KRAS (G12V) inhibitors

Abstract

Provided are compounds of Formula I: and pharmaceutically acceptable salts and compositions, as well as their use in the treatment of conditions responsive to inhibition of KRAS (G12V).

Description

[0001] Related applications

[0002] This application claims the benefit of priority of International Application No. PCT / CN2022 / 136811, filed on December 6, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] The Kirsten rat sarcoma virus homolog (KRAS) gene, discovered as a human oncogene in the early 1980s, encodes a small, monomeric 21kDa GTPase that has long been a difficult 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 assistance of GTPase-activating proteins (GAPs). This GDP-bound state "turns off" KRAS growth-promoting signaling. KRAS can then be turned “on” again 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 cancer (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. KRAS with a glycine (G) to valine (V) mutation at the 12th codon produces a long-lived active KRAS (G12V) oncoprotein. This KRAS (G12V) mutation is observed in 31% of pancreatic adenocarcinomas, 20% of colorectal adenocarcinomas, and 19% of non-small cell lung cancers (Huang et al., Signal Trans Targ Thera, 2021, 6:386). 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 made it possible to search for small molecule inhibitors that target the glycine 12 to cysteine (G12C) mutation (Ostrem et al., Nature, 2013, 503:548-51). The G12C mutation is analogous to the G12V mutation. Incremental work against the G12C mutation has propelled efforts to target the G12V mutation. Furthermore, because the G12V mutation encodes a substitution of a hydrophobic amino acid residue (V) for a small flexible amino acid residue (G) with only a hydrogen side chain, the G12V mutation also presents a unique chemical moiety binding space. This alteration in the KRAS protein structure presents a unique space that can serve as a target for small molecule drugs that selectively inhibit the oncogenic activity of KRAS (G12V). Thus, it is desirable to design and develop small molecule drugs that target KRAS (G12V) to treat diseases such as cancer. SUMMARY

[0005] Provided herein are small molecule inhibitors of KRAS (G12V) mutant oncoproteins. KRAS (G12V) inhibitors include those having the following structural Formula I:

[0006]

[0007] and pharmaceutically acceptable salts and compositions comprising the same, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10and X is as defined herein. Also disclosed are uses of these compounds, salts, and compositions for treating a disease (e.g., a cancer) that is responsive to inhibition of KRAS(G12V). DETAILED DESCRIPTION

[0008] 1. COMPOUND OVERVIEW

[0009] As part of the first embodiment, provided are compounds of structural Formula I:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein

[0012] X is N or CR’;

[0013] R’ is selected from hydrogen, halogen, (C1-C4)alkyl, (C2-C4)alkenyl, cyano, cyano(C1-C4)alkyl, -S[halo(C1-C4)alkyl], and (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from R a

[0014] R 1 is selected from -C(=O)R 11 , -C(=O)NR 11 R 12 , -C(=O)OR 11 , -SO2R 11 , -SOR 11 , -SO2NR 11 R 12 , C(=S)NR 11 R 12 , C(=NH)NR 11 R 12 , C(=O)NR 11 NR 11 R 12 , cyano(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkyl[4 or 5-membered heterocyclyl], halo(C1-C4)alkyl, and 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R 1a

[0015] R 2 is selected from hydrogen, halogen, hydroxyl, (C1-C4)alkyl, (C1-C4)haloalkyl, cyano(C1-C4)alkyl, (C1-C4)hydroxyalkyl, -CHO, -CO2R a , -CO2NR a R b ​​or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R 2a ;

[0016] R 3 is selected from -NR c R d and -NR c C(O)R e ;

[0017] R 4 is selected from hydrogen, halogen, (Ci-C4)alkyl, cyano, and (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from R 4a ;

[0018] R 5 is selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, deuterated (Ci-C4)alkoxy, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, (C2-C4)alkynyl, (Ci-C4)alkenyl, halogen, (C3-C6)cycloalkyl, -O(C3-C6)cycloalkyl, cyano, NH2, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, -P(O)[(Ci-C4)alkyl]2, and -S(Ci-C4)alkyl;

[0019] R 6 , R 7 , and R 8 are each independently selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)cyanalkyl, (Ci-C4)hydroxyalkyl, -(Ci-C4)alkylNR a R b , -(Ci-C4)alkylC(O)NR a R b , (Ci-C4)alkylO(Ci-C4)alkyl, -(Ci-C4)alkylC(O)OR a , -(Ci-C4)alkylNR a C(O)OR b , -(Ci-C4)alkylC(O)R a , -(Ci-C4)alkylheterocyclyl, -(Ci-C4)alkylaryl, -(Ci-C4)alkylheteroaryl, (C2-C4)alkenyl, (C2-C4)haloalkenyl, (C2-C4)cyanalkenyl, (C2-C4)hydroxyalkenyl, -(C2-C4)alkenylNR a R b(C2-C4)alkynyl, (C2-C4)haloalkynyl, (C2-C4)cyanoalkynyl, (C2-C4)hydroxyalkynyl, -(C2-C4)alkynylNR a R b (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, cyano, oxo, hydroxy, -S(C1-C4)alkyl, -S(C1-C4)haloalkyl, -NR a R b (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, cyano, oxo, hydroxy, -S(C1-C4)alkyl, -S(C1-C4)haloalkyl, -NR a C(O)R b (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, cyano, oxo, hydroxy, -S(C1-C4)alkyl, -S(C1-C4)haloalkyl, -NR a (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, cyano, oxo, hydroxy, -S(C1-C4)alkyl, -S(C1-C4)haloalkyl, -NR a (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, cyano, oxo, hydroxy, -S(C1-C4)alkyl, -S(C1-C4)haloalkyl, -NR a (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, cyano, oxo, hydroxy, -S(C1-C4)alkyl, -S(C1-C4)haloalkyl, -NR a (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, cyano, oxo, hydroxy, -S(C1-C4)alkyl, -S(C1-C4)haloalkyl, -NR a (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, cyano, oxo, hydroxy, -S(C1-C4)alkyl, -S(C1-C4)haloalkyl, -NR b (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, cyano, oxo, hydroxy, -S(C1-C4)alkyl, -S(C1-C4)haloalkyl, -NR a (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, cyano, oxo, hydroxy, -S(C1-C4)alkyl, -S(C1-C4)haloalkyl, -NR b (C3-C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl, wherein said heterocyclyl, aryl, and heteroaryl of -(C1-C4)alkylheterocyclyl, -(C1-C4)alkylaryl, and -(C1-C4)alkylheteroaryl, and said (C3-C6)cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally and independently substituted with 1 to 3 groups selected from R 6a ;

