Tetrahydropyrido[3,4-d]pyrimidine derivatives as KRAS inhibitors

Abstract

The present disclosure provides a KRAS inhibitor. Also provided is a method of treating cancer using this compound.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 351,134, filed on June 10, 2022, which is hereby incorporated by reference in its entirety.

[0002] The present disclosure provides a KRAS inhibitor. A method of treating cancer using this inhibitor is also provided.

Background Art

[0003] The KRAS oncogene is a member of the RAS family of GTPases involved in many cell signaling processes. KRAS mutations are gain - of - function mutations present in up to 30% of all tumors, including about 90% of pancreatic cancers. KRAS functions as a molecular switch cycling between an inactive (GDP - bound or G12C (OFF) ) state and an active (GTP - bound or G12C (ON) ) state, transducing upstream cell signals received from multiple tyrosine kinases to downstream effectors to regulate diverse processes including cell proliferation. A single nucleotide substitution resulting in missense mutations at codons 12 and 13 of the KRAS primary amino acid sequence accounts for about 40% of KRAS driver mutations in lung adenocarcinoma, and the G12C transversion is the most commonly seen activating mutation. KRAS G12C mutations occur in about 13% of lung adenocarcinomas and about 3% of colorectal adenocarcinomas, and are also present in breast cancer, bladder cancer, cervical cancer, ovarian cancer, pancreatic cancer, and uterine cancer.

[0004] Despite several failed attempts to target KRAS, compounds that inhibit KRAS activity, including those that disrupt effectors such as guanine nucleotide exchange factors and target KRAS G12C, are highly desirable. Clearly, the interest and attempts to develop inhibitors of KRAS, particularly inhibitors that activate KRAS mutants such as KRAS G12C, continue.

Summary of the Invention

Means for Solving the Problem

[0005] In part, the present disclosure is based on the discovery that, unlike other KRAS G12C inhibitors, the compounds of the present disclosure target the active KRAS G12C (ON) type of KRAS G12C protein. By inhibiting G12C ON type of KRAS, the claimed compounds are expected to reduce cancer resistance to KRAS G12C inhibition and / or show increased clinical efficacy. Without being bound by theory, inhibition of G12C ON type of KRAS G12C may be the result of substituents at the 4-position of the tetrahydropyridopyrimidine ring of formula (I).

[0006] In a first aspect, the present disclosure provides a compound of formula (I):

Chemical formula

[0007] In some embodiments, Y is a bond.

[0008] In some embodiments, A is a 4- to 9-membered monocyclic or bicyclic bridged or fused saturated ring system optionally containing one or two nitrogen atoms.

[0009] In some embodiments, A-U is

Chemical formula

Chemical formula

Chemical formula

[0010] In some embodiments, A-U is

Chemical formula

Chemical formula

Chemical formula

[0011] In some embodiments, n is 0.

[0012] In some embodiments, R 4 is selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl and triazolyl, and each ring is optionally substituted with one, two or three groups independently selected from C2-C4 alkenyl, C1-C3 alkyl, halo, halo C1-C3 alkoxy, halo C1-C3 alkyl, nitro and oxo.

[0013] In some embodiments, R 4 is selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridinyl, pyrimidinyl, thiazolyl and triazolyl, and each ring is optionally substituted with methyl or halo.

[0014] In some embodiments, X is O.

[0015] In some embodiments, R 5 is

Chemical formula

[0016] In some embodiments, R 5 is -(C1-C3 alkyl)-R 6 where R6 is a monocyclic ring system of 3 to 5 members, a bicyclic fused saturated ring system of 8 or 9 members or a tricyclic saturated ring system of 10 members, each ring system optionally contains one nitrogen atom, and each ring system is optionally substituted with one or two groups independently selected from C1-C3 alkyl, halo and (4-6 membered heterocyclyl)C1-C3 alkyl; the heterocyclyl moiety of (4-6 membered heterocyclyl)C1-C3 alkyl is further optionally substituted with a halo group.

[0017] In some embodiments, R 5 is [Chemical formula] wherein, [Chemical formula] represents the point of attachment to X.

[0018] In some embodiments, R 5 is [Chemical formula] wherein, n is 0, 1 or 2; each R 20 is halo; and [Chemical formula] represents the point of attachment to X.

[0019] In some embodiments, Z is a bond.

[0020] In some embodiments, R 1is a monocyclic heteroaryl ring containing 1, 2 or 3 nitrogen atoms, and the ring is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, halo C1-C3 alkyl, hydroxy and hydroxy C1-C3 alkyl.

[0021] In some embodiments, R 1 is

Chemical formula

Chemical formula

[0022] In some embodiments, R 1 is a C6-C 10 aryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, halo C1-C3 alkyl, hydroxy and hydroxy C1-C3 alkyl.

[0023] In some embodiments, R 1 is a naphthyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from C1-C3 alkyl, C2-C4 alkynyl, halo and hydroxy.

[0024] In some embodiments, R 1 is naphthyl, and the naphthyl is substituted with 1, 2 or 3 groups independently selected from C2-C4 alkynyl, halo and hydroxy.

[0025] In some embodiments, R 1 is [Chemistry] and wherein [Chemistry] represents a point of attachment to the parent molecular moiety.

[0026] In some embodiments, R’ is fluoro.

[0027] In some embodiments, R’ is chloro.

[0028] In some embodiments, the present disclosure provides a compound of formula (Ia): [Chemistry] (wherein R x is selected from -CH2CN and methyl; R 4 is selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridinyl, pyrimidinyl, thiazolyl and triazolyl, each ring being optionally substituted with methyl or halo; and R 5 is [Chemistry] ) or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the present disclosure provides [Chemistry] [Chemistry] a compound selected from or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the present disclosure provides 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-3-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-4-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(oxazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoro-3-(isothiazol-5-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(6-methylpyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(4-methylpyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(5-methylpyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(3-methylpyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (Z)-1-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(isoxazol-3-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(isoxazol-5-yl)piperazin-2-yl)acetonitrile; and 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)piperazin-2-yl)acetonitrile To provide a compound selected from the following or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the present disclosure provides atropisomers of the compounds of any of the preceding embodiments. In certain embodiments, the compound is a stable atropisomer as described herein.

[0032] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0033] In some embodiments, the present disclosure provides an oral dosage form comprising a compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0034] In some embodiments, the present disclosure provides a method for treating cancer expressing KRAS G12C, G12D, and / or G12V mutations in a subject in need thereof, the method comprising administering to the subject a compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the present disclosure provides a method for treating cancer expressing KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the present disclosure provides a method of treating cancer sensitive to KRAS G12C inhibition in a subject in need thereof, the method comprising administering to the subject a compound of any of the previous embodiments or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, gastric cancer or uterine cancer.

[0038] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer.

[0039] In some embodiments of the method, the compound is an atropisomer of a compound of any of the previous embodiments. In certain embodiments, the compound is a stable atropisomer as described herein.

[0040] In another embodiment, the present disclosure provides a method of inhibiting KRAS G12C activity in a cell, the method comprising contacting the cell with a therapeutically effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0041] In some embodiments, the present disclosure provides a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with a therapeutically effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0042] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in inhibiting KRAS G12C.

[0043] In another aspect, the present disclosure provides a compound of formula (I) as defined herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment of a KRAS G12C-related disease or disorder.

[0044] In another aspect, the present disclosure provides the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer. In some aspects, the cancer is lung cancer. In some aspects, the cancer is non-small cell lung cancer.

[0045] In another aspect, the present disclosure provides the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the activity of KRAS G12C.

[0046] In another aspect, the present disclosure provides the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a KRAS G12C-related disease or disorder.

DETAILED DESCRIPTION OF THE INVENTION

[0047] Unless otherwise indicated, any atom with an unfilled valence is assumed to have sufficient hydrogen atoms to satisfy its valence.

[0048] The singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0049] As used herein, the term "or" is an inclusive disjunction (i.e., and / or) and does not denote an exclusive disjunction unless explicitly stated otherwise, such as by the terms "either", "otherwise", "instead", and similar terms.

[0050] As used herein, the phrase "or a pharmaceutically acceptable salt thereof" refers to at least one compound or at least one salt of a compound or a combination thereof. For example, "a compound of formula (I) or a pharmaceutically acceptable salt thereof" includes, but is not limited to, a compound of formula (I), two compounds of formula (I), a pharmaceutically acceptable salt of a compound of formula (I), a compound of formula (I) and one or more pharmaceutically acceptable salts of a compound of formula (I), and two or more pharmaceutically acceptable salts of a compound of formula (I).

[0051] As used herein, the term "C2-C4 alkenyl" refers to a group derived from a straight-chain or branched-chain hydrocarbon containing 2 to 4 carbon atoms and one double bond.

[0052] As used herein, the term "C1-C3 alkoxy" refers to a C1-C3 alkyl group bonded to the parent molecular moiety through an oxygen atom.

[0053] As used herein, the term "C1-C3 alkoxy C1-C6 alkyl" refers to a C1-C3 alkoxy group bonded to the parent molecular moiety through a C1-C6 alkyl group.

[0054] As used herein, the term "C1-C3 alkoxycarbonyl" refers to a C1-C3 alkoxy group bonded to the parent molecular moiety through a carbonyl group.

[0055] As used herein, the term "C1-C3 alkyl" refers to a group derived from a straight-chain or branched-chain saturated hydrocarbon containing 1 to 3 carbon atoms.

