes.

[0051] The term "SOS1" refers to the protein product of the SOS1 gene, which functions as a guanine nucleotide exchange factor for RAS proteins.

[0052] The compounds described herein may have chiral centers and / or geometric centers (E- and Z-isomers). It will be understood that the present disclosure encompasses all stereoisomers and geometric isomers. Tautomeric forms of the compounds described herein are also part of the present disclosure.

[0053] When the stereochemistry of a disclosed compound is named or depicted in a structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to all other stereoisomers. The percent purity by weight relative to all other stereoisomers is the ratio of the weight of one stereoisomer to the weight of that stereoisomer plus the weight of the other stereoisomers.

[0054] When used in medicine, a pharmaceutically acceptable salt of the disclosed compounds refers to a non-toxic "pharmaceutically acceptable salt". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic salts or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid). Compounds of the present invention having acidic groups (such as carboxylic acids) can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base salts include, for example, ammonium salts, alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and calcium salts). Compounds having quaternary ammonium groups also contain counteranions such as chloride ions, bromide ions, iodide ions, acetate ions, perchlorate ions, etc. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts formed with amino acids (such as glutamic acid).

[0055] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulosics, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0056] As used herein, the term "subject" refers to humans and non-human animals, including veterinary subjects. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, mice, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles. In a preferred embodiment, the subject is a human, which can be referred to as a patient.

[0057] As used herein, the terms "treat," "treating," or "treatment" preferably refer to actions that achieve a benefit or desired clinical outcome, including but not limited to alleviating or ameliorating one or more signs or symptoms of a disease or condition, reducing the extent of the disease, stabilizing (i.e., not worsening) the disease state, improving or relieving the disease state, reducing the rate or time of disease progression, and remission (whether partial or complete). "Treatment" may also mean prolonging survival compared to the expected survival without treatment. Treatment does not require a cure.

[0058] "Therapeutically effective amount" refers to an amount sufficient to treat a disease in a subject. A therapeutically effective amount can be administered in one or more doses. In one aspect, a therapeutically effective amount refers to a dosage of about 0.01 to about 100 mg / kg body weight / day.

[0059] The terms "administer," "adeministering," or "administration" include any method of delivering a pharmaceutical composition or agent to a specific area in or on the body of a subject. In certain embodiments, the agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, transdermally, or through a mucosa. In certain embodiments, the agent is administered intravenously. In certain embodiments, the agent is administered orally. Administration of the agent can be performed by multiple people working together. Administration of the agent includes, for example, providing a prescription for the agent to be administered to the subject and / or providing instructions for taking a specific preparation directly or through another person, and can also be self-delivered, such as oral delivery, subcutaneous delivery, intravenous delivery through a central catheter, etc.; or delivered by a trained professional, such as intravenous delivery, intramuscular delivery, intratumoral delivery, etc.

[0060] 3. Compounds

[0061] As part of a second embodiment, the compound of formula I is a compound of formula II:

[0062]

[0063] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0064] As part of a third embodiment, the compound of formula I is a compound of formula III:

[0065]

[0066] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0067] As part of a fourth embodiment, the compound of formula I is a compound of formula IV:

[0068]

[0069] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0070] As part of a fifth embodiment, the compound of formula I is a compound of formula V:

[0071]

[0072] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0073] As part of a sixth embodiment, in the compound of Formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, wherein the variables are as described above for Formula I.

[0074] As part of a seventh embodiment, X in the compound of Formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof, is N, wherein the variables are as described above for Formula I or the sixth embodiment.

[0075] As part of an eighth embodiment, in the compound of Formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, R 3 is halogen, wherein the variables are as described above for Formula I or the sixth or seventh embodiment. Alternatively, as part of the eighth embodiment, R in the compound of Formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof is 3 is fluoro, wherein the variables are as described above for Formula I or the sixth or seventh embodiment.