[0020] R 9 and R 10 are each independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)cyanoalkyl; or R 9 and R 10 together with the carbon to which they are attached form a (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, or (C2-C4)alkenyl, each of which is optionally substituted with 1 to 3 groups selected from R 9a ;

[0021] R 11 is selected from -(C1-C 10 )alkyl, (C1-C 10 )alkynyl, (C1-C 10 )alkenyl, cyano, phenyl, 4- to 9-membered heterocyclyl, 5- to 9-membered heteroaryl, and (C3-C6)cycloalkyl, wherein said (C1-C 10 )alkyl, (C1-C 10 )alkynyl, (C1-C 10 )alkenyl, 4- to 9-membered heterocyclyl, 5- to 9-membered heteroaryl, phenyl, and (C3-C6)cycloalkyl are each optionally substituted with one or more groups selected from R 11asubstituted with 1 to 3 groups selected from R 10 ; and wherein one or more hydrogen atoms on said -(C1-C4)alkyl is optionally replaced with deuterium;

[0022] R 12 is selected from hydrogen, -(C1-C4)alkyl, and halo(C1-C4)alkyl;

[0023] R’a, R 1a , R 2a , R 4a , R 6a , R 9a , R 11a , and R cd are each independently selected from halogen, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, cyano, hydroxy, oxo, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, =CH2, -C(O)OR e , -C(O)R e , -SO2R e , -S(O)R e , -SO2NR e R f , -NR e C(O)R f , -NR e SO2R f , -NR e R f , and NO2;

[0024] R a , R b , R c , and R d are each independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)cycloalkyl, (C1-C4)cyanoalkyl, (C1-C4)hydroxyalkyl, and (C1-C4)haloalkyl; or R a and R b , when on the same nitrogen atom, can together form a heterocyclyl optionally substituted with 1 to 3 groups selected from R ab ; or when R 3 is -NR c R d , R c and R d can together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted with 1 to 3 groups selected from R cd ; and

[0025] R e and R feach independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, and (Ci-C4)haloalkyl;

[0026] provided that R 1 is not COCF3.

[0027] 2. Definitions

[0028] As used herein, the articles "a" and "an" are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. By the use of the word "a" or "an" it is intended that "one", but also "one or more" "at least one", and "one or more than one" are contemplated.

[0029] The terms "comprising" or "including," as used herein, are intended to be open-ended and permit the inclusion of unspecified elements.

[0030] As used herein, unless otherwise indicated, the term "alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, e.g., (Ci-C6)alkyl or (Ci-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 representative branched alkyl groups include isopropyl, sec-butyl, isobutyl, t-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, and the like.

[0031] As used herein, the term "alkenyl" means a saturated straight chain or branched non-cyclic hydrocarbon having, unless otherwise indicated, 2 to 10 carbon atoms (e.g., (C2-C6)alkenyl or (C2-C4)alkenyl), and having at least one carbon-carbon double bond. Representative straight chain and branched (C2-C6)alkenyl groups include ethylene, propylene, n-butenylene, n-pentenylene, n-hexenylene, n-heptenylene, n-octenylene, n-nonenylene, n-decenylene, isopropylene, sec-butylene, isobutylene, t-butylene, isopentenylene, 2-methylbutenylene, 3-methylbutenylene, 2-methylpentenylene, 3-methylpentenylene, 4-methylpentenylene, 2-methylhexenylene, 3-methylhexenylene, 4-methylhexenylene, 5-methylhexenylene, 2,3-dimethylbutenylene, 2,3-dimethylpentenylene, 2,4-dimethylpentenylene, 2,3-dimethylhexenylene, 2,4-dimethylhexenylene, 2,5-dimethylhexenylene, 2,2-dimethylpentenylene, 3,3-dimethylhexenylene, 2,2-dimethylhexenylene, 3,3-dimethylhexenylene, 4,4-dimethylhexenylene, 2-ethylpentenylene, 3-ethylpentenylene, 2-ethylhexenylene, 3-ethylhexenylene, 4-ethylhexenylene, 2-methyl-2-ethylpentenylene, 2-methyl-3-ethylpentenylene, 2-methyl-4-ethylpentenylene, 2-methyl-2-ethylhexenylene, 2-methyl-3-ethylhexenylene, 2-methyl-4-ethylhexenylene, 2,2-diethylpentenylene, 3,3-diethylhexenylene, 2,2-diethylhexenylene, 3,3-diethylhexenylene, and the like. 10)alkenyl includes ethenyl, allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, and the like.

[0032] As used herein, unless otherwise indicated, the term "alkynyl" means a saturated straight-chain or branched noncyclic hydrocarbon having 2 to 10 carbon atoms, and having at least one carbon-carbon triple bond (e.g., (C2-C6)alkynyl or (C2-C4)alkynyl). Representative straight-chain 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, and the like.

[0033] The term "aryl" used alone or as part of a larger moiety, as in "-(C1-C4)alkyl aryl," refers to monocyclic and bicyclic carbon ring systems having from 6 to 10 ring members in the ring system, wherein at least one ring in the system is aromatic. Examples include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. It is understood that optional substituents on aryl groups, when designated, can be present on any substitutable position.

[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 one or more (including all) hydrogen atoms in an alkyl group are replaced with a halogen group, wherein each halogen 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 linked through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propyloxy, and butyloxy.