[0056] As used herein, the term "C1-C3 alkylcarbonyl" refers to a C1-C3 alkyl group bonded to the parent molecular moiety through a carbonyl group.

[0057] As used herein, the term "C2-C4 alkynyl" refers to a group derived from a straight or branched chain hydrocarbon containing 2 to 4 carbon atoms and 1 triple bond.

[0058] As used herein, the term "amino" refers to -NH2.

[0059] As used herein, the term "amino C1-C3 alkyl" refers to an amino group bonded to the parent molecular moiety via a C1-C3 alkyl group.

[0060] As used herein, the term "aryl" refers to a phenyl group or a bicyclic fused ring system in which one or both of the rings are phenyl groups. The bicyclic fused ring system consists of a phenyl group fused to a 4- to 6-membered aromatic or non-aromatic carbocyclic ring. The aryl groups of the present disclosure can be bonded to the parent molecular moiety via any substitutable carbon atom of the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.

[0061] As used herein, the term "aryl C1-C6 alkyl" refers to an aryl group bonded to the parent molecular moiety via a C1-C6 alkyl group.

[0062] As used herein, the term "carboxy" refers to -CO2H.

[0063] As used herein, the term "carboxy C1-C6 alkyl" refers to a C1-C6 alkyl group substituted with 1, 2, or 3 carboxy groups.

[0064] As used herein, the term "cyano" refers to -CN.

[0065] As used herein, the term "C3-C4 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring system having 3 or 4 carbon atoms and 0 heteroatoms.

[0066] The term "C3-C6 cycloalkyl" as used herein refers to a saturated monocyclic hydrocarbon ring system having 3 to 6 carbon atoms and 0 heteroatoms.

[0067] The term "C3-C6 cycloalkyl C1-C6 alkyl" as used herein refers to C3-C6 cycloalkyl bonded to the parent molecular moiety via a C1-C6 alkyl group.

[0068] The term "di(C1-C6 alkyl)amino" as used herein refers to -NR z R z’ (wherein R z and R z’ are the same or different C1-C6 alkyl groups).

[0069] The term "di(C1-C3 alkyl)amino C2-C6 alkyl" as used herein refers to -(C2-C6 alkyl)NR z R z’ (wherein R z and R z’ are the same or different C1-C6 alkyl groups).

[0070] The terms "halo" and "halogen" as used herein refer to F, Cl, Br or I.

[0071] The term "halo C1-C3 alkoxy" as used herein refers to a C1-C3 alkoxy group substituted with 1, 2 or 3 halogen atoms.

[0072] The term "halo C1-C3 alkyl" as used herein refers to a C1-C3 alkyl group substituted with 1, 2 or 3 halogen atoms.

[0073] The term "halo C1-C6 alkyl" as used herein refers to a C1-C6 alkyl group substituted with 1 to 6 halogen atoms.

[0074] As used herein, the term "heteroaryl" refers to an aromatic 5- or 6-membered ring in which at least one atom is selected from N, O, and S and the remaining atoms are carbon. The term "heteroaryl" includes bicyclic systems in which the heteroaryl ring is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S; and tricyclic systems in which the bicyclic system is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S. A heteroaryl group is attached to the parent molecular moiety via any replaceable carbon or nitrogen atom in the group. Representative examples of heteroaryl groups include, but are not limited to, alloxazine, benzo[1,2-d:4,5-d']bisthiazole, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.

[0075] As used herein, the term "heteroaryl C1-C6 alkyl" refers to a heteroaryl group attached to the parent molecular moiety via a C1-C6 alkyl group.

[0076] As used herein, the term "heterocyclyl" refers to a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered saturated or partially unsaturated ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The term "heterocyclyl" also includes groups in which the heterocyclyl ring is fused to 1, 2 or 3 four- to six-membered aromatic or non-aromatic carbocyclic rings or monocyclic heterocyclyl groups. The term "heterocyclyl" also includes the above-mentioned monocyclic or polycyclic heterocyclyl groups further substituted with one or more spirocyclic groups attached to the heterocyclyl group via a spiro carbon. Examples of heterocyclyl groups include, but are not limited to, dihydro-1’H,3’H,5’H-dispiro[cyclopropane-1,2’-pyrrolidine-6’,1’’-cyclopropane], hexahydro-2H-1,4-dioxa-2a1-azacyclopenta[cd]pentalenyl, hexahydropyrrolidinyl, indolinyl, morpholinyl, octahydroindolizinyl, octahydroquinolizinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl and thiomorpholinyl.

[0077] As used herein, the term "heterocyclyl C1-C6 alkyl" refers to a heterocyclyl group attached to the parent molecular moiety via a C1-C6 alkyl group.

[0078] As used herein, the term "hydroxy" refers to -OH.

[0079] As used herein, the term "hydroxy C1-C3 alkyl" refers to a hydroxy group attached to the parent molecular moiety via a C1-C3 alkyl group.

[0080] As used herein, the term "hydroxy C1-C6 alkyl" refers to a hydroxy group attached to the parent molecular moiety via a C1-C6 alkyl group.

[0081] 「NR a R bThe term "-C(O)", as used herein, refers to an NR group bonded to the parent molecular moiety through a carbonyl group a R b .

[0082] "NR a R b -C(O)-C1-C6 alkyl", as used herein, refers to an NR a R b -C(O)- group bonded to the parent molecular moiety through a C1-C6 alkyl group.

[0083] "NR a R b C1-C6 alkyl", as used herein, refers to an NR a R b group bonded to the parent molecular moiety through a C1-C6 alkyl group.

[0084] The term "nitro", as used herein, refers to -NO2.

[0085] The term "oxo", as used herein, refers to =O.

[0086] This disclosure is intended to include all isotopes of atoms present in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. As common examples, without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Compounds of this disclosure labeled with isotopes can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described herein using appropriately labeled reagents in place of the unlabeled reagents originally used. Such compounds can have various potential uses, such as as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0087] Further aspects of the subject matter described herein are the development of ligand binding assays, or the use of the disclosed compounds as radiolabeled ligands for monitoring in vivo adsorption, metabolism, distribution, receptor binding or occupancy, or compound disposition. For example, the compounds described herein can be prepared using radioactive isotopes, and the resulting radiolabeled compounds can be used for developing binding assays or for metabolism studies. Alternatively and for the same purpose, the compounds described herein can be converted to radiolabeled forms by catalytic tritiation using methods known to those skilled in the art.

[0088] Certain compounds of the present disclosure exist as stereoisomers. When stereochemistry is not specified, it should be understood that the present disclosure encompasses any stereochemical isomeric form or mixture thereof having the ability to inhibit KRAS G12C. The individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products followed by separation, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatography, or direct separation of enantiomers on a chiral chromatography column. Starting compounds of specific stereochemistry are either commercially available or can be made and resolved by techniques known in the art.

[0089] Certain compounds of the present disclosure exist as atropisomers. The term "atropisomer" refers to conformational stereoisomers that occur when rotation around a single bond in a molecule is prevented or significantly retarded as a result of steric interactions with other parts of the molecule, and the substituents at both ends of the single bond are non-symmetrical (i.e., optical activity occurs without the need for an asymmetric carbon center or stereocenter). If the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of the isomeric species may be possible. Atropisomers are enantiomers (or epimers) that do not have a single chiral atom.

[0090] Atropisomers can be considered stable if the barrier to interconversion is high enough to allow the atropisomers to undergo little or no interconversion at room temperature for at least one week. In some embodiments, the atropisomers undergo little or no interconversion at room temperature for at least one year. In some embodiments, the atropisomeric compounds of the present disclosure, when the atropisomeric compound is in a substantially pure form and generally in the solid state, do not undergo more than about 5% interconversion to the opposite atropisomer at room temperature for one week. In some embodiments, the atropisomeric compounds of the present disclosure do not undergo more than about 5% interconversion to the opposite atropisomer at room temperature (about 25 °C) for one year. In some embodiments, the atropisomeric compounds of the present disclosure are stable enough to undergo no more than about 5% interconversion in an aqueous pharmaceutical formulation held at 0 °C for at least one week. The present chemical substances, pharmaceutical compositions, and methods are intended to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of single atropisomers, and intermediate mixtures.

[0091] The energy barrier to thermal racemization of atropisomers can be determined by the steric hindrance to the free rotation of one or more bonds forming the chiral axis. Certain biaryl compounds exhibit atropisomerism when rotation around the inter-ring bond lacking C2 symmetry is restricted. The free energy barrier to isomerization (enantiomerization) is a measure of the stability of the inter-ring bond to rotation. Optical and thermal excitation can promote the racemization of such isomers depending on electronic and steric factors.

[0092] Ortho-substituted biaryl compounds can exhibit rotational isomerism of this type of conformation. Such biaryls are chiral atropisomers of enantiomers, with sp 2 -sp 2 The carbon-carbon inter-ring bond has an energy barrier high enough to prevent free rotation, with substituents W 1 ≠W 2 and W 3 ≠W 4makes the molecule asymmetric.

Chem.

[0093] W 1 :W 3 , W 1 :W 4 and / or W 2 :W 4 , W 2 :W 3 The steric interaction between them is large enough to make the planar conformation the highest in energy. At this time, two non-planar axial chiral enantiomers exist as atropisomers if their interconversion is slow enough so that they can be isolated without containing each other. The thick and dashed lines in the figure shown above indicate parts or portions of the molecule that are sterically restricted due to the rotational energy barrier. The bold parts exist perpendicular to the plane of the paper, and the dashed parts exist perpendicular to the bottom of the paper. The "flat" part of the molecule (the ring on the left side of each of the two biaryls shown) is in the plane of the paper.