[0076] As part of a ninth embodiment, in the compound of Formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, R 5 is (C2)alkynyl, wherein the variables are as described above for Formula I or any one of the sixth through eighth embodiments.

[0077] As part of the tenth embodiment, in the compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, R 6 is halogen, wherein the variables are as described above for Formula I or any one of the sixth through ninth embodiments. Alternatively, as part of the tenth embodiment, R in the compound of Formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof, is 6 is fluoro, wherein the variables are as described above for Formula I or any one of the sixth through ninth embodiments.

[0078] As part of an eleventh embodiment, in the compound of Formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, R 7 is OH, wherein the variables are as described above for Formula I or any one of the sixth through tenth embodiments.

[0079] As part of the twelfth embodiment, in the compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, R 4 is selected from hydrogen, (C1-C4)alkoxy, deuterated (C1-C4)alkoxy, -N[(C1-C4)alkyl]2, halogen, (C3-C6)cycloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkyl, and NH2, wherein the variables are as described above for Formula I or any one of the sixth to eleventh embodiments. Alternatively, as part of the twelfth embodiment, R in the compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is 4 is selected from hydrogen, methyl, methoxy, isopropoxy, OCDF2, -OCHF2, -N(CH3)2, NH2, chloro, and cyclopropyl, wherein the variables are as described above for Formula I or any one of the sixth to eleventh embodiments.

[0080] As part of a thirteenth embodiment, in the compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, R 2 is 1 to 3 selected from R c substituted 4 to 6-membered nitrogen-containing monocyclic heterocyclic group, or optionally substituted by 1 to 3 groups selected from R d substituted 7- to 10-membered nitrogen-containing fused or spiro bicyclic heterocyclic group, wherein the variables are as described above for Formula I or any one of the sixth to twelfth embodiments. Alternatively, as part of the thirteenth embodiment, R in the compound of Formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof is 2 is azetidinyl, piperidinyl, morpholinyl or pyrrolidinyl, each of which is replaced by 1 to 3 groups selected from R cor R in the compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof 2 is 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[3.1.0]hexyl, 1,4-dioxa-8-azaspiro[4.5]decyl or 1,2,3,6-tetrahydropyridinyl, each of which is replaced by 1 to 3 groups selected from R d wherein the variables are as described above for Formula I or any one of the sixth to twelfth embodiments.

[0081] As part of a fourteenth embodiment, in the compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, R c and R d are each independently selected from halogen, cyano, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkoxy, -S(O)R a and -SO2NR a R b , wherein the variables are as described above for Formula I or any one of the sixth through thirteenth embodiments. Alternatively, as part of the fourteenth embodiment, R in the compound of Formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof c and R d Each is independently selected from fluoro, cyano, CF3, methoxy, isopropyl, OCF3, -S(O)CH3 and -SO2N(CH3)2, wherein the variables are as described above for Formula I or any one of the sixth to thirteenth embodiments.

[0082] As part of a fifteenth embodiment, in the compound of formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, R 8 and R 9 Together they form a cyclopropyl group, wherein the variables are as described above for Formula I or any one of the sixth through fourteenth embodiments.

[0083] As part of a sixteenth embodiment, Y in a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is hydrogen or -C(O)OCH(CH3)OC(O)CH3, wherein the variables are as described above for Formula I or any one of the sixth through fifteenth embodiments. Alternatively, Y in a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the variables are as described above for Formula I or any one of the sixth through fifteenth embodiments.

[0084] The examples further disclose other compounds, which are also included in the present disclosure. The compounds themselves also include their pharmaceutically acceptable salts and neutral forms.

[0085] 4. Use, preparation and administration

[0086] The compounds and compositions described herein are generally useful in anti-cancer therapy. In one aspect, the disclosed compounds and compositions can be used as inhibitors of KRAS(G12D). Their mechanism of action includes, but is not limited to, inhibiting KRAS(G12D), thereby preventing downstream signaling that may lead to inhibition of cancer cell growth and / or induction of cancer cell apoptosis or other KRAS or KRAS(G12D) functions. In one aspect, the disclosed compounds can effectively inhibit KRAS(G12D).