[0038] "Heteroaryloxy" means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Examples of heteroaryloxy groups include, but are not limited to, -O-pyridyl, -O-thienyl, and the like.

[0039] As used herein, the term "halogen" or "halo" means F, CI, Br, or I.

[0040] As used herein, unless otherwise indicated, the term "heterocyclyl" means a 4- to 12-membered monocyclic or polycyclic (e.g., bridged bicyclic, fused bicyclic, or spiro bicyclic) saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocycle can be attached through any heteroatom or carbon atom, as valency permits. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, oxiranyl, dioxanyl, oxetanyl, dihydrofuranyl, dihydropyranyl, isoindolinyl, dihydropyridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, diazabicyclooctanyl, hexahydropyrrolizinyl, 2-azaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, octahydro-lH-pyrrolo[2,3-c]pyridinyl, and the like. Optional substituents on a heterocyclyl group can be present on any substitutable

[0041] As used herein, the term "heteroaryl" means a 5- to 12-membered aromatic group containing 1-4 heteroatoms selected from N, O, and S. The heteroaryl group can be monocyclic or bicyclic. The heteroaryl group can be attached through any heteroatom or carbon atom, as valency permits. Representative heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridinyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridinyl, quinazolinyl, purinyl, benzothienyl, and the like. Optional substituents on a heteroaryl group can be present on any substitutable position and include, for example, the position at which the heteroaryl group is attached, as valency permits.

[0042] A hyphen (-) indicates the point of attachment of the group to the variable defining it when used to describe a chemical group that can have multiple points of attachment. For example, -(Ci-C4)alkylaryl means that the point of attachment of these groups occurs on the alkyl group.

[0043] As The wavy line in the structure indicates the point of attachment of the described group to the defined variable.

[0044] The term "KRAS" refers to the protein product of the KRAS proto-oncogene, GTPase gene.

[0045] The term "KRAS(G12V)" refers to the protein product of a KRAS gene carrying a mutation that results in a substitution of valine for glycine at position 12 of KRAS.

[0046] The term "SOS1" refers to the protein product of the SOS1 gene, which functions as a guanine nucleotide exchange factor for RAS proteins.

[0047] The compounds described herein can have chiral centers and / or geometric centers (E- and Z-isomers). It will be understood that the disclosure encompasses all stereoisomers and geometric isomers. Tautomeric forms of the compounds described herein are also part of the disclosure.

[0048] When the stereochemistry of a disclosed compound is named or described in a structure, the named or described 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 weight of one stereoisomer divided by the weight of the described stereoisomer plus the weight of the other stereoisomers.

[0049] When used in medicine, the pharmaceutically acceptable salts of the disclosed compounds refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid / anionic or base / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (such as hydrochloric, hydrobromic, phosphoric, nitric, and sulfuric acids) and salts of organic acids (such as acetic, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present application having an acidic group (such as a carboxylic acid) 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 and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts). Compounds having a quaternary ammonium group also contain a counterion such as chloride, bromide, iodide, acetate, perchlorate, and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates, and salts with amino acids such as glutamic acid.

[0050] The term "pharmaceutically acceptable carrier" means 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 (e.g., human serum albumin), buffer substances (e.g., phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0051] 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, e.g., non-human primates, mice, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles. In preferred embodiments, the subject is a human, which can be referred to as a patient.

[0052] As used herein, the terms "treat," "treating" or "treatment" refer to an action that achieves a benefit or desired clinical outcome, including, but not limited to, reducing or ameliorating one or more signs or symptoms of a disease or condition, reducing the severity of a disease, stabilizing (i.e., not worsening) a disease state, ameliorating or relieving a disease state, reducing the rate of disease progression or time to disease progression, and remission (whether partial or total). "Treatment" can also mean prolonging survival as compared with expected survival if not treated. Treatment does not require cure.

[0053] A "therapeutically effective amount" refers to an amount that is sufficient to treat a disease in a subject. A therapeutically effective amount can be administered in one or more administrations. In one aspect, a therapeutically effective amount refers to a dosage of about 0.01 to about 100 mg / kg body weight / day.

[0054] The terms "administer," "administering," or "administration" include any method of delivering a pharmaceutical composition or agent to a particular location in a subject's system or in or on a subject's body. In certain embodiments, the agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, transdermally, or mucosally. In certain embodiments, the agent is administered intravenously. In certain embodiments, the agent is administered orally. Administration of the agent can be performed collaboratively by multiple people. Administration of the agent includes, for example, prescribing the agent to be administered to a subject and / or directly or through another providing instructions for taking a particular formulation, as well as self-delivery, such as oral delivery, subcutaneous delivery, intravenous delivery through a central catheter, etc.; or delivery by a trained professional, such as intravenous delivery, intramuscular delivery, intratumoral delivery, etc.

[0055] 3. The compound of claim 1 or 2, wherein R

[0056] As part of the second embodiment, in the compound of structural formula I, R 1 is selected from -C(=O)R 11 , -C(=O)NR 11 R 12 , -C(=O)OR 11 , -SO2R 11 , -SOR 11 , -SO2NR 11 R 12 , and 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R 1a ;

[0057] R 2 is selected from hydrogen, halogen, hydroxyl, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, -CHO, -CO2R a , -CO2NR a R b , or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R 2a ;

[0058] R 5 is selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (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)alkyl]2, -P(O)[(C1-C4)alkyl]2, and -S(C1-C4)alkyl;

[0059] R 11 is selected from -(C1-C 10 )alkyl, (C1-C 10 )alkynyl, (C1-C 10 )alkenyl, cyano, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl, wherein each of the (C1-C 10 )alkyl, (C1-C 10 )alkynyl, (C1-C 10 )alkenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from R 11a , and wherein one or more hydrogen atoms on the -(C1-C 10 )alkyl is optionally replaced with deuterium;

[0060] R'a, R 1a , R 2a , R 4a , R 6a , R 9a , R 11a and R cd are each independently selected from the group consisting of halogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, cyano, hydroxyl, oxo, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, -C(0)OR e , -C(0)R e , -SO2R e , -S(0)R e , -SO2NR e R f , -NR e C(0)R f , -NR e SO2R f , -NR e R f and NO2; and

[0061] R e and R f are each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl and (Ci-C4)haloalkyl. Alternatively, as part of a second embodiment, the compound of structural formula I has structural 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, R 2 in the compound of formula I or II is hydrogen or cyano(Ci-C4)alkyl, wherein the remaining variables are as described above for formula I. Alternatively, as part of a third embodiment, R 2 in the compound of formula I or II is hydrogen, wherein the remaining variables are as described above for formula I.

