KRAS inhibitors

Abstract

The present disclosure provides KRAS inhibitors, as well as methods of using the compounds to treat cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 371,191, filed August 11, 2022, and U.S. Provisional Patent Application No. 63 / 483,876, filed February 8, 2023, both of which are incorporated by reference herein in their entireties.

[0002] The present disclosure provides KRAS inhibitors, as well as methods of using the inhibitors to treat cancer. [Background technology]

[0003] The KRAS oncogene is a member of the RAS family of GTPases involved in many cell signaling processes. KRAS mutations are gain-of-function mutations present in up to 30% of all tumors, including approximately 90% of pancreatic cancers. KRAS functions as a molecular switch cycling between an inactive (GDP-bound) and an active (GTP-bound) state, transducing upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate diverse processes, including cell proliferation. Single nucleotide substitutions resulting 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 adenocarcinomas, with the 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. Summary of the Invention [Problem to be solved by the invention]

[0004] Although some attempts to target KRAS have failed, compounds that inhibit KRAS activity, including compounds that disrupt effectors such as guanine nucleotide exchange factors and target KRAS G12C, are highly desirable. Clearly, there is still ongoing interest and effort in developing inhibitors of KRAS, particularly inhibitors that activate KRAS mutants such as KRAS G12C. [Means for solving the problem]

[0005] The present disclosure is based in part on the fact that, unlike other KRAS G12C inhibitors, the compounds of the present disclosure are active KRAS G12C inhibitors. (ON) This is based on the discovery that it targets the G12C form of the KRAS protein. ON By inhibiting the G12C form of KRAS, the claimed compounds are expected to reduce cancer resistance to KRAS G12C inhibition and / or demonstrate increased clinical efficacy. Without being bound by theory, it is believed that the G12C of KRAS G12C ON The inhibition of conformation may be the result of an alkenylcarbonyl group attached to ring A of formula (I).

[0006] In a first aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, Z is a bond, O, or NR e or CR e R f where R e and R f are independently hydrogen or C1-C3 alkyl; R 1is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkoxy, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; R 2 and R 3 is independently selected from hydrogen, C-C alkoxy, C-C alkyl, cyano, halo, haloC-C alkyl, —C(O)NH, —C(O)NH(C-C alkyl), —C(O)N(C-C alkyl) and hydroxy; U is a bond, CHNH, or NH; Y is a bond, O, or NR g (CR e R f ) m , N.R. f or CR e R f where m is 1, 2, or 3; R e , R f and R g are independently hydrogen or C1-C3 alkyl; A is a 4-10 membered monocyclic, bicyclic or tricyclic bridged, fused or spirocyclic saturated, unsaturated or partially unsaturated ring system which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen and sulfur, and which ring system is optionally substituted with one, two or three groups independently selected from C-C alkoxy, C-C alkoxyC-C alkyl, C-C alkyl, amidoC-C alkyl, cyano, cyanoC-C alkyl, halo, haloC-C alkyl, amino, aminoC-C alkyl, hydroxy, hydroxyC-C alkyl and oxo, with the proviso that when Y is a bond, A contains at least one nitrogen atom; R' is halo; R 4is an aryl or heteroaryl ring optionally substituted with 1, 2, or 3 substituents independently selected from C2-C4 alkenyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halo, 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 hydrogen, C1-C6 alkoxyC1-C6 alkyl, C1-C6 alkyl, aryl, arylC1-C6 alkyl, carboxyC1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, di(C1-C3 alkyl)aminoC2-C6 alkyl, haloC1-C6 alkyl, heteroaryl, heteroarylC1-C6 alkyl, heterocyclyl, heterocyclylC1-C6 alkyl, hydroxyC1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR a R bC1-C6 alkyl, and the aryl, aryl portion of arylC1-C6 alkyl, C3-C6 cycloalkyl, cycloalkyl portion of C3-C6 cycloalkylC1-C6 alkyl, heteroaryl, heteroaryl portion of heteroarylC1-C6 alkyl, heterocyclyl, heterocyclyl portion of heterocyclylC1-C6 alkyl are selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)aminoC1-C3 alkyl, amino, aminoC1-C3 alkyl, carboxy, cyano, di(C1-C di(C-C alkyl)amino, di(C-C alkyl)aminoC-C alkyl, halo, haloC-C alkoxy, haloC-C alkyl, heterocyclyl, heterocyclylC-C alkyl, hydroxy, hydroxyC-C alkyl, nitro, and oxo; wherein the heterocyclyl portion of the heterocyclyl and heterocyclylC-C alkyl is optionally further substituted with 1, 2, or 3 groups independently selected from C-C alkoxy, C-C alkyl, halo, and haloC-C alkyl; or R 5 and R 16 together with the nitrogen atom to which they are attached form a heterocyclic group optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from 1, 2, 3, or 4 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; R a and R b one of which 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 or a pharmaceutically acceptable salt thereof.

[0007] In certain aspects, the present disclosure provides 4 is a 5- or 6-membered aromatic ring optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a pharmaceutically acceptable salt thereof.

[0008] In certain aspects, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Y is a bond.

[0009] In certain aspects, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is NH.

[0010] In certain aspects, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Y is NCH3.

[0011] In certain aspects, the present disclosure provides compounds of Formula (I) or pharmaceutically acceptable salts thereof, wherein A is a 6-10 membered monocyclic, or bicyclic or tricyclic bridged, fused, or spirocyclic saturated ring system containing 1 or 2 nitrogen atoms.

[0012] In certain aspects, the present disclosure provides compounds of Formula (I) or pharmaceutically acceptable salts thereof, wherein A is a 5-10 membered monocyclic, or bicyclic or tricyclic bridged, fused, or spirocyclic saturated ring system containing 1 or 2 nitrogen atoms.

[0013] In certain embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, where U is a bond. In certain embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, where U is CHNH. In certain embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, where U is NH.

[0014] In certain aspects, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein AU is selected from: [ka] During the ceremony, [ka] represents the point of attachment to the carbonyl group; and [ka] represents the point of attachment to Y.