[0087] Therefore, provided herein is a method for treating a condition that is responsive to the inhibition of KRAS (G12D), comprising administering a therapeutically effective amount of one or more compounds or compositions described herein to a subject in need thereof. The application also provides the use of one or more compounds or compositions described herein in the preparation of a medicament for treating a condition that is responsive to the inhibition of KRAS (G12D). The application further provides the use of compounds or compositions described herein for treating a condition that is responsive to the inhibition of KRAS (G12D).

[0088] In one aspect, the condition treated by the present compounds and compositions is cancer. The term "cancer" or "tumor" is well known in the art and refers to cells with typical oncogenic characteristics such as uncontrolled proliferation, immortality, potential metastasis, rapid growth and proliferation rate, reduced cell death / apoptosis, and certain characteristic morphological features present in a subject. Cancer cells typically exist in the form of solid tumors. However, cancer also includes non-solid tumors, such as blood tumors, such as leukemias, in which cancer cells are derived from the bone marrow. As used herein, the term "cancer" includes pre-malignant cancers as well as malignant cancers. Cancers include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytoma, medulloblastoma, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic leukemia, and myeloblastic leukemia), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia disease, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt lymphoma, proliferative disorders (dysplasia and variants), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythrocytic leukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, flat Lymphosarcoma, liposarcoma, lung cancer, lymphoendothelial sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, sarcoma, neuroblastoma, non-small cell lung cancer Lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Weil's tumor.Other cancers include primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gallbladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, kidney cancer, urethra cancer, female genital tract cancer, uterine cancer, gestational trophoblastic disease, male genital tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary cancer, hemangioma, bone and soft tissue sarcoma, Kaposi sarcoma, nerve cancer, eye cancer, meningeal cancer, glioblastoma, neuroma, neuroblastoma, Schwann tumor, solid tumors caused by leukemia and other hematopoietic malignancies, metastatic melanoma, recurrent or refractory ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumors, colorectal cancer, gastric cancer, melanoma, glioblastoma multiforme, non-squamous non-small cell lung cancer, malignant glioma, upper Cutaneous ovarian cancer, primary peritoneal serous carcinoma, metastatic liver cancer, neuroendocrine cancer, refractory malignancies, triple-negative breast cancer, HER2-amplified breast cancer, nasopharyngeal cancer, oral cancer, bile duct cancer, hepatocellular carcinoma, squamous cell carcinoma of the head and neck (SCCHN), non-medullary thyroid cancer, recurrent glioblastoma multiforme, neurofibromatosis type 1, CNS cancers, liposarcoma, myometrial sarcoma, salivary gland cancer, mucosal melanoma, condyloma acuminata / lichen planus melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumors, triple-negative breast cancer, colorectal cancer, sarcoma, melanoma, renal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancies.

[0089] As used herein, the term "solid tumor" is understood to mean any pathogenic tumor that can be palpated or detected using imaging methods as a three-dimensional abnormal growth. Solid tumors are distinguished from hematologic tumors such as leukemia. However, the cells of hematologic tumors originate from the bone marrow; therefore, the tissue in which the cancer cells arise is likely to be hypoxic, solid tissue.

[0090] "Tumor tissue" or "tumor-like tissue" is understood to be the cells, extracellular matrix and other naturally occurring components associated with solid tumors.

[0091] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound described herein in the composition will also depend on the specific compound in the composition.

[0092] Example

[0093] Chemical synthesis

[0094] The following representative examples are intended to help illustrate the present disclosure and are not intended to limit the scope of the present invention, nor should they be construed as limiting the scope of the present invention. Unless otherwise stated, the general starting materials used were obtained from commercial sources or prepared in other examples.