[0094] The pharmaceutical compounds of the present disclosure may include one or more pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refer to salts that retain the desired biological activity of the parent compound and do not impart any undesirable toxicological effects (see, e.g., Berge, S.M. et al., J. Pharm. Sci., 66:1-19 (1977)). The salts can be obtained during the final isolation and purification of the compounds described herein, or by separately reacting the free base functional groups of the compounds with appropriate acids or reacting the acidic groups of the compounds with appropriate bases. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous, and non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, calcium, and non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine.

[0095] Pharmaceutical composition In another aspect, the present disclosure provides a composition, such as a pharmaceutical composition, containing one or a combination of the compounds described within the present disclosure formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present disclosure can also be administered in combination therapies, i.e., in combination with other agents described herein.

[0096] As used herein, "pharmaceutically acceptable carrier" includes any physiologically compatible solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. In some aspects, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound can be coated onto a substance to protect the compound from the action of acids and other natural conditions that can inactivate the compound.

[0097] The pharmaceutical compositions of the present disclosure can be administered via one or more routes of administration using one or more of the various methods known in the art. As will be understood by those skilled in the art, the route of administration and / or mode of administration will vary depending on the desired result. In some embodiments, the route of administration of the compounds of the present disclosure includes intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral routes of administration, such as by injection or infusion. The term "parenteral administration" as used herein means a mode of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intra-articular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intra-articular, sub-synovial, subdural, intraspinal, epidural, and intrasternal injections and infusions.

[0098] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound into a suitable solvent, with one or a combination of the ingredients listed above as required, followed by sterile filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, some methods of preparation are vacuum drying and freeze-drying, whereby a powder of the active ingredient and any additional desired ingredients is obtained from its solution that has been pre-sterilized by filtration.

[0099] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils, and injectable organic esters. Suitable fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0100] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. Such media and agents for pharmaceutically active substances are known in the art. Their use in the pharmaceutical compositions of the present disclosure is contemplated, except in cases where any conventional media or agent is incompatible with the active compound. Auxiliary active compounds can also be incorporated into the compositions.

[0101] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The compositions can be formulated as solutions or liquids having an ordered structure suitable for high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.) and suitable mixtures thereof. Suitable fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions and by the use of surfactants. In many cases, it is desirable to include in the composition isotonic agents, for example sugars, polyhydric alcohols such as mannitol, sorbitol or sodium chloride. Sustained absorption of injectable compositions can be brought about by including in the composition agents that delay absorption, for example monostearates and gelatin.

[0102] Alternatively, the compounds of the present disclosure can be administered by parenteral routes, such as topical, dermal or mucosal administration routes, such as intranasal, oral, intravaginal, rectal, sublingual or topical administration.

[0103] Any pharmaceutical composition contemplated herein can be orally delivered, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. A pharmaceutical composition intended for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable formulation, the pharmaceutical compositions according to the present disclosure can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, lubricants, antioxidants, and preservatives.

[0104] Tablets can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets.

[0105] An aqueous suspension can be prepared by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension, including but not limited to suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum and gum arabic; dispersing agents or wetting agents such as naturally occurring phosphatides such as lecithin; condensation products of alkylene oxides and fatty acids such as polyoxyethylene stearate; condensation products of ethylene oxide and long-chain aliphatic alcohols such as heptadecatylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. The aqueous suspension can also contain at least one preservative such as ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent including but not limited to sucrose, saccharin and aspartame.

[0106] An oily suspension can be prepared, for example, by suspending at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in any of vegetable oils such as peanut oil, sesame oil and coconut oil; or mineral oils such as liquid paraffin. The oily suspension can also contain at least one thickening agent such as beeswax, hard paraffin and cetyl alcohol. In order to provide an oily suspension with a good taste, at least one of the sweeteners already described above and / or at least one flavoring agent can be added to the oily suspension. The oily suspension can further contain at least one preservative including, but not limited to, antioxidants such as butylated hydroxyanisole and alpha-tocopherol.

[0107] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersant and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersants, wetting agents and suspending agents have already been described above. Exemplary preservatives include, but are not limited to, antioxidants such as ascorbic acid. Further, the dispersible powders and granules can contain at least one excipient including, but not limited to, sweeteners, flavoring agents and coloring agents.

[0108] The active compound can be prepared using a controlled release formulation that includes a carrier that protects the compound from rapid release, such as implants, transdermal patches, and microencapsulation delivery systems. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods for preparing such formulations are patented or generally known to those skilled in the art. See, for example, Robinson, J.R., ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0109] The therapeutic composition can be administered using medical devices known in the art. For example, in one aspect, the therapeutic composition of the present disclosure can be administered using a needleless subcutaneous injection device such as the devices disclosed in U.S. Patent Nos. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556. Examples of well-known implants and modules useful in the present disclosure include: U.S. Patent No. 4,487,603, which discloses an implantable microinjection pump for dispensing a drug at a controlled rate; U.S. Patent No. 4,486,194, which discloses a therapeutic device for administering a drug through the skin; U.S. Patent No. 4,447,233, which discloses a drug injection pump for delivering a drug at an accurate injection rate; U.S. Patent No. 4,447,224, which discloses a variable flow rate implantable injection device for continuous drug delivery; U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system having multiple chambers and compartments; and U.S. Patent No. 4,475,196, which discloses an osmotic drug delivery system. These patents are hereby incorporated by reference herein. Many other such implants, delivery systems, and modules are known to those skilled in the art.

[0110] In certain embodiments, the compounds of the present disclosure can be administered parenterally, i.e., by injection and / or infusion including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injections and / or infusions.

[0111] In some embodiments, the compounds of the present disclosure can be administered orally, i.e., via gelatin capsules, tablets, hard or soft capsules or liquid capsules.

[0112] Use / Treatment Method of KRAS Inhibitor Administration of the therapeutic agents described herein can include administration of a therapeutically effective amount of the therapeutic agent. The term "therapeutically effective amount" as used herein refers to, but is not limited to, the amount of a therapeutic agent for treating a condition treatable by administration of a composition comprising a KRAS inhibitor described herein. This amount is an amount sufficient to exhibit a detectable therapeutic or ameliorating effect. Effects can include, by way of example and without limitation, treatment of the conditions listed herein. The exact effective amount for a particular subject will depend upon the size and health of the subject, the nature and extent of the condition being treated, the advice of the treating physician and the therapeutic agent or combination of therapeutic agents selected for administration.

[0113] For administration of the compounds described herein, the dosage ranges from about 0.0001 to 100 mg / kg of host body weight, more typically from 0.01 to 40 mg / kg. Exemplary treatment regimens require administration once daily, twice weekly, three times weekly, once weekly, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months or once every three to six months.

[0114] The disclosed compounds potently inhibit anchorage-independent cell growth and thus have the potential to inhibit tumor metastasis. Accordingly, in another aspect, the present disclosure provides a method of inhibiting tumor metastasis, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of any of the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0115] Ras mutations, including but not limited to KRAS mutations, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain aspects relate to the administration of the disclosed compounds (e.g., in the form of a pharmaceutical composition) to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the compounds of the present disclosure can be used in the treatment of diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other aspects, the compounds are useful in the treatment of lymphomas, such as all subtypes of Hodgkin lymphoma or non-Hodgkin lymphoma.

[0116] Determination of whether a tumor or cancer contains a KRAS mutation can be made by assessing the nucleotide sequence encoding the KRAS protein, by assessing the amino acid sequence of the KRAS protein, or by assessing the properties of a putative KRAS mutant protein. The sequence of the wild-type human KRAS protein is known in the art.

[0117] Methods for detecting KRAS mutations are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, the sample is evaluated for KRAS mutations, including those by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRAS mutation is used. If the mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRAS mutation is identified using, for example, a direct sequencing method of a specific region (e.g., exon 2 and / or exon 3) in the KRAS gene. This technique will identify all possible mutations in the sequenced region.

[0118] Methods for detecting mutations in the KRAS protein are known to those skilled in the art. These methods include, but are not limited to, detection of KRAS mutants using binders specific for the mutant protein (e.g., antibodies), protein electrophoresis and Western blotting, and direct sequencing of peptides.

[0119] Methods for determining whether a tumor or cancer contains a KRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is taken from a subject having cancer or a tumor. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to become a cell lysate. In some embodiments, the sample is processed to DNA or RNA. The present disclosure also relates to a method for treating a mammalian hyperproliferative disorder, comprising administering to the mammal a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.In some embodiments, the method relates to the treatment of cancers such as acute myeloid leukemia, adolescent cancers, pediatric adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, osteosarcoma, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid rhabdoid tumor, germinoma, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T cell lymphoma, ductal carcinoma in situ (DCIS), germinoma, CNS cancer, endometrial cancer, epithelioma, esophageal cancer, nasal neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary, midline ductal carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, fungating polypoid tumor, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal and paranasal cancer, oropharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, pediatric dysplastic cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer. In some embodiments, the method relates to the treatment of non-cancerous hyperproliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)).