[0015] In certain aspects, the present disclosure provides a method for preparing a medicament for the treatment of a malaria parasite comprising administering to [ka] is selected from the group consisting of During the ceremony, [ka] represents the point of attachment to the carbonyl group; and [ka] represents the point of attachment to the quinazoline ring, or a pharmaceutically acceptable salt thereof.

[0016] In certain aspects, the present disclosure provides 2 is halo; or a pharmaceutically acceptable salt thereof.

[0017] In certain aspects, the present disclosure provides 3 is halo; or a pharmaceutically acceptable salt thereof.

[0018] In certain aspects, the present disclosure provides 4 is selected from isothiazolyl, pyridinyl, pyrimidinyl, and thiazolyl; or a pharmaceutically acceptable salt thereof.

[0019] In certain aspects, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is O.

[0020] In certain aspects, the present disclosure provides 5but: [ka] wherein each ring is optionally substituted with 1, 2 or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl and oxo; or a pharmaceutically acceptable salt thereof.

[0021] In certain aspects, the present disclosure provides 5 -(C1-C3 alkyl)-R 6 and R 6 is a 3- to 5-membered monocyclic ring system, an 8- or 9-membered bicyclic fused saturated ring system, or a 10-membered tricyclic saturated ring system, each ring system optionally containing one nitrogen atom, and each ring system is optionally substituted with one or two groups independently selected from C1-C3 alkyl, halo, and (4- to 6-membered heterocyclyl)C1-C3 alkyl, wherein the heterocyclyl portion of the (4- to 6-membered heterocyclyl)C1-C3 alkyl is optionally further substituted with a halo group; or a pharmaceutically acceptable salt thereof.

[0022] In certain aspects, the present disclosure provides 5 but [ka] and [ka] represents the point of attachment to X, or a pharmaceutically acceptable salt thereof.

[0023] In certain aspects, the present disclosure provides 5 but [ka] where: n is 0, 1 or 2; Each R 20is a halo; and [ka] represents the point of attachment to X, or a pharmaceutically acceptable salt thereof.

[0024] In certain aspects, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

[0025] In certain aspects, the present disclosure provides 1 is a monocyclic heteroaryl ring containing 1, 2, or 3 nitrogen atoms, and the ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

[0026] In certain aspects, the present disclosure provides 1 but [ka] where: [ka] indicates the point of attachment to the parent molecular moiety, or a pharmaceutically acceptable salt thereof.

[0027] In certain aspects, the present disclosure provides 1 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; 10The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0028] In certain aspects, the present disclosure provides 1 is naphthyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C3 alkyl, C2-C4 alkynyl, halo, and hydroxy; or a pharmaceutically acceptable salt thereof.

[0029] In certain aspects, the present disclosure provides 1 is naphthyl, and naphthyl is substituted with 1, 2 or 3 groups independently selected from C2-C4 alkynyl, halo and hydroxy; or a pharmaceutically acceptable salt thereof.

[0030] In certain aspects, the present disclosure provides 1 but [ka] where: [ka] provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, indicating the point of attachment to the parent molecular moiety.

[0031] In certain aspects, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R' is fluoro.

[0032] In certain aspects, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R' is chloro.

[0033] In some aspects, the present disclosure provides a method for treating a cancer cell comprising: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0034] In some aspects, the present disclosure provides: (Z)-1-((3S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((3S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-((3S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(5-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(6-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)—N-((1S,3s)-3-(((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)amino)cyclobutyl)-2-fluoro-3-(thiazol-2-yl)acrylamide; (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-9-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.2.0]heptan-6-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one (isomer 1); (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.2.0]heptan-6-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one (isomer 2); (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,7-diazabicyclo[4.2.0]octan-7-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((3aR,4S,7R,7aS)-8-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-2H-4,7-epiminoisoindol-2-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)—N-((1R,4R)-2-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-yl)-2-fluoro-3-(thiazol-2-yl)acrylamide; (Z)-1-((2S,5R)-4-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (2Z)-1-{3-[6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl}-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one (isomer 1); (2Z)-1-{3-[6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl}-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one (isomer 2); (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; 2-((S)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)-4-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)-4-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; (Z)-1-(4-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one (isomer 1); (Z)-1-(4-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one (isomer 2); (Z)-1-(5-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one (isomer 1); (Z)-1-(5-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one (isomer 2); (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (S,Z)-2-fluoro-1-(4-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one; (S,Z)-2-fluoro-1-(4-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; 2-((S)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)-4-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; (S,Z)-2-fluoro-1-(4-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)-3-(pyrimidin-2-yl)prop-2-en-1-one; 2-((S)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(6-methylpyridin-2-yl)acryloyl)-4-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(6-methylpyridin-2-yl)prop-2-en-1-one; 2-((S)-1-((Z)-2-fluoro-3-(6-methylpyridin-2-yl)acryloyl)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (2Z)-N-[(1S,4S)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-4-yl]-2-fluoro-3-(pyridin-2-yl)prop-2-enamide; (2Z)—N-({1-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]piperidin-4-yl}methyl)-2-fluoro-3-(pyridin-2-yl)prop-2-enamide; (2Z)-N-[(1R,4R,7R)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-7-yl]-2-fluoro-3-(pyridin-2-yl)prop-2-enamide 2-[(2S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-1-[(2Z)-2-fluoro-3-(thiazol-2-yl)prop-2-enoyl]piperazin-2-yl]acetonitrile 2-[(2S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-1-[(2Z)-2-fluoro-3-(thiazol-2-yl)prop-2-enoyl]piperazin-2-yl]acetamide (2Z)-N-[(1S,4S)-2-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-4-yl]-2-fluoro-3-(thiazol-2-yl)prop-2-enamide; (2Z)-N-[(1R,4R,7R)-2-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-7-yl]-2-fluoro-3-(1,3-thiazol-2-yl)prop-2-enamide; 2-((2S)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)-4-(8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)-4-(8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)-4-(8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)-4-(8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyridazin-2-yl)acryloyl)-4-(8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyridazin-2-yl)acryloyl)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrazin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(piperazin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrazin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (Z)—N-((1S,4S)-2-(7M-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-yl)-2-fluoro-3-(thiazol-2-yl)acrylamide; (Z)-1-((1R,6S)-3-(7M-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonan-9-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((1R,6S)-3-(7M-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonan-9-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (S,Z)-2-(4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(3-methoxypropyl)piperidin-4-yl)oxy)quinazolin-4-yl)-1-(2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (S,Z)-2-(4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(3-methoxypropyl)piperidin-4-yl)oxy)quinazolin-4-yl)-1-(2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 8-(4-((S)-3-(cyanomethyl)-4-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-naphthonitrile; 8-(4-((S)-3-(cyanomethyl)-4-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-1-naphthonitrile; (Z)-1-((1R,5S)-3-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((3R)-3-((7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((3R)-3-((7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrazin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (Z)-1-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; and (Z)-1-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the present disclosure provides atropisomers of the compounds of any of the previous embodiments. In certain embodiments, the compounds are stable atropisomers as described herein.

