4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-naphthalene-pyrido[4,3-d]pyrimidine derivatives as inhibitors of KRAS(G12D) mutant oncoprotein for cancer treatment

Abstract

1. A small molecule inhibitor of the KRAS(G12D) mutant oncoprotein having the structural formula (I): TIFF2025529368000052.tif4987 and pharmaceutically acceptable salts thereof, and compositions thereof, which are useful in the treatment of cancer and related conditions.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority from International Application No. PCT / CN2022 / 118115, filed September 9, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Discovered as a human oncogene in the early 1980s, the Kirstin rat sarcoma virus homolog (KRAS) gene encodes a small, monomeric 21-kDa GTPase and has long been an elusive target for cancer therapeutics (Chang et al., PNAS, 1982, 79:4848-52; McCoy et al., Nature, 1983, 302:79-8). KRAS functions as a molecular switch that promotes cell proliferation by cycling between GTP-bound and GDP-bound states. In the GTP-bound state, KRAS signals proliferation 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 "turns off" KRAS's 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). Blocking this exchange by locking KRAS in the GDP-bound state is a practical way to inhibit its growth-promoting activity.

[0003] The human KRAS gene, encoded on chromosome 12p12.1, 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, reprogramming cells for persistent proliferation. KRAS mutations at codon 12, glycine (G) to aspartic acid (D), create the chronically active KRAS(G12D) oncoprotein, which has been observed in 6.8% of cancer cases analyzed by next-generation sequencing (Zhou et al., Pathol Oncol Res, 2020;26:2835-2837). In tumor-type-specific studies, KRAS(G12D) is associated with poor clinical outcomes and is observed in 17% of lung tumors, 14.3% of colorectal tumors, and 48% of pancreatic tumors (Aredo et al., Lung Cancer, 2019, 133:144-150; Olmedillas-Lopez 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). Historically, oncogenic KRAS mutations have been considered undruggable (McCormick F, Biochem J, 2019, 476:356-74). However, the discovery of an allosteric pocket in GDP-bound KRAS has enabled the search for small molecule inhibitors (Ostrem et al., Nature, 2013, 503:548-51). The G12D mutation encodes an acidic amino acid residue (D) instead of a small, flexible amino acid residue (G) with only hydrogen side chains, further providing unique chemical site binding space. This change in KRAS protein structure provides a unique space that can be targeted by small molecule drugs that specifically inhibit the oncogenic activity of KRAS(G12D). Therefore, it is desirable to design and develop small molecule drugs that target KRAS(G12D) and have sufficient bioavailability to treat diseases such as cancer. Summary of the Invention

[0004] Provided herein are small molecule inhibitors of the KRAS(G12D) mutant oncoprotein. Inhibitors of KRAS(G12D) have the structural formula I: [ka] and pharmaceutically acceptable salts thereof and compositions containing them, 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is as defined herein. Also disclosed is the use of these compounds, salts and compositions for treating diseases that respond to the inhibition of KRAS (G12D), such as cancer. In one embodiment, the disclosed compounds show improved bioavailability. See, for example, Table 3. [Brief explanation of the drawings]

[0005] [Figure 1] 1 shows tumor growth inhibition data for female NOD SCID mice treated with Compound 3. [Figure 2] 1 shows the percent change in body weight of female NOD SCID mice treated with Compound 3. [Figure 3] 1 shows tumor growth inhibition data from female NOD SCID mice treated with Compound 34. [Figure 4] Figure 1 shows the percent change in body weight of female NOD SCID mice treated with Compound 34. DETAILED DESCRIPTION OF THE INVENTION

[0006] 1. General description of the compound As part of the first embodiment, compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, Y is hydrogen or -C(O)OCHR a OC(O)R b and; X is CH or N; R 1 is hydrogen, halo, OH, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) hydroxyalkyl, -CHO, -C(O)OR b , -C(O)ONR a R b or a 5-6 membered heteroaryl optionally substituted with 1-3 groups selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and cyano; R 2 is R c or R d is a 6- to 10-membered bicyclic heterocyclyl optionally substituted by 1 to 3 groups selected from R 3 is selected from hydrogen, halo, (C1-C4)alkyl, cyano, and (C3-C6)cycloalkyl optionally substituted with 1 to 3 groups selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and cyano; R 4 is hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, deuterated (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) alkynyl, (C1-C4) alkenyl, halo, (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, wherein the (C3-C6)cycloalkyl of the (C3-C6)cycloalkyl and -O(C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and cyano; R 5 is (C2-C4)alkynyl; R 6 is hydrogen or halo; R 7 is hydrogen or OH; R 8 and R 9 and together 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 halo, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, cyano, OH, oxo, or -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; However, R 4 is (C3) alkyl, R 2 is (C1-C4) alkyl, -C(O)OR a , or -C(O)R a is not a piperazinyl substituted with