[0120] In certain aspects, the present disclosure relates to a method for treating lung cancer, the method comprising administering to a subject in need thereof an effective amount of any of the above compounds (or a pharmaceutical composition comprising the same). In certain aspects, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell carcinoma, or large cell lung cancer. In other aspects, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, adenoid cystic tumors, carcinoid tumors, and undifferentiated carcinomas.Subjects treatable with the compounds of the present disclosure or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates or derivatives of said compounds include, according to the methods of the present disclosure, for example, acute myeloid leukemia, acute myeloid leukemia, adolescent cancer, pediatric adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi sarcoma), anal cancer, appendiceal cancer, astrocytoma, anaplastic teratoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, osteosarcoma, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, anaplastic teratoma, germinoma, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), germinoma, CNS cancer, endometrial cancer, epithelioma, esophageal cancer, nasal neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary, midline ductal carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, fungating polyp, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal and paranasal cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, pediatric dysplastic cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer.In some embodiments, subjects to be treated with the compounds of the present disclosure include subjects diagnosed with non-cancerous hyperproliferative diseases such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)). The present disclosure further provides a method of modulating the activity of a mutant KRAS protein by contacting the protein with an effective amount of a compound of the present disclosure. The modulation can be inhibiting or activating the protein activity. In some embodiments, the present disclosure provides a method of inhibiting the activity of a mutant KRAS protein by contacting the mutant KRAS protein with an effective amount of a compound of the present disclosure in solution. In some embodiments, the present disclosure provides a method of inhibiting the activity of a mutant KRAS protein by contacting cells, tissues, or organs that express the protein of interest. In some embodiments, the present disclosure provides a method of inhibiting the activity of a protein in a subject by administering to the subject, including but not limited to, rodents and mammals (e.g., humans), an effective amount of a compound of the present disclosure. In some embodiments, the percentage of modulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibition exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the present disclosure provides a method of inhibiting KRAS activity in a cell by contacting the cell with an amount of a compound of the present disclosure sufficient to inhibit the activity of an intracellular KRAS mutant. In some embodiments, the present disclosure provides a method of inhibiting mutant KRAS in a tissue by contacting the tissue with an amount of a compound of the present disclosure sufficient to inhibit the activity of mutant KRAS in the tissue. In some embodiments, the present disclosure provides a method of inhibiting KRAS in an organism by contacting the organism with an amount of a compound of the present disclosure sufficient to inhibit the activity of KRAS in the organism. In some embodiments, the present disclosure provides a method of inhibiting the activity of KRAS in an animal by contacting the animal with an amount of a compound of the present disclosure sufficient to inhibit the activity of KRAS in the animal.In some aspects, the present disclosure provides a method of inhibiting KRAS, including that in a mammal, by contacting the mammal with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the mammal. In some aspects, the present disclosure provides a method of inhibiting the activity of KRAS in a human by contacting the human with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the human. The present disclosure provides a method of treating a disease mediated by KRAS activity in a subject in need of such treatment. The present disclosure also provides a method of combination therapy in which an agent known to modulate other pathways or other components of the same pathway, or a target enzyme of an overlapping set, is used in combination with a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative thereof. In one aspect, such therapies include, but are not limited to, combinations of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies and radiation therapy.

[0121] Currently, many chemotherapeutic agents are known in the art and can be used in combination with the compounds of the present disclosure. In some aspects, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormonal agents, angiogenesis inhibitors and antiandrogens.

[0122] The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the disclosure will be co-administered with the other agents described above. When used in combination therapy, the compounds described herein are administered simultaneously with or separately from the second agent. Such co-administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration of separate dosage forms, and separate administrations. That is, the compounds described herein and any of the above agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the disclosure and any of the above agents can be administered simultaneously, and both agents are present in separate formulations. In another alternative, following administration of the compounds of the disclosure, any of the above agents can be administered or vice versa. In some embodiments of separate administration protocols, the compounds of the disclosure and any of the above agents are administered at intervals of minutes, or hours, or days.

[0123] Compounds can be made by methods known in the art, including those described below and including variations within the skill of the artisan. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. Any variable used to describe the synthesis of a compound (e.g., numbered "R" substituents) is intended only to illustrate the method of making the compound and should not be confused with variables used in the claims or other sections of this specification. The following methods are for illustrative purposes only and are not intended to limit the scope of the disclosure.

Examples

[0124] Synthesis The aspects described in this specification are further defined in the following examples. It should be understood that the examples are merely illustrative. From the above description, consideration, and examples, those skilled in the art can identify the essential features of the aspects described in this specification and make various changes and modifications to adapt them to various uses and conditions without departing from the spirit and scope thereof. As a result, the aspects described in this specification are not limited by the exemplary embodiments described below, but rather are defined by the claims appended hereto.

[0125] Abbreviations The following abbreviations are used in the examples section below and elsewhere in this specification: DIPEA is diisopropylethylamine; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; MeCN or ACN is acetonitrile; TFA is trifluoroacetic acid;

Chem.

Chem.

Chem.

[0126] All three compounds were prepared according to the synthetic procedures described in U.S. Patent No. 10,689,377 B2.

[0127] Preparation of Heteroaryl Intermediate

Chemical Formula

[0128] Step 2: Preparation of Ethyl (Z)-2-Fluoro-3-(pyridin-2-yl)acrylate Ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate (420 mg, 2.1 mmol) was dissolved in toluene (10 mL), and iodine (27 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0→100% EtOAc / hexane) to give ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate (240 mg, 1.2 mmol, 58% yield). LC / MS (ESI) m / z: [M+H] + C 10 H 11 Calculated for C10H9FNO2 196.1; found 196.1; 1 1H NMR (500 MHz, CDCl3) δ 8.66 (ddd, J = 5.0, 1.8, 0.8 Hz, 1H), 7.88 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H), 7.75 (ddd, J = 8.0, 7.8, 1.8 Hz, 1H), 7.25 (ddd, J = 7.8, 5.0, 1.2 Hz, 1H), 7.14 (d, J = 34.9 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

[0129] Step 3: Preparation of (Z)-2-Fluoro-3-(pyridin-2-yl)acrylic Acid Ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate (415 mg, 2.1 mmol) was dissolved in MeOH (15 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 2.1 mL, 2.1 mmol) was added. The reaction mixture was stirred for 5 h. The solution was concentrated to remove methanol. Additional water (2.0 mL) was added and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 2.1 mL, 2.1 mmol) was added dropwise. After 10 min, a white solid precipitated. The solid was collected by filtration and washed with Et2O. The solid was dried under reduced pressure to give (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (235 mg, 1.4 mmol, 66% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated for C8H7FNO2 168.0; found 167.8. 1 1H NMR (500 MHz, DMSO-d6) δ 8.66 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.89 (ddd, J = 8.0, 7.5, 1.8 Hz, 1H), 7.81 (ddd, J = 8.0, 1.1, 0.8 Hz, 1H), 7.40 (dd, J = 7.5, 4.8, 1.1 Hz, 1H), 6.97 (d, J = 35.3 Hz, 1H).

[0130]

Chemical Structure

[0131] Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate Ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate (592 mg, 3.0 mmol) was dissolved in toluene (15 mL) and iodine (38 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to give ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate (253 mg, 1.3 mmol, 43% yield). LC / MS (ESI) m / z: [M+H] + C9H 10Calculated value for FN2O2: 197.2; Measured value: 196.6; 1 1H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 4.9 Hz, 2H), 7.21 (t, J = 4.9 Hz, 1H), 7.13 (d, J = 30.8 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H).

[0132] Step 3: Preparation of (Z)-2-Fluoro-3-(pyrimidin-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate (253 mg, 1.3 mmol) was dissolved in MeOH (10 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 1.3 mL, 1.3 mmol) was added. The reaction mixture was stirred for 2 hours. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added, and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 2.5 mL, 2.5 mmol) was added dropwise. After 10 minutes, a white solid precipitated. The solid was collected by filtration and dried under reduced pressure to give (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylic acid (190 mg, 1.1 mmol, 88% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated value for C7H6FN2O2: 169.1; Measured value: 168.8; 1 1H NMR (500 MHz, DMSO-d6) δ 8.90 (d, J = 4.9 Hz, 2H), 7.46 (t, J = 4.9 Hz, 1H), 6.94 (d, J = 31.5 Hz, 1H).

[0133]

Chemical Structure

[0134] Step 2: Preparation of ethyl (Z)-2-fluoro-3-(thiazol-2-yl)acrylate Ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate (620 mg, 3.1 mmol) was dissolved in toluene (15 mL) and iodine (39 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to give ethyl (Z)-2-fluoro-3-(thiazol-2-yl)acrylate (509 mg, 2.5 mmol, 82% yield). LC / MS (ESI) m / z: [M+H] +Calculated value for C8H9FNO2S: 202.0; Measured value: 202.0; 1 1H NMR (500 MHz, CDCl3) δ 7.96 (dd, J = 3.2, 2.6 Hz, 1H), 7.57 (d, J = 3.2 Hz, 1H), 7.43 (dd, J = 33.3, 0.8 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H).

[0135] Step 3: Preparation of (Z)-2-Fluoro-3-(thiazol-2-yl)acrylic Acid (Z)-2-Fluoro-3-(thiazol-2-yl)acrylate (510 mg, 2.5 mmol) was dissolved in MeOH (15 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 2.5 mL, 2.5 mmol) was added. The reaction mixture was stirred for 5 h. The solution was concentrated to remove methanol. Additional water (1.5 mL) was added, and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 2.5 mL, 2.5 mmol) was added dropwise. After 10 min, a white solid precipitated. The solid was collected by filtration and washed with MeCN. The solid was dried under reduced pressure to give (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (337 mg, 1.9 mmol, 77% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated value for C6H5FNO2S: 174.0; Measured value: 173.8; 1 1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 2H), 7.29 (d, J = 34.5 Hz, 1H).