[0095] The compounds described herein were prepared according to the procedures outlined in Scheme 1.

[0096] Solution 1

[0097]

[0098] Preparation of Example 1

[0099] Step 1: 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine. To a mixture of Intermediate 1-1 (50.0 g, 232 mmol, 1.00 eq) in toluene (150 mL) at 25°C was added POCl₃ (178 g, 1.16 mol, 108 mL, 5.00 eq). DIEA (65.9 g, 510 mmol, 88.9 mL, 2.20 eq) was then added to the mixture at 40°C. The mixture was stirred at 110°C for 12 hours. LC-MS indicated the presence of the desired MS. The reaction mixture was distilled under reduced pressure at 90°C to remove POCl₃. The residue was slowly poured into saturated NaHCO₃ (maintaining pH = 8). During this time, a yellow precipitate formed. The precipitate was collected by filtration and washed with H₂O. The solid was used directly in the next step. Intermediate 1-2 (101 g, 400 mmol, 86.2% yield) was obtained as a brown solid. HNMR (DMSO-d 6, 400MHz): δ8.92-8.86(m,1H). LC-MS: m / z 253.9[M+H] + .

[0100] Step 2: tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a mixture of intermediate 1-2 (48.5 g, 192 mmol, 1.00 eq) in DCM (485 mL) was added a solution of compound 2a (38.7 g, 183 mmol, 0.950 eq) in DCM (120 mL). DIEA (49.7 g, 384 mmol, 66.9 mL, 2.00 eq) was then added to the mixture at -40°C and stirred under N₂ at -40°C for 0.5 hr. LCMS indicated consumption of intermediate 1-2, and the desired MS was detected. The mixture was quenched with HCl (0.5 M), and the aqueous phase was acidified to pH 6-7 before separation and the organic layer dried over Na₂SO₄. The residue was purified by column chromatography (SiO2, TLC: petroleum ether: ethyl acetate = 3:1, R f =0.4, petroleum ether:ethyl acetate=10:1 to 1:1, R f =0.4). Intermediate 1-3 was obtained as a white solid (120 g, 280 mmol, yield 72.9%). H NMR (DMSO-d6, 400 MHz): δ 9.13-8.98 (m, 1H), 4.67-4.36 (m, 2H), 4.35-4.21 (m, 2H), 3.87-3.50 (m, 2H), 1.85-1.71 (m, 2H), 1.66-1.56 (m, 2H), 1.46 (s, 9H). LC-MS: m / z 428.0 [M+H] + .

[0101] Step 3: tert-Butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a stirred mixture of [1-(hydroxymethyl)cyclopropyl]methanol (14.31 g, 140 mmol, 3 eq) and t-BuONa (13.46 g, 140 mmol, 3 eq) in THF at 0°C was added portionwise tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 g, 46.697 mmol, 1 eq) under a nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere for 1 h. The reaction was quenched with water at 0°C. The resulting mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with saturated aqueous NaCl (2 x 5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give Intermediate 1-4 (14.5 g, 62.86%) as a white solid. LCMS (ES, m / z): 494 [M+H]+

[0102] Step 4: tert-Butyl 3-(8-fluoro-7-(7-fluoro-2-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-((l-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Under nitrogen atmosphere, a solution of intermediate 1-4 (3 g, 6.073 mmol, 1.0 eq) and ((3-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.63 g, 9.110 mmol, 1.5 eq) in 1,4-dioxane (40 mL) was treated with Pd(PPh3)4 (1.40 g, 1.215 mmol, 0.2 eq) and K3PO4 (3.87 g, 18.219 mmol, 3.0 eq). The resulting mixture was stirred overnight at 80 ° C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CHCl (3 x 10 mL). The combined organic layers were washed with saturated aqueous NaCl (2 x 5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH2Cl2 / MeOH (10:1) as the eluent to afford Intermediate 1-5 (2.5 g, 66.38%) as a yellow solid. LCMS (ES, m / z): 620 [M+H] +