[0007] 2.Definition As used herein, the articles "a" and "an" refer to one or to a plurality of one or more than one, e.g., to at least one of the grammatical object of the article. As used herein, when used in conjunction with the word "comprising," the use of the word "a" or "an" may mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more than one."

[0008] As used herein, the terms "comprising" or "comprises" are used in reference to compositions, methods, and respective components present in a given embodiment, and are open to the inclusion of unspecified elements.

[0009] As used herein, the term "alkyl" refers to a saturated straight-chain or branched acyclic hydrocarbon, and unless otherwise specified, refers to one having 1 to 10 carbon atoms, e.g., (C1-C6) alkyl or (C1-C4) alkyl. Representative straight-chain alkyls include, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl; while examples of saturated branched alkyls include, for example, 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-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylpentyl, 2,4-dimethylhex ... Examples include methylhexyl, 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, and 3,3-diethylhexyl.

[0010] As used herein, the term "alkynyl" means a saturated straight-chain or branched acyclic hydrocarbon, and unless otherwise specified, has 2 to 10 carbon atoms (e.g., (C2-C6)alkynyl or (C2-C4)alkynyl) and at least one carbon-carbon triple bond. Representative straight-chain and branched alkynyls include, for example, acetylenyl, 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.

[0011] As used herein, the term "cycloalkyl" refers to a saturated monocyclic alkyl radical, e.g., having 3 to 10 carbon atoms (e.g., 3 to 6 carbon atoms). Representative cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecanyl.

[0012] The term "oxo" refers to the group =O.

[0013] As used herein, the term "haloalkyl" means an alkyl group in which one or more (including all) hydrogen radicals are replaced with halo groups, where each halo group is independently selected from -F, -Cl, -Br, and -I. Representative haloalkyl groups include, for example, trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.

[0014] "Alkoxy" refers to an alkyl radical attached through an oxygen linking atom and is represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes, for example, methoxy, ethoxy, propoxy, and butoxy.

[0015] "Deuterated alkoxy" refers to an alkoxy group in which one or more hydrogens (eg, one or two hydrogens) have been replaced with deuterium.

[0016] A "haloalkoxy" is a haloalkyl group that is attached to another moiety through an oxygen atom, for example, --OCHF.sub.2 or --OCF.sub.3.

[0017] As used herein, the term "halogen" or "halo" means F, Cl, Br, or I.

[0018] As used herein, the term "heterocyclyl" refers to a 4- to 12-membered monocyclic or polycyclic (e.g., bridged, fused, or spiro-linked bicyclic) saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocycle may be attached via any heteroatom or carbon atom, valence permitting. Representative heterocycles include, for example, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, oxiranyl, dioxanyl, oxetanyl, dihydrofuranyl, dihydropyranyl, isoindolinyl, dihydropyridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, diazabicyclooctanyl, hexahydropyrrolidinyl, 2-azaspiro[3.3]heptanyl, 2,7-diazaspiro [3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 2-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-1H-pyrrolo[2,3-c]pyridinyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, or 1,2,3,6-tetrahydropyridinyl. Optional substituents on a heterocyclyl group may be present at any substitutable position, including, for example, the position to which the heterocyclyl is attached, if valence allows.

[0019] The term "spiro" refers to two rings that share one ring atom (eg, carbon).

[0020] The term "fused" refers to two rings that share two adjacent ring atoms.

[0021] The term "bridged" refers to two rings that share three ring atoms with each other.

[0022] As used herein, the term "heteroaryl" means a 5- to 12-membered aromatic radical containing 1 to 4 heteroatoms selected from N, O, and S. A heteroaryl group can be monocyclic or bicyclic. A heteroaryl may be attached via any heteroatom or carbon atom, valence permitting. Representative heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, benzothienyl, etc. Optional substituents on a heteroaryl group may be located at any available position, including, for example, the position at which the heteroaryl is attached, if valence allows.