[0065] As part of a fourth embodiment, X in the compound of formula I or II is N, wherein the remaining variables are as described above for formula I or as described for the third embodiment.

[0066] As part of a fifth embodiment, R 6 , R 7 and R 8each independently selected from the group consisting of (C2-C4)alkynyl, hydroxyl, and halogen, wherein the remaining variables are as described above for Formula I or as described in the third or fourth embodiment.

[0067] As part of the sixth embodiment, R 6 is halogen, wherein the remaining variables are as described above for Formula I or as described in any of the third through fifth embodiments. Alternatively, as part of the sixth embodiment, R 6 is fluorine, wherein the remaining variables are as described above for Formula I or as described in any of the third through fifth embodiments.

[0068] As part of the seventh embodiment, R 7 is (C2-C4)alkynyl, wherein the remaining variables are as described above for Formula I or as described in any of the third through sixth embodiments. Alternatively, as part of the seventh embodiment, R 7 is ethynyl, wherein the remaining variables are as described above for Formula I or as described in any of the third through sixth embodiments.

[0069] As part of the eighth embodiment, R 8 is hydroxyl, wherein the remaining variables are as described above for Formula I or as described in any of the third through seventh embodiments.

[0070] As part of the ninth embodiment, R 5 is hydrogen, (C2-C4)alkynyl, deuterated (C1-C4)alkoxy, or (C1-C4)alkoxy, wherein the remaining variables are as described above for Formula I or as described in any of the third through eighth embodiments. Alternatively, as part of the ninth embodiment, R 5 is hydrogen or (C1-C4)alkoxy, wherein the remaining variables are as described above for Formula I or as described in any of the third through eighth embodiments. Alternatively, as part of the ninth embodiment, R 5 is hydrogen or methoxy, wherein the remaining variables are as described above for Formula I or as described in any of the third through eighth embodiments.

[0071] As part of the tenth embodiment, R 4 is halogen, wherein the remaining variables are as described above for Formula I or as described in any of the third through ninth embodiments. Alternatively, as part of the tenth embodiment, R 4fluoro, wherein the remaining variables are as described above for Formula I or as described in any of the third through eleventh embodiments. Alternatively, as part of the thirteenth embodiment, R

[0072] As part of the eleventh embodiment, R 9 and R 10 together with the carbon to which they are attached form a (C3-C6)cycloalkyl group, wherein the remaining variables are as described above for Formula I or as described in any of the third through tenth embodiments. Alternatively, as part of the eleventh embodiment, R 9 and R 10 together with the carbon to which they are attached form a cyclopropyl group, wherein the remaining variables are as described above for Formula I or as described in any of the third through tenth embodiments.

[0073] As part of the twelfth embodiment, R 3 is -NR c R d , wherein the remaining variables are as described above for Formula I or as described in any of the third through eleventh embodiments. Alternatively, as part of the twelfth embodiment, R 3 is -NR c R d ; and R c and R d together with the nitrogen atom to which they are attached form a 5- to 7- membered heterocyclyl group optionally substituted with one or more groups selected from R cd , wherein the remaining variables are as described above for Formula I or as described in any of the third through eleventh embodiments. In another alternative embodiment, as part of the twelfth embodiment, R 3 is 3-azabicyclo[3.1.0]hexyl or piperidinyl optionally substituted with one or more groups selected from R cd , wherein the remaining variables are as described above for Formula I or as described in any of the third through eleventh embodiments. In another alternative embodiment, as part of the twelfth embodiment, R 3 is piperidinyl optionally substituted with one or more groups selected from R cd , wherein the remaining variables are as described above for Formula I or as described in any of the third through eleventh embodiments.

[0074] As part of the thirteenth embodiment, R cd=CH2, cyano, halo(Ci-C4)alkyl, or halo, wherein the remaining variables are as described above for Formula I or as described in any of the third through twelfth embodiments. Alternatively, as part of the thirteenth embodiment, R cd is halo, wherein the remaining variables are as described above for Formula I or as described in any of the third through twelfth embodiments. Alternatively, as part of the thirteenth embodiment, R cd is fluoro, wherein the remaining variables are as described above for Formula I or as described in any of the third through twelfth embodiments.

[0075] As part of the fourteenth embodiment, R 1 is selected from -C(=O)R 11 , -C(=O)NR 11 R 12 , -C(=O)OR 11 , -SO2R 11 , C(=S)NR 11 R 12 , C(=NH)NR 11 R 12 , C(=O)NR 11 NR 11 R 12 , cyano(Ci-C4)alkyl, (Ci-C4)alkyl, (Ci-C4)alkyl[4 or 5-membered heterocyclyl], halo(Ci-C4)alkyl, and -SO2NR 11 R 12 , wherein the remaining variables are as described above for Formula I or as described in any of the third through thirteenth embodiments. Alternatively, as part of the fourteenth embodiment, R 1 is selected from -C(=O)R 11 , -C(=O)NR 11 R 12 , -C(=O)OR 11 , -SO2R 11 , and -SO2NR 11 R 12 , wherein the remaining variables are as described above for Formula I or as described in any of the third through thirteenth embodiments.