[0036] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of any of the previous aspects, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0037] In some aspects, the present disclosure provides an oral dosage form comprising a compound of any of the previous aspects, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0038] In some aspects, the present disclosure provides a method of treating a cancer expressing a KRAS G12C, G12D and / or G12V mutation in a subject in need thereof, the method comprising administering to the subject a compound of any of the previous aspects, or a pharmaceutically acceptable salt thereof.

[0039] 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 of the previous aspects, or a pharmaceutically acceptable salt thereof.

[0040] In some aspects, the present disclosure provides a method of treating a cancer sensitive to KRAS G12C inhibition in a subject in need thereof, comprising administering to the subject a compound of any of the previous aspects, or a pharmaceutically acceptable salt thereof.

[0041] In some aspects, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a compound of any of the previous aspects, or a pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, colon cancer, pancreatic cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, gastric cancer, or uterine cancer.

[0042] In some aspects, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a compound of any of the previous aspects, or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer.

[0043] In some embodiments of the method, the compound is an atropisomer of the compound of any of the previous embodiments. In certain embodiments, the compound is a stable atropisomer as described herein.

[0044] In another aspect, the present disclosure provides a method for inhibiting KRAS G12C activity in a cell, comprising contacting the cell with a therapeutically effective amount of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one aspect, the contacting is in vitro. In one aspect, the contacting is in vivo.

[0045] In some aspects, the present disclosure provides a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with a therapeutically effective amount of a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0046] In another aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in inhibiting KRAS G12C.

[0047] In another aspect, the present disclosure provides a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a KRAS G12C-associated disease or disorder.

[0048] In another aspect, the disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein in the manufacture of a medicament for the treatment of cancer. In some aspects, the cancer is lung cancer. In some aspects, the cancer is non-small cell lung cancer.

[0049] In another aspect, the disclosure provides the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of the activity of KRAS G12C.

[0050] In another aspect, the present disclosure provides the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a KRAS G12C-associated disease or disorder. DETAILED DESCRIPTION OF THE INVENTION

[0051] Unless otherwise specified, any atom with unsatisfied valences is assumed to have enough hydrogen atoms to satisfy the valences.

[0052] The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise.

[0053] As used herein, the term "or" is a logical or (i.e., and / or) and does not indicate an exclusive or unless expressly indicated by words such as "either," "otherwise," "alternatively," and words of similar effect.

[0054] As used herein, the phrase "or a pharmaceutically acceptable salt thereof" refers to at least one compound or at least one salt of a compound, or a combination thereof. For example, "a compound of Formula (I) or a pharmaceutically acceptable salt thereof" includes, but is not limited to, a compound of Formula (I), two compounds of Formula (I), a pharmaceutically acceptable salt of a compound of Formula (I), a compound of Formula (I) and one or more pharmaceutically acceptable salts of a compound of Formula (I), and two or more pharmaceutically acceptable salts of a compound of Formula (I).

[0055] The term "C2-C4 alkenyl," as used herein, refers to a group derived from a straight or branched chain hydrocarbon containing from 2 to 4 carbon atoms and one double bond.

[0056] The term "C1-C3 alkoxy," as used herein, refers to a C1-C3 alkyl group attached to the parent molecular moiety through an oxygen atom.

[0057] The term "C1-C6 alkoxy," as used herein, refers to a C1-C6 alkyl group attached to the parent molecular moiety through an oxygen atom.

[0058] The term "C1-C3 alkoxy C1-C3 alkyl," as used herein, refers to a C1-C3 alkoxy group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0059] The term "C1-C6 alkoxy C1-C6 alkyl," as used herein, refers to a C1-C6 alkoxy group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0060] 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.

[0061] The term "C1-C3 alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 3 carbon atoms.

[0062] The term "C1-C6 alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 6 carbon atoms.

[0063] The term "(C1-C6 alkyl)amino" as used herein refers to R-NH, where R is a C1-C6 alkyl group.

[0064] The term "(C1-C6 alkyl)amino C1-C3 alkyl," as used herein, refers to a (C1-C6 alkyl)amino group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0065] 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.

[0066] The term "C2-C4 alkynyl," as used herein, refers to a group derived from a straight or branched chain hydrocarbon containing from 2 to 4 carbon atoms and one triple bond.

[0067] The term "amide" as used herein refers to NHC(O)-.

[0068] The term "amido C1-C3 alkyl," as used herein, refers to an amide group attached to the parent molecular group through a C1-C3 alkyl group.

[0069] The term "amino," as used herein, refers to --NH.sub.2.

[0070] 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.

[0071] The term "aryl," as used herein, refers to a phenyl group or a bicyclic fused ring system in which one or both of the rings is a phenyl group. A bicyclic fused ring system consists of a phenyl group fused to a 4- to 6-membered aromatic or non-aromatic carbocyclic ring. The aryl groups of the present disclosure can be attached to the parent molecular moiety through any substitutable carbon atom of the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.

[0072] The term "aryl C1-C6 alkyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0073] The term "carboxy" as used herein refers to -CO2H.

[0074] The term "carboxy C1-C6 alkyl," as used herein, refers to a C1-C6 alkyl group substituted with one, two, or three carboxy groups.