[0136]

Chemical Structure

[0137] Step 2: Preparation of ethyl (Z)-2-fluoro-3-(oxazol-2-yl)acrylate Ethyl (E)-2-fluoro-3-(oxazol-2-yl)acrylate (165 mg, 0.89 mmol) was dissolved in toluene (2 mL) and iodine (11 mg, 0.045 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to give ethyl (Z)-2-fluoro-3-(oxazol-2-yl)acrylate (22 mg, 0.12 mmol, 13% yield). LC / MS (ESI) m / z: [M+H] +Calculated value for C8H9FNO3: 186.0; Measured value: 185.9 1 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.32 (s, 1H), 6.96 (d, J = 31.0 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

[0138] Step 3: Preparation of (Z)-2-Fluoro-3-(oxazol-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(oxazol-2-yl)acrylate (22 mg, 0.12 mmol) was dissolved in MeOH (1 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 0.12 mL, 0.12 mmol) was added. The reaction mixture was stirred for 4 h. The solution was concentrated to remove methanol. Additional water (0.3 mL) was added, and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.12 mL, 0.12 mmol) was added dropwise. The solution was frozen and freeze-dried directly to obtain (Z)-2-fluoro-3-(oxazol-2-yl)acrylic acid (18 mg, 0.12 mmol, assuming quantitative yield; containing 1 equivalent of NaCl) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated value for C6H5FNO3: 158.0; Measured value: 157.8; 1 1H NMR (600 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.47 (s, 1H), 6.90 (d, J = 32.2 Hz, 1H).

[0139]

Chemical Structure

[0140] Step 2: Preparation of (Z)-2-Fluoro-3-(isoxazol-3-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(isoxazol-3-yl)acrylate (21 mg, 0.11 mmol) was dissolved in MeOH (1.1 mL) and sodium hydroxide solution (1.0 M, 160 μL, 0.16 mmol) was added dropwise. The mixture was stirred for 15 minutes. The reaction mixture was concentrated and used directly in the next step as the sodium salt without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + Calculated for C6H5FNO3 158.1; found 157.8.

[0141]

Chemical Structure

[0142] Step 2: Preparation of (Z)-2-Fluoro-3-(isoxazol-5-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(isoxazol-5-yl)acrylate (31 mg, 0.11 mmol) was dissolved in MeOH (1.7 mL), and sodium hydroxide solution (1.0 M, 230 μL, 0.23 mmol) was added dropwise. The mixture was stirred for 15 minutes. The reaction mixture was concentrated and used directly in the next step as the sodium salt without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + Calculated for C6H5FNO3 158.1; found 157.9.

[0143] [Chemical formula] Intermediate J (Z)-2-Fluoro-3-(isothiazol-5-yl)acrylic acid Step 1: Preparation of Ethyl (Z)-2-Fluoro-3-(isothiazol-5-yl)acrylate (2-Ethoxy-1-fluoro-2-oxoethyl)triphenylphosphonium bromide (790 mg, 1.77 mmol) was stirred in THF (9 mL) at 0 °C. To the mixture, nBuLi solution (2.5 M in hexane, (0.71 mL, 1.77 mmol) was added dropwise. The mixture was stirred for 10 minutes, and then isothiazole-5-carbaldehyde (100 mg, 0.88 mmol) was added as a solution in THF (1 mL). The reaction mixture was warmed to room temperature over 2 hours. The reaction mixture was concentrated, and the residue was purified directly by column chromatography (5→100% EtOAc / hexane) to give ethyl (Z)-2-fluoro-3-(isothiazol-5-yl)acrylate (71 mg, 0.35 mmol, 40% yield). LC / MS (ESI) m / z: [M+H] + Calculated for C8H9FNO2S 202.0; Found 201.9; 1 1H NMR (500 MHz, CDCl3) δ 8.49 (t, J = 2.0 Hz, 1H), 7.39 (dd, J = 2.0, 1.0 Hz, 1H), 7.27 (d, J = 33.4 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H).

[0144] Step 2: Preparation of (Z)-2-Fluoro-3-(isothiazol-5-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(isothiazol-5-yl)acrylate (71 mg, 0.35 mmol) was dissolved in MeOH (3.5 mL), and sodium hydroxide solution (1.0 M, 420 μL, 0.420 mmol) was added dropwise. The mixture was stirred for 2 hours. The reaction mixture was concentrated and used directly in the next step as the sodium salt without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] +Calculated value for C6H5FNO2S: 174.1; Measured value: 173.9.

[0145] [Chemical formula] Intermediate K (Z)-2-Fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)acrylate (2-Ethoxy-1-fluoro-2-oxoethyl)triphenylphosphonium bromide (1.1 g, 2.5 mmol) was stirred in THF (10 mL) at 0 °C. To the mixture, nBuLi solution (2.5 M in hexane, (1.0 mL, 2.5 mmol) was added dropwise. The mixture was stirred for 10 minutes, and then 1-methyl-1H-1,2,3-triazol-4-yl-4-carbaldehyde (140 mg, 1.26 mmol) was added as a solution in THF (2 mL). The reaction mixture was warmed to room temperature over 2 hours. The reaction mixture was concentrated and the residue was purified directly by column chromatography (5 → 100% EtOAc / hexane) to give ethyl (Z)-2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)acrylate (132 mg, 0.66 mmol, 53% yield). LC / MS (ESI) m / z: [M+H] + C8H 11 Calculated value for FN3O2: 200.1; Measured value: 199.9; 1 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 1.9 Hz, 1H), 7.24 (d, J = 34.9 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.14 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H).

[0146] Step 2: Preparation of (Z)-2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)acrylate (132 mg, 0.66 mmol) was dissolved in MeOH (5 mL), and sodium hydroxide solution (1.0 M, 920 μL, 0.92 mmol) was added dropwise. The mixture was stirred for 2 h. The reaction mixture was concentrated, diluted with water (1 mL), and hydrochloric acid solution (1.0 M, 920 μL, 0.92 mmol) was added. This solution was purified by HPLC (column: Xbridge C18, 19 mm × 200 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25 °C; gradient: 5:95 MeCN:H2O (containing 10 mM AA) → 95:5 MeCN:H2O (containing 10 mM AA); λ = 220, 254 nm) to give (Z)-2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)acrylic acid (11 mg, 0.06 mmol, 10% yield). LC / MS (ESI) m / z: [M+H] + Calculated for C6H7FN3O2 172.0; found 171.9; 1 H NMR (500 MHz, CD3OD) δ 8.28 (s, 1H), 7.09 (d, J = 34.0 Hz, 1H), 4.15 (s, 3H).

[0147]

Chemical Structure

[0148] Step 2: Preparation of (Z)-2-fluoro-3-(6-methylpyridin-2-yl)acrylic acid (Z)-Ethyl 2-fluoro-3-(6-methylpyridin-4-yl)acrylate (31 mg, 0.15 mmol) was dissolved in MeOH (1.5 mL), and sodium hydroxide solution (1.0 M, 150 μL, 0.15 mmol) was added dropwise. The mixture was stirred for 2 h. The reaction mixture was concentrated, diluted with water (1 mL), and hydrochloric acid solution (1.0 M, 150 μL, 0.14 mmol) was added. This solution was lyophilized and used without further purification of the crude material (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + Calculated for C9H9FNO2 182.1; found 182.1; 1 H NMR (500 MHz, DMSO-d6) δ 7.80 (t, J = 7.7 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 35.4 Hz, 1H), 2.50 (s, 3H).

[0149] [Chemical formula] Intermediate M (Z)-2-Fluoro-3-(3-methylpyridin-2-yl)acrylic acid Step 1: Preparation of (Z)-ethyl 2-fluoro-3-(3-methylpyridin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and 3-methylpyridine-2-carbaldehyde (125 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by HPLC (column: Xbridge C18, 5 μm particles; gradient: 5:95 MeCN:H2O (containing 0.05% TFA) → 95:5 MeCN:H2O (containing 0.05% TFA); λ = 220 nm) to give ethyl (Z)-2-fluoro-3-(3-methylpyridin-2-yl)acrylate (30 mg, 0.14 mmol, 13% yield). LC / MS (ESI) m / z: [M+H] + C 11 H 13 Calculated for C11H10FNO2 210.1; found 209.7; 1 1H NMR (500 MHz, CDCl3) δ 8.53 (dd, J = 4.2, 0.8 Hz, 1H), 7.52 (dd, J = 7.7, 0.8 Hz, 1H), 7.16 (dd, J = 7.7, 4.2 Hz, 1H), 7.15 (d, J = 32.4 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H).

[0150] Step 2: Preparation of (Z)-2-fluoro-3-(3-methylpyridin-2-yl)acrylic acid (Z)-2-Fluoro-3-(3-methylpyridin-4-yl)ethyl acrylate (30 mg, 0.14 mmol) was dissolved in MeOH (1.5 mL), and sodium hydroxide solution (1.0 M, 140 μL, 0.15 mmol) was added dropwise. The mixture was stirred for 2 hours. The reaction mixture was concentrated, diluted with water (1 mL), and hydrochloric acid solution (1.0 M, 140 μL, 0.14 mmol) was added. This solution was lyophilized and the crude material was used without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + Calculated for C9H9FNO2 182.1; found 181.8; NMR: 1 H NMR (500 MHz, DMSO-d6) δ 8.48 (dd, J = 4.3, 0.8 Hz, 1H), 7.68 (dd, J = 7.7, 0.8 Hz, 1H), 7.29 (dd, J = 7.7, 4.3 Hz, 1H), 7.11 (d, J = 32.9 Hz, 1H), 2.33 (s, 3H).