[0103] Step 5: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a stirred solution of Intermediate 5 (200 mg, 0.323 mmol, 1 eq) in DCM was added Dess-Martin (410.38 mg, 0.969 mmol, 3 eq) portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated aqueous NaHCO at 0°C. The resulting mixture was quenched with CHCl (3 x 10 mL). The combined organic layers were washed with saturated NaCl (aq) (3 x 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ES, m / z): 618 [M+H] +

[0104] Step 6: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a stirred solution of Intermediate 1-6 (100 mg, 0.162 mmol, 1 eq) and 4-fluoropiperidine hydrochloride (45.17 mg, 0.324 mmol, 2 eq) in DMF was added STAB (102.87 mg, 0.486 mmol, 3 eq) portionwise at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated aqueous NaCl (2 x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ES, m / z): 605 [M+H] +

[0105] Step 7: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. To a stirred solution of Intermediate 1-7 (80 mg, 0.132 mmol, 1.0 eq) in DCM was added TFA (1 mL, 13.463 mmol, 101.84 eq) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column, XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (30% ACN to 80% in 10 min); detector, UV 220 nm) to give the compound of Example 1 (38.15 mg, 47.69%) as a white solid. 1 H NMR (DMSO-d6, 400MHz): δ10.15(s,1H),9.03(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),4.69(dt,J=7.6,3.6Hz,1H),4.48(d,J=12.0Hz,1H),4.3 4–4.22(m,3H),3.93(d,J=1.2Hz,1H),3.67–3.59(m,1H),3.54(t,J=5.6Hz,3H),2.74(s,1H),2.56(s,2 H), 2.30 (t, J = 7.6Hz, 4H), 1.88–1.76 (m, 2H), 1.66 (s, 6H), 0.64 (q, J = 3.2Hz, 2H), 0.40 (t, J = 3.2Hz, 2H). LC-MS: m / z 628.9[M+H] + .

[0106] The following compounds in Table 1 were prepared according to the methods described above using appropriate starting materials.

[0107] Table 1

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127] The compounds described herein are also selected from any one of the following:

[0128]

[0129]

[0130]

[0131]

[0132]

[0133] or a pharmaceutically acceptable salt of any one of the foregoing.

[0134] Bioassay / Detection

[0135] cell lines

[0136] The following cancer cell lines were used: AGS gastric carcinoma [heterozygous G12D] (ATCC, CRL-1739); A-427 lung carcinoma [heterozygous G12D] (ATCC, HTB-53); ASPC1 pancreatic carcinoma [homozygous G12D] (ATCC, CRL-1682); and SW1990 pancreatic carcinoma [homozygous G12D] (ATCC CRL-2172). Cell lines were cultured essentially according to ATCC recommendations.

[0137] KRAS(G12D) / SOS1 homogeneous time-resolved fluorescence (HTRF) assay

[0138] Unless otherwise stated, the KRAS-G12D / SOS1 binding assay kit (Cisbio, 63ADK000CB17PEH) was used to measure the binding of the test compound to the KRAS (G12D) target protein by homogeneous time-resolved fluorescence in the absence of GTP, thereby blocking the interaction between KRAS (G12D) and SOS1 protein. A 3-fold serial dilution of each test compound was prepared, ranging from 20 μM to 1.02 nM. The test compound was mixed and incubated with the reaction components, incubated at 4 ° C for 3 hr in a sealed plate, and fluorescence was measured using a PerkinElmer Envision plate reader. The IC of KRAS (G12D) -SOS1 was calculated using GraphPad Prism 7 software. 50 The results are listed.