[0075] The term "cyano," as used herein, refers to --CN.

[0076] The term "cyano C1-C3 alkyl," as used herein, refers to a C1-C3 alkyl group substituted with one, two, or three cyano atoms.

[0077] The term "C3-C4 cycloalkyl," as used herein, refers to a saturated monocyclic hydrocarbon ring system having 3 or 4 carbon atoms and 0 heteroatoms.

[0078] The term "C3-C6 cycloalkyl," as used herein, refers to a saturated monocyclic hydrocarbon ring system having from 3 to 6 carbon atoms and 0 heteroatoms.

[0079] The term "C3-C6 cycloalkyl C1-C6 alkyl," as used herein, refers to a C3-C6 cycloalkyl attached to the parent molecular moiety through a C1-C6 alkyl group.

[0080] The term "di(C1-C6 alkyl)amino" as used herein refers to -NR z R z’ (where R z and R z’ are the same or different C1-C6 alkyl groups).

[0081] The term "di(C1-C3 alkyl)aminoC2-C6 alkyl" as used herein means -(C2-C6 alkyl)NR z R z’ (where R z and R z’ are the same or different C1-C6 alkyl groups).

[0082] The terms "halo" and "halogen" as used herein refer to F, Cl, Br, or I.

[0083] The term "haloC1-C3 alkoxy," as used herein, refers to a C1-C3 alkoxy group substituted with one, two, or three halogen atoms.

[0084] The term "haloC1-C3 alkyl," as used herein, refers to a C1-C3 alkyl group substituted with one, two, or three halogen atoms.

[0085] The term "haloC1-C6 alkyl," as used herein, refers to a C1-C6 alkyl group substituted with one to six halogen atoms.

[0086] The term "heteroaryl," as used herein, refers to an aromatic 5- or 6-membered ring in which at least one atom is selected from N, O, and S, and the remaining atoms are carbon. The term "heteroaryl" also includes bicyclic systems in which a heteroaryl ring is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S; and tricyclic systems in which a bicyclic system is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S. A heteroaryl group is attached to the parent molecular moiety 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']bisthiazole, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.

[0087] The term "heteroaryl C1-C6 alkyl," as used herein, refers to a heteroaryl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0088] The term "heterocyclyl," as used herein, refers to a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-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 a heterocyclyl ring is fused to one, two, or three 4- to 6-membered aromatic or non-aromatic carbocyclic rings or monocyclic heterocyclyl groups. The term "heterocyclyl" also includes monocyclic or polycyclic heterocyclyl groups as described above that are further substituted with one or more spirocyclic groups attached to the heterocyclyl group via a spirocarbon. Examples of heterocyclyl groups include, but are not limited to, dihydro-1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolidine-6',1''-cyclopropane], hexahydro-2H-1,4-dioxa-2a1-azacyclopenta[cd]pentalenyl, hexahydropyrrolidinyl, indolinyl, morpholinyl, octahydroindolizinyl, octahydroquinolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thiomorpholinyl.

[0089] The term "heterocyclylC1-C6 alkyl," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0090] The term "hydroxy," as used herein, refers to --OH.

[0091] 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.

[0092] The term "hydroxy C1-C6 alkyl," as used herein, refers to a hydroxy group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0093] "NR a R bThe term "-C(O)", as used herein, refers to an NR attached to the parent molecular moiety through a carbonyl group. a R b Refers to the base.

[0094] "NR a R b The term "-C(O)-C1-C6 alkyl," as used herein, refers to an NR2 linked to the parent molecular moiety through a C1-C6 alkyl group. a R b refers to the —C(O)— group.

[0095] "NR a R b The term "C1-C6 alkyl," as used herein, refers to an NR2 group attached to the parent molecular moiety through a C1-C6 alkyl group. a R b Refers to the base.

[0096] The term "nitro," as used herein, refers to --NO.sub.2.

[0097] The term "oxo" as used herein refers to =O.

[0098] The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described herein, substituting an appropriate isotopically labeled reagent for the unlabeled reagent originally used. Such compounds may have a variety of potential uses, for example, 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.

[0099] A further aspect of the subject matter described herein is the use of the disclosed compounds as radiolabeled ligands for the development of 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 forms by catalytic tritiation using methods known to those skilled in the art.

[0100] Certain compounds of the present disclosure exist as stereoisomers. When stereochemistry is not specified, it should be understood that the present disclosure encompasses all stereochemically isomeric forms or mixtures thereof that have the ability to inhibit KRAS G12C. Individual stereoisomers of a compound can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products and then separating them, for example, by converting them into a diastereomeric mixture, followed by separation or recrystallization, or by directly separating enantiomers using chromatographic methods or chiral chromatography columns. Starting compounds of a specific stereochemistry are commercially available, or can be prepared and resolved by techniques known in the art.

[0101] 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 significantly retarded as a result of steric interactions with other parts of the molecule, and the substituents on both ends of the single bond are asymmetric (i.e., optical activity occurs without the need for an asymmetric carbon center or stereocenter). If the rotation barrier around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of isomeric species may be possible. Atropisomers are enantiomers (or epimers) that do not have a single asymmetric atom.

[0102] Atropisomers can be considered stable if the barrier to interconversion is high enough to allow the atropisomers to undergo little or no interconversion at room temperature for at least one week. In some embodiments, the atropisomers undergo little or no interconversion at room temperature for at least one year. In some embodiments, the atropisomer compounds of the present disclosure do not undergo more than about 5% interconversion to their opposite atropisomers at room temperature for one week when the atropisomer compounds are in substantially pure form, typically in the solid state. In some embodiments, the atropisomer compounds of the present disclosure do not undergo more than about 5% interconversion to their opposite atropisomers at room temperature (about 25°C) for one year. In some embodiments, the atropisomer compounds of the present disclosure are sufficiently stable to undergo no more than about 5% interconversion in aqueous pharmaceutical formulations held at 0°C for at least one week. The present chemical compounds, pharmaceutical compositions and methods are intended to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of single atropisomers and intermediate mixtures.

