Tetrahydropyrido 3, 4-D pyrimidine derivatives as KRAS inhibitors

Abstract

The present disclosure provides KRAS inhibitors. Methods of treating cancer using the compounds are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 351,134, filed on June 10, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0002] The present disclosure provides KRAS inhibitors. Also provided are methods of using these inhibitors to treat cancer. Background Art

[0003] The KRAS oncogene is a member of the RAS family of GTPases involved in many cellular signaling processes. KRAS mutations are gain-of-function mutations present in up to 30% of all tumors, including up to 90% of pancreatic cancers. KRAS acts as a regulator of the inactive (GDP-bound or G12C (OFF) ) and activity (GTP-bound or G12C (ON) ) states to convert upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate multiple processes, including cell proliferation. Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRAS primary amino acid sequence account for approximately 40% of KRAS driver mutations in lung adenocarcinoma, with G12C transversion being the most common activating mutation. KRAS G12C mutations occur in approximately 13% of lung adenocarcinomas and approximately 3% of colorectal adenocarcinomas, and are also present in breast, bladder, cervical, ovarian, pancreatic, and uterine cancers.

[0004] Although several efforts to target KRAS have been unsuccessful, compounds that inhibit KRAS activity, including those that disrupt effectors such as guanine nucleotide exchange factors and target KRAS G12C, are highly desirable. Clearly, there remains a continuing interest and effort in developing KRAS inhibitors, particularly inhibitors of activating KRAS mutants such as KRAS G12C. Summary of the invention

[0005] The present disclosure is based in part on the discovery that, unlike other KRAS G12C inhibitors, the compounds of the present disclosure target the active KRAS G12C protein. (ON) Form. By inhibiting KRAS, G12C ON In the present invention, it is expected that the claimed compounds will reduce cancer resistance to KRAS G12C inhibition and / or show increased efficacy in the clinic. Without being bound by theory, the G12C inhibition of KRAS G12C ON The inhibition of the form may be due to the substituent at the 4-position of the tetrahydropyridopyrimidine ring in formula (I).

[0006] In a first aspect, the present disclosure provides a compound having formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0007] U is a bond or NH;

[0008] n is 0, 1, or 2;

[0009] Z is a bond, C(O), or CR e R f , where R e and R f are independently hydrogen or C1-C3 alkyl;

[0010] R 1 is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, haloC1-C3 alkyl, hydroxyl, and hydroxyC1-C3 alkyl;

[0011] Each R 2 Independently selected from C1-C3 alkoxy, C1-C3 alkyl, cyano, halogen, halogenated C1-C3 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, hydroxyl and oxo;

[0012] Y is a bond, O, NR g (CR e R f ) m NR f , or CR e R f , wherein m is 1, 2, or 3, and wherein R e , R f and R g are independently hydrogen or C1-C3 alkyl;

[0013] A is a four- to ten-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, wherein the ring system is optionally substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, cyano, halogen, haloC1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo;

[0014] R' is a halogen;

[0015] R 4 is a five-membered or six-membered aromatic ring optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of C2-C4 alkenyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halogen, haloC1-C3 alkoxy, haloC1-C3 alkyl, nitro and oxo;

[0016] X is O or NR 16 , where R 16 is hydrogen or C1-C3 alkyl;

[0017] R 5 is selected from hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di(C1-C3 alkyl)amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR a R b C1-C6 alkyl, wherein the aryl, the aryl portion of the arylC1-C6 alkyl, the C3-C6 cycloalkyl, the cycloalkyl portion of the C3-C6 cycloalkylC1-C6 alkyl, the heteroaryl, the heteroaryl portion of the heteroarylC1-C6 alkyl, the heterocyclyl, the heterocyclyl portion of the heterocyclylC1-C6 alkyl is optionally substituted by one, two, three, or four groups independently selected from the following: C1-C3 alkoxy, C1-C3 alkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)aminoC1-C3 alkyl, amino, amino C1-C3 alkyl, halogen, halogenated C1-C3 alkoxy, halogenated C1-C3 alkyl, heterocyclic radical, heterocyclic radical C1-C3 alkyl, hydroxyl, hydroxy C1-C3 alkyl, nitro and oxo; wherein the heterocyclic radical and the heterocyclic radical portion of the heterocyclic radical C1-C3 alkyl are further optionally substituted by one, two, or three groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen and halogenated C1-C3 alkyl; or

[0018] R 5 and R 16together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted by one, two, three, four, or five groups independently selected from: one, two, three, or four groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxyl and hydroxyC1-C3 alkyl; and

[0019] R a and R b One of them is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, arylC1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkylC1-C6 alkyl.

[0020] In some aspects, Y is a bond.

[0021] In some aspects, A is a four- to nine-membered monocyclic or bicyclic bridged or fused saturated ring system optionally containing one or two nitrogen atoms.

[0022] In some ways, AU is in

[0023] represents the point of attachment to the carbonyl group; and

[0024] Indicates the point of attachment to Y.

[0025] In some ways, AU is in

[0026] represents the point of attachment to the carbonyl group; and

[0027] Indicates the point of attachment to Y.

[0028] In some aspects, n is 0.

[0029] In some respects, R 4 Selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl and triazolyl, wherein each ring is optionally substituted with one, two, or three groups independently selected from the following: C2-C4 alkenyl, C1-C3 alkyl, halogen, halo-substituted C1-C3 alkoxy, halo-substituted C1-C3 alkyl, nitro and oxo.

[0030] In some respects, R 4 Selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridinyl, pyrimidinyl, thiazolyl and triazolyl, wherein each ring is optionally substituted with methyl or halogen.

[0031] In some aspects, X is O.

[0032] In some respects, R 5 Selected from: Wherein each ring is optionally substituted by 1, 2, or 3 groups independently selected from the following: C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halogen, halogenated C1-C3 alkyl, hydroxyl, hydroxyC1-C3 alkyl and oxo.

[0033] In some respects, R 5 is -(C1-C3 alkyl)-R 6 , where R 6 is a three- to five-membered monocyclic ring system, an eight- or nine-membered bicyclic fused saturated ring system, or a ten-membered tricyclic saturated ring system, wherein each ring system optionally contains one nitrogen atom, and wherein each ring system is optionally substituted by one or two groups independently selected from C1-C3 alkyl, halogen and (4- to 6-membered heterocyclyl)C1-C3 alkyl; wherein the heterocyclyl portion of the (4- to 6-membered heterocyclyl)C1-C3 alkyl is further optionally substituted by a halogen group.

[0034] In some respects, R 5 yes in Indicates the point of attachment to X.

[0035] In some respects, R 5 yes in

[0036] n is 0, 1, or 2;

[0037] Each R 20 is a halogen; and

[0038] Indicates the point of attachment to X.

[0039] In some aspects, Z is a bond.

[0040] In some respects, R 1 is a monocyclic heteroaryl ring containing one, two, or three nitrogen atoms, wherein the ring is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, haloC1-C3 alkyl, hydroxyl, and hydroxyC1-C3 alkyl.

[0041] In some respects, R1 yes in The point of attachment to the parent molecule is indicated.

[0042] In some respects, R 1 is a C6-C 10 Aryl: C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, halogenated C1-C3 alkyl, hydroxyl and hydroxyC1-C3 alkyl.

[0043] In some respects, R 1 is naphthyl substituted with one, two, three, four, or five substituents independently selected from C1-C3 alkyl, C2-C4 alkynyl, halogen and hydroxy.

[0044] In some respects, R 1 is naphthyl, wherein the naphthyl is substituted with one, two, or three groups independently selected from C2-C4 alkynyl, halogen and hydroxy.

[0045] In some respects, R 1 yes in The point of attachment to the parent molecule is indicated.

[0046] In some aspects, R' is fluoro.

[0047] In some aspects, R' is chloro.

[0048] In some aspects, the present disclosure provides a compound having formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: R x Selected from -CH2CN and methyl; R 4 is selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridinyl, pyrimidinyl, thiazolyl and triazolyl, wherein each ring is optionally substituted with methyl or halogen; and R 5 yes

[0049] In some aspects, the present disclosure provides a compound selected from or a pharmaceutically acceptable salt thereof.

[0050] In some aspects, the disclosure provides a compound selected from: 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-pyrrolazin-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-pyrrolazin-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; or a pharmaceutically acceptable salt thereof.

[0051] In some aspects, the disclosure provides an atropisomer of the compound of any of the preceding aspects. In certain aspects, the compound is a stable atropisomer as described herein.

[0052] In some aspects, the present disclosure provides a pharmaceutical composition comprising the compound according to any one of the preceding aspects or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0053] In some aspects, the present disclosure provides an oral dosage form comprising a compound according to any one of the preceding aspects or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0054] In some aspects, the disclosure provides a method of treating a 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 one of the preceding aspects or a pharmaceutically acceptable salt thereof.

[0055] In some aspects, the present disclosure provides a method of treating a cancer expressing a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a compound of any one of the preceding aspects or a pharmaceutically acceptable salt thereof.

[0056] In some aspects, the disclosure provides a method for treating a cancer sensitive to KRAS G12C inhibition in a subject in need thereof, the method comprising administering to the subject a compound of any one of the preceding aspects or a pharmaceutically acceptable salt thereof.

[0057] In some aspects, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of any one of the preceding aspects 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.

[0058] In some aspects, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of any one of the preceding aspects or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer.

[0059] In some aspects of the method, the compound is an atropisomer of the compound of any of the preceding aspects. In certain aspects, the compound is a stable atropisomer as described herein.

[0060] In another aspect, the disclosure provides a method for 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 described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one aspect, the contact is in vitro. In one aspect, the contact is in vivo.

[0061] In some aspects, the 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 described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0062] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in inhibiting KRAS G12C.

[0063] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, for use in treating a disease or disorder associated with KRAS G12C.

[0064] In another aspect, the disclosure provides the use of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer. In some aspects, the cancer is lung cancer. In some aspects, the cancer is non-small cell lung cancer.

[0065] In another aspect, the disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for inhibiting the activity of KRAS G12C.

[0066] In another aspect, the disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for treating a disease or disorder associated with KRAS G12C. DETAILED DESCRIPTION

[0067] Unless otherwise stated, any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0068] The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise.

[0069] As used herein, the term "or" is a logical disjunction (ie, and / or) and does not indicate a mutually exclusive disjunction unless expressly indicated by the terms "or," "unless," "alternatively," and words of similar effect.

[0070] 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 a pharmaceutically acceptable salt of one or more compounds of formula (I), and pharmaceutically acceptable salts of two or more compounds of formula (I).

[0071] As used herein, the term "C2-C4 alkenyl" refers to a group derived from a straight or branched chain hydrocarbon containing two to four carbon atoms and one double bond.

[0072] As used herein, the term "C1-C3 alkoxy" refers to a C1-C3 alkyl group attached to the parent molecular moiety through an oxygen atom.

[0073] As used herein, the term "C1-C3 alkoxy C1-C6 alkyl," refers to a C1-C3 alkoxy group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0074] The term "C1-C3 alkoxycarbonyl," as used herein, refers to a C1-C3 alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0075] As used herein, the term "C1-C3 alkyl" refers to a group derived from a straight-chain or branched saturated hydrocarbon containing one to three carbon atoms.

[0076] The term "C1-C3 alkylcarbonyl," as used herein, refers to a C1-C3 alkyl group attached to the parent molecular moiety through a carbonyl group.

[0077] As used herein, the term "C2-C4 alkynyl" refers to a group derived from a straight or branched chain hydrocarbon containing two to four carbon atoms and one triple bond.