[0023] When used in conjunction to describe chemical groups that may have multiple points of attachment, a hyphen (-) indicates the point of attachment of the group to the variable for which it is defined. For example, -(C1-C4)alkylaryl means that the point of attachment of such groups is on the alkyl group. [ka] A hashed bond, such as represents the point at which the depicted group is attached to the defined variable.

[0024] The term "KRAS" refers to the protein product of the KRAS proto-oncogene, a GTPase gene.

[0025] The term "KRAS(G12D)" refers to the protein product of the KRAS gene that has a mutation in which the glycine amino acid at position 12 of KRAS is replaced by aspartic acid.

[0026] "KRAS G12D "Chemical entities that bind to KRAS" refers to small molecules or KRAS G12D In some embodiments, KRAS refers to a specific portion of a macromolecule that binds to a portion of KRAS. G12D In some embodiments, the chemical entity that binds to KRAS is a small molecule. G12D In some embodiments, the chemical entity that binds to KRAS is a small molecule having a molecular weight of less than 2,000 g / mol. G12D Chemical entities that bind to KRAS G12D Induces structural changes in the

[0027] The term "SOS1" refers to the protein product of the SOS1 gene, which functions as a guanine nucleotide exchange factor for RAS proteins.

[0028] The compounds described herein may have chiral and / or geometric centers (E- and Z-isomers). It is 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.

[0029] Where the stereochemistry of a disclosed compound is named or depicted by 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. Percent by weight pure relative to all other stereoisomers is the ratio of the weight of the depicted one stereoisomer to the weight of that stereoisomer plus the weights of the other stereoisomers.

[0030] When used in pharmaceuticals, pharmaceutically acceptable salts of the disclosed compounds refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include, for example, 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 teachings 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 salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts). Compounds having a quaternary ammonium group also include counteranions such as chloride, bromide, iodide, acetate, and perchlorate. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates, salts with amino acids such as glutamic acid, and the like.

[0031] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound being 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, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, wool fat, etc.

[0032] As used herein, the term "subject" refers to human 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, reptiles, etc. In a preferred embodiment, the subject is a human, and may be referred to as a patient.

[0033] As used herein, the terms "treat," "treating," or "treatment" preferably refer to an activity for obtaining a beneficial or desired clinical result, including, but not limited to, alleviation or amelioration of one or more signs or symptoms of a disease or condition, reduction in the extent of the disease, stabilization of the disease state (i.e., not worsening), improvement or temporary suppression of the disease state, reduction in the rate or time to progression, and remission (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. Treatment need not be curative.

[0034] A "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 divided doses. In one embodiment, a therapeutically effective amount refers to a dose of about 0.01 to about 100 mg / kg body weight / day.

[0035] The terms "administer," "administering," or "administration" include, for example, any method of delivering a pharmaceutical composition or agent to a particular site in or on a subject's system. In certain embodiments, an agent is administered intravenously, intramuscularly, subcutaneously, intradermally, nasally, orally, transdermally, or mucosally. In certain embodiments, an agent is administered intravenously. In certain embodiments, an agent is administered orally. Administration of an agent can be performed collaboratively by multiple people. Administering an agent includes, for example, prescribing the agent to be administered to a subject and / or providing instructions, directly or through another person, for taking a particular agent, for example, by self-delivery, such as oral delivery, subcutaneous delivery, or intravenous delivery via a central venous line, or delivery by a trained professional, such as intravenous delivery, intramuscular delivery, or intratumoral delivery.

[0036] 3.Compound As part of a second embodiment, compounds of formula I may be of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0037] As part of a third embodiment, compounds of formula I may be of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0038] As part of a fourth embodiment, compounds of formula I may be of formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0039] As part of a fifth embodiment, the compound of formula I may be a compound of formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0040] As part of the sixth embodiment, R in a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 1 is hydrogen, and the variables are as described above for Formula I.

[0041] As part of the seventh embodiment, X in a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is N, and the variables are as described above for Formula I or the sixth embodiment.

[0042] As part of the eighth embodiment, R in a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 3 is halo, and the variables are as described above for Formula I or the sixth or seventh embodiment. Alternatively, as part of the eighth embodiment, R in a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is 3 is fluoro and the variables are as described above for Formula I or the sixth or seventh embodiment.