[0139] Cancer cell line proliferation ( Determination)

[0140] AGS, A-427, ASPC1, SW1990, and GP2D cells were plated at 4,000 cells / well in 96-well tissue culture plates and incubated at 37°C / 5% CO2 for 72 hours in 100 μl of culture medium. 3-fold serial dilutions of each test compound were prepared from 20 μM to 1.02 nM. Each cell line was then treated with various concentrations of the test compound at a final concentration of 0.5% DMSO / well and incubated at 37°C / 5% CO2. 100 μl of Reagents (Promega Corporation, Madison, WI) were added to each well and processed according to the manufacturer's protocol. Results were analyzed in GraphPad 7 software and IC was calculated. 50The results are listed in Table 2. KRAS (G12D) / SOS1 HTRF assay: A. IC50 < 100 nM; B. IC50 = 100-1000 nM; C. IC50 > 1000 nM; AGS proliferation assay: A. EC50 < 100 nM; B. EC50 = 100-1000 nM; C. EC50 > 1000 nM; A427 proliferation assay: A. EC50 < 100 nM; B.EC50=100-1000nM; C.EC50>1000nM; ASPC proliferation assay; A.EC50<100nM; B.EC50=100-1000nM; C.EC50>1000nM; SW1990 proliferation assay: A.EC50<100nM; B.EC50=100-1000nM; C.EC50>1000nM.

[0141] Table 2: Biochemical and cell-based assays of compounds

[0142]

[0143]

[0144] Oral bioavailability

[0145] CD-1 mice were randomly divided into 6 groups, with 3 male mice in each compound group. The control group included reference compound 1 (50 mg / kg), reference compound 2 (25 mg / kg), and Example 1 (25 mg / kg). The compound group of the present invention included the prodrug compound of Example 52 (50 mg / kg), the compound of Example 2 (50 mg / kg), the compound of Example 3 (50 mg / kg), and the compound of Example 4 (25 mg / kg). The compounds were administered orally (PO) to each mouse in their group in a single dose. Blood samples were collected within 72 hours. Bioavailability (F%) was determined by liquid chromatography-mass spectrometry (LC-MS / MS). The average oral F% is provided in Table 3.

[0146] Table 3

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153] Compound 3 was evaluated in a human lung cancer A427 xenograft tumor model using female NOD SCID mice (6-8 weeks old). Each mouse was inoculated subcutaneously in the right flank with A427 tumor cells (1 x 10 7 ) to initiate tumor development. Once tumors reach an average size of ~170 mm 3 Mice were randomly assigned to treatment groups and then administered with the test compound or vehicle. Compound 3 was administered orally (PO) once daily at 200 mg / kg for 5 weeks. The vehicle was administered orally (PO) twice daily. Body weight and tumor volume were measured twice a week until the end of the study. The results are shown in Figure 1 and Figure 2 middle.

[0154] Compound 34 was evaluated in a human colon adenocarcinoma GP2D xenograft tumor model using female BALB / c nude mice (6-8 weeks old). Each mouse was subcutaneously inoculated with GP2D tumor cells (1×10 7 ) to initiate tumor development. Once tumors reach an average size of ~230 mm 3 Mice were randomly assigned to treatment groups and then administered with the test compound or vehicle. Compound 34 was administered orally (PO) once daily for 4 weeks at 200 mg / kg, and the vehicle was administered orally (PO) once daily for 4 weeks. Body weight and tumor volume were measured twice a week until the end of the study. The results are shown in Figure 3 and Figure 4 middle.

[0155] Although the present disclosure has been described in conjunction with specific embodiments, it should be understood that the claimed disclosure should not be unduly limited to such specific embodiments. Indeed, those skilled in the art to which the present disclosure pertains intend and appreciate that various modifications of the described manner of carrying out the disclosure are within the scope of the present disclosure as expressed by the following claims.