[0076] As part of the fifteenth embodiment, R 11 is selected from -(Ci-C 10 )alkyl, (Ci-C 10 )alkynyl, phenyl, 4 to 9-membered heterocyclyl, 5 to 9-membered heteroaryl, and (C3-C6)cycloalkyl, wherein the (Ci-C10 )alkyl, (C1-C 10 )alkynyl, 4- to 9-membered heterocyclyl, phenyl 5- to 9-membered heteroaryl and (C3-C6)cycloalkyl, each optionally substituted with one or more groups selected from R 11a , wherein the remaining variables are as described above for Formula I or as described in any of the third through fourteenth embodiments. Alternatively, as part of a fifteenth embodiment, R 11 in a compound of Formula I or II is selected from -(C1-C 10 )alkyl, (C1-C 10 )alkynyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and (C3-C6)cycloalkyl, wherein the (C1-C 10 )alkyl, (C1-C 10 )alkynyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and (C3-C6)cycloalkyl are each optionally substituted with 1 to 3 groups selected from R 11a , wherein the remaining variables are as described above for Formula I or as described in any of the third through fourteenth embodiments. Alternatively, as part of a fifteenth embodiment, R 11 in a compound of Formula I or II is selected from -(C1-C4)alkyl, (C1-C4)alkynyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyrazolyl, tetrazolyl, imidazolyl, cyclopropyl and cyclopentyl, each optionally substituted with 1 to 3 groups selected from R 11a , wherein the remaining variables are as described above for Formula I or as described in any of the third through fourteenth embodiments.

[0077] As part of a sixteenth embodiment, R 11a in a compound of Formula I or II is selected from halogen, (C1-C4)alkoxy, cyano, hydroxy, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, -C(O)OR e , -C(O)R e and -NR e R f , wherein the remaining variables are as described above for Formula I or as described in any of the third through fifteenth embodiments. Alternatively, as part of a sixteenth embodiment, R 11a in a compound of Formula I or II is selected from halogen, (C1-C4)alkoxy, cyano, hydroxy, cyclopropyl, morpholinyl, -C(O)OR e , -C(O)R e and -NR e R f , wherein the remaining variables are as described above for Formula I or as described in any of the third through fifteenth embodiments.

[0078] As part of the seventeenth embodiment, R 1 Selected from -COCH2CN, -CO(CH2)2CN, -COCH2CH(CH3)2, -COCH2C(CH3)3, -CONHC(CH3)3, -CONHCH(CH3)2, -CON(CH3)2, C(O)OCH2CH3, S(O)2CH2CH(CH3)2, COCH(OH)2, C(O)OCH2CH(CH3)2, CONHCO(CH3)3, COCH2CF3, CONH(CH3)3, S(O)2NHCH(CH3)2、CONHCH2CF3、 CH2CH3, S(O)2CH2CN, CONHCH2CN, C(O)O(CH3)3, COCH3, C(O)OCH(CH3)2, C(O)(CH3)3 and wherein the remaining variables are as described above for Formula I or as described in any one of the third to fifteenth embodiments.

[0079] Additional compounds and salts thereof are disclosed in the Examples section, which are included herein.

[0080] 4. Use, preparation and administration

[0081] 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(G12V). Their mechanism of action includes, but is not limited to, inhibiting KRAS(G12V), 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(G12V) functions. In one aspect, the disclosed compounds can effectively inhibit KRAS(G12V).

[0082] Therefore, provided herein is a method for treating a condition that is responsive to the inhibition of KRAS (G12V), 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 (G12V). The application further provides the use of a compound or composition described herein for treating a condition that is responsive to the inhibition of KRAS (G12V).

[0083] In one aspect, the conditions treated by the compounds and compositions of the present application are cancer. The term "cancer" or "neoplasm" as is well known in the art refers to cells having the characteristic features of a typical cancer cell, e.g., uncontrolled proliferation, immortality, potential for metastasis, rapid growth and proliferation rate, decreased cell death / apoptosis, and certain characteristic morphological features, present, for example, in a subject. Cancer cells are typically present in the form of a solid tumor. However, cancer also includes non-solid tumors (e.g., blood tumors, such as leukemia), where cancer cells originate 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 lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, biliary duct cancer, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, dysproliferative lesions (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaria, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell 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, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.Other cancers include primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gallbladder cancer, bile duct cancer, small bowel cancer, urinary tract cancer, kidney cancer, urethral cancer, female genital tract cancer, uterine cancer, gestational trophoblastic disease, male genital tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumor, endocrine gland tumor, thyroid cancer, adrenal cancer, pituitary cancer, hemangioma, bone and soft tissue sarcoma, Kaposi's sarcoma, neural cancer, ocular cancer, meningeal cancer, glioblastoma, neuroma, neuroblastoma, schwannoma, solid tumors resulting from hematopoietic malignancies (e.g., leukemia), metastatic melanoma, recurrent or refractory ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumor, colorectal cancer, gastric cancer, melanoma, glioblastoma multiforme, non-squamous non-small cell lung cancer, malignant glioma, epithelial 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, cholangiocarcinoma, hepatocellular carcinoma, squamous cell carcinoma of the head and neck (SCCHN), non-medullary thyroid cancer, recurrent glioblastoma multiforme, neurofibromatosis type 1, CNS cancer, liposarcoma, leiomyosarcoma, salivary gland cancer, mucosal melanoma, acral / lentiginous melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumors, triple negative breast cancer, colorectal cancer, sarcoma, melanoma, kidney cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancies.

[0084] "Solid tumor" as used herein is understood to be any pathogenic tumor that is palpable or detected as a three-dimensional abnormal growth using imaging methods. Solid tumors are distinguished from blood tumors (e.g., leukemia). However, the cells of blood tumors originate in the bone marrow; thus, the tissue from which the cancer cells arise is a solid tissue that can be hypoxic.

[0085] "Tumor tissue" or "neoplastic tissue" is understood to be the cells, extracellular matrix, and other naturally occurring components associated with a solid tumor.

[0086] The specific dose and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the particular compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend on the particular compound in the composition.

[0087] Examples

[0088] Chemical synthesis

[0089] The following representative examples are intended to aid in illustrating the present disclosure and are not intended to limit the scope of the present application, nor should they be interpreted as limiting the scope of the present application. General starting materials used, unless otherwise stated, were obtained from commercial sources or prepared by other examples.