[0043] As part of the ninth embodiment, R in a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 5 is (C2)alkynyl, and the variables are as described above for Formula I or any one of the sixth through eighth embodiments.

[0044] As part of the tenth embodiment, R in a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 6is halo, and 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 a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 6 is fluoro, and the variables are as described above for Formula I or any one of the sixth through ninth embodiments.

[0045] As part of the eleventh embodiment, R in a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 7 is OH, and the variables are as described above for Formula I or any one of the sixth through tenth embodiments.

[0046] As part of the twelfth embodiment, R in a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 4 is selected from hydrogen, (C1-C4)alkoxy, deuterated (C1-C4)alkoxy, —N[(C1-C4)alkyl]2, halo, (C3-C6)cycloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkyl, and NH2, and the variables are as described above for Formula I or any one of the sixth through eleventh embodiments. Alternatively, as part of the twelfth embodiment, R in a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, can be 4 is selected from hydrogen, methyl, methoxy, isopropoxy, OCDF, —OCHF, —N(CH), NH, chloro, and cyclopropyl, and the variables are as described above for Formula I or any one of the sixth through eleventh embodiments.

[0047] As part of the thirteenth embodiment, R in a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 2 is R c or R dand the variables are as described above for Formula I or any one of the sixth through twelfth embodiments. Alternatively, as part of the thirteenth embodiment, R in a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is 2 is azetidinyl, piperidinyl, morpholinyl, or pyrrolidinyl, which are c or R in a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is substituted with 1 to 3 groups selected from 2 is 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, or 1,2,3,6-tetrahydropyridinyl, which are R d and optionally substituted with 1 to 3 groups selected from: wherein the variables are as described above for Formula I or any one of the sixth to twelfth embodiments.

[0048] As part of the fourteenth embodiment, R in a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, c and R d are each independently halo, cyano, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkoxy, -S(O)R a , and -SO2NR a R b and 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 a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is selected from: c and R dare each independently selected from fluoro, cyano, CF, methoxy, isopropyl, OCF, —S(O)CH, and —SON(CH), and the variables are as described above for Formula I or any one of the sixth through thirteenth embodiments.

[0049] As part of the fifteenth embodiment, R in a compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, 8 and R 9 together form a cyclopropyl, and the variables are as described above for Formula I or any one of the sixth through fourteenth embodiments.

[0050] As part of the 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, and the variables are as described above for Formula I or any one of the sixth through fifteenth embodiments. Alternatively, as part of the sixteenth embodiment, Y in a compound of Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, is hydrogen, and the variables are as described above for Formula I or any one of the sixth through fifteenth embodiments.

[0051] Additional compounds are further disclosed in the Examples and are included in the present disclosure, including pharmaceutically acceptable salts and neutral forms thereof.

[0052] 4. Use, Formulation and Administration The compounds and compositions described herein are generally useful as anti-cancer therapy.In one embodiment, the disclosed compounds and compositions act as inhibitors of KRAS(G12D).Their mechanism of action includes, but is not limited to, inhibiting KRAS(G12D), thereby inhibiting cancer cell proliferation, and / or disrupting downstream signals that can lead to cancer cell death or other KRAS or KRAS(G12D) functions.In one embodiment, the disclosed compounds effectively inhibit KRAS(G12D).

[0053] Thus, provided herein is a method for treating a condition that responds 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. Also provided is the use of one or more compounds or compositions described herein in the manufacture of a medicament for treating a condition that responds to the inhibition of KRAS(G12D). Also provided is the use of a compound or composition described herein for treating a condition that responds to the inhibition of KRAS(G12D).