[0078] As used herein, the term "amino" refers to -NH2.

[0079] The term "amino C1-C3 alkyl," as used herein, refers to an amino group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0080] As used herein, the term "aryl" refers to a phenyl group or a bicyclic fused ring system in which one or both rings are phenyl groups. The bicyclic fused ring system consists of a phenyl group fused to a four- to six-membered aromatic or non-aromatic carbocyclic ring. The aryl group of the present disclosure may be attached to the parent molecular moiety by any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl and tetrahydronaphthyl.

[0081] As used herein, the term "aryl C1-C6 alkyl" refers to an aryl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0082] As used herein, the term "carboxyl" refers to -CO2H.

[0083] As used herein, the term "carboxy C1-C6 alkyl" refers to a C1-C6 alkyl group substituted with one, two, or three carboxyl groups.

[0084] As used herein, the term "cyano" refers to -CN.

[0085] As used herein, the term "C3-C4 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring system having three or four carbon atoms and zero heteroatoms.

[0086] As used herein, the term "C3-C6 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring system having three to six carbon atoms and zero heteroatoms.

[0087] As used herein, the term "C3-C6 cycloalkylC1-C6 alkyl," refers to a C3-C6 cycloalkyl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0088] As used herein, the term "di(C1-C6 alkyl)amino" refers to -NR z R z’ , where R z and R z’ are the same or different C1-C6 alkyl groups.

[0089] As used herein, the term "di(C1-C3 alkyl)amino C2-C6 alkyl" refers to -(C2-C6 alkyl)NR z R z’ , where R z and R z’ are the same or different C1-C6 alkyl groups.

[0090] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, or I.

[0091] As used herein, the term "halogenated C1-C3 alkoxy" refers to a C1-C3 alkoxy group substituted by one, two, or three halogen atoms.

[0092] As used herein, the term "haloC1-C3 alkyl" refers to a C1-C3 alkyl group substituted by one, two, or three halogen atoms.

[0093] As used herein, the term "halogenated C1-C6 alkyl" refers to a C1-C6 alkyl group substituted with one to six halogen atoms.

[0094] As used herein, the term "heteroaryl" refers to an aromatic five- or six-membered ring in which at least one atom is selected from N, O, and S, and the remaining atoms are carbon. The term "heteroaryl" also includes: a bicyclic system in which the heteroaryl ring is fused to a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S; and a tricyclic system in which the bicyclic system is fused to a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S. The heteroaryl group is attached to the parent molecular moiety through any substitutable 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']bithiazole, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.

[0095] As used herein, the term "heteroaryl C1-C6 alkyl" refers to a heteroaryl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0096] As used herein, the term "heterocyclyl" refers to a five-, six-, seven-, eight-, nine-, ten-, eleven-, or twelve-membered saturated or partially unsaturated ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" also includes groups in which the heterocyclyl ring is fused to one, two, or three four- to six-membered aromatic or non-aromatic carbocyclic or monocyclic heterocyclyl groups. The term "heterocyclyl" also includes monocyclic or polycyclic heterocyclyl groups as described above, which are further substituted by one or more spirocyclic groups attached to the heterocyclyl group through a spiro carbon. Examples of heterocyclyl groups include, but are not limited to, dihydro-1'H,3'H,5'H-bispiro[cyclopropane-1,2'-pyrrolazine-6',1"-cyclopropane], hexahydro-2H-1,4-dioxa-2a1-azacyclopenta[cd]cyclopentadienyl, hexahydropyrrolazinyl, indolinyl, morpholinyl, octahydroindolizinyl, octahydroquinolizinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thiomorpholinyl.

[0097] As used herein, the term "heterocyclyl C1-C6 alkyl" refers to a heterocyclyl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0098] As used herein, the term "hydroxy" refers to -OH.

[0099] The term "hydroxy C1-C3 alkyl," as used herein, refers to a hydroxy group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0100] As used herein, the term "hydroxy C1-C6 alkyl," refers to a hydroxy group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0101] As used herein, the term “NR a R b -C(O)" refers to an NR attached to the parent molecular moiety through a carbonyl group a R b Group.

[0102] As used herein, the term “NR a R b "-C(O)-C1-C6 alkyl" refers to an NR group attached to the parent molecular moiety through a C1-C6 alkyl group a R b -C(O)- group.

[0103] As used herein, the term “NR a R b "C1-C6 alkyl" refers to an NR group attached to the parent molecular moiety through a C1-C6 alkyl group a R b Group.

[0104] As used herein, the term "nitro" refers to -NO2.

[0105] As used herein, the term "oxo" refers to =0.

[0106] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotope-labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein using appropriate isotope-labeled reagents in place of otherwise employed unlabeled reagents. Such compounds may have a variety of 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 favorably alter biological, pharmacological, or pharmacokinetic properties.

[0107] Another aspect of the subject matter described herein is the use of the disclosed compounds as radiolabeled ligands for developing ligand binding assays or for monitoring in vivo adsorption, metabolism, distribution, receptor binding or occupancy, or compound disposition. For example, the compounds described herein can be prepared using radioisotopes, and the resulting radiolabeled compounds can be used to develop binding assays or for metabolic studies. Alternatively, and for the same purpose, the compounds described herein can be converted to radiolabeled form by catalytic tritiation using methods known to those skilled in the art.

[0108] Certain compounds disclosed herein exist as stereoisomers. It should be understood that when stereochemistry is not specified, the disclosure encompasses all stereochemical isomeric forms, or mixtures thereof, having the ability to inhibit KRAS G12C. 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 into a mixture of diastereoisomers, followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers on a chiral chromatographic column. Starting compounds of specific stereochemistry are commercially available or can be prepared and resolved by techniques known in the art.

[0109] Certain compounds of the present disclosure exist as atropisomers. The term "atropisomer" refers to a conformational stereoisomer that occurs when rotation around a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule, and the substituents at both ends of the single bond are asymmetric (i.e., optical activity is produced without the need for an asymmetric carbon center or stereocenter). Where the barrier to rotation around a single bond is high enough and the interconversion between conformations is slow enough, separation and isolation of isomeric species may be permitted. Atropisomers are enantiomers (or diastereomers) in the absence of a single asymmetric atom.

[0110] If the barrier to interconversion is high enough to allow little or no interconversion at room temperature for at least one week, the atropisomer can be considered stable. In some aspects, the atropisomer experiences little or no interconversion at room temperature for at least one year. In some aspects, when the atropisomer compound is in a substantially pure form (which is generally a solid state), the atropisomer compound of the present disclosure does not experience more than about 5% of the interconversion to its relative atropisomer during one week at room temperature. In some aspects, the atropisomer compound of the present disclosure does not experience more than about 5% of the interconversion to its relative atropisomer during one year at room temperature (approximately 25°C). In some aspects, the atropisomer compound of the present disclosure is sufficiently stable to experience no more than about 5% of the interconversion in the aqueous pharmaceutical formulation at 0°C for at least one week. The chemical entity, pharmaceutical composition and method of the present invention are intended to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure single atropisomer forms and intermediate mixtures.

[0111] The energy barrier to the 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, in which the rotation around the inter-ring bonds lacking C2 symmetry is restricted. The free energy barrier to isomerization (enantiomerization) is a measure of the stability of the inter-ring bonds relative to rotation. Optical and thermal excitations can promote the racemization of such isomers, depending on electronic and steric factors.

[0112] Ortho-substituted biaryl compounds can exhibit this type of conformational, rotational isomerism. Such biaryl compounds are enantiomeric, chiral atropisomers, where sp 2 -sp 2 The carbon-carbon, intercyclic bonds between the aromatic rings have sufficiently high energy barriers to prevent free rotation, and wherein the substituents W 1 ≠W 2 and W 3 ≠W 4 This makes the molecule asymmetric.

[0113] W 1 :W 3 , W 1 :W 4 , and / or W 2 :W 4 , W 2 :W 3The steric interactions between are large enough to place the planar conformation at an energy maximum. When the interconversion of two non-planar, axial chiral enantiomers is slow enough so that they can freely separate from each other, they exist as atropisomers. The bold and dotted lines in the figures shown above indicate those parts, or parts of the molecule, that are spatially restricted due to the rotational energy barrier. The bold parts exist orthogonally above the plane of the page, and the dotted parts exist orthogonally below the plane of the page. The 'flat' part of the molecule (the left ring in each of the two depicted biaryls) is in the plane of the page.

[0114] The pharmaceutical composition of the present disclosure may include one or more pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the parent compound and do not impart any undesirable toxicological effects (see, for example, Berge, SM et al., J. Pharm. Sci. [Journal of Pharmaceutical Sciences], 66: 1-19 (1977)). These salts can be obtained during the final separation and purification of the compounds described herein, or by reacting the free base functional group of the compound with a suitable acid alone, or by reacting the acidic group of the compound with a suitable base. Acid addition salts include salts derived from nontoxic inorganic acids (such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, etc.) and derived from nontoxic organic acids (such as aliphatic monocarboxylic acids and aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.). Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, calcium, and the like, as well as from nontoxic organic amines such as N,N′-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like. Pharmaceutical composition

[0115] In another aspect, the present disclosure provides a composition, e.g., a pharmaceutical composition, containing a compound or a combination of compounds described in the present disclosure formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present disclosure may also be administered in combination therapy, i.e., administered in combination with other agents as described herein.

[0116] As used herein, "pharmaceutically acceptable carriers" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. 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 may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0117] The pharmaceutical composition of the present disclosure can be administered via one or more routes of administration using various methods known in the art. As will be appreciated by those skilled in the art, routes of administration and / or mode will vary depending on the desired result. In some aspects, the route of administration for the compound of the present disclosure includes intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, such as by injection or infusion. As used herein, the phrase "parenteral administration" means the mode of administration except for intestinal and topical administration, usually administered by injection, and includes but is not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intra-epidermal, intraarticular, subcapsular, subarachnoid, intraspinal, extradural and intrasternal injection and infusion.

[0118] Sterile injectable solutions can be prepared by incorporating the active compound in the desired amount into a suitable solvent containing one or a combination of the above-listed ingredients, as required, followed by sterilization microfiltration. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing an alkaline dispersion medium and the desired other ingredients from those described above. In the case of sterile powders for the preparation of sterile injectable solutions, some preparation methods are reduced pressure drying and freeze drying (lyophilization), which produces a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution of the active ingredient plus any additional desired ingredients.

[0119] 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 desired particle size in the case of dispersions, and by the use of surfactants.

[0120] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and medicaments as pharmaceutically active substances is known in the art. Unless any conventional media or medicaments are incompatible with the active compound, the use of the media or medicaments in the pharmaceutical compositions of the present disclosure is considered. Supplementary active compounds can also be incorporated into the composition.

[0121] Therapeutic compositions typically must be sterile and stable under manufacturing and storage conditions. The composition can be formulated as a solution or a liquid with an ordered structure suitable for high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.) and a suitable mixture thereof. For example, suitable fluidity can be maintained by using a coating (such as lecithin), by maintaining the required particle size in the case of a dispersion, and by using a surfactant. In many cases, it will be desirable to include an isotonic agent in the composition, for example, sugar, polyols (such as mannitol, sorbitol), or sodium chloride. The extended absorption of the injectable composition can be achieved by including a medicament (for example, monostearate and gelatin) that delays absorption in the composition.

[0122] Alternatively, the compounds of the disclosure may be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.

[0123] Any pharmaceutical composition considered herein can be delivered orally, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, for example, tablets, lozenges, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for making pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, the pharmaceutical composition according to the present disclosure can contain at least one medicament selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0124] 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 which is suitable for the manufacture of tablets.