[0090] Preparation of compounds

[0091] The compounds claimed herein were prepared following the procedures outlined in Scheme 1, with reference to the example in the synthesis of compound (1).

[0092] Scheme 1

[0093]

[0094] Preparation Example 1

[0095] 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) was added POCl3(178 g, 1.16 mol, 108 mL, 5.00 eq) at 25 °C. Subsequently, DIEA (65.9 g, 510 mmol, 88.9 mL, 2.20 eq) was added to the mixture at below 40 °C. The mixture was stirred at 110 °C for 12 hr. LC-MS showed detection of desired MS. The reaction mixture was distilled at 90 °C under reduced pressure to remove POCl3. The residue was poured into saturated NaHCO3(maintained pH = 8). During this period, a yellow precipitate was generated. It was collected by filtration and washed with H2O. The solid was used directly for the next step. Intermediate 1-2 (101 g, 400 mmol, 86.2% yield) was obtained as a brown solid. HNMR (DMSO-d6, 400 MHz): δ 8.92-8.86 (m, 1H). LC-MS: m / z 253.9 [M+H] + .

[0096] 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 at -40°C under N2 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) was purified. The obtained intermediate 1-3 (120 g, 280 mmol, 72.9% yield) was obtained as a white solid. HNMR (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] + .

[0097] Step 3: 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-carboxylic acid tert-butyl ester. 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 was added 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 (20 g, 46.697 mmol, 1 eq) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h under nitrogen atmosphere. 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 afford intermediate 1-4 (14.5 g, 62.86%) as a white solid. LCMS (ES, m / z): 494 [M+H]+.

[0098] Step 4: 3-(8-fluoro-7-(7-fluoro-2-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. 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) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. The reaction was quenched with water at room temperature. 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 CH2Cl2 / MeOH (10:1) to afford intermediate 1-5 (2.5 g, 66.38%) as a yellow solid. LCMS (ES, m / z): 620 [M+H]+. + .

[0099] Step 5: 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-carboxylic acid tert-butyl ester. 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) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHC03(aq.) at 0 °C. The resulting mixture was extracted with CH2Cl2(3 x 10 mL). The combined organic layers were washed with saturated NaCl (aq.) (3 x 5 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly for the next step without further purification. LCMS (ES, m / z): 618 [M+H] + .

[0100] Step 6: 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-carboxylic acid tert-butyl ester. 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) in portions 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 NaCl (aq.) (2 x 5 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly for the next step without further purification. LCMS (ES, m / z): 605 [M+H] + .

[0101] 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 using the following conditions (column, XBridge Prep OBD C18 column, 30x150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (30% ACN increased to 80% in 10 min); detector, UV 220 nm) to give 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),4.34–4.2 2(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,2H),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] + .

[0102] The compounds in Table 1 below were prepared according to the methods described above using appropriate starting materials and conditions for amide formation, urea formation, sulfonamide formation, carbamate formation, and amine alkylation.

[0103] Table 1

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181] Bioassay / assay

[0182] Cell line

[0183] The following cancer cell lines were used: SW620 colorectal adenocarcinoma homozygous G12V (ATCC, CCL-227); NCIH727 lung carcinoid homozygous G12V (ATCC, CRL-5815). Cell lines were cultured essentially according to ATCC recommendations.

[0184] KRAS(G12V) / SOS1 homogeneous time-resolved fluorescence (HTRF) assay

[0185] Unless otherwise stated, the KRAS-G12V / SOS1 binding assay kit (Cisbio, 63ADK000CB18PEH) was used according to the manufacturer's instructions to measure the binding of test compounds to the KRAS (G12V) target protein by homogeneous time-resolved fluorescence in the absence of GTP, which in turn blocked the interaction between KRAS (G12V) and SOS1 proteins. 3-fold serial dilutions of each test compound ranging from 20 μM to 1.02 nM were prepared. The test compound was mixed and incubated with the reaction components, incubated at 4 ° C for 3 hr in a sealed plate, and the fluorescence was measured using a PerkinElmer Envision plate reader. The IC of KRAS (G12V) -SOS1 was calculated using GraphPad Prism 8.0 software. 50 The results are shown in Table 2.

[0186] Cancer cell line proliferation (CellTiter- Determination)

[0187] SW620 and NCIH727 cells were plated at 1,000 cells / well in 384-well tissue culture plates and incubated in 40 μl of culture medium at 37°C / 5% CO2 for 72 hours. 3-fold serial dilutions of each test compound ranging from 10 μM to 0.51 nM were prepared. 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 for 72 hours. 40 μl of CellTiter- Reagents (Promega Corporation, Madison, WI) were added to each well and processed according to the manufacturer's protocol. The results were analyzed and the IC was calculated using GraphPad 8.0 software. 50 The results are listed in Table 2.

[0188] Table 2: Biochemical and cell-based assays of compounds

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195] KRAS(G12V) / SOS1 HTRF assay: A. IC50 < 100 nM; B. IC50 = 100-1000 nM; C. IC50 > 1000 nM; SW620 proliferation assay: A. EC50 < 100 nM; B. EC50 = 100-1000 nM; C. EC50 > 1000 nM; NCI-H727 proliferation assay: A. EC50 < 100 nM; B. EC50 = 100-1000 nM; C. EC50 > 1000 nM.

[0196] Although the present disclosure has been described in conjunction with specific embodiments, it should be understood that the disclosure claimed should not be unduly limited to these specific embodiments. In fact, it is intended and understood by those skilled in the art to which the present disclosure relates that various modifications to the described manner of implementing the present disclosure are within the scope of the present disclosure as represented by the following claims.