[0151] [Chemical formula] Intermediate N (Z)-2-Fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and 1-methylimidazole-2-carbaldehyde (114 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by reverse phase HPLC (column: Xbridge C18, 30 mm × 100 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25 °C; gradient: 95:5 H2O:MeCN:10 mM AA → 100% 5:95 H2O:MeCN:10 nM AA; λ = 220 nm) to give ethyl (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylate (16 mg, 0.08 mmol, 8% yield). LC / MS (ESI) m / z: [M+H] + C9H 12 Calculated for FN2O2 199.1; found 198.9; 1 H NMR (500 MHz, CDCl3) δ 7.22 (d, J = 0.7 Hz, 1H), 6.94 (d, J = 0.7 Hz, 1H), 6.84 (d, J = 30.5 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.71 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).

[0152] Step 2: Preparation of (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylate (16 mg, 0.08 mmol) was dissolved in MeOH (1 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 0.08 mL, 0.08 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (0.3 mL) was added and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.08 mL, 0.08 mmol) was added dropwise. The solution was frozen and freeze-dried directly to give (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylic acid (13 mg, 0.08 mmol, assuming quantitative yield; containing 1 equivalent of NaCl) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated for C7H8FN2O2 171.0; found 170.9; 1 1H NMR (500 MHz, DMSO-d6) δ 7.31 (s, 1H), 7.11 (s, 1H), 6.87 (d, J = 31.6 Hz, 1H), 3.72 (s, 3H).

[0153] [Chemical formula] Intermediate O (Z)-2-Fluoro-3-(5-methylpyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(5-methylpyridin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and 5-methylpicolinaldehyde (125 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (15 mL). The solution was diluted with water (20 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by reverse phase HPLC (column: Xbridge C18, 30 mm × 100 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25 °C; gradient: 95:5 H2O:MeCN:0.05% TFA → 100% 5:95 H2O:MeCN:0.05% TFA; λ = 220 nm) to give ethyl (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylate (12 mg, 0.06 mmol, 6% yield). LC / MS (ESI) m / z: [M+H] + C 11 H 13 Calculated for C10H10FNO2 210.2; found 210.1 1 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.55 (dd, J = 8.2, 1.8 Hz, 1H), 7.12 (d, J = 35.3 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).

[0154] Step 2: Preparation of (Z)-2-fluoro-3-(5-methylpyridin-2-yl)acrylic acid (Z)-Ethyl 2-fluoro-3-(5-methylpyridin-2-yl)acrylate (12 mg, 0.06 mmol) was dissolved in MeOH (0.5 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 0.06 mL, 0.06 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.06 mL, 0.06 mmol) was added dropwise. The solution was frozen and freeze-dried directly to give (Z)-2-fluoro-3-(5-methylpyridin-2-yl)acrylic acid (10 mg, 0.06 mmol, assuming quantitative yield; containing 1 equivalent of NaCl) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated for C9H8FNO2 182.1; found 181.6; 1 H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.74 - 7.69 (m, 2H), 6.95 (d, J = 35.4 Hz, 1H), 2.33 (s, 3H).

[0155]

Chemical Structure

[0156] Step 2: Preparation of (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylate (32 mg, 0.15 mmol) was dissolved in MeOH (1.5 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 0.15 mL, 0.15 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added, and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.15 mL, 0.15 mmol) was added dropwise. The solution was frozen and freeze-dried directly to give (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylic acid (27 mg, 0.15 mmol, assuming quantitative yield; containing 1 equivalent of NaCl) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated for C9H8FNO2 182.1; found 182.1. 1 H NMR (500 MHz, DMSO-d6) δ 8.51 (d, J = 4.9 Hz, 1H), 7.65 (s, 1H), 7.24 (d, J = 4.9 Hz, 1H), 6.94 (d, J = 35.3 Hz, 1H), 2.36 (s, 3H).

[0157]

Chemical Structure

[0158] Step 2: Preparation of (Z)-2-fluoro-3-(pyridin-4-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(pyridin-4-yl)acrylate (60 mg, 0.3 mmol) was dissolved in MeOH (1.5 mL), and an aqueous solution of sodium hydroxide (1.0 M, 0.46 mL, 0.46 mmol) was added dropwise. The reaction mixture was stirred for 1 h and concentrated. An aqueous solution of hydrochloric acid (1.0 M, 0.46 mL, 0.46 mmol) was added dropwise. The solution was frozen and lyophilized to afford (Z)-2-fluoro-3-(pyridin-4-yl)acrylic acid as a white solid (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + Calculated for C8H7FNO2 168.0; found 168.0.

[0159] Preparation of KRAS inhibitor

Chemical Structure

[0160]

Chem.

[0161]

Chem.

[0162]

Chem.

[0163]

Chem.

[0164] [Chemical formula] Example 6 2 - ((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(oxazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (Intermediate A, 10 mg, 0.019 mmol) and (Z)-2-fluoro-3-(oxazol-2-yl)acrylic acid (Intermediate F, 4 mg, 0.038 mmol) were combined as solids and dissolved in DMF (0.5 mL). After adding 1-methylimidazole (0.015 mL, 0.188 mmol), chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (5.3 mg, 0.019 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm × 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 74% of 5:95 MeCN:H2O (containing 10 mM AA) / 26% of 95:5 MeCN:H2O (containing 10 mM AA) → 100% of 95:5 MeCN:H2O (containing 10 mM AA); λ = 220 nm) to give 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(oxazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile (2.9 mg, 0.004 mmol, 23% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + C 35 H 37 Calculated for ClFN8O3 671.3; found 671.2; NMR: Note: Spectrum reported as obtained; water suppression method used; the presence of atropisomers and amide rotational isomers complicates the analysis. 11H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.63 - 7.48 (m, 2H), 7.45 (s, 1H), 7.48 - 7.42 (m, 1H), 7.42 - 7.28 (m, 1H), 6.67 (br d, J = 35.1 Hz, 1H), 5.00 - 4.37 (m, 1H), 4.28 - 4.11 (m, 2H), 4.09 - 3.92 (m, 3H), 3.85 - 3.70 (m, 1H), 3.53 - 3.43 (m, 1H), 3.15 - 3.04 (m, 2H), 3.00 - 2.88 (m, 1H), 2.72 - 2.55 (m, 1H), 2.44 - 2.35 (m, 1H), 2.33 (br s, 3H), 2.21 - 2.11 (m, 1H), 1.96 - 1.90 (m, 2H), 1.71 - 1.63 (m, 2H), 1.60 - 1.52 (m, 1H).

[0165] [Chemical formula] Example 7 2 - ((S)-4-(7-(8-chloronaphthalen-1-yl)-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (Intermediate B, 40 mg, 0.069 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (Intermediate C, 5.8 mg, 0.035 mmol) were combined as solids and dissolved in DMF (3.5 mL). After adding 1-methylimidazole (0.055 mL, 0.69 mmol), chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (10 mg, 0.035 mmol) was added and the reaction mixture was stirred at room temperature for 5 minutes. An additional portion of (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (5.8 mg, 0.035 mmol) and chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (10 mg, 0.035 mmol) was added and the reaction mixture was stirred for 5 minutes. This process was repeated 6 more times. The reaction mixture was purified directly by reverse phase HPLC (column: Xbridge C18, 19 mm × 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 65% of 5:95 MeCN:H2O (containing 10 mM AA) / 35% of 95:5 MeCN:H2O (containing 10 mM AA) → 100% of 95:5 MeCN:H2O (containing 10 mM AA); λ = 220 nm) to give 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile (8.5 mg, 0.012 mmol, 17% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + C 39 H 39Calculated value for ClF2N8O2: 725.3; Measured value: 725.2; NMR: Note: Spectrum reported as obtained; Water suppression method used; The presence of atropisomers and amide rotational isomers complicates the analysis. 1 H NMR (500 MHz, DMSO-d6) δ 8.65 (br d, J = 4.1 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.47 - 7.42 (m, 1H), 7.40 - 7.30 (m, 1H), 7.38 (dd, J = 7.6, 4.1 Hz, 1H), 6.61 (d, J = 39.2 Hz, 1H), 5.26 (d, J = 53.7 Hz, 1H), 5.00 - 4.26 (m, 1H), 4.24 - 4.11 (m, 1H), 4.11 - 3.84 (m, 4H), 3.80 - 3.64 (m, 1H), 3.55 - 3.36 (m, 1H), 3.20 - 2.92 (m, 4H), 2.85 - 2.77 (m, 1H), 2.73 - 2.64 (m, 1H), 2.14 - 1.92 (m, 3H), 1.88 - 1.65 (m, 3H).

[0166]

Chem.