[0125] Aqueous suspensions 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 excipient suitable for the manufacture of aqueous suspensions, including, but not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents, such as, for example, naturally occurring phospholipids, such as lecithin; condensation products of alkylene oxides with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example, heptadecanedelene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as, for example, polyoxyethylene sorbitan monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative, such as, for example, ethyl 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, for example, sucrose, saccharin, and aspartame.

[0126] Oily suspensions can be prepared, for example, by suspending at least one compound with formula (I) and / or at least one pharmaceutically acceptable salt thereof in a vegetable oil (e.g., such as peanut oil, sesame oil and coconut oil) or in a mineral oil (e.g., such as liquid paraffin). Oily suspensions can also contain at least one thickening agent, such as, for example, beeswax, hard paraffin and cetyl alcohol. In order to provide a delicious oily suspension, at least one sweetener and / or at least one flavoring agent already described above can be added to the oily suspension. Oily suspensions can further contain at least one preservative, including but not limited to, for example, an antioxidant, such as, for example, butylated hydroxyanisole and alpha-tocopherol.

[0127] 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 been described above. Exemplary preservatives include, but are not limited to, for example, antioxidants, such as ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweeteners, flavoring agents and coloring agents.

[0128] The active compound can be prepared with a carrier that will prevent the compound from being rapidly released, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, 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, JR, ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0129] 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 needle-free subcutaneous injection device, such as the devices disclosed in U.S. Pat. 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 that can be used for the present disclosure include: U.S. Pat. No. 4,487,603, which discloses an implantable microinfusion pump for dispensing drugs at a controlled rate; U.S. Pat. No. 4,486,194, which discloses a therapeutic device for administering drugs through the skin; U.S. Pat. No. 4,447,233, which discloses a drug infusion pump for delivering drugs at a precise infusion rate; U.S. Pat. No. 4,447,224, which discloses a variable flow implantable infusion device for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system with a multi-chamber compartment; and U.S. Pat. No. 4,475,196, which discloses an osmotic drug delivery system. These patents are incorporated herein by reference. Many other such implants, delivery systems, and modules are known to those skilled in the art.

[0130] In certain aspects, the compounds of the disclosure can be administered parenterally, i.e., by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and / or infusion.

[0131] In some aspects, the compounds of the disclosure can be administered orally, ie, via gelatin capsules, tablets, hard or soft capsules, or liquid capsules. Uses / treatments of KRAS inhibitors

[0132] Administration of therapeutic agents described herein may include administration of therapeutically effective amounts of therapeutic agents. As used herein, the term "therapeutically effective amount" refers to, but is not limited to, the amount of a therapeutic agent for treating a condition treatable by administering a composition comprising a KRAS inhibitor described herein. The amount is sufficient to exhibit a detectable therapeutic or ameliorative effect. The effect may include, for example, but is not limited to, the treatment of the conditions listed herein. The precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition being treated, the advice of the treating physician, and the therapy or combination of therapies selected for administration.

[0133] For administration of the compounds described herein, dosages range from about 0.0001 to 100 mg / kg host body weight and more typically 0.01 to 40 mg / kg host body weight. Exemplary treatment regimens entail administration once a day, twice a week, three times a week, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months, or once every three to 6 months.

[0134] The disclosed compounds strongly inhibit anchorage-independent cell growth and thus have the potential to inhibit tumor metastasis. Therefore, in another aspect, the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising any compound disclosed herein and a pharmaceutically acceptable carrier.

[0135] 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). Therefore, certain aspects relate to administering the disclosed compounds (e.g., in the form of a pharmaceutical composition) to patients in need of treatment of hematological malignancies. Such malignancies include but are not limited to leukemias and lymphomas. For example, the compounds disclosed in the present invention can be used to treat diseases such as acute lymphocytic 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, these compounds can be used to treat lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0136] Determining whether a tumor or cancer contains a KRAS mutation can be performed by evaluating the nucleotide sequence encoding the KRAS protein, by evaluating the amino acid sequence of the KRAS protein, or by evaluating the characteristics of a putative KRAS mutant protein.The sequence of the wild-type human KRAS protein is known in the art.

[0137] 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 aspects, samples are evaluated for KRAS mutations, including by real-time PCR. In real-time PCR, a fluorescent probe specific to KRAS mutations is used. When there is a mutation, the probe binds and detects fluorescence. In some aspects, a direct sequencing method such as a specific region (e.g., exon 2 and / or exon 3) in a KRAS gene is used to identify KRAS mutations. This technology will identify all possible mutations in the sequenced region.

[0138] Methods for detecting mutations in KRAS proteins are known to those skilled in the art. These methods include, but are not limited to, detecting KRAS mutants using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0139] Methods for determining whether a tumor or cancer contains a KRAS mutation can use multiple samples. In some aspects, the sample is taken from a subject with a tumor or cancer. In some aspects, the sample is taken from a subject with a cancer or tumor. In some aspects, the sample is a fresh tumor / cancer sample. In some aspects, the sample is a frozen tumor / cancer sample. In some aspects, the sample is a formalin-fixed paraffin-embedded sample. In some aspects, the sample is processed into a cell lysate. In some aspects, the sample is processed into DNA or RNA. The present disclosure also relates to a method for treating a hyperproliferative disorder in a mammal, 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 aspects, the method relates to the treatment of cancer, such as acute myeloid leukemia, juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory glioma, Ewing's 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, pancreas Neuroendocrine tumors, renal cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oral Pharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity 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, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancers. In some aspects, the method relates to treating a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)).

[0140] In some aspects, the disclosure relates to a method for treating lung cancer, the method comprising administering an effective amount of any of the above compounds (or a pharmaceutical composition comprising the same) to a subject in need thereof. In some aspects, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, 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, glandular tumors, carcinoid tumors, and undifferentiated carcinomas.Subjects that can be treated with a compound of the disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative of the compound according to the methods of the disclosure include, for example, subjects who have been diagnosed with acute myeloid leukemia, acute myeloid leukemia, juvenile cancers, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germinal tumor, ovarian cancer, ovarian cancer, cerebral infarction, cerebral infarction, leukemia, leukemia, necrosis ... Cell tumors, primary lymphomas, cervical cancer, childhood cancer, chordoma, heart tumors, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory glioma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, bone fibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), SCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity 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, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancers. In some aspects, subjects treated with the compounds of the disclosure include subjects who have been diagnosed with a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or the prostate (e.g., benign prostatic hyperplasia (BPH)).The present disclosure further provides a method for regulating the activity of mutant KRAS proteins by contacting the protein with an effective amount of the compound disclosed herein. Regulation can be to inhibit or activate protein activity. In some aspects, the present disclosure provides a method for inhibiting protein activity by contacting mutant KRAS proteins with an effective amount of compounds disclosed herein in a solution. In some aspects, the present disclosure provides a method for inhibiting the activity of mutant KRAS proteins by contacting cells, tissues, and organs expressing target proteins. In some aspects, the present disclosure provides a method for inhibiting protein activity in subjects (including but not limited to rodents and mammals (e.g., humans)) by administering an effective amount of compounds disclosed herein to the subject. In some aspects, the percentage of regulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the percentage of inhibition exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the disclosure provides a method of inhibiting KRAS activity in a cell by contacting the cell with a compound of the disclosure in an amount sufficient to inhibit the activity of a KRAS mutant in the cell. In some aspects, the disclosure provides a method of inhibiting mutant KRAS in a tissue by contacting the tissue with a compound of the disclosure in an amount sufficient to inhibit the activity of mutant KRAS in the tissue. In some aspects, the disclosure provides a method of inhibiting KRAS in an organism by contacting the organism with a compound of the disclosure in an amount sufficient to inhibit the activity of KRAS in the organism. In some aspects, the disclosure provides a method of inhibiting KRAS activity in an animal by contacting the animal with a compound of the disclosure in an amount sufficient to inhibit the activity of KRAS in the animal. In some aspects, the disclosure provides a method of inhibiting KRAS activity in an animal by contacting the mammal with a compound of the disclosure in an amount sufficient to inhibit the activity of KRAS in the mammal. In some aspects, the disclosure provides a method of inhibiting KRAS included in a mammal by contacting the mammal with a compound of the disclosure in an amount sufficient to inhibit the activity of KRAS in the mammal. In some aspects, the disclosure provides a method of inhibiting KRAS activity in a human by contacting the human with a compound of the disclosure in an amount sufficient to inhibit the activity of KRAS in the human. The present disclosure provides methods for treating diseases mediated by KRAS activity in subjects in need of such treatment. The present disclosure also provides methods for combination therapy, in which agents known to regulate other pathways, or other components of the same pathway, or even overlapping target enzyme groups are used in combination with compounds of the present disclosure or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates or derivatives thereof. In one aspect, such therapy includes, but is not limited to, combinations of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies and radiation therapy.

[0141] Many chemotherapeutic agents are currently 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, anti-hormones, angiogenesis inhibitors and anti-androgens.

[0142] The compounds described herein can be used in combination with the medicaments disclosed herein or other suitable medicaments, depending on the condition being treated. Therefore, in some aspects, the one or more compounds disclosed herein will be co-administered with other medicaments as described above. When used in combination therapy, the compounds described herein are administered simultaneously or individually with the second medicament. The combined administration may include the simultaneous administration of the two medicaments in the same dosage form, the simultaneous administration of different dosage forms, and the separate administration. That is, the compounds described herein and any medicament described above can be formulated together with the same dosage form and administered simultaneously. Alternatively, the compounds disclosed herein and any medicament described above can be administered simultaneously, wherein the two medicaments are present in separate preparations. In another alternative, the compounds disclosed herein can be administered first, followed by the administration of any medicament described above, or vice versa. In some aspects of the separate administration scheme, the compounds disclosed herein and any medicament described above are administered at intervals of a few minutes, or at intervals of a few hours, or at intervals of a few days.