[0197] 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 having the structural formula I: or a pharmaceutically acceptable salt thereof, wherein X is N or CR’; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R' is selected from the group consisting of hydrogen, halogen, (Ci-C4)alkyl, (C2-C4)alkenyl, cyano, cyano(Ci-C4)alkyl, -S[halo(Ci-C4)alkyl], and (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from R' a ; R 1 selected from -C(=O)R 11 , -C(=O)NR 11 R 12 , -C(=O)OR 11 , -SO2R 11 , -SOR 11 , -SO2NR 11 R 12 , C(=S)NR 11 R 12 , C(=NH)NR 11 R 12 , C(=O)NR 11 NR 11 R 12 , cyano(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkyl[4- or 5-membered heterocyclyl], halo(C1-C4)alkyl and 5- to 6-membered heteroaryl, wherein said 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R 1a ; R 2 selected from hydrogen, halogen, hydroxyl, (Ci-C4)alkyl, (Ci-C4)haloalkyl, cyano(Ci-C4)alkyl, (Ci-C4)hydroxyalkyl, -CHO, -C02R a , -C02NR a R b or 5- to 6-membered heteroaryl, wherein said 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R 2a ; R 3 selected from -NR c R d and -NR c C(O)R e ; R 4 selected from hydrogen, halogen, (Ci-C4)alkyl, cyano and (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from R 4a of the formula (R1)a-R2, wherein a is 1 or 2, R1is selected from hydrogen, halogen, (Ci-C4)alkyl, cyano and (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from R R 5 selected from the group consisting of hydrogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, deuterated (Ci-C4)alkoxy, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, (C2-C4)alkynyl, (Ci-C4)alkenyl, halogen, (C3-C6)cycloalkyl, -0(C3-C6)cycloalkyl, cyano, NH2, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, -P(O)[(Ci-C4)alkyl]2, and -S(Ci-C4)alkyl; R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)cyanoalkyl, (Ci-C4)hydroxyalkyl, -(Ci-C4)alkylNR a R b , -(Ci-C4)alkylC(O)NR a R b , (Ci-C4)alkylO(Ci-C4)alkyl, -(Ci-C4)alkylC(O)OR a , -(Ci-C4)alkylNR a C(O)OR b , -(Ci-C4)alkylC(O)R a , -(Ci-C4)alkylheterocyclyl, -(Ci-C4)alkylaryl, -(Ci-C4)alkylheteroaryl, (C2-C4)alkenyl, (C2-C4)haloalkenyl, (C2-C4)cyanoalkenyl, (C2-C4)hydroxyalkenyl, -(C2-C4)alkenylNR a R b , (C2-C4)alkynyl, (C2-C4)haloalkynyl, (C2-C4)cyanoalkynyl, (C2-C4)hydroxyalkynyl, -(C2-C4)alkynylNR a R b , (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, halogen, cyano, oxo, hydroxyl, -S(Ci-C4)alkyl, -S(Ci-C4)haloalkyl, -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -SO2R a , -S(O)R a , -SO2NR a R b , -NR a SO2R b , (C3-C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl, wherein the heterocyclyl, aryl, and heteroaryl of -(Ci-C4)alkylheterocyclyl, -(Ci-C4)alkylaryl, and -(Ci-C4)alkylheteroaryl, and the (C3-C6)cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally and independently substituted with 1 to 3 groups selected from R 6a ; R 9 and R 10 are each independently selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)cyanoalkyl; or R 9 and R 10 together with the carbon to which they are attached form a (C3-C6)cycloalkyl, (C3-C6)heterocyclyl, or (C2-C4)alkenyl, each of which is optionally substituted with 1 to 3 groups selected from R 9a ; R 11 selected from -(Ci-C 10 )alkyl, (Ci-C 10 )alkynyl, (Ci-C 10 )alkenyl, cyano, phenyl, 4- to 9-membered heterocyclyl, 5- to 9-membered heteroaryl, and (C3-C6)cycloalkyl, wherein each of said (Ci-C 10 )alkyl, (Ci-C 10 )alkynyl, (Ci-C 10 )alkenyl, 4- to 9-membered heterocyclyl, 5- to 9-membered heteroaryl, phenyl, and (C3-C6)cycloalkyl is optionally substituted with one or more groups selected from R 11a , and wherein one or more hydrogen atoms on said -(Ci-C 10 )alkyl is optionally replaced with deuterium; R 12 selected from hydrogen, -(Ci-C4)alkyl, and halo(Ci-C4)alkyl; R a , R 1a , R 2a , R 4a , R 6a , R 9a , R 11a and R cd are each independently selected from halogen, (Ci-C4)alkyl, (C2-C4)alkenyl, (Ci-C4)haloalkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, cyano, hydroxy, oxo, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, =CH2, -C(O)OR e , -C(O)R e , -SO2R e , -S(O)R e , -SO2NR e R f , -NR e C(O)R f , -NR e SO2R f , -NR e R f and NO2; R a , R b , R c and R d are each independently selected from hydrogen, (Ci-C4)alkyl, (Ci-C4)cya noalkyl, (Ci-C4)hydroxyalkyl and (Ci-C4)haloalkyl; or R a and R b , when on the same nitrogen atom, can together form a heterocyclyl group optionally substituted with 1 to 3 groups selected from R ab ; or when R 3 is -NR c R d , R c and R d , together with the nitrogen atom to which they are attached, can form a heterocyclyl group optionally substituted with 1 to 3 groups selected from R cd ; and R e and R f are each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, and (Ci-C4)haloalkyl; provided that R 1 is not COCF3.