[0167]

Chemical Structure

[0168] [Chem.] Example 10 2 - ((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (10 mg, 0.019 mmol) and (Z)-2-Fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylic acid (4 mg, 0.019 mmol) were combined as solids and dissolved in DMF (0.5 mL). After adding 1-methylimidazole (0.015 mL, 0.188 mmol), chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (5 mg, 0.019 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm×200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 79% of 5:95 MeCN:H2O (containing 10 mM AA) / 21% of 95:5 MeCN:H2O (containing 10 mM AA) → 100% of 95:5 MeCN:H2O (containing 10 mM AA); λ = 220 nm) to obtain the desired product (2.3 mg, 0.003 mmol, 17% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + C 36 H 40 Calculated for ClFN9O2 684.3; found 684.3; NMR: Note: Spectrum reported as obtained; water suppression method used; the presence of atropisomers and amide rotational isomers complicates the analysis. 11H NMR (500 MHz, DMSO-d6) δ 7.92 (br d, J = 8.0 Hz, 1H), 7.78 - 7.66 (m, 1H), 7.63 - 7.49 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.39 - 7.30 (m, 1H), 7.28 (s, 1H), 7.07 (s, 1H), 6.64 (d, J = 35.0 Hz, 1H), 5.00 - 4.56 (m, 1H), 4.27 - 4.13 (m, 2H), 4.09 - 3.92 (m, 3H), 3.85 - 3.73 (m, 1H), 3.73 - 3.65 (m, 3H), 3.56 - 3.36 (m, 1H), 3.16 - 3.05 (m, 2H), 3.02 - 2.90 (m, 2H), 2.77 - 2.63 (m, 1H), 2.39 - 2.29 (m, 3H), 2.22 - 2.11 (m, 1H), 1.97 - 1.91 (m, 1H), 1.70 - 1.61 (m, 2H), 1.61 - 1.53 (m, 1H).

[0169]

Chem.

[0170]

Chem.

[0171]

Chem.

[0172]

Chem.

[0173]

Chem.

[0174]

Chemical Structure

[0175] [Chemical formula] Example 17 2 - ((S)-4-(7-(8 - Chloronaphthalen - 1 - yl)-2 - (((S)-1 - methylpyrrolidin - 2 - yl)methoxy)-5,6,7,8 - tetrahydropyrido[3,4 - d]pyrimidin - 4 - yl)-1 - ((Z)-2 - fluoro - 3 - (isoxazol - 5 - yl)piperazin - 2 - yl)acetonitrile 2 - ((S)-4-(7-(8 - Chloronaphthalen - 1 - yl)-2 - (((S)-1 - methylpyrrolidin - 2 - yl)methoxy)-5,6,7,8 - tetrahydropyrido[3,4 - d]pyrimidin - 4 - yl)piperazin - 2 - yl)acetonitrile (10 mg, 0.019 mmol) and (Z)-2 - fluoro - 3 - (isoxazol - 5 - yl)acrylic acid, Na +(7 mg, 0.038 mmol) were combined as solids and dissolved in DMF (1.0 mL). After adding DIPEA (10 μL, 0.056 mmol), COMU® ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate) (12 mg, 0.028 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solution was purified directly by HPLC (column: Xbridge C18, 19 mm × 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 87% of 5:95 MeCN:H2O (containing 0.1% TFA) / 13% of 95:5 MeCN:H2O (containing 0.1% TFA) → 100% of 95:5 MeCN:H2O (containing 0.1% TFA); λ = 220 nm) to give the desired product (4.4 mg, 0.005 mmol, 12% yield) as the bis-TFA salt. LC / MS (ESI) m / z: [M+H] + C 35 H 37 Calculated for ClFN8O3 671.3; found 671.2; NMR: spectrum reported as obtained; water suppression method used; the presence of atropisomers and amide rotational isomers complicates the analysis. 1 H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.65 - 7.51 (m, 3H), 7.50 - 7.43 (m, 1H), 7.40 - 7.31 (m, 1H), 6.94 (d, J = 36.6 Hz, 1H), 6.84 (s, 1H), 5.01 - 4.68 (m, 1H), 4.62 - 4.54 (m, 1H), 4.51 - 4.41 (m, 1H), 4.28 - 4.13 (m, 1H), 4.12 - 3.98 (m, 1H), 3.84 - 3.71 (m, 1H), 3.56 - 3.45 (m, 1H), 3.40 - 3.32 (m, 1H), 3.22 - 3.05 (m, 4H), 2.95 - 2.88 (m, 3H), 2.80 - 2.70 (m, 1H), 2.60 - 2.54 (m, 1H), 2.29 - 2.18 (m, 1H), 2.13 - 2.00 (m, 1H), 1.97 - 1.79 (m, 2H).

[0176] [Chemical] Example 18 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)piperazin-2-yl)acetonitrile 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (11 mg, 0.021 mmol) and (Z)-2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)acrylic acid (10.6 mg, 0.062 mmol) were combined as solids and dissolved in DMF (1.0 mL). After adding DIPEA (14 μL, 0.083 mmol), COMU® ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate) (27 mg, 0.062 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solution was purified directly by HPLC (column: Xbridge C18, 19 mm × 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 85% of 5:95 MeCN:H2O (containing 0.1% TFA) / 15% of 95:5 MeCN:H2O (containing 0.1% TFA) → 100% of 95:5 MeCN:H2O (containing 0.1% TFA); λ = 220 nm) to give the desired product as the bis-TFA salt (6.6 mg, 0.007 mmol, 12% yield). LC / MS (ESI) m / z: [M+H] + C 35 H 39 ClFN 10 Calculated for O2 685.3; found 685.0; NMR: spectrum reported as obtained; water suppression method used; the presence of atropisomers and amide rotational isomers complicates the analysis.1 1H NMR (500 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.79 - 7.72 (m, 1H), 7.61 - 7.50 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.39 - 7.31 (m, 1H), 6.78 (d, J = 38.6 Hz, 1H), 4.99 - 4.69 (m, 1H), 4.62 - 4.51 (m, 1H), 4.49 - 4.39 (m, 1H), 4.28 - 4.14 (m, 1H), 4.13 - 4.09 (m, 3H), 4.08 - 3.97 (m, 1H), 3.85 - 3.72 (m, 1H), 3.62 - 3.55 (m, 1H), 3.24 - 3.07 (m, 4H), 2.99 - 2.90 (m, 3H), 2.81 - 2.69 (m, 1H), 2.61 - 2.51 (m, 1H), 2.29 - 2.19 (m, 1H), 2.09 - 2.00 (m, 1H), 1.95 - 1.79 (m, 2H).

[0177] Biological activity KRAS G12C RAF disruption assay This is a functional assay that measures the activity of the compound against the active form of G12C, i.e., KRAS G12C. Recombinant GMPPNP-loaded KRAS G12C (5 nM) was treated with the compound for 20 minutes at room temperature in assay buffer (50 mM Tris pH 7.5, 100 mM NaCl, 1 mM MgCl2, 1 mM DTT, 100 ug / ml BSA). Recombinant GST-RAF1 RBD (9 nM) was added and the reaction mixture was incubated for 20 minutes. SA-Tb (0.25 nM) was added and the reaction mixture was incubated for 3 hours. The HTRF signal was measured (PerkinElmer Envision), and the signal ratio (λ (ON) 520 / λ em 520 / λ em 495) was calculated, and the IC 50 value was calculated from the dose-response curve.

[0178] The IC 50 values of the compounds described in this specification are shown in Table 1.

[0179] [Table 1]

[0180] It should be understood that the detailed description section is used to interpret the claims, and the abstract and summary sections are not intended to be used. The abstract and summary sections may show one or more, but not all, exemplary aspects of the present disclosure as contemplated by the inventors, and thus are not intended to limit the present disclosure and the appended claims in any way.

[0181] The present disclosure has been described above using functional components that exemplify the implementation of the specified functions and their relationships. The boundaries of these functional components are arbitrarily defined herein for convenience of explanation. Alternative boundaries can be defined as long as the specified functions and their relationships are properly implemented.

[0182] All references cited herein are hereby incorporated by reference in their entirety.

[0183] The foregoing description of specific embodiments will so fully reveal the general nature of the present disclosure that others can, without undue experimentation and without departing from the general concept of the present disclosure, readily modify and / or adapt such specific embodiments by applying knowledge within the skill of those in the art. Accordingly, such adaptations and modifications are intended to be within the meaning and scope of the equivalents of the disclosed embodiments based on the teachings and guidance provided herein. It should be understood that the terminology or phraseology herein is for the purpose of description and not of limitation, and thus the terminology or phraseology herein should be interpreted in light of the teachings and guidance by those skilled in the art.

[0184] The breadth and scope of the present disclosure should not be limited by any of the above exemplary aspects, but should be defined only by the following claims and their equivalents.