[0054] In one embodiment, the condition treated by the compound and composition of the present invention is cancer.The term "cancer" or "tumor" is well known in the art, and refers to the presence of cells in a subject that have the typical characteristics of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, reduced cell death / apoptosis, and certain characteristic morphological features.In many cases, cancer cells are in the form of solid tumors.However, cancer also includes non-solid tumors, such as blood tumors such as leukemia, and these cancer cells originate from bone marrow.As used herein, the term "cancer" includes not only malignant cancer but also pre-cancer.Examples of cancers include acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), 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 (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, and craniopharynx cancer. Cephaloma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt lymphoma, proliferation abnormalities (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, 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 carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung lymphatic sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors 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, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, bone marrow cancer These include, but are not limited to, 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 (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, Wilms' tumor, and the like.Other cancers include, for example, primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gallbladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, kidney cancer, urothelial cancer, female reproductive organ cancer, uterine cancer, gestational trophoblastic disease, male reproductive organ cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary cancer, hemangioma, sarcoma arising from bone and soft tissue, Kaposi's sarcoma, nerve cancer, eye cancer, meningeal cancer, glioblastoma, neuroma, neuroblastoma, schwannoma, solid tumors arising from hematopoietic malignancies such as leukemia, metastatic melanoma, recurrent or persistent 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, These include: cell lung cancer, malignant glioma, epithelial ovarian cancer, primary peritoneal serous carcinoma, metastatic liver cancer, neuroendocrine carcinoma, refractory malignancies, triple-negative breast cancer, HER2-amplified breast cancer, nasopharyngeal cancer, oral cancer, biliary tract, hepatocellular carcinoma, squamous cell carcinoma of the head and neck (SCCHN), non-medullary thyroid cancer, recurrent glioblastoma multiforme, neurofibromatosis type 1, central nervous system 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, renal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancies.

[0055] As used herein, " solid tumor " is understood to mean any pathogenic tumor that can be detected by palpation or imaging diagnostic method as a three-dimensional abnormal growth.Solid tumor is distinct from blood tumors such as leukemia.However, because the cells of blood tumors originate from bone marrow, the tissue that produces cancer cells is solid tissue that can be hypoxic.

[0056] "Tumor tissue" or "tumorous tissue" is understood to refer to the cells, extracellular matrix, and other naturally occurring components associated with a solid tumor.

[0057] The specific dosage and treatment regimen for a particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, the severity of the particular disease being treated, etc. The amount of a compound described herein in the composition will also depend on the particular compound in the composition. [Example]

[0058] chemical synthesis The representative examples presented below are intended to help illustrate the disclosure and are not intended to, and should not be construed as, limiting the scope of the invention. Typical starting materials used were obtained from commercial sources or prepared in other examples unless otherwise noted.

[0059] The compounds claimed herein were prepared according to the procedures outlined in Scheme 1. [ka]

[0060] Preparation of Example 1 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 equiv.) (150 mL) in toluene (Tol.) was added POCl3 (178 g, 1.16 mol, 108 mL, 5.00 equiv.) at 25 °C. Next, DIEA (65.9 g, 510 mmol, 88.9 mL, 2.20 equiv.) was added to the mixture at below 40 °C. The mixture was stirred at 110 °C for 12 h. LC-MS showed the desired product. The reaction mixture was distilled under reduced pressure to remove POCl3 at 90 °C. The residue was slowly poured into saturated NaHCO3 (maintaining pH = 8). During this time, a yellow precipitate formed. It 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-d6, 400 MHz): δ 8.92-8.86 (m, 1H). LC-MS: m / z 253.9 [M+H] + .

[0061] 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 equiv.) in DCM (485 mL) was added a solution of compound 2a (38.7 g, 183 mmol, 0.950 equiv.) in DCM (120 mL). DIEA (49.7 g, 384 mmol, 66.9 mL, 2.00 equiv.) was then added to the mixture at -40 °C and stirred at -40 °C for 0.5 h under a N atmosphere. LCMS indicated that intermediate 1-2 had been consumed, and the desired product was detected. The mixture was quenched with hydrochloric acid (0.5 M) and the aqueous phase was acidified to pH 6-7. After separation, the organic layer was dried over NaSO. The residue was purified by column chromatography (SiO, 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 (120 g, 280 mmol, yield 72.9%) was obtained as a white solid. HNMR (DMSO-d6, 400 MHz): δ9.13-8.98 (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] + .

[0062] 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 equiv.) and t-BuONa (13.46 g, 140 mmol, 3 equiv.) in THF was added 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 equiv.) in portions at 0 °C 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 CHCl (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaCl (2 × 5 mL) and dried over anhydrous NaSO. 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]

[0063] Step 4: tert-Butyl 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-carboxylate. A solution of intermediate 1-4 (3 g, 6.073 mmol, 1.0 equiv.) 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 equiv.) in 1,4-dioxane (40 mL) was treated with Pd(PPh) (1.40 g, 1.215 mmol, 0.2 equiv.) and KPO (3.87 g, 18.219 mmol, 3.0 equiv.) under a nitrogen atmosphere. 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 × 10 mL). The combined organic layers were washed with saturated aqueous NaCl (2 × 5 mL) and dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give intermediate 1-5 (2.5 g, 66.38%) as a yellow solid. LCMS (ES, m / z): 620 [M+H] +