[0143] These compounds can be prepared by methods known in the art (including those methods described below and including variations within the art technology). Some reagents and intermediates are known in the art. Other reagents and intermediates can be prepared by methods known in the art using readily available materials. Any variables (e.g., numbered "R" substituents) used to describe the synthesis of a compound are intended only to illustrate how to prepare the compound and should not be confused with the variables used in the claims or other parts of this specification. The following methods are for illustrative purposes and are not intended to limit the scope of this disclosure. synthesis

[0144] The aspects described herein are further defined in the following examples. It should be understood that these examples are given by way of illustration only. From the above discussion and examples, those skilled in the art can determine the essential features of the aspects described herein, and, without departing from its spirit and scope, various changes and modifications can be made to adapt it to various uses and conditions. Therefore, the aspects described herein are not limited by the illustrative examples set forth below herein, but are limited by the appended claims. abbreviation

[0145] The following abbreviations are used in the Examples section below and elsewhere herein: for diisopropylethylamine, DIPEA; for N,N-dimethylformamide, DMF; for dimethyl sulfoxide, DMSO; for acetonitrile, MeCN or ACN; for trifluoroacetic acid, TFA; 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; 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile); as well as

[0146] All three compounds were prepared according to the synthetic procedures described in US Pat. No. 10,689,377 B2. Preparation of heteroaryl intermediates or or (Z)-2-Fluoro-3-(pyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate

[0147] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (1.5g, 6.2mmol) was dissolved in THF (31mL). The solution was cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 0.25g, 6.2mmol) was added in batches as a solid. The reaction mixture was stirred for 10min and pyridine carboxaldehyde (0.66g, 6.2mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1h. The mixture was quenched by adding saturated aqueous ammonium chloride solution (15mL). The solution was diluted with water (20mL) and EtOAc (100mL). The layers were separated, and the aqueous phase was further extracted with EtOAc (2×50mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexane) to obtain (E)-2-fluoro-3-(pyridin-2-yl) ethyl acrylate (3:1E / Z mixture, as obtained by 1 H NMR, 910 mg, 4.6 mmol, 75% yield). LC / MS (ESI) m / z: for C 10 H 11 [M+H] calculated for FNO2 + 196.1; Found 196.1; Reported E isomer: 1 H NMR (500MHz, CDCl3) δ8.59 (dd, J=4.9, 1.8Hz, 1H), 7.67 (ddd, J=7.9, 7.6, 1.8Hz, 1H), 7.56 (d, J=7.9Hz, 1H), 7.21 (dd, J=7.6, 4.9Hz, 1H), 6.90 (d, J=20.4Hz, 1H), 4.25 (q, J=7.2Hz, 2H), 1.23 (t, J=7.1Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate

[0148] (E)-2-fluoro-3-(pyridin-2-yl)ethyl 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 (Z)-2-fluoro-3-(pyridin-2-yl)ethyl acrylate (240 mg, 1.2 mmol, 58% yield). LC / MS (ESI) m / z: for C 10 H 11 [M+H] calculated for FNO2 + The measured value is 196.1; 1H NMR (500MHz, CDCl3) δ8.66(ddd,J=5.0,1.8,0.8Hz,1H),7.88(ddd,J=8.0,1.2,0.8Hz,1H),7.75(ddd,J=8.0,7.8,1 .8Hz, 1H), 7.25 (ddd, J=7.8, 5.0, 1.2Hz, 1H), 7.14 (d, J=34.9Hz, 1H), 4.36 (q, J=7.2Hz, 2H), 1.38 (t, J=7.2Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid

[0149] (Z) -2- fluoro-3- (pyridin-2-yl) ethyl acrylate (415mg, 2.1mmol) was dissolved in MeOH (15mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0M, 2.1mL, 2.1mmol) was added. The reaction mixture was stirred for 5h. The solution was concentrated to remove methanol. Additional water (2.0mL) was added and the aqueous solution was cooled to 0 ° C. HCl solution (1.0M, 2.1mL, 2.1mmol) was added dropwise. After 10min, a white solid was precipitated. The solid was collected by filtration and washed with Et2O. The solid was dried under vacuum to obtain (Z) -2- fluoro-3- (pyridin-2-yl) acrylic acid (235mg, 1.4mmol, 66% yield) as a white solid. LC / MS (ESI) m / z: [M+H] calculated for C8H7FNO2 + is 168.0; the measured value is 167.8. 1 H NMR(500MHz,DMSO-d6)δ8.66(ddd,J=4.8,1.8,0.8Hz,1H),7.89(ddd,J=8.0,7.5,1.8Hz,1H) ,7.81(ddd,J=8.0,1.1,0.8Hz,1H),7.40(dd,J=7.5,4.8,1.1Hz,1H),6.97(d,J=35.3Hz,1H). (Z)-2-Fluoro-3-(pyrimidin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate

[0150] 2-(diethoxyphosphoryl)-2-ethyl fluoroacetate (1.6 g, 6.6 mmol) was dissolved in THF (50 mL). The solution was cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 0.26 g, 6.6 mmol) was added in batches as solid. The reaction mixture was stirred for 10 min and pyrimidine-2-carboxaldehyde (0.71 g, 6.6 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The solution was diluted with water (20 mL) and EtOAc (150 mL). The layers were separated, and the aqueous phase was further extracted with EtOAc (2 × 50 mL). The combined organic layer was dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→90% EtOAc / hexanes) to give (E)-ethyl 2-fluoro-3-(pyrimidin-2-yl)acrylate (5:1 E / Z, as judged by 1H NMR, 592 mg, 3.0 mmol, 46% yield). LC / MS (ESI) m / z: for C9H 10 [M+H] calculated for FN2O2 + is 197.2; the measured value is 197.1; 1 H NMR (500MHz, CDCl3) δ 8.70 (d, J = 4.9 Hz, 2H), 7.18 (t, J = 4.9 Hz, 1H), 6.77 (d, J = 17.5 Hz, 1H), 4.28 (q, J = 7.2 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate

[0151] (E)-2-fluoro-3-(pyrimidin-2-yl) ethyl 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 (Z)-2-fluoro-3-(pyrimidin-2-yl) ethyl acrylate (253 mg, 1.3 mmol, 43% yield). LC / MS (ESI) m / z: for C9H 10 [M+H] calculated for FN2O2 + is 197.2; the measured value is 196.6; 1H NMR (500MHz, 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). Step 3: Preparation of (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylic acid

[0152] (Z) -2- fluoro-3- (pyrimidin-2-yl) ethyl acrylate (253mg, 1.3mmol) was dissolved in MeOH (10mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0M, 1.3mL, 1.3mmol) was added. The reaction mixture was stirred for 2h. The solution was concentrated to remove methanol. Additional water (1.0mL) was added and the aqueous solution was cooled to 0 ° C. HCl solution (1.0M, 2.5mL, 2.5mmol) was added dropwise. After 10min, a white solid was precipitated. The solid was collected by filtration and dried under vacuum to obtain (Z) -2- fluoro-3- (pyrimidin-2-yl) acrylic acid (190mg, 1.1mmol, 88% yield) as a white solid. LC / MS (ESI) m / z: [M + H] calculated for C7H6FN2O2 + is 169.1; the measured value is 168.8; 1 H NMR (500MHz, 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). (Z)-2-Fluoro-3-(thiazol-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate

[0153] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (1.1 g, 4.5 mmol) was dissolved in THF (25 mL). The solution was cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 0.18 g, 4.5 mmol) was added in batches as a solid. The reaction mixture was stirred for 10 min and thiazole-2-carboxaldehyde (0.51 g, 4.5 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The solution was diluted with water (20 mL) and EtOAc (150 mL). The layers were separated, and the aqueous phase 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 column chromatography (0 → 60% acetone / hexane) to obtain (E) -2-fluoro-3- (thiazol-2-yl) ethyl acrylate (10: 1E / Z, as obtained by 1 H NMR, 620 mg, 3.1 mmol, 68% yield). LC / MS (ESI) m / z: [M+H] calculated for C8H9FNO2S + is 202.0; the measured value is 202.2; 1 H NMR (500MHz, CDCl3) δ7.94 (d, J = 3.2 Hz, 1H), 7.52 (d, J = 3.2 Hz, 1H), 7.34 (d, J = 22.2 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(thiazol-2-yl)acrylate

[0154] (E) -2- fluoro-3- (thiazol-2-yl) ethyl 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 (Z) -2- fluoro-3- (thiazol-2-yl) ethyl acrylate (509 mg, 2.5 mmol, 82% yield). LC / MS (ESI) m / z: [M + H] calculated for C8H9FNO2S + The measured value is 202.0; 1 H NMR (500MHz, CDCl3) δ7.96 (dd, J=3.2, 2.6Hz, 1H), 7.57 (d, J=3.2Hz, 1H), 7.43 (dd, J=33.3, 0.8Hz, 1H), 4.38 (q, J=7.2Hz, 2H), 1.39 (t, J=7.1Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid

[0155] (Z) -2- fluoro-3- (thiazole -2- bases) ethyl acrylate (510mg, 2.5mmol) was dissolved in MeOH (15mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0M, 2.5mL, 2.5mmol) was added. The reaction mixture was stirred for 5h. The solution was concentrated to remove methanol. Additional water (1.5mL) was added and the aqueous solution was cooled to 0 ° C. HCl solution (1.0M, 2.5mL, 2.5mmol) was added dropwise. After 10min, a white solid was precipitated. The solid was collected by filtration and washed with MeCN. The solid was dried under vacuum to obtain (Z) -2- fluoro-3- (thiazole -2- bases) acrylic acid (337mg, 1.9mmol, 77% yield) as a white solid. LC / MS (ESI) m / z: [M + H] calculated for C6H5FNO2S + is 174.0; the measured value is 173.8; 1 H NMR (500MHz, DMSO-d6) δ 8.04 (s, 2H), 7.29 (d, J = 34.5Hz, 1H). (Z)-2-Fluoro-3-(oxazol-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(oxazol-2-yl)acrylate

[0156] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added in batches as solid. The reaction mixture is stirred for 10min and oxazole-2-carboxaldehyde (100mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stir for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). The layers are separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to give (E)-ethyl 2-fluoro-3-(oxazol-2-yl)acrylate (6:1 E / Z, as judged by 1H NMR, 165 mg, 0.89 mmol, 86% yield). LC / MS (ESI) m / z: [M+H] calculated for C8H9FNO3 + 186.0; Found 186.0; Reported E isomer: 1 H NMR (500MHz, CDCl3) δ7.69 (d, J = 0.7Hz, 1H), 7.25 (d, J = 0.7Hz, 1H), 6.62 (d, J = 17.6Hz, 1H), 4.35 (q, J = 7.2Hz, 2H), 1.32 (t, J = 7.2Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(oxazol-2-yl)acrylate

[0157] (E) -2- fluoro-3- (oxazole -2- bases) ethyl acrylate (165mg, 0.89mmol) was dissolved in toluene (2mL), and iodine (11mg, 0.045mmol) 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 obtain (Z) -2- fluoro-3- (oxazole -2- bases) ethyl acrylate (22mg, 0.12mmol, 13% yield). LC / MS (ESI) m / z: [M+H] calculated for C8H9FNO3 + is 186.0; the measured value is 185.9 1 H NMR (500MHz, CDCl3) δ7.77 (s, 1H), 7.32 (s, 1H), 6.96 (d, J = 31.0Hz, 1H), 4.37 (q, J = 7.2Hz, 2H), 1.38 (t, J = 7.2Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(oxazol-2-yl)acrylic acid

[0158] (Z)-2-fluoro-3-(oxazole-2-yl) ethyl 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 directly lyophilized to obtain (Z)-2-fluoro-3-(oxazole-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 for C6H5FNO3 + is 158.0; the measured value is 157.8; 1 H NMR (600MHz, DMSO-d6) δ8.30 (s, 1H), 7.47 (s, 1H), 6.90 (d, J = 32.2Hz, 1H). (Z)-2-Fluoro-3-(isoxazol-3-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(isoxazol-3-yl)acrylate

[0159] At 0 ° C, (2-ethoxy-1-fluoro-2-oxoethyl) triphenylphosphonium bromide (922mg, 2.06mmol) was stirred in THF (10mL). nBuLi solution (2.5M in hexane, 0.82mL, 2.06mmol) was added dropwise into the mixture. The mixture was stirred for 10 minutes, and then isoxazole-3-carboxaldehyde (100mg, 1.030mmol) was added as a solid. The reaction mixture was allowed to warm to room temperature over two hours. The reaction mixture was concentrated, and the residue was directly purified by column chromatography (5→100% EtOAc / hexane) to obtain (Z)-2-fluoro-3-(isoxazole-3-yl) ethyl acrylate (21mg, 0.11mmol, 11% yield). LC / MS (ESI) m / z: [M+H] calculated for C8H9FNO3 + is 186.1; the measured value is 185.9; 1H NMR (500MHz, CDCl3) δ8.47 (dd, J=1.7, 0.8Hz, 1H), 7.16 (d, J=33.0Hz, 1H), 6.78 (dd, J=2.9, 1.7Hz, 1H), 4.38 (q, J=7.2Hz, 2H), 1.38 (t, J=7.2Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(isoxazol-3-yl)acrylic acid