Claims

1. Formula (I): 【Chemical 1】 wherein U is a bond or NH; n is 0, 1 or 2; Z is a bond, C(O) or CR ｅ R ｆ wherein R ｅ and R ｆ are independently hydrogen or C １ to C ３ alkyl; R １ is aryl or heteroaryl, and the aryl and the heteroaryl are each independently selected from 1, 2, 3, 4 or 5 substituents independently selected from C １ -C ３ alkoxy, C １ -C ３ alkyl, C ２ -C ４ alkenyl, C ２ -C ４ alkynyl, amino, amino C １ -C ３ alkyl, cyano, C ３ -C ４ cycloalkyl, halo, halo C １ -C ３ alkyl, hydroxy and hydroxy C １ -C ３ alkyl, and is optionally substituted with 1, 2, 3, 4 or 5 substituents; Each R ２ is independently selected from C １ to C ３ alkoxy, C １ to C ３ alkyl, cyano, halo, halo C １ to C ３ alkyl, -C(O)NH ２ , -C(O)NH(C １ to C ３ alkyl), -C(O)N(C １ to C ３ alkyl); ２ and is selected from hydroxy and oxo; Y is a bond, O, NR ｇ (CR ｅ R ｆ ) ｍ , NR ｆ or CR ｅ R ｆ , where m is 1, 2 or 3, and R ｅ , R ｆ and R ｇ are independently hydrogen or C １ -C ３ alkyl; A is a 4- to 10-membered nitrogen-containing monocyclic or bicyclic bridged, fused or spirocyclic saturated, unsaturated or partially unsaturated ring system optionally containing one or two heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring system being C １ -C ３ alkoxy, C １ -C ３ alkoxyalkyl, C １ -C ３ alkyl, cyano, halo, haloC １ -C ３ alkyl, amino, aminoC １ -C ３ alkyl, hydroxy, hydroxyC １ -C ３ alkyl and is optionally substituted with one, two or three groups independently selected from oxo; R' is halo; R ４ is a 5- or 6-membered aromatic ring optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; said ring is C ２ -C ４ alkenyl, C １ -C ３ alkyl, cyano, cyanoC １ -C ３ alkyl, halo, haloC １ -C ３ alkoxy, haloC １ -C ３ alkyl, nitro and oxo, and is optionally substituted with 1, 2 or 3 substituents independently selected therefrom; X is O or NR １６ wherein R １６ is hydrogen or C １ to C ３ alkyl; R ５ is hydrogen, C １ ~C ６ alkoxy C １ ~C ６ alkyl, C １ ~C ６ alkyl, aryl, aryl C １ ~C ６ alkyl, carboxy C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, C ３ ~C ６ cycloalkyl C １ ~C ６ alkyl, di(C １ ~C ３ alkyl)amino C ２ ~C ６ alkyl, halo C １ ~C ６ alkyl, heteroaryl, heteroaryl C １ ~C ６ alkyl, heterocyclyl, heterocyclyl C １ ~C ６ alkyl, hydroxy C １ ~C ６ alkyl, NR ａ R ｂ -C(O)-C １ ~C ６ alkyl), NR ａ R ｂ C １ ~C ６ selected from alkyl, and the aryl, the aryl C １ ~C ６ alkyl aryl moiety, the C ３ ~C ６ cycloalkyl, the C ３ ~C ６ cycloalkyl C １ ~C ６ alkyl cycloalkyl moiety, the heteroaryl, the heteroaryl C １ ~C ６ alkyl heteroaryl moiety, the heterocyclyl, the heterocyclyl C １ ~C ６ alkyl heterocyclyl moiety is C １ to C ３ alkoxy, C １ to C ３ alkyl, (C １ to C ６ alkyl)amino, (C １ to C ６ alkyl)aminoC １ to C ３ alkyl, amino, aminoC １ to C ３ alkyl, carboxy, cyano, di(C １ to C ６ alkyl)amino, di(C １ to C ６ alkyl)aminoC １ to C ３ alkyl, halo, haloC １ to C ３ alkoxy, haloC １ to C ３ alkyl, heterocyclyl, heterocyclylC １ to C ３ alkyl, hydroxy, hydroxyC １ to C ３ alkyl, nitro and oxo, and is optionally substituted with one, two, three or four groups independently selected therefrom; the heterocyclyl and the heterocyclylC １ to C ３ alkyl heterocyclyl moiety is further optionally substituted with one, two or three groups independently selected from C １ to C ３ alkoxy, C １ to C ３ alkyl, halo and haloC １ to C ３ alkyl, or alternatively R ５ and R １６ together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted with 1, 2, 3 or 4 groups independently selected from C １ -C ３ alkoxy, C １ -C ３ alkoxyalkyl, C １ -C ３ alkyl, amino, amino C １ -C ３ alkyl, hydroxy and hydroxy C １ -C ３ alkyl; and R ａ and R ｂ One of them is selected from hydrogen and C １ ~C ３ alkyl, and the other is hydrogen, C １ ~C ３ alkyl, C １ ~C ３ alkoxycarbonyl, C １ ~C ３ alkylcarbonyl, aryl C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl and C ３ ~C ６ cycloalkyl C １ ~C ６ (selected from alkyl) or a pharmaceutically acceptable salt thereof.

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

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is a 4- to 9-membered monocyclic or bicyclic bridged or fused saturated ring system optionally containing one or two nitrogen atoms.

4. A-U is 【Chemical 2】 wherein 【Chemical Formula 3】 represents the point of attachment to the carbonyl group; and [Chemical Formula 4] represents the point of attachment to Y. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. A-U is [Chemical Formula 5] wherein 【Chemical Formula 6】 represents the point of attachment to the carbonyl group; and [Chemical Formula 7] represents the point of attachment to Y. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is 0.

7. R ４ is selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl and triazolyl, and each ring is C ２ -C ４ alkenyl, C １ -C ３ alkyl, halo, haloC １ -C ３ alkoxy, haloC １ -C ３ alkyl, nitro and oxo, and is optionally substituted with one, two or three groups independently selected therefrom, the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. R ４ is selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridinyl, pyrimidinyl, thiazolyl and triazolyl, each ring being optionally substituted with methyl or halo, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X is O.

10. R ５ is 【Chemical 8】 selected from, wherein each ring is C １ to C ３ alkoxy, C １ to C ３ alkoxy C １ to C ３ alkyl, C １ to C ３ alkyl, benzyl, halo, halo C １ to C ３ alkyl, hydroxy, hydroxy C １ to C ３ alkyl and oxo, and is optionally substituted with one, two or three groups independently selected therefrom, the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. R ５ is -(C １ ~C ３ alkyl)-R ６ wherein R ６ is a 3- to 5-membered monocyclic ring system, an 8- or 9-membered bicyclic fused saturated ring system, or a 10-membered tricyclic saturated ring system, each ring system optionally contains one nitrogen atom, and each ring system is optionally substituted with one or two groups independently selected from C １ ~C ３ alkyl, halo, and (4- to 6-membered heterocyclyl)C １ ~C ３ alkyl; and the heterocyclyl moiety of said (4- to 6-membered heterocyclyl)C １ ~C ３ alkyl is further optionally substituted with a halo group, the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10.

12. R ５ is 【Chemical Formula 9】 and 【Chemical 10】 represents the point of attachment to X. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. R ５ is 【Chemical 11】 wherein n is 0, 1 or 2; Each R ２０ is a halo; and 【Chemical 12】 represents the point of attachment to X. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

15. R １ is a monocyclic heteroaryl ring containing 1, 2 or 3 nitrogen atoms, and said ring is C １ -C ３ alkoxy, C １ -C ３ alkyl, C ２ -C ４ alkenyl, C ２ -C ４ alkynyl, amino, amino C １ -C ３ alkyl, cyano, C ３ -C ４ cycloalkyl, halo, halo C １ -C ３ alkyl, hydroxy and hydroxy C １ -C ３ alkyl, and is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from those mentioned above, the compound according to any one of claims 1 to 14.

16. R １ is 【Chemical 13】 wherein 【Chemical 14】 represents the point of attachment to the parent molecular moiety. The compound according to any one of claims 1 to 15.

17. R １ is C １ to C ３ alkoxy, C １ to C ３ alkyl, C ２ to C ４ alkenyl, C ２ to C ４ alkynyl, amino, amino C １ to C ３ alkyl, cyano, C ３ to C ４ cycloalkyl, halo, halo C １ to C ３ alkyl, hydroxy and hydroxy C １ to C ３ alkyl, and is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C ６ to C １０ aryl, a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

18. R １ is naphthyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from C １ -C ３ alkyl, C ２ -C ４ alkynyl, halo and hydroxy, a compound according to any one of claims 1 to 14 or 17 or a pharmaceutically acceptable salt thereof.

19. R １ is naphthyl, and the naphthyl is substituted with one, two or three groups independently selected from C ２ to C ４ alkynyl, halo and hydroxy, the compound according to any one of claims 1 to 14, 17 or 18, or a pharmaceutically acceptable salt thereof.

20. R １ is 【Chemical Formula 15】 wherein 【Chemical 16】 represents the point of attachment to the parent molecular moiety. The compound according to any one of claims 1 to 14 or 17 to 19, or a pharmaceutically acceptable salt thereof.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R' is fluoro.

22. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R' is chloro.

23. 【Fig. 17】 【Chemical 18】 or a pharmaceutically acceptable salt thereof, selected from

24. 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-3-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-4-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(oxazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-(((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-(((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-(((S)-4-(7-(8-chloronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoro-3-(isothiazol-5-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-(((S)-4-(7-(8-chloronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-(((S)-4-(7-(8-chloronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(6-methylpyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-(((S)-4-(7-(8-chloronaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(4-methylpyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(5-methylpyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(3-methylpyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (Z)-1-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(isoxazol-3-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(isoxazol-5-yl)piperazin-2-yl)acetonitrile; and 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)piperazin-2-yl)acetonitrile A compound selected from the above or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

26. An oral dosage form comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

27. A method for treating cancer expressing a KRAS G12C, G12D and / or G12V mutation in a subject in need thereof, the method comprising administering to the subject the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

28. A method for treating cancer expressing a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

29. A method for treating cancer sensitive to KRAS G12C inhibition in a subject in need thereof, the method comprising administering to the subject the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

30. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, gastric cancer or uterine cancer.

31. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer.

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