[0064] 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 1-5 (200 mg, 0.323 mmol, 1 equiv) in DCM was added Dess-Martin (410.38 mg, 0.969 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (aq) at 0 °C. The resulting mixture was extracted with CHCl (3 × 10 mL). The combined organic layers were washed with saturated NaCl (aq) (3 × 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] +

[0065] 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 equiv.) and 4-fluoropiperidine hydrochloride (45.17 mg, 0.324 mmol, 2 equiv.) in DMF was added STAB (102.87 mg, 0.486 mmol, 3 equiv.) in portions at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaCl (2 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): 605 [M+H] +

[0066] 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 equiv) in DCM was added TFA (1 mL, 13.463 mmol, 101.84 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30 × 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 Example 1 (38.15 mg, 47.69%) as a white solid. 1 H NMR (DMSO-d6, 400 MHz): δ 10.15 (s, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 4.69 (dt, J = 7.6, 3.6 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.34 - 4.22 (m, 3H), 3.93 (d, J = 1.2 Hz, 1H), 3.67 - 3.59 (m, 1H), 3.54 (t, J = 5.6 Hz, 3H), 2.74 (s, 1H), 2.56 (s, 2H), 2.30 (t, J = 7.6 Hz, 4H), 1.88 - 1.76 (m, 2H), 1.66 (s, 6H), 0.64 (q, J = 3.2 Hz, 2H), 0.40 (t, J = 3.2 Hz, 2H).LC-MS:m / z 628.9[M+H] + .

[0067] The following compounds in Table 1 were prepared according to the methods described above using the appropriate starting materials.

[0068] [Table 1-1]

[0069] [Table 1-2]

[0070] [Table 1-3]

[0071] [Table 1-4]

[0072] [Table 1-5]

[0073] [Table 1-6]

[0074] [Table 1-7]

[0075] [Table 1-8]

[0076] [Table 1-9]

[0077] [Table 1-10]

[0078] [Table 1-11]

[0079] [Table 1-12]

[0080] [Table 1-13]

[0081] [Table 1-14]

[0082] The compounds described herein may be any one of the following: [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt of any one of the foregoing.

[0083] Biological Assays / Tests cell line 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 adenocarcinoma [homozygous G12D] (ATCC, CRL-1682), and SW1990 pancreatic adenocarcinoma [homozygous G12D] (ATCC CRL-2172). Cell lines were cultured essentially according to the ATCC recommended method.

[0084] KRAS(G12D) / SOS1 homogeneous time-resolved fluorescence (HTRF) assay Binding of test compounds to the KRAS(G12D) target protein (thereby inhibiting the interaction between KRAS(G12D) and SOS1 protein) was measured by homogeneous time-resolved fluorescence in the absence of GTP using a KRAS-G12D / SOS1 Binding Assay Kit (Cisbio, 63ADK000CB17PEH) according to the manufacturer's instructions unless otherwise noted. Three-fold serial dilutions of each test compound were prepared ranging from 20 μM to 1.02 nM. Test compounds were mixed with the reaction components and incubated in a sealed plate at 4°C for 3 hours, and fluorescence was measured using a PerkinElmer Envision plate reader. The IC50 value (concentration of 50% of maximum inhibition) of KRAS(G12D)-SOS1 was calculated using GraphPad Prism7 software. Results are shown for cancer cell line proliferation (CellTiter-Glo® assay).

[0085] AGS, A-427, ASPC1, SW1990, and GP2D cells were seeded at 4,000 cells / well in 96-well tissue culture plates and incubated in 100 μl of medium at 37°C and 5% CO2 for 72 hours. Three-fold serial dilutions of each test compound were prepared ranging from 20 μM to 1.02 nM. Each cell line was then treated with various concentrations of test compound containing a final concentration of 0.5% DMSO / well and cultured at 37°C and 5% CO2 for 72 hours. 100 μl of CellTiter-Glo® Reagent (Promega Corporation, Madison, WI) was added to each well and processed according to the manufacturer's protocol. Results were analyzed, and IC50 values ​​were calculated using GraphPad 7 software. The results are shown in Table 2. KRAS(G12D) / SOS1 HTRF assay: A. IC50<100nM; B. IC50=100-1000nM; C. IC50>1000nM; AGS proliferation assay: A. EC50<100nM; B. EC50=100-1000nM; C. EC50>1000nM; A427 proliferation assay: A. EC50<100nM; 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.