[0160] (Z)-2-Fluoro-3-(isoxazol-3-yl)ethyl 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 min. The reaction mixture was concentrated and used directly in the next step as the sodium salt without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] calculated for CHFNO + is 158.1; the measured value is 157.8. (Z)-2-Fluoro-3-(isoxazol-5-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(isoxazol-5-yl)acrylate

[0161] At 0 ° C, (2-ethoxy-1-fluoro-2-oxoethyl) triphenylphosphonium bromide (922mg, 2.06mmol) was stirred in THF (10mL). nBuLi solution (2.5M in hexane, 0.82mL, 2.06mmol) was added dropwise to the mixture. The mixture was stirred for 10 minutes, and then isoxazole-5-carboxaldehyde (100mg, 1.030mmol) was added as a solid. The reaction mixture was allowed to warm to room temperature over two hours. The reaction mixture was concentrated, and the residue was directly purified by column chromatography (5→100% EtOAc / hexane) to obtain (Z)-2-fluoro-3-(isoxazole-5-yl) ethyl acrylate (31mg, 0.11mmol, 16% yield). LC / MS (ESI) m / z: [M+H] calculated for C8H9FNO3 + is 186.1; the measured value is 185.9; 1 H NMR (500MHz, CDCl3) δ8.32 (dd, J=1.7, 0.8Hz, 1H), 7.09 (d, J=31.6Hz, 1H), 6.71 (t, J=1.7Hz, 1H), 4.38 (q, J=7.2Hz, 2H), 1.39 (t, J=7.2Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(isoxazol-5-yl)acrylic acid

[0162] (Z)-2-Fluoro-3-(isoxazol-5-yl)ethyl 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 min. The reaction mixture was concentrated and used directly in the next step as the sodium salt without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] calculated for CHFNO + is 158.1; the measured value is 157.9. (Z)-2-Fluoro-3-(isothiazol-5-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(isothiazol-5-yl)acrylate

[0163] At 0 ° C, (2-ethoxy-1-fluoro-2-oxoethyl) triphenylphosphonium bromide (790mg, 1.77mmol) was stirred in THF (9mL). nBuLi solution (2.5M in hexane, 0.71mL, 1.77mmol) was added dropwise to the mixture. The mixture was stirred for 10 minutes, and then isothiazole-5-carboxaldehyde (100mg, 0.88mmol) was added as a solution in THF (1mL). The reaction mixture was allowed to warm to room temperature over two hours. The reaction mixture was concentrated, and the residue was directly purified by column chromatography (5→100% EtOAc / hexane) to obtain (Z)-2-fluoro-3-(isothiazol-5-yl) ethyl acrylate (71mg, 0.35mmol, 40% yield). LC / MS (ESI) m / z: [M+H] calculated for C8H9FNO2S + is 202.0; the measured value is 201.9; 1 H NMR (500MHz, 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). Step 2: Preparation of (Z)-2-fluoro-3-(isothiazol-5-yl)acrylic acid

[0164] (Z)-2-Fluoro-3-(isothiazol-5-yl)ethyl 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 h. The reaction mixture was concentrated and used directly in the next step as the sodium salt without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] calculated for CHFNOS + is 174.1; the measured value is 173.9. (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

[0165] At 0 ° C, (2-ethoxy-1-fluoro-2-oxoethyl) triphenylphosphonium bromide (1.1g, 2.5mmol) is stirred in THF (10mL). nBuLi solution (2.5M in hexane, 1.0mL, 2.5mmol) is added dropwise into the mixture. The mixture is stirred for 10 minutes, and then 1-methyl-1H-1,2,3-triazole-4-yl-4-formaldehyde (140mg, 1.26mmol) in a solution in THF (2mL) is added. The reaction mixture is allowed to warm up to room temperature over two hours. The reaction mixture is concentrated, and the residue is directly purified by column chromatography (5 → 100% EtOAc / hexanes) to obtain (Z)-2-fluoro-3-(1-methyl-1H-1,2,3-triazole-4-yl) ethyl acrylate (132mg, 0.66mmol, 53% yield). LC / MS (ESI) m / z: for C8H 11 [M+H] calculated for FN3O2 + is 200.1; the measured value is 199.9; 1 H NMR (500MHz, CDCl3) δ7.93 (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). Step 2: Preparation of (Z)-2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)acrylic acid

[0166] (Z)-2-Fluoro-3-(1-methyl-1H-1,2,3-triazole-4-yl)ethyl 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. The solution was purified by HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25°C; gradient: 5:95 MeCN:H2O with 10 mM AA→95:5 MeCN:H2O with 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 + is 172.0; the measured value is 171.9; 1 H NMR (500MHz, CD3OD) δ8.28 (s, 1H), 7.09 (d, J = 34.0Hz, 1H), 4.15 (s, 3H). (Z)-2-Fluoro-3-(6-methylpyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(6-methylpyridin-2-yl)acrylate

[0167] 2-(diethoxyphosphoryl)-2-ethyl fluoroacetate (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added in batches as solid. The reaction mixture is stirred for 10min and 6-methylpyridine-2-carboxaldehyde (125mg, 1.0mmol) is added. The reaction mixture is allowed to warm up to room temperature and stir for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is 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 with 0.05% TFA→95:5 MeCN:H2O with 0.05% TFA; λ=220 nm) to give (Z)-ethyl 2-fluoro-3-(6-methylpyridin-2-yl)acrylate (31 mg, 0.15 mmol, 14% yield). LC / MS (ESI) m / z: for C 11 H 13 [M+H] calculated for FNO2 + is 210.1; the measured value is 209.7; 1 H NMR (500MHz, CDCl3) δ7.71(d,J=7.8Hz,1H),7.63(t,J=7.8Hz,1H),7.10(d,J=7.8Hz,1 H), 7.11 (d, J = 35.2Hz, 1H), 4.34 (q, J = 7.2Hz, 2H), 2.56 (s, 3H), 1.36 (t, J = 7.2Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(6-methylpyridin-2-yl)acrylic acid

[0168] (Z)-2-Fluoro-3-(6-methylpyridin-4-yl)ethyl 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. The solution was lyophilized and the crude material was used without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] calculated for C9H9FNO2 + The measured value is 182.1; 1H NMR (500MHz, DMSO-d6) δ7.80 (t, J = 7.7Hz, 1H), 7.65 (d, J = 7.7Hz, 1H), 7.29 (d, J = 7.7Hz, 1H), 6.94 (d, J = 35.4Hz, 1H), 2.50 (s, 3H). (Z)-2-Fluoro-3-(3-methylpyridin-2-yl)acrylic acid Step 1: Preparation of (Z)-ethyl 2-fluoro-3-(3-methylpyridin-2-yl)acrylate

[0169] 2-(diethoxyphosphoryl)-2-ethyl fluoroacetate (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added in batches as solid. The reaction mixture is stirred for 10min and 3-methylpyridine-2-carboxaldehyde (125mg, 1.0mmol) is added. The reaction mixture is allowed to warm up to room temperature and stir for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is 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 with 0.05% TFA→95:5 MeCN:H2O with 0.05% TFA; λ=220 nm) to give (Z)-ethyl 2-fluoro-3-(3-methylpyridin-2-yl)acrylate (30 mg, 0.14 mmol, 13% yield). LC / MS (ESI) m / z: for C 11 H 13 [M+H] calculated for FNO2 + is 210.1; the measured value is 209.7; 1 H NMR (500MHz, CDCl3) δ8.53 (dd, J=4.2, 0.8Hz, 1H), 7.52 (dd, J=7.7, 0.8Hz, 1H), 7.16 (dd, J=7.7 ,4.2Hz,1H),7.15(d,J=32.4Hz,1H),4.37(q,J=7.2Hz,2H),2.37(s,3H),1.38(t,J=7.2Hz,3H). Step 2: Preparation of (Z)-2-fluoro-3-(3-methylpyridin-2-yl)acrylic acid

[0170] (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 h. The reaction mixture was concentrated, diluted with water (1 mL), and hydrochloric acid solution (1.0 M, 140 μL, 0.14 mmol) was added. The solution was lyophilized and the crude material was used without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] calculated for C9H9FNO2 + is 182.1; the measured value is 181.8; NMR: 1 H NMR (500MHz, DMSO-d6) δ8.48 (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). (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

[0171] 2-(diethoxyphosphoryl)-2-ethyl fluoroacetate (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added in batches as solid. The reaction mixture is stirred for 10min and 1-methylimidazole-2-carboxaldehyde (114mg, 1.0mmol) is added. The reaction mixture is allowed to warm up to room temperature and stir for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by reverse phase HPLC (column: Xbridge C18, 30 mm x 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 (Z)-ethyl 2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylate (16 mg, 0.08 mmol, 8% yield). LC / MS (ESI) m / z: for C9H 12 [M+H] calculated for FN2O2 + is 199.1; the measured value is 198.9; 1 H NMR (500MHz, CDCl3) δ7.22 (d, J = 0.7Hz, 1H), 6.94 (d, J = 0.7Hz, 1H), 6.84 (d, J = 30.5Hz, 1H), 4.33 (q, J = 7.1Hz, 2H), 3.71 (s, 3H), 1.35 (t, J = 7.1Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylic acid

[0172] (Z)-2-fluoro-3-(1-methyl-1H-imidazole-2-yl) ethyl 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 directly lyophilized to obtain (Z)-2-fluoro-3-(1-methyl-1H-imidazole-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 + is 171.0; the measured value is 170.9; 1 H NMR (500MHz, DMSO-d6) δ7.31 (s, 1H), 7.11 (s, 1H), 6.87 (d, J = 31.6Hz, 1H), 3.72 (s, 3H). (Z)-2-Fluoro-3-(5-methylpyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(5-methylpyridin-2-yl)acrylate

[0173] 2-(diethoxyphosphoryl)-2-ethyl fluoroacetate (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added in batches as solid. The reaction mixture is stirred for 10min and 5-methylpyridine carboxaldehyde (125mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stir for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (15mL). The solution is diluted with water (20mL) and EtOAc (100mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×50mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by reverse phase HPLC (column: Xbridge C18, 30 mm x 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 (Z)-ethyl 2-fluoro-3-(4-methylpyridin-2-yl)acrylate (12 mg, 0.06 mmol, 6% yield). LC / MS (ESI) m / z: for C 11 H 13 [M+H] calculated for FNO2 + is 210.2; the measured value is 210.1 1 H NMR (500MHz, CDCL3) δ8.49(d,J=1.8Hz,1H),7.79(d,J=8.2Hz,1H),7.55(dd,J=8.2,1.8H z, 1H), 7.12 (d, J = 35.3Hz, 1H), 4.35 (q, J = 7.2Hz, 2H), 2.37 (s, 3H), 1.37 (t, J = 7.2Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(5-methylpyridin-2-yl)acrylic acid

[0174] (Z)-2-fluoro-3-(5-methylpyridin-2-yl)ethyl 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 directly lyophilized to obtain (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 + is 182.1; the measured value is 181.6; 1 H NMR (500MHz, DMSO-d6) δ8.51 (s, 1H), 7.74-7.69 (m, 2H), 6.95 (d, J = 35.4Hz, 1H), 2.33 (s, 3H). (Z)-2-Fluoro-3-(4-methylpyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylate

[0175] 2-(diethoxyphosphoryl)-2-ethyl fluoroacetate (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added in batches as solid. The reaction mixture is stirred for 10min and 2-formyl-4-methylpyridine (125mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stir for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by reverse phase HPLC (column: Xbridge C18, 30 mm x 100 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25°C; gradient: 95:5 H2O:MeCN:0.05% TFA→5:95 H2O:MeCN:0.05% TFA; λ=220 nm) to give (Z)-ethyl 2-fluoro-3-(4-methylpyridin-2-yl)acrylate (32 mg, 0.15 mmol, 15% yield). LC / MS (ESI) m / z: for C 11 H 13 [M+H] calculated for FNO2 + is 210.2; the measured value is 209.8; 1 H NMR(500MHz, CDCl3)δ8.51(d,J=5.0Hz,1H),7.70(s,1H),7.11(d,J=35.0Hz,1H), 7.07 (d, J = 5.0 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylic acid

[0176] (Z)-2-fluoro-3-(4-methylpyridin-2-yl)ethyl 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 directly lyophilized to obtain (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 + is 182.1; the measured value is 182.1. 1 H NMR (500MHz, 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). (Z)-2-Fluoro-3-(pyridin-4-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(pyridin-4-yl)acrylate

[0177] Isonicotinaldehyde (100 mg, 0.9 mmol) and ethyl 2-fluoroacetate (200 mg, 1.9 mmol) were dissolved in THF (4.7 mL). ethyl 2-fluoroacetate (198 mg, 1.867 mmol) was added and the reaction mixture was heated at 60 ° C for 1 h. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution (5 mL). Ethyl acetate (5 mL) was added and the layers were separated. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (30 → 50% EtOAc / hexane) to give (Z)-2-fluoro-3-(pyridin-4-yl) ethyl acrylate (62 mg, 0.318 mmol, 34.0% yield). LC / MS (ESI) m / z: for C 10 H 11 [M+H] calculated for FNO2 + is 196.1; the measured value is 195.6. 1H NMR (500MHz, CDCl3) δ 8.68-8.65 (m, 2H), 7.48-7.45 (m, 2H), 6.85 (d, J = 33.7Hz, 1H), 4.37 (q, J = 7.2Hz, 2H), 1.37 (t, J = 7.2Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(pyridin-4-yl)acrylic acid

[0178] (Z)-2-fluoro-3-(pyridin-4-yl) ethyl 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 hydrochloric acid solution (1.0 M, 0.46 mL, 0.46 mmol) was added dropwise. The solution was frozen and lyophilized to give (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 CHFNO + is 168.0; the actual measured value is 168.0. Preparation of KRAS inhibitors or Example 1 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

[0179] 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, 15 mg, 0.028 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (Intermediate C, 14 mg, 0.085 mmol) were combined as solids and dissolved in DMF (1 mL). DIPEA (0.020 mL, 0.113 mmol) was added followed by the addition of ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino-carbonium hexafluorophosphate) (36.2 mg, 0.085 mmol), and the reaction mixture was stirred at room temperature overnight. The solution was directly concentrated and purified by HPLC (column: Xbridge C18, 5 μm particles; gradient: 5:95 MeCN:H2O with 0.05% TFA→95:5 MeCN:H2O with 0.05% TFA; λ=220 nm) to afford 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 as 2TFA salt as an off-white solid (4.1 mg, 4.19 μmol, 15% yield). LC / MS (ESI) m / z: for C 37 H 39 [M+H] calculated for ClFN8O2 + is 681.3; the measured value is 681.1; 1 H NMR(500MHz,DMSO-d6)δ8.65(d,J=4.1Hz,1H),7.93-7.86(m,2H),7.81-7.77(m ,1H),7.76-7.71(m,1H),7.58(dt,J=7.5,1.3Hz,1H),7.56-7.51(m,1H),7.47-7 .42(m,1H),7.40-7.31(m,2H),6.61(d,J=38.9Hz,1H),5.03-4.58(m,1H),4.28 -4.13(m,2H),4.10-3.88(m,4H),3.83-3.69(m,2H),3.56-3.46(m,2H),3.31(br d,J=3.7Hz,1H),3.19-3.04(m,4H),3.01-2.88(m,2H),2.75-2.65(m,1H),2.56-2.51(m,1H),2. 32(s,3H),2.15(qd,J=8.6,2.6Hz,1H),1.95-1.90(m,1H),1.70-1.62(m,2H),1.61-1.53(m,1H). Example 2 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

[0180] Prepared by a procedure similar to that used in Example 1. LC / MS (ESI) m / z: for C 37 H 39 [M+H] calculated for ClFN8O2 + is 681.3; the measured value is 681.2. Example 3 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

[0181] 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-(pyridin-4-yl)acrylic acid (6 mg, 0.038 mmol) were combined as solids and dissolved in DMF (300 μL). DIPEA (10 μL, 0.056 mmol) was added followed by the addition of ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinium hexafluorophosphate) (12 mg, 0.028 mmol), and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25° C.; gradient: 88% 5:95 MeCN: HO with 0.1% TFA / 12% 95:5 MeCN: HO with 0.1% TFA→100% 95:5 MeCN: HO with 0.1% TFA TFA in H2O; λ = 220 nm) was directly purified to afford 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 as a TFA salt as a white solid (10.6 mg, 0.013 mmol, 70% yield). LC / MS (ESI) m / z: for C 37 H 39 [M+H] calculated for ClFN8O2 + 681.3; found 681.2; NMR: NB spectrum as reported obtained; water peak suppression method used; presence of atropisomers and amide rotamers complicates analysis. 1 H NMR(500MHz,DMSO-d6)δ8.76(br s,2H),7.93(br d,J=8.1Hz,1H),7.78(br s,2H),7.77-7.73(m,1H),7.61-7.57(m,1H),7.56-7.51(m,1H),7.49-7 .42(m,1H),7.39-7.32(m,1H),6.79(d,J=38.1Hz,1H),4.98-4.89(m,1H ),4.61-4.54(m,1H),4.48-4.39(m,1H),4.26-4.13(m,3H),4.11-3.93( m,2H),3.83-3.73(m,2H),3.25-3.06(m,1H),3.00-2.95(m,1H),2.93(br s,3H),2.80-2.69(m,1H),2.62-2.52(m,1H),2.29-2.20(m,1H),2.09-1.99(m,1H),1.96-1.75(m,3H). Example 4 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

[0182] 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-(pyrimidin-2-yl)acrylic acid (Intermediate D, 6 mg, 0.038 mmol) were combined as solids and dissolved in DMF (300 μL). DIPEA (10 μL, 0.056 mmol) was added followed by the addition of ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino-carbonium hexafluorophosphate) (12 mg, 0.028 mmol), and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25° C.; gradient: 79% 5:95 MeCN: HO with 0.1% TFA / 21% 95:5 MeCN: HO with 0.1% TFA→100% 95:5 MeCN: HO with 0.1% TFA TFA in H2O; λ = 220 nm) was directly purified to afford 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 as a TFA salt as a white solid (4.5 mg, 0.006 mmol, 30% yield). LC / MS (ESI) m / z: for C 36 H 38 [M+H] calculated for ClFN9O2 + 682.3; found 682.2 NMR: NB spectrum as obtained as reported; water peak suppression method used; presence of atropisomers and amide rotamers complicates analysis. 1H NMR(500MHz,DMSO-d6)δ8.89(d,J=4.8Hz,2H),7.93(d,J=8.1Hz,1H),7.78-7.73(m,1H),7.60-7.5 6(m,1H),7.56-7.52(m,1H),7.46(t,J=4.8Hz,1H),7.49-7.42(m,1H),7.39-7.31(m,1H),6.58(br d,J=35.2Hz,1H),4.57(br d,J=12.2Hz,1H),4.49-4.40(m,1H),4.24-3.96(m,3H),3.83-3.70(m,2H),3.67-3.53(m,1H),3.24-3.05(m,5H),3.00-2.95(m,1H),2.93(br s,3H),2.81-2.70(m,1H),2.28-2.19(m,1H),2.08-2.00(m,1H),1.94-1.78(m,2H). Example 5 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

[0183] 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 (20 mg, 0.019 mmol) and (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (Intermediate E, 6 mg, 0.038 mmol) were combined as solids and dissolved in DMF (300 μL). DIPEA (20 μL, 0.056 mmol) was added followed by the addition of ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate) (16 mg, 0.028 mmol), and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25°C; gradient: 74% 5:95 MeCN: HO with 10 mM AA / 26% 95:5 MeCN: HO with 10 mM AA→100% 95:5 MeCN: HO with 10 mM AA AA (H2O; λ = 220 nm) was directly purified to provide 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 (5.6 mg, 0.008 mmol, 22% yield) as a white solid. LC / MS (ESI) m / z: for C 35 H 37 [M+H] calculated for ClFN8O2S + 687.2; found 687.2; NMR: NB spectrum as reported obtained; water peak suppression method used; presence of atropisomers and amide rotamers complicates analysis. 1 H NMR (500MHz, DMSO-d6) δ8.04-7.99(m,2H),7.92(d,J=8.2Hz,1H),7.77-7.72(m,1H),7.61-7.51(m,2H),7.47-7.42(m,1H),7.38-7.31(m,1H),7. 06(d,J=38.8Hz,1H),5.02-4.30(m,1H),4.29-3.89(m,6H),3.83-3.70( m,1H),3.53-3.44(m,1H),3.19-2.88(m,3H),2.75-2.61(m,1H),2.36(br s,3H),2.28-2.12(m,1H),1.96-1.91(m,1H),1.72-1.54(m,3H). 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

[0184] 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). 1-Methylimidazole (0.015 mL, 0.188 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (5.3 mg, 0.019 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25°C; gradient: 74% 5:95 MeCN:H2O with 10 mM AA / 26% 95:5 MeCN:H2O with 10 mM AA→100% 95:5 MeCN:H2O with 10 mM AA). AA (H2O; λ = 220 nm) was directly purified to provide 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: for C 35 H 37 Calculated [M+H] for ClFN8O3 + 671.3; found 671.2; NMR: NB spectrum as reported obtained; water peak suppression method used; presence of atropisomers and amide rotamers complicates analysis. 1H NMR(500MHz,DMSO-d6)δ8.28(s,1H),7.92(d,J=8.2Hz,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=35.1Hz,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). Example 7 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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

[0185] 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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). 1-Methylimidazole (0.055 mL, 0.69 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (10 mg, 0.035 mmol) and the reaction mixture was stirred at room temperature for 5 min. Additional portions of (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (5.8 mg, 0.035 mmol) and chloro-N,N,N',N'-tetramethylcarbamidinium hexafluorophosphate (10 mg, 0.035 mmol) were added and the reaction mixture was stirred for 5 min. The process was repeated 6 more times. The reaction mixture was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 65% 5:95 MeCN: HO with 10 mM AA / 35% 95:5 MeCN: HO with 10 mM AA→100% 95:5 MeCN: HO with 10 mM AA (H2O; λ = 220 nm) was directly purified to provide 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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: for C 39 H 39 [M+H] calculated for ClF2N8O2 + 725.3; found 725.2; NMR: NB spectrum as reported obtained; water peak suppression method used; presence of atropisomers and amide rotamers complicates analysis. 1H NMR(500MHz,DMSO-d6)δ8.65(br d,J=4.1Hz,1H),7.89(t,J=7.6Hz,1H),7.91(d,J=8.1Hz,1H),7.78(d,J=7.7Hz,1H),7.77-7.70(m,1H ),7.47-7.42(m,1H),7.40-7.30(m,1H),7.38(dd,J=7.6,4.1Hz,1H),6.61(d,J=39.2Hz,1H),5.26(d,J =53.7Hz,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). Example 8 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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