[0103] The energy barrier to thermal racemization of atropisomers can be determined by steric hindrance to free rotation of one or more bonds forming the chiral axis. Certain biaryl compounds exhibit atropisomerism when rotation around an intercyclic bond lacking C2 symmetry is restricted. The free energy barrier to isomerization (enantiomerization) is a measure of the stability of the intercyclic bond against rotation. Optical and thermal excitation can promote the racemization of such isomers, depending on electronic and steric factors.

[0104] Ortho-substituted biaryl compounds may exhibit this type of conformational rotational isomerism. Such biaryls are enantiomeric chiral atropisomers, with sp between the aryl rings. 2 -sp 2 The carbon-carbon intercyclic bond has a sufficiently high energy barrier to prevent free rotation, and the substituent W 1 ≠W 2 and W 3 ≠W 4makes the molecule asymmetric. [ka]

[0105] W 1 :W 3 , W 1 :W 4 and / or W 2 :W 4 , W 2 :W 3 The steric interactions between the two are large enough to make the planar conformation the energy maximum. Two nonplanar, axially chiral enantiomers then exist as atropisomers if their interconversion is slow enough so that they can be isolated without each other. The bold and dashed lines in the diagram shown above indicate moieties or portions of molecules that are sterically restricted due to rotational energy barriers. The bolded portions lie perpendicularly above the plane of the paper, and the dashed portions lie perpendicularly below the plane of the paper. The "planar" portions of the molecules (the left rings of each of the two biaryls shown) lie in the plane of the paper.

[0106] The pharmaceutical compounds of the present disclosure may include one or more pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see, for example, Berge, SM et al., J. Pharm. Sci., 66:1-19 (1977)). Salts can be obtained during the final isolation and purification of the compounds described herein, or by separately reacting a free base functional group of the compound with a suitable acid or by reacting an acidic group of the compound with a suitable base. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like, as well as non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium, and such non-toxic organic amines as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like.

[0107] Pharmaceutical Composition In another aspect, the present disclosure provides compositions, e.g., pharmaceutical compositions, containing one or a combination of compounds described within this disclosure formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present disclosure can also be administered in combination therapy, i.e., in combination with other agents described herein.

[0108] As used herein, "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. In some embodiments, 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.

[0109] The pharmaceutical compositions of the present disclosure can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by those skilled in the art, the route and / or mode of administration will vary depending on the desired results. In some embodiments, the route of administration of the compounds of the present disclosure includes intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral routes of administration, for example, by injection or infusion. The term "parenteral administration," as used herein, refers to a mode of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0110] Sterile injectable solution can be prepared by incorporating the required amount of active compound into suitable solvent with one or combination of the above-listed components as needed, and then sterilizing by microfiltration.Generally, dispersion is prepared by incorporating active compound into sterile vehicle that contains basic dispersion medium and other components required from above-listed.For the preparation of sterile injectable solution, some preparation methods are vacuum drying and freeze-drying (lyophilization), thereby obtaining the powder of active ingredient and any additional desired components from its solution that has been previously sterilized and filtered.

[0111] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils, and injectable organic esters. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0112] 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 agents for pharmaceutically active substances is well known in the art.Except insofar as any conventional media or agent is incompatible with the active compound, its use in the pharmaceutical compositions of the present disclosure is contemplated.Auxiliary active compounds can also be incorporated into the composition.

[0113] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The compositions can be formulated as a solution or liquid with an ordered structure suitable for high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In many cases, it is desirable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0114] Alternatively, the compounds of the present disclosure can be administered parenterally, including topical, epidermal, or mucosal routes of administration, such as intranasally, orally, intravaginally, rectally, sublingually, or topically.

[0115] Any pharmaceutical composition contemplated herein can be orally delivered, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable formulation, pharmaceutical compositions according to the present disclosure can contain at least one agent selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0116] 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 that is suitable for the manufacture of tablets.

[0117] Aqueous suspensions, for example, comprise at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in a suspension containing, for example, a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum arabic; a dispersing or wetting agent, such as a naturally occurring phosphatide, for example, lecithin; a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; a condensation product of an alkylene oxide with a long-chain aliphatic alcohol, for example, a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum arabic; a dispersing or wetting agent, such as a naturally occurring phosphatide, for example, lecithin; a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; a condensation product of an alkylene oxide with a long-chain aliphatic alcohol, for example, a condensation product of an alkylene oxide with a long-chain aliphatic alcohol, for example, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; ... a condensation product of an alkylene oxide with a The aqueous suspension may be prepared by mixing the aqueous suspension with at least one excipient suitable for the preparation of an aqueous suspension, including, but not limited to, condensation products of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as, for example, heptadecathylene-oxycetanol; condensation products of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as, for example, polyoxyethylene sorbitol monooleate; condensation products of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as, for example, polyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative, such as, for example, ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, including, but not limited to, sucrose, saccharin, and aspartame.

[0118] Oily suspensions can be prepared, for example, by suspending at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in a vegetable oil, such as peanut oil, sesame oil, and coconut oil; or a mineral oil, such as liquid paraffin. Oily suspensions can also contain at least one thickening agent, such as beeswax, hard paraffin, and cetyl alcohol. To provide a palatable oily suspension, at least one sweetener and / or at least one flavoring agent described herein above can be added to the oily suspension. Oily suspensions can further contain at least one preservative, including, but not limited to, an antioxidant, such as butylated hydroxyanisole and alpha-tocopherol.

[0119] 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 dispersing agent and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents have already been described above. Exemplary preservatives include, but are not limited to, antioxidants, such as ascorbic acid. Furthermore, dispersible powders and granules can contain at least one excipient, including, but not limited to, sweeteners, flavoring agents, and coloring agents.

[0120] Active compounds can be prepared using carriers that protect the compound from rapid release, such as controlled release formulations, 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.For example, see Robinson, JR, ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0121] Therapeutic compositions can be administered using medical devices known in the art. For example, in one embodiment, the therapeutic compositions of the present disclosure can be administered using needleless hypodermic injection devices, such as those disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824 or 4,596,556. Examples of well-known implants and modules useful in the present disclosure include U.S. 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 rate implantable infusion device for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system with multi-chamber compartments; 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.