[0086] [Table 2-1]

[0087] [Table 2-2]

[0088] Oral bioavailability CD-1 mice were randomly assigned to six groups, each containing three male mice. The control group included Control Compound 1 (50 mg / kg), Control Compound 2 (25 mg / kg), and Example 1 (25 mg / kg). The inventive compound group 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). Compounds were administered orally (PO) in a single dose to each mouse in the group. Blood samples were collected within 72 hours. Bioavailability (F%) was determined by liquid chromatography-mass spectrometry (LC-MS / MS). The mean oral %F is shown in Table 3.

[0089] [Table 3-1]

[0090] [Table 3-2]

[0091] [Table 3-3]

[0092] [Table 3-4]

[0093] [Table 3-5]

[0094] [Table 3-6]

[0095] Compound 3 was evaluated in a human lung cancer A427 xenograft model using female NOD SCID mice (6-8 weeks old). A427 tumor cells (1 × 10 cells) in 0.1 ml of a mixture of medium and Matrigel (1:1 ratio) were cultured in the same culture medium. 7 ) was inoculated subcutaneously into the right flank of each mouse to initiate tumor development. Tumors averaged approximately 170 mm 3 After reaching a median age of 10 days, mice were randomly assigned to treatment groups and administered the test article or vehicle. Compound 3 was administered by oral gavage (PO) at 200 mg / kg once daily for 5 weeks. Vehicle was administered by oral gavage twice daily. Body weight and tumor volume were measured twice weekly until the end of the study. The results are depicted in Figures 1 and 2.

[0096] Compound 34 was evaluated in a human colon adenocarcinoma GP2D xenograft model using female BALB / c nude mice (6-8 weeks old). GP2D tumor cells (1 × 10) were cultured in 0.1 ml of a mixture of medium and Matrigel (1:1 ratio). 7 ) was inoculated subcutaneously into the right flank of each mouse to initiate tumor development. Tumors averaged approximately 230 mm 3 After reaching a median age of 10 days, mice were randomly assigned to treatment groups and administered the test article or vehicle. Compound 34 was administered by oral gavage (PO) at 200 mg / kg once daily for 4 weeks, and vehicle was administered by oral gavage once daily for 4 weeks. Body weight and tumor volume were measured twice weekly until the end of the study. The results are depicted in Figures 3 and 4.

[0097] Although the present disclosure has been described in connection with specific embodiments, it should be understood that the claimed disclosure should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the disclosure are contemplated and understood by those skilled in the relevant arts to which the present disclosure resides to be within the scope of the present disclosure as expressed by the following claims.

[0098] All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each individual patent and publication was specifically and individually indicated to be incorporated by reference.