[0186] 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (Intermediate B, 7 mg, 0.012 mmol) and (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (Intermediate E, 1.1 mg, 0.006 mmol) were combined as solids and dissolved in DMF (0.6 mL). 1-Methylimidazole (0.01 mL, 0.122 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (1.7 mg, 0.006 mmol) and the reaction mixture was stirred at room temperature for 5 min. Additional portions of (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (1.1 mg, 0.006 mmol) and chloro-N,N,N',N'-tetramethylcarbamidinium hexafluorophosphate (1.7 mg, 0.006 mmol) were added and the reaction mixture was stirred for 5 min. This process was repeated 6 more times. The reaction mixture was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 80% 5:95 MeCN: HO with 10 mM AA / 20% 95:5 MeCN: HO with 10 mM AA→100% 95:5 MeCN: HO with 10 mM AA (H2O; λ = 220 nm) was directly purified to provide 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 (1.4 mg, 0.002 mmol, 16% yield) as a white solid. LC / MS (ESI) m / z: for C 37 H 38 [M+H] calculated for ClF2N8O2S + 731.2; found 731.2; NMR: NB spectrum as reported obtained; water peak suppression method used; presence of atropisomers and amide rotamers complicates analysis. 1H NMR(500MHz,DMSO-d6)δ8.04-7.97(m,2H),7.92(d,J=8.2Hz,1H),7.82-7.6 6(m,1H),7.62-7.48(m,2H),7.48-7.41(m,1H),7.41-7.23(m,1H),7.06(br d,J=38.8Hz,1H),5.26(br d,J=54.1Hz,1H),5.04-4.33(m,1H),4.26-4.11(m,1H),4.10-3.92(m,2H),3.86-3.72(m,1H),3.59-3.3 1(m,2H),3.22-2.89(m,3H),2.87-2.80(m,1H),2.73-2.63(m,1H),2.15-1.93(m,3H),1.90-1.63(m,3H). Example 9 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

[0187] 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 2-fluoro-3-(isothiazol-5-yl)acrylic acid (approximately 1.5:1 mixture of Z / E isomers, 7 mg, 0.038 mmol) were combined as solids and dissolved in DMF (1 mL). DIPEA (10 μL, 0.056 mmol) was added followed by the addition of ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate) (12 mg, 0.028 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 ° C; gradient: 80% 5:95 MeCN: HO with 10 mM AA / 20% 95:5 MeCN: HO with 10 mM AA → 100% 95:5 MeCN: HO with 10 mM AA; λ = 220 nm) to give the desired product (9.1 mg, 0.013 mmol, 68% yield, about 1:1 mixture of Z / E isomers) as a white solid. LC / MS (ESI) m / z: for C 35 H 37 [M+H] calculated for ClFN8O2S + 687.2; Found 687.2; NMR: NB spectrum as reported obtained; two compounds are present, the (Z) olefin isomer and the (E) olefin isomer; water peak suppression method was used; the presence of atropisomers and amide rotamers complicates the analysis. 1 H NMR(500MHz,DMSO-d6)δ8.67-8.62(m,1H),8.54-8.47(m,1H),7.97-7.90(m,2H), 7.79-7.73(m,2H),7.70-7.67(m,1H),7.62-7.28(m,11H),5.05-4.73(m,1H),4.64 -4.52(m,2H),4.51-4.36(m,2H),4.28-4.14(m,3H),4.12-3.91(m,3H),3.87 -3.69(m,4H),3.66-3.34(m,2H),3.23-3.05(m,7H),3.01-2.92(m,4H),2.81 -2.69(m,1H),2.60-2.51(m,2H),2.29-2.13(m,2H),2.11-2.00(m,2H),1.97 -1.74(m,4H). 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

[0188] 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). 1-Methylimidazole (0.015 mL, 0.188 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (5 mg, 0.019 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25°C; gradient: 79% 5:95 MeCN:H2O with 10 mM AA / 21% 95:5 MeCN:H2O with 10 mM AA→100% 95:5 MeCN:H2O with 10 mM AA; λ=220 nm) to give the desired product (2.3 mg, 0.003 mmol, 17% yield) as a white solid. LC / MS (ESI) m / z: for C 36 H 40 [M+H] calculated for ClFN9O2 + 684.3; found 684.3; NMR: NB spectrum as reported obtained; water peak suppression method used; presence of atropisomers and amide rotamers complicates analysis. 1HNMR(500MHz,DMSO-d6)δ7.92(br d,J=8.0Hz,1H),7.78-7.66(m,1H),7.63-7.49(m,2H),7.45(t,J=7.8Hz,1H),7.39-7.30(m,1H),7.28( s,1H),7.07(s,1H),6.64(d,J=35.0Hz,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). Example 11 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

[0189] 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-(6-methylpyridin-2-yl)acrylic acid (5 mg, 0.019 mmol) were combined as solids and dissolved in DMF (0.5 mL). 1-Methylimidazole (0.015 mL, 0.188 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (5 mg, 0.019 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25°C; gradient: 68% 5:95 MeCN:H2O with 10 mM AA / 32% 95:5 MeCN:H2O with 10 mM AA→100% 95:5 MeCN:H2O with 10 mM AA; λ=220 nm) to give the desired product (7.4 mg, 0.011 mmol, 56% yield) as a white solid. LC / MS (ESI) m / z: for C 38 H 41 [M+H] calculated for ClFN8O2 + 695.3; found 695.0; NMR: NB spectrum as reported obtained; water peak suppression method used; presence of atropisomers and amide rotamers complicated analysis. 1 H NMR (500 MHz, DMSO-d6) δ7.92(d,J=8.3 Hz,1H),7.80-7.71(m,2H),7.62-7.50(m,3H),7.44(t,J=7.8 Hz,1H),7.38-7.30(m,1H),7.24(d,J=7.6 Hz,1H),6.54(br d,J=39.4 Hz,1H),5.05-4.57(m,1H),4.29-4.11(m,2H),4.10-3.90(m,3H),3.82-3.69(m,1H),3.32-3.25(m,1H),3.18-3.05(m,3H),3.02-2.89(m ,2H),2.74-2.63(m,1H),2.49(brs,3H),2.36-2.30(m,3H),2.20-2.10(m,1H),1.95-1.90(m,1H),1.71-1.61(m,2H),1.61-1.52(m,1H). Example 12 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

[0190] 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-(4-methylpyridin-2-yl)acrylic acid (5 mg, 0.019 mmol) were combined as solids and dissolved in DMF (0.5 mL). 1-Methylimidazole (0.015 mL, 0.188 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (5 mg, 0.019 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25°C; gradient: 69% 5:95 MeCN:H2O with 10 mM AA / 31% 95:5 MeCN:H2O with 10 mM AA→100% 95:5 MeCN:H2O with 10 mM AA; λ=220 nm) to give the desired product (7.7 mg, 0.011 mmol, 59% yield) as a white solid. LC / MS (ESI) m / z: for C 38 H 41 [M+H] calculated for ClFN8O2 + 695.3; found 695.0; NMR: NB spectrum as reported obtained; water peak suppression method used; presence of atropisomers and amide rotamers complicated analysis. 1H NMR(500MHz,DMSO-d6)δ8.49(d,J=5.0Hz,1H),7.92(d,J=8.3Hz,1H),7.79-7.70(m, 1H),7.62(s,1H),7.60-7.50(m,2H),7.47-7.42(m,1H),7.38-7.30(m,1H),7.22(br d,J=5.0Hz,1H),6.56(d,J=40.6Hz,1H),5.00-4.58(m,1H),4.29-4.12(m, 2H),4.11-3.92(m,3H),3.83-3.71(m,1H),3.54-3.44(m,1H),3.18-3.02( m,3H),2.98-2.86(m,2H),2.66(s,1H),2.36(s,3H),2.35-2.30(m,3H),2. 20-2.11(m,1H),1.96-1.90(m,1H),1.70-1.62(m,2H),1.61-1.52(m,1H). Example 13 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

[0191] 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-(5-methylpyridin-2-yl)acrylic acid (5 mg, 0.019 mmol) were combined as solids and dissolved in DMF (0.5 mL). 1-Methylimidazole (0.015 mL, 0.188 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (5 mg, 0.019 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25°C; gradient: 72% 5:95 MeCN:H2O with 10 mM AA / 28% 95:5 MeCN:H2O with 10 mM AA→100% 95:5 MeCN:H2O with 10 mM AA; λ=220 nm) to give the desired product (4.3 mg, 0.006 mmol, 33% yield) as a white solid. LC / MS (ESI) m / z: for C 38 H 41 [M+H] calculated for ClFN8O2 + 695.3; found 695.0; NMR: NB spectrum as reported obtained; presence of atropisomers and amide rotamers complicates analysis. 1 H NMR(500MHz,DMSO-d6)δ8.46(s,1H),7.89(br d,J=8.4Hz,1H),7.74-7.66(m,3H),7.57-7.49(m,2H),7.45-7.41(m,1H),7.36-7.29(m,1H),6.56( d,J=40.2Hz,1H),5.00-4.56(m,1H),4.28-4.13(m,2H),4.12-3.95(m,3H),3.63-3.55(m,2H),3.52 -3.43(m,1H),3.34-3.26(m,1H),3.14-3.03(m,3H),3.01-2.86(m,2H),2.72-2.58(m,1H),2.40-2. 34(m,3H),2.31(s,3H),2.29-2.21(m,1H),2.00-1.90(m,1H),1.72-1.62(m,2H),1.62-1.51(m,1H). Example 14 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

[0192] 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-(3-methylpyridin-2-yl)acrylic acid (5 mg, 0.019 mmol) were combined as solids and dissolved in DMF (0.5 mL). 1-Methylimidazole (0.015 mL, 0.188 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (5 mg, 0.019 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25°C; gradient: 72% 5:95 MeCN:H2O with 10 mM AA / 28% 95:5 MeCN:H2O with 10 mM AA→100% 95:5 MeCN:H2O with 10 mM AA; λ=220 nm) to give the desired product (4.4 mg, 0.006 mmol, 34% yield) as a white solid. LC / MS (ESI) m / z: for C 38 H 41 [M+H] calculated for ClFN8O2 + 695.3; found 695.0; NMR: NB spectrum as reported obtained; presence of atropisomers and amide rotamers complicates analysis. 1H NMR(500MHz,DMSO-d6)δ8.44(br d,J=4.5Hz,1H),7.89(d,J=8.3Hz,1H),7.74-7.70(m,1H),7.67(d,J=7.5Hz,1H),7.58-7.49(m,2H),7.46-7.40(m,1H),7. 36-7.30(m,1H),7.27(dd,J=7.5,4.5Hz,1H),6.70(d,J=36.3Hz,1H),4.98-4.60(m,1H),4.29-4.21(m,1H),4.20-4.03(m,3 H),4.01-3.90(m,1H),3.82-3.74(m,1H),3.58-3.46(m,1H),3.37-3.30(m,1H),3.14-3.04(m,3H),3.03-2.88(m,2H),2.74 -2.63(m,1H),2.41-2.34(m,3H),2.31(s,3H),2.30-2.25(m,1H),1.99-1.90(m,1H),1.74-1.63(m,2H),1.62-1.51(m,1H). Example 15 (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

[0193] 7-(8-Chloronaphthalen-1-yl)-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (3 mg, 0.006 mmol) and (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (3 mg, 0.018 mmol) were combined as solids and dissolved in DMF (0.3 mL). 1-Methylimidazole (0.003 mL, 0.035 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (5 mg, 0.018 mmol) and the reaction mixture was stirred at room temperature for 5 min. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25°C; gradient: 69% 5:95 MeCN: HO with 10 mM AA / 31% 95:5 MeCN: HO with 10 mM AA → 100% 95:5 MeCN: HO with 10 mM AA; λ = 220 nm) to give the desired product (0.6 mg, 0.9 μmol, 15% yield) as a white solid. LC / MS (ESI) m / z: for C 34 H 38 [M+H] calculated for ClFN7O2S + The actual measured value is 662.2. Example 16 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