[0122] In certain aspects, the compounds of the present 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, subcuticular, intraarticular, subcapsular, intrathecal, intraspinal, epidural, and intrasternal injection and / or infusion.

[0123] In some aspects, the compounds of the present disclosure can be administered orally, i.e., via gelatin capsules, tablets, hard or soft capsules, or liquid capsules.

[0124] KRAS inhibitor use / treatment methods Administration of a therapeutic agent described herein can include administration of a therapeutically effective amount of the therapeutic agent. The term "therapeutically effective amount," as used herein, refers to, but is not limited to, the amount of a therapeutic agent to treat a condition treatable by administration of a composition comprising a KRAS inhibitor described herein. This amount is sufficient to produce a detectable therapeutic effect or an effect that leads to improvement. The effect can include, by way of example and without limitation, treatment of the conditions listed herein. The precise effective amount for a given subject will depend on the subject's size and health, the nature and extent of the condition being treated, the advice of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration.

[0125] For administration of the compounds described herein, dosages range from about 0.0001 to 100 mg / kg, and more usually 0.01 to 40 mg / kg, of the host body weight. Exemplary treatment regimens entail administration once daily, twice weekly, three times weekly, once every week, once every two weeks, once every three weeks, once every four weeks, once every month, once every three months, or once every three to six months.

[0126] The disclosed compounds potently inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, in another aspect, the present disclosure provides a method for inhibiting tumor metastasis, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of any of the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0127] Ras mutations, including but not limited to KRAS mutations, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to the administration of the disclosed compounds (e.g., in the form of pharmaceutical compositions) to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the disclosed compounds can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, the compounds are useful for treating lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0128] Determining whether a tumor or cancer contains a KRAS mutation can be done 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.

[0129] 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) assay, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting assay, and microarray analysis. In some embodiments, samples are evaluated for KRAS mutations, including by real-time PCR. In real-time PCR, a fluorescent probe specific to the KRAS mutation is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRAS mutations are identified using, for example, direct sequencing of a specific region (e.g., exon 2 and / or exon 3) in the KRAS gene. This technique will identify all possible mutations in the sequenced region.

[0130] Methods for detecting mutations in KRAS protein 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 to mutant proteins, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0131] The method for determining whether a tumor or cancer contains a KRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is taken from a subject with a cancer or tumor. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, 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 embodiments, the methods include the treatment of acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, osteosarcoma, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder (CMD), and / or pulmonary arterial leukemia (PAL). Colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), germinoma, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, Lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell neck cancer of occult primary, midline duct cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, nipple The present invention relates to the treatment of cancers such as ovarian tumors, 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, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, childhood anomaly cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some embodiments, the method relates to the treatment of non-cancerous hyperproliferative diseases such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)).

[0132] In certain aspects, the present disclosure relates to a method for treating lung cancer, comprising administering an effective amount of any of the above-mentioned compounds (or a pharmaceutical composition comprising same) to a subject in need thereof. In certain 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 that can be treated with the disclosed compounds include, but are not limited to, ductal tumors, carcinoid tumors, and undifferentiated carcinomas.Subjects that can be treated with the compounds of the present disclosure or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates, or derivatives of said compounds according to the methods of the present disclosure include, for example, acute myeloid leukemia, acute myeloid leukemia, adolescent cancer, pediatric adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, osteosarcoma, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary thyroid cancer, ... Lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), germinoma, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer , Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell neck cancer of unknown primary, midline duct cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral and subjects diagnosed with cancer of the rectum, lip and oral cavity, 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, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, childhood anomalies, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some embodiments, subjects treated with compounds of the present disclosure include those diagnosed with a non-cancerous hyperproliferative disease, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)). The present disclosure further provides methods of modulating the activity of a mutant KRAS protein by contacting the protein with an effective amount of a compound of the present disclosure. Modulation can be inhibiting or activating protein activity. In some embodiments, the present disclosure provides methods of inhibiting protein activity by contacting a mutant KRAS protein in solution with an effective amount of a compound of the present disclosure. In some embodiments, the present disclosure provides methods of inhibiting the activity of a mutant KRAS protein by contacting a cell, tissue, or organ expressing the protein of interest. In some embodiments, the present disclosure provides methods of inhibiting the activity of a protein in a subject, including, but not limited to, a rodent and a mammal (e.g., a human), by administering to the subject an effective amount of a compound of the present disclosure. In some embodiments, the percentage of modulation is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the present disclosure provides methods of inhibiting KRAS activity in a cell by contacting the cell with a compound of the present disclosure in an amount sufficient to inhibit the activity of a mutant KRAS in the cell. In some embodiments, the present disclosure provides methods of inhibiting mutant KRAS in a tissue by contacting the tissue with a compound of the present disclosure in an amount sufficient to inhibit the activity of mutant KRAS in the tissue. In some embodiments, the present disclosure provides methods of inhibiting KRAS in an organism by contacting the organism with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the organism. In some aspects, the present disclosure provides methods of inhibiting the activity of KRAS in an animal by contacting the animal with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the animal.In some embodiments, the present disclosure provides methods for inhibiting KRAS, including in a mammal, by contacting the mammal with a compound of the present disclosure in an amount sufficient to inhibit KRAS activity in the mammal. In some embodiments, the present disclosure provides methods for inhibiting KRAS activity in a human by contacting the human with a compound of the present disclosure in an amount sufficient to inhibit KRAS activity in the human. The present disclosure also provides methods for treating diseases mediated by KRAS activity in a subject 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 overlapping sets of target enzymes, are used in combination with a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate, or derivative thereof. In one embodiment, 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.

[0133] 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 antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0134] The compounds described herein can be used in combination with the drugs disclosed herein or other suitable drugs, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure will be co-administered with the other drugs described above. When used in combination therapy, the compounds described herein are administered simultaneously with the second drug or separately. This combined administration can include simultaneous administration of the two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the drugs described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds disclosed herein and any of the drugs described above can be administered simultaneously, with both drugs being in separate formulations. In another alternative, the compounds disclosed herein can be administered followed by any of the drugs described above, or vice versa. In some embodiments of the separate administration protocol, the compounds disclosed herein and any of the drugs described above are administered within minutes, hours, or days.