Claims

1. Compound of formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof Y is hydrogen or -C(O)OCHR ａ OC(O)R ｂ And; X is either CH or N; R １ represents hydrogen, halo, OH, (C １ -C ４ )alkyl, (C １ -C ４ )haloalkyl, (C １ -C ４ )hydroxyalkyl, -CHO, -C(O)OR ｂ , -C(O)ONR ａ R ｂ , or 5-6 membered heteroaryl optionally substituted with 1 to 3 groups selected from halo, (C １ -C ４ )alkyl, (C １ -C ４ )alkoxy, halo(C １ -C ４ )alkoxy, and cyano; R ２ R ｃ A 4-6 member monocyclic heterocycline substituted with 1-3 groups selected from, or R ｄ A 6-10 member bicyclic heterocycline, optionally substituted with 1-3 groups selected from; R ３ is hydrogen, halo, (C １ ~C ４ ) alkyl, cyano, and halo, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, Halo (C １ ~C ４ )Optionally substituted with 1 to 3 groups selected from alkoxy and cyano (C ３ ~C ６ ) Selected from cycloalkyl; R ４ is hydrogen, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Haloalkyl, (C １ ~C ４ ) Alkoxy, deuterated (C １ ~C ４ ) Alkoxy, (C １ ~C ４ ) Haloalkoxy, (C １ ~C ４ ) Alkinyl, (C １ ~C ４ ) Alkenil, Halo, (C ３ ~C ６ ) Cycloalkyl, -O(C ３ ~C ６ ) Cycloalkyl, cyano, NH ２ ,-NH(C １ ~C ４ ) alkyl, -N[(C １ ~C ４ ) Alkyl] ２ , -P(O)[(C １ ~C ４ ) Alkyl] ２ , and -S(C １ ~C ４ ) Selected from alkyl, and the (C ３ ~C ６ ) Cycloalkyl and -O(C ３ ~C ６ ) The cycloalkyl (C ３ ~C ６ ) Cycloalkyl is halo, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, Halo (C １ ~C ４ ) optionally substituted with 1 to 3 groups selected from alkoxy and cyano groups; R ５ is, (C ２ ~C ４ ) is alkinyl; R ６ is hydrogen or halo; R ７ is hydrogen or OH; R ８ and R ９ This means that =CH or cyclopropyl forms together; R ａ and R ｂ These are, independently, hydrogen and (C) １ ~C ４ ) Selected from alkyl; and R ｃ and R ｄ are each independently selected from halo, (C １ to C ４ )alkyl, (C １ to C ４ )haloalkyl, (C １ to C ４ )alkoxy, (C １ to C ４ )haloalkoxy, cyano, OH, oxo, -C(O)OR ａ , -C(O)R ａ , -SO ２ R ａ , -S(O)R ａ , -SO ２ NR ａ R ｂ , -NR ａ C(O)R ｂ , -NR ａ SO ２ R ｂ , -NR ａ R ｂ , and NO ２ ; However, R ４ But (C ３ ) If it is alkyl, R ２ is, (C １ ~C ４ ) alkyl, -C(O)OR ａ , or -C(O)R ａ A compound other than piperazinyl substituted with, or a pharmaceutically acceptable salt thereof.

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

3. The aforementioned compound is a compound of formula III: 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The aforementioned compound is a compound of formula IV: 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. The aforementioned compound is a compound of formula V: 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

8. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a halo.

9. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

10. R ５ is (C ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an alkynyl.

11. R ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a halo.

12. R ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

13. R ７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is an OH group.

14. R ４ is hydrogen, (C １ ~C ４ ) Alkoxy, deuterated (C １ ~C ４ ) Alkoxy, -N[(C １ ~C ４ ) Alkyl] ２ Hello, (C ３ ~C ６ ) Cycloalkyl, (C １ ~C ４ ) Haloalkoxy, (C １ ~C ４ ) alkyl and NH ２ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

15. R ４ These are hydrogen, methyl, methoxy, isopropoxy, and OCDF. ２ , OCHF ２ , -N(CH ３ ) ２ NH ２ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from chloro and cyclopropyl.

16. R ２ R ｃ A 4-6 member nitrogen-containing monocyclic heterocycline substituted with 1-3 groups selected from, or R ｄ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a 7-10 member nitrogen-containing condensate or spironicyclic heterocycline optionally substituted with 1-3 groups selected from the above.

17. R ２ These are azetidinil, piperidinil, morpholinil, or pyrrolidinil, and these are R ｃ It is substituted with 1 to 3 groups selected from, or R ２ These are 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, or 1,2,3,6-tetrahydropyridinyl, and these are R ｄ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is optionally substituted with one to three groups selected from the above.

18. R ｃ and R ｄ These are, independently, Halo, Cyano, (C １ ~C ４ ) Haloalkyl, (C １ ~C ４ ) Alkoxy, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Haloalkoxy, -S(O)R ａ , and -SO ２ NR ａ R ｂ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

19. R ｃ and R ｄ These are, independently, fluoro, cyano, and CF. ３ Methoxypropyl, OCF ３ , -S(O)CH ３ , and -SO ２ N(CH ３ ) ２ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

20. R ８ and R ９ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which together forms a cyclopropyl group.

21. Y is hydrogen or -C(O)OCH(CH ３ )OC(O)CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is hydrogen.

23. The aforementioned compound, 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 【Chemistry 6-4】 【Transformation 6-5】 【Transformation 6-6】 [Transformation 6-7] [Transformation 6-8] 【Transformation 6-9】 【Chemistry 6-10】 The compound according to claim 1, or selected from any of the pharmaceutically acceptable salts described above.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition for use in the treatment of cancer, comprising a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

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