[0194] 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-3-yl)acrylic acid as a Na salt (7 mg, 0.038 mmol) were combined as solids and dissolved in DMF (1.0 mL). DIPEA (10 μL, 0.056 mmol) was added followed by the addition of ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate) (12 mg, 0.028 mmol). The reaction mixture was stirred at room temperature overnight. The solution was directly purified by HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 87% 5:95 MeCN: HO with 0.1% TFA / 13% 95:5 MeCN: HO with 0.1% TFA → 100% 95:5 MeCN: HO with 0.1% TFA; λ = 220 nm) to give the desired product as a bis-TFA salt (8.7 mg, 0.010 mmol, 25% yield). LC / MS (ESI) m / z: for C 35 H 37 Calculated [M+H] for ClFN8O3 + 671.3; found 671.2; NMR: spectrum as reported obtained; water peak suppression method used; presence of atropisomers and amide rotamers complicated analysis. 1 H NMR(500MHz,DMSO-d6)δ9.13-8.91(m,1H),7.93(d,J=8.3Hz,1H),7.84-7.67(m,1H),7.65-7.49(m,2H),7.49-7.42(m,1H),7.42-7.32(m,1H),6.91 -6.87(m,1H),6.77(d,J=37.4Hz,1H),5.07-4.82(m,1H),4.65-4.51(m,1H),4.47 -4.38(m,1H),4.24-4.15(m,2H),4.11-3.99(m,2H),3.88-3.71(m,3H),3.70-3.4 5(m,2H),3.41-3.27(m,1H),3.26-3.09(m,1H),2.98-2.87(m,1H),2.81-2.69(m, 1H),2.62-2.52(m,1H),2.30-2.17(m,1H),2.11-2.01(m,1H),1.94-1.79(m,2H). 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

[0195] 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 as a Na salt (7 mg, 0.038 mmol) were combined as solids and dissolved in DMF (1.0 mL). DIPEA (10 μL, 0.056 mmol) was added followed by the addition of ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate) (12 mg, 0.028 mmol). The reaction mixture was stirred at room temperature overnight. The solution was directly purified by HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 87% 5:95 MeCN: HO with 0.1% TFA / 13% 95:5 MeCN: HO with 0.1% TFA → 100% 95:5 MeCN: HO with 0.1% TFA; λ = 220 nm) to give the desired product as a bis-TFA salt (4.4 mg, 0.005 mmol, 12% yield). LC / MS (ESI) m / z: for C 35 H 37 Calculated [M+H] for ClFN8O3 + 671.3; found 671.2; NMR: spectrum as reported obtained; water peak suppression method used; presence of atropisomers and amide rotamers complicated analysis. 1H NMR (500MHz, DMSO-d6) δ8.71 (s, 1H), 7.93 (d, J = 8.2Hz, 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=36.6Hz,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). 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

[0196] 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). DIPEA (14 μL, 0.083 mmol) was added followed by the addition of ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate) (27 mg, 0.062 mmol). The reaction mixture was stirred at room temperature overnight. The solution was directly purified by HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 85% 5:95 MeCN: HO with 0.1% TFA / 15% 95:5 MeCN: HO with 0.1% TFA → 100% 95:5 MeCN: HO with 0.1% TFA; λ = 220 nm) to give the desired product as a bis-TFA salt (6.6 mg, 0.007 mmol, 12% yield). LC / MS (ESI) m / z: for C 35 H 39 CIF 10 [M+H] calculated for O2 + 685.3; found 685.0; NMR: spectrum as reported obtained; water peak suppression method used; presence of atropisomers and amide rotamers complicated analysis. 1 H NMR (500MHz, DMSO-d6) δ8.42(s,1H),7.93(d,J=8.1Hz,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=38.6Hz,1H),4.99-4.69(m,1H),4.62-4.51(m,1H),4.49-4.39(m,1H),4.2 8-4.14(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). Biological Activity KRAS G12C RAF disruption assay

[0197] This is to measure compounds targeting KRAS-G12C (ON)Functional assay of the activity of (i.e., the active form of KRAS G12C). Recombinant GMPPNP-loaded KRAS G12C (5 nM) was treated with compounds in assay buffer (50 mM Tris pH 7.5, 100 mM NaCl, 1 mM MgCl2, 1 mM DTT, 100 ug / ml BSA) at room temperature for 20 minutes. 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. HTRF signals were measured (PerkinElmer Envision) and the signal ratio (λ) was calculated. em 520 / λ em 495), and the IC was calculated from the dose-response curve 50 value.

[0198] IC of the compounds described herein 50 The values ​​are shown in Table 1. Table 1

[0199] It should be understood that the detailed description section, rather than the summary and abstract sections, is intended to be used to interpret the claims. The summary and abstract sections may set forth one or more but not all exemplary aspects of the present disclosure as contemplated by the inventor(s), and therefore, are not intended to limit the present disclosure and the appended claims in any way.

[0200] The disclosure is described above with the aid of functional building blocks that illustrate the implementation of specified functions and their relationships. For ease of description, the boundaries of these functional building blocks are arbitrarily defined herein. Alternative boundaries may be defined as long as the specified functions and their relationships are appropriately performed.

[0201] All references cited herein are hereby incorporated by reference in their entirety.

[0202] The foregoing description of specific aspects will fully reveal the general nature of the present disclosure, so that others can easily modify and / or adapt to such specific aspects of multiple applications by applying the knowledge within the technology of the art, without excessive experimentation, without departing from the general concept of the present disclosure. Therefore, based on the teachings and guidance presented herein, such adaptations and modifications are intended to be within the meaning and scope of the equivalents of the disclosed aspects. It should be understood that the wording or terminology herein is for the purpose of description rather than limitation, so that the terms or wording of this specification should be interpreted by the technician according to teaching and guidance.

[0203] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. A compound having formula (I): or a pharmaceutically acceptable salt thereof, wherein: U is a bond or NH; n is 0, 1, or 2; Z is a bond, C(O), or CR e R f , where R e and R f are independently hydrogen or C1-C3 alkyl; R 1 is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, haloC1-C3 alkyl, hydroxyl, and hydroxyC1-C3 alkyl; Each R 2 Independently selected from C1-C3 alkoxy, C1-C3 alkyl, cyano, halogen, halogenated C1-C3 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, hydroxyl and oxo; Y is a bond, O, NR g (CR e R f ) m NR f , or CR e R f , wherein m is 1, 2, or 3, and wherein R e , R f and R g are independently hydrogen or C1-C3 alkyl; A is a four- to ten-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, wherein the ring system is optionally substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, cyano, halogen, haloC1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo; R' is a halogen; R 4 is a five-membered or six-membered aromatic ring optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of C2-C4 alkenyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halogen, haloC1-C3 alkoxy, haloC1-C3 alkyl, nitro and oxo; X is O or NR 16 , where R 16 is hydrogen or C1-C3 alkyl; R 5 is selected from hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di(C1-C3 alkyl)amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR a R b C1-C6 alkyl, wherein the aryl, the aryl portion of the arylC1-C6 alkyl, the C3-C6 cycloalkyl, the cycloalkyl portion of the C3-C6 cycloalkylC1-C6 alkyl, the heteroaryl, the heteroaryl portion of the heteroarylC1-C6 alkyl, the heterocyclyl, the heterocyclyl portion of the heterocyclylC1-C6 alkyl is optionally substituted by one, two, three, or four groups independently selected from the following: C1-C3 alkoxy, C1-C3 alkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)aminoC1-C3 alkyl, amino, amino C1-C3 alkyl, halogen, halogenated C1-C3 alkoxy, halogenated C1-C3 alkyl, heterocyclic radical, heterocyclic radical C1-C3 alkyl, hydroxyl, hydroxy C1-C3 alkyl, nitro and oxo; wherein the heterocyclic radical and the heterocyclic radical portion of the heterocyclic radical C1-C3 alkyl are further optionally substituted by one, two, or three groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen and halogenated C1-C3 alkyl; or R 5 and R 16 together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted by one, two, three, four, or five groups independently selected from: one, two, three, or four groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxyl and hydroxyC1-C3 alkyl; and R a and R b One of them is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, arylC1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkylC1-C6 alkyl.

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 four- to nine-membered monocyclic or bicyclic bridged or fused saturated ring system optionally containing one or two nitrogen atoms.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: AU is in represents the point of attachment to the carbonyl group; and Indicates the point of attachment to Y.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: AU is in represents the point of attachment to the carbonyl group; and Indicates the point of attachment to Y.

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

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: R 4 Selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl and triazolyl, wherein each ring is optionally substituted with one, two, or three groups independently selected from the following: C2-C4 alkenyl, C1-C3 alkyl, halogen, halo-substituted C1-C3 alkoxy, halo-substituted C1-C3 alkyl, nitro and oxo.

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

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

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 5 Selected from: Wherein each ring is optionally substituted by 1, 2, or 3 groups independently selected from the following: C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halogen, halogenated C1-C3 alkyl, hydroxyl, hydroxyC1-C3 alkyl and oxo.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: R 5 is -(C1-C3 alkyl)-R 6 , where R 6 is a three- to five-membered monocyclic ring system, an eight- or nine-membered bicyclic fused saturated ring system, or a ten-membered tricyclic saturated ring system, wherein each ring system optionally contains one nitrogen atom, and wherein each ring system is optionally substituted by one or two groups independently selected from C1-C3 alkyl, halogen and (4- to 6-membered heterocyclyl)C1-C3 alkyl; wherein the heterocyclyl portion of the (4- to 6-membered heterocyclyl)C1-C3 alkyl is further optionally substituted by a halogen group.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: R 5 yes and Indicates the point of attachment to X.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: R 5 yes Where n is 0, 1, or 2; Each R 20 is a halogen; and Indicates the point of attachment to X.

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

15. The compound according to any one of claims 1 to 14, wherein R 1 is a monocyclic heteroaryl ring containing one, two, or three nitrogen atoms, wherein the ring is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, haloC1-C3 alkyl, hydroxyl, and hydroxyC1-C3 alkyl.

16. The compound according to any one of claims 1 to 15, wherein R 1 yes in The point of attachment to the parent molecule is indicated.

17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein: R 1 is a C6-C 10 Aryl: C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, halogenated C1-C3 alkyl, hydroxyl and hydroxyC1-C3 alkyl.

18. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 and 17, wherein R 1 is naphthyl substituted with one, two, three, four, or five substituents independently selected from C1-C3 alkyl, C2-C4 alkynyl, halogen and hydroxy.

19. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, 17 and 18, wherein: R 1 is naphthyl, wherein the naphthyl is substituted with one, two, or three groups independently selected from C2-C4 alkynyl, halogen and hydroxy.

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 and 17 to 19, wherein: R 1 yes in The point of attachment to the parent molecule is indicated.

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

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

23. A compound selected from or a pharmaceutically acceptable salt thereof.

24. A compound selected from: 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-pyrrolazin-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-pyrrolazin-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 or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a 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 a 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 of treating a 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 one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

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

29. A method for treating a cancer sensitive to KRAS G12C inhibition in a subject in need thereof, the method comprising administering to the subject a compound of 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 a compound as described in 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, stomach cancer, or uterine cancer.

31. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound as described in 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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