[0135] The compounds can be made by methods known in the art, including those described below, and including variations within the skill of one in the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. Any variables used to describe the synthesis of the compounds (e.g., numbered "R" substituents) are intended only to illustrate how the compounds are made and should not be confused with variables used in the claims or other sections of this specification. The following methods are for illustrative purposes and are not intended to limit the scope of this disclosure. [Example]

[0136] synthesis The embodiments described herein are further defined in the following examples. It should be understood that the examples are provided by way of illustration only. From the above discussion and examples, those skilled in the art can ascertain the essential features of the embodiments described herein, and can make various changes and modifications to adapt them to various uses and conditions without departing from the spirit and scope thereof. Consequently, the embodiments described herein are not limited by the illustrative examples set forth below, but rather are defined by the claims appended hereto.

[0137] Abbreviation The following abbreviations are used in the Examples section below and elsewhere in this specification: AA is ammonium acetate; ACN is acetonitrile; Boc or Boc is tert-butoxycarbonyl; Cbz is carbobenzyloxy; DCM is dichloromethane; DEA is diethylamine; DIPEA or DIEA is diisopropylethylamine; DMA is dimethylacetamide; DMF is N,N-dimethylformamide; DMSO is dimethylsulfoxide; dppf is 1,1'-bis(diphenylphosphino)ferrocene; Et is ethyl; EtOAc is ethyl acetate; EtOH is ethanol; h is hour; HDMS is hexamethoxy IPA is isopropyl alcohol; min is minute; LiHDMS is lithium hexamethyldisilazide; MOM is methoxymethyl; Me is methyl; MeCN or ACN is acetonitrile; MeOH is methanol; NIS is N-iodosuccinimide; OAc is acetate; Ph is phenyl; PMB is paramethoxybenzyl; RT or rt is room temperature or retention time (as indicated by context); ToS is tosyl; TBAF is tetrabutylammonium fluoride; TEA or EtN is trimethylamine; TES-H is triethylsilane; TFA is trifluoroacetic acid; and THF is tetrahydrofuran. [ka] 6-chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline [ka]

[0138] Step 1: tert-butyl (3S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate tert-Butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (U.S. Pat. No. 11,236,068, 46 mg, 0.08 mmol), 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (35 mg, 0.12 mmol), sodium carbonate (43 mg, 0.4 mmol), and tetrakistriphenylphosphinepalladium(0) (9 mg, 0.008 mmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (0.9 mL) and water (0.3 mL) were added, and the reaction mixture was heated at 100° C. overnight. The reaction mixture was concentrated and the crude residue was directly purified by column chromatography (0→100% EtOAc / hexanes) to give the desired product (33 mg, 0.05 mmol, 63% yield). LC / MS (ESI) m / z: [M+H] + C 34 H 39 Cl2FN5O3 calculated 654.2; found 654.2.

[0139] Step 2: 6-chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline tert-Butyl (3S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (from Step 1, 33 mg, 0.050 mmol) was dissolved in DCM (0.5 mL) and TFA (0.2 mL). The reaction mixture was stirred at room temperature for 15 minutes, at which point LC / MS analysis indicated complete conversion to the desired mass of product. The reaction mixture was concentrated directly and used in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 29 H 31 Calculated for Cl2FN5O3 554.2; found 554.1. [ka] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka]

[0140] Step 1: tert-butyl (1R,5S)-3-(6-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (prepared according to the procedure described in WO 2022 / 002102, 0.25 g, 0.43 mmol), ((2-fluoro)-2-(2-fluoro-4-methyl-2-pyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in dioxane (12 mL) and water (4 mL). A suspension of 6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (prepared according to the procedure described in WO 2021 / 041671, 0.26 g, 0.51 mmol) and sodium carbonate (0.11 g, 1.1 mmol) was degassed by bubbling nitrogen gas through it for 15 minutes. 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.03 g, 0.04 mmol) was added, and the red suspension was heated at 100 °C for 24 hours. The dark suspension was diluted with EtOAc (20 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→10% MeOH / DCM) to give the desired product (110 mg, 0.12 mmol, 29% yield). LC / MS (ESI) m / z: [M+H] + C 48 H 63 Calculated value for ClF2N5O5Si: 890.4; Found: 890.5.

[0141] Step 2: tert-butyl (1R,5S)-3-(6-chloro-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(6-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (from Step 1, 135 mg, 0.152 mmol) was dissolved in DMF (2 mL) and solid CsF (69 mg, 0.46 mmol) was added. The reaction mixture was heated at 60° C. for 30 min. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 mL) and water (10 mL). The layers were separated and the organic phase was further washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was pure enough to be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 39 H 43 Calculated for ClF2N5O5 734.3; Found 734.3.

[0142] Step 3: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol tert-Butyl (1R,5S)-3-(6-chloro-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (from Step 2, 80 mg, 0.11 mmol) was dissolved in dioxane (0.5 mL) and HCl solution (4.0 M in dioxane, 1 mL, 4.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was directly concentrated and the crude residue was purified by column chromatography (0→15% MeOH / DCM) to give the desired product as the HCl salt (60 mg, 0.095 mmol, 88% yield). LC / MS (ESI) m / z: [M+H]+ C 32 H 31 Calculated for ClF2N5O5 590.2; found 590.4. [ka] (S)-4-(8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)naphthalen-2-ol [ka]

[0143] Step 1: tert-butyl 4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate 7-Bromo-2,4-dichloro-8-fluoroquinazoline (250 mg, 0.85 mmol) was dissolved in dioxane (15 mL) and DIPEA (0.44 mL, 2.5 mmol) was added, followed by tert-butyl piperazine-1-carboxylate (160 mg, 0.85 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (20 mL) and quenched by the addition of NaOH solution (1.0 M, 2 mL). The layers were separated and the organic phase was washed with brine (10 mL). The combined aqueous layers were back-extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (5 → 45% EtOAc / hexanes) to give the desired product (230 mg, 0.52 mmol, 61% yield) as a white solid. LC / MS(ESI)m / z:[M+H] + C 17 H 20 Calculated for BrClFN4O2 445.0; found 444.8. NMR: 1 H NMR (500MHz, CD3OD) δ 7.80(dd,J=9.1,1.6Hz,1H),7.68(dd,J=9.1,6.5Hz,1H),3.99-3.93(m,4H),3.69-3.63(m,4H),1.49(s,9H).