[0156] All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and individually indicated to be incorporated by reference.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein Y is hydrogen or -C(O)OCHR a OC(O)R b ; X is CH or N; R 1 is hydrogen, halogen, OH, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) hydroxyalkyl, -CHO, -C(O)OR b 、-C(O)ONR a R b or a 5- to 6-membered heteroaryl group optionally substituted by 1 to 3 groups selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and cyano; R 2 is 1 to 3 selected from R c substituted 4 to 6 membered monocyclic heterocyclic group or optionally substituted by 1 to 3 groups selected from R d A 6- to 10-membered bicyclic heterocyclic group substituted with a group; R 3 is selected from hydrogen, halogen, (C1-C4)alkyl, cyano and (C3-C6)cycloalkyl optionally substituted by 1 to 3 groups selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy and cyano; R 4 selected from hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, deuterated (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) alkynyl, (C1-C4) alkenyl, halogen, (C3-C6) cycloalkyl, -O(C3-C6) cycloalkyl, cyano, NH2, -NH(C1-C4) alkyl, -N[(C1-C4) alkoxy] -C4)alkyl]2, -P(O)[(C1-C4)alkyl]2 and -S(C1-C4)alkyl, wherein the (C3-C6)cycloalkyl and the (C3-C6)cycloalkyl of -O(C3-C6)cycloalkyl are optionally substituted with 1 to 3 groups selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy and cyano; R 5 is (C2-C4)alkynyl; R 6 is hydrogen or a halogen; R 7 is hydrogen or OH; R 8 and R 9 Together they form =CH or cyclopropyl; R a and R b are each independently selected from hydrogen and (C1-C4)alkyl; and R c and R d are each independently selected from halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, cyano, OH, oxo, -C(O)OR a 、-C(O)R a 、-SO2R a 、-S(O)R a 、-SO2NR a R b 、-NR a C(O)R b 、-NR a SO2R b 、-NR a R b and NO2; The condition is that when R 4 When it is (C3) alkyl, R 2 Not (C1-C4) alkyl, -C(O)OR a or -C(O)R a Substituted piperazinyl.

2. The compound according to claim 1, wherein the compound is a compound of formula II: or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound is a compound of formula III: or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein the compound is a compound of formula IV: or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4, wherein the compound is a compound of formula V: or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 1 It's hydrogen. 7 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 3 It's a halogen.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 It's fluorine.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 5 It is a (C2)alkynyl group.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 6 It's a halogen.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 6 It's fluorine.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 7 It's OH.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen, (C1-C4)alkoxy, deuterated (C1-C4)alkoxy, -N[(C1-C4)alkyl]2, halogen, (C3-C6)cycloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkyl and NH2.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, methyl, methoxy, isopropoxy, OCDF2, OCHF2, -N(CH3)2, NH2, chlorine and cyclopropyl.

16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 2 is 1 to 3 selected from R c substituted 4 to 6-membered nitrogen-containing monocyclic heterocyclic ring, or optionally substituted by 1 to 3 groups selected from R d A 7- to 10-membered nitrogen-containing fused or spiro bicyclic heterocyclic ring substituted by a group.

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 2 is azetidinyl, piperidinyl, morpholinyl or pyrrolidinyl, each of which is replaced by 1 to 3 groups selected from R c The group substituted, or R 2 is 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[3.1.0]hexyl, 1,4-dioxa-8-azaspiro[4.5]decyl or 1,2,3,6-tetrahydropyridinyl, each of which is optionally substituted by 1 to 3 groups selected from R d The group is substituted.

18. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R c and R d are each independently selected from halogen, cyano, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkoxy, -S(O)R a and -SO2NR a R b .

19. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R c and R d Each is independently selected from fluorine, cyano, CF3, methoxy, isopropyl, OCF3, -S(O)CH3 and -SO2N(CH3)2.

20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 Together they form a cyclopropyl group.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Y is hydrogen or -C(O)OCH(CH3)OC(O)CH3.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Y is hydrogen.

23. The compound according to claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt of any one of the foregoing. 24 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

25. A method of treating cancer in a subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition according to claim 24.

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