3. The compound of claim 1 or 2, wherein the compound has the structural formula II: or a pharmaceutically acceptable salt thereof. R 1 selected from -C(=O)R 11 , -C(=O)NR 11 R 12 , -C(=O)OR 11 , -SO2R 11 , -SOR 11 , -SO2NR 11 R 12 and 5- to 6-membered heteroaryl, wherein said 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R 1a R R 2 selected from hydrogen, halogen, hydroxyl, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)hydroxyalkyl, -CHO, -C02R a , -C02NR a R b or 5- to 6-membered heteroaryl, wherein said 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from R 2a ; R 5 selected from the group consisting of hydrogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, (Ci-C4)alkynyl, (Ci-C4)alkenyl, halogen, (C3-C6)cycloalkyl, -0(C3-C6)cycloalkyl, cyano, NH2, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, -P(O)[(Ci-C4)alkyl]2, and -S(Ci-C4)alkyl; R 11 selected from -(Ci-C 10 )alkyl, (Ci-C 10 )alkynyl, (Ci-C 10 )alkenyl, cyano, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl, wherein each of said (Ci-C 10 )alkyl, (Ci-C 10 )alkynyl, (Ci-C 10 )alkenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from R 11a , and wherein one or more hydrogen atoms on said -(Ci-C 10 )alkyl is optionally replaced with deuterium; R' a 、R 1a 、R 2a 、R 4a 、R 6a 、R 9a 、R 11a and R cd each independently selected from halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, cyano, hydroxy, oxo, (C3-C6) cycloalkyl, 4 to 6 membered heterocyclyl, -C(O)OR e 、-C(O)R e 、-SO2R e 、-S(O)R e 、-SO2NR e R f 、-NR e C(O)R f 、-NR e SO2R f 、-NR e R f and NO2; and R e and R f are each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl and (Ci-C4)haloalkyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X is N.

35. The compound of claim 1, wherein the compound is selected from any one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or cyano(Ci-C4)alkyl.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

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

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , and R 8 are each independently selected from (C2-C4)alkynyl, hydroxyl, and halogen.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 6 is halogen.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 6 is fluoro.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 7 is (C2-C4)alkynyl.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 7 is ethyne.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydroxyl.

13. The compound of any one of claims 1 and 3 to 12, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, (C2-C4)alkynyl, deuterated (C1-C4)alkoxy, or (C1-C4)alkoxy.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or methoxy.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 5 is methoxy.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is fluoro.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 together with the carbon to which they are attached form a (C3-C6)cycloalkyl.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 together with the carbon to which they are attached form a cyclopropyl group.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R 3 is -NR c R d .

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 3 is -NR c R d ; and R c and R d together with the nitrogen atom to which they are attached form a 5- to 7- membered heterocyclyl optionally substituted with one or more groups selected from R cd .

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 3 is 3-azabicyclo[3.1.0]hexyl or piperidinyl, optionally substituted with one or more groups selected from R cd .

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 3 is piperidinyl optionally substituted with one or more groups selected from R cd .

24. The compound of any one of claims 1 and 3 to 23, or a pharmaceutically acceptable salt thereof, wherein R cd is =CH2, cyano, halo(Ci-C4)alkyl, or halogen.

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R cd is halogen.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R cd is fluoro.

27. The compound of any one of claims 1 and 3 to 26, or a pharmaceutically acceptable salt thereof, wherein R 1 selected from -C(=O)R 11 , -C(=O)NR 11 R 12 , -C(=O)OR 11 , -SO2R 11 , C(=S)NR 11 R 12 , C(=NH)NR 11 R 12 , C(=O)NR 11 NR 11 R 12 , cyano(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkyl[4- or 5-membered heterocyclyl], halo(C1-C4)alkyl, and -SO2NR 11 R 12 .

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 1 selected from -C(=O)R 11 , -C(=O)NR 11 R 12 , -C(=O)OR 11 , -SO2R 11 , and -SO2NR 11 R 12 .

29. The compound of any one of claims 1 and 3 to 28, or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from -(Ci-C 10 )alkyl, (Ci-C 10 )alkynyl, phenyl, 4- to 9-membered heterocyclyl, 5- to 9-membered heteroaryl, and (C3-C6)cycloalkyl, wherein each of said (Ci-C 10 )alkyl, (Ci-C 10 )alkynyl, 4- to 9-membered heterocyclyl, phenyl, 5- to 9-membered heteroaryl, and (C3-C6)cycloalkyl is optionally substituted with one or more groups selected from R 11a .

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from -(Ci-C 10 )alkyl, (Ci-C 10 )alkynyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl, wherein each of said (Ci-C 10 )alkyl, (Ci-C 10 )alkynyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and (C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from R 11a .

31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from -(Ci-C4)alkyl, (Ci-C4)alkynyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyrazolyl, tetrazolyl, imidazolyl, cyclopropyl, and cyclopentyl, each of which is optionally substituted with 1 to 3 groups selected from R 11a .

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 11a is selected from halogen, (Ci-C4)alkoxy, cyano, hydroxy, (C3-C6)cycloalkyl, 4- to 6- membered heterocyclyl, -C(0)OR e , -C(0)R e , and -NR e R f .

33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R 11a selected from halogen, (Ci-C4)alkoxy, cyano, hydroxy, cyclopropyl, morpholinyl, -C(0)OR e , -C(0)R e , and -NR e R f .

34. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from -COCH2CN, -(CH2)2CN, -(CH2)3CN, -(CH2)3CH2F, -(CH2)2CH2F, -CO(CH2)2CN, -CO(CH2)3CN, -COCH(CH2CN)2, -COCH2CH(CH3)2, -COCH2C(CH3)3, -CONHCH2CH3, -CONHC(CH3)3, -CONHCH(CH3)2, -CONHCH2CF(CH3)2, -CONHCH2CF2CH2OH, -CON(CH3)2, -C(O)OCH2CH3, -C(O)OCH2CF3, -S(O)2CH2CH(CH3)2, -COCH(OH)2, -C(O)OCH2CH(CH3)2, -CONHCOC(CH3)3, -COCH2CF3, -CONH(CH3)3, -S(O)2NHCH(CH3)2, -CONHCH2CH2F, -CONHCH2CF3, -CH3, -CH2CH3, -CH(CH3)2, -S(O)2CH2CN, -CONHCH2CN, -CON(CH3)CH2CN, -CON(CH3)CH2CF3, -C(O)OC(CH3)3, -COCH3, -C(O)OCH(CH3)2, -C(O)C(CH3)3, COCH2COCH3, -COCH2OCH3, -COCH2OCF3-CO(CH2)2OCH3, -CO(CH2)2OCF3, -CO(CF2)2OCF3, -CO(CH2)2NHCH3, 37. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof. ​ ​

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