[0144] Step 2: tert-butyl (S)-4-(7-bromo-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (from Step 1, 250 mg, 0.56 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (194 mg, 1.68 mmol) were suspended in THF (4 mL). A LiHMDS solution (1.0 M in THF, 0.62 mL, 0.62 mmol) was added dropwise, and the reaction mixture was heated at 65° C. for 3 h. The mixture was diluted with EtOAc (20 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→8% MeOH / DCM) to give the desired product (120 mg, 0.23 mmol, 41% yield) as a white solid. LC / MS(ESI)m / z:[M+H] + C 23 H 32 Calculated for BrFN5O3: 524.2; Found: 524.1. NMR: 1 H NMR(500MHz,CD3OD)δ 7.70(dd,J=9.1,1.5Hz,1H),7.47(dd,J=9.1,6.4Hz,1H),4.50(br dd,J=11.0,5.8Hz,1H),4.44(dd,J=11.0,5.6Hz,1H),3.90-3.84(m,4H),3.69-3.61(m,4H),3.14-3.06(m,1H),2.85 -2.78(m,1H),2.53(s,3H),2.42-2.34(m,1H),2.17-2.07(m,1H),1.88-1.80(m,2H),1.80-1.73(m,1H),1.49(s,9H).

[0145] Step 3: tert-butyl (S)-4-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate tert-Butyl (S)-4-(7-bromo-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (from Step 2, 120 mg, 0.23 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (72 mg, 0.23 mmol), and potassium phosphate tribasic solution (2.0 M, 0.34 mL, 0.67 mmol) were dissolved in dioxane (2 mL). The solution was purged with a stream of nitrogen for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (7.5 mg, 0.01 mmol) was added, and the resulting solution was heated at 100 °C for 24 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→6% MeOH / DCM) to give the desired product (120 mg, 0.19 mmol, 83% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 35 H 43 Calculated for FN5O5 632.3; Found 632.2. NMR: 1 H NMR(500MHz,CD3OD)δ 7.91(d,J=8.6Hz,1H),7.86(d,J=8.3Hz,1H),7.55(d,J=2.4Hz,1H),7.52-7.45(m,2H),7.35- 7.29(m,2H),7.25(d,J=2.5Hz,1H),5.36(s,2H),4.57-4.51(m,1H),4.50-4.43(m,1H),4.00- 3.91(m,4H),3.75-3.67(m,4H),3.53(s,3H),3.14-3.09(m,1H),2.88-2.79(m,1H),2.55(s,3 H),2.42-2.35(m,1H),2.18-2.09(m,1H),1.90-1.81(m,2H),1.80-1.75(m,1H),1.51(s,9H).

[0146] Step 4: (S)-4-(8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)naphthalen-2-ol tert-Butyl (S)-4-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (from Step 3, 120 mg, 0.19 mmol) was suspended in HCl solution (4.0 M in dioxane, 2 mL, 8.0 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated and azeotroped from DCM (3 x 5 mL). The crude residue was further dried under high vacuum to give the desired product as its HCl salt (assuming quantitative yield). The crude material was pure enough to be used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 28 H 31 Calculated FN5O2 488.2; measured 488.1. [ka] 2-((S)-4-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0147] Step 1: Benzyl (S)-4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate 7-Bromo-2,4-dichloro-8-fluoroquinazoline (500 mg, 1.7 mmol) was dissolved in dioxane (15 mL) and DIPEA (0.89 mL, 5.1 mmol) was added, followed by benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylate (440 mg, 1.7 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (20 mL) and quenched by the addition of NaOH solution (1.0 M, 2 mL). The layers were separated and the organic phase was washed with brine (10 mL). The combined aqueous layers were back-extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (5 → 50% EtOAc / hexanes) to give the desired product (760 mg, 1.5 mmol, 87% yield) as a white solid. LC / MS(ESI)m / z:[M+H] + C 22 H 19 Calculated for BrClFN5O2 518.0; Found 517.9. NMR: 1 H NMR(500MHz, CD3OD)δ 7.80(dd,J=9.1,1.5Hz,1H),7.68(dd,J=9.1,6.5Hz,1H),7.45-7.28(m,5H),5.24-5.12(m,2H),4.79-4.71(m,1H), 4.50-4.34(m,2H),4.14-4.08(m,1H),3.81-3.70(m,1H),3.69-3.61(m,1H),3.59-3.46(m,1H),3.04-2.88(m,2H).

[0148] Step 2: Benzyl (S)-4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (from Step 1, 150 mg, 0.29 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (100 mg, 0.87 mmol) were suspended in THF (8 mL). A LiHMDS solution (1.0 M in THF, 0.32 mL, 0.32 mmol) was added dropwise, and the reaction mixture was heated at 65° C. for 5 h. The mixture was diluted with EtOAc (20 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→8% MeOH / DCM) to give the desired product (139 mg, 0.23 mmol, 80% yield) as a white solid. LC / MS(ESI)m / z:[M+H]+C 28 H 31 Calculated for BrFN6O3: 597.2; found: 59.0. 1H NMR (500 MHz, CD3OD) δ 7.72 (dd, J = 9.1, 1.4 Hz, 1H), 7.48 (dd, J = 9.0, 6.4 Hz, 1H), 7.42-7.29 (m, 5H), 5.25-5.14 (m, 2H), 4.79-4.72 (m, 1H), 4.50 (br dd,J=11.0,6.0Hz,1H),4.45(dd,J=11.0,5.2Hz,1H),4.39-4.28(m,2H),4.15-4.08(m,1H),3.73-3.67(m,1H),3.54-3.49(m,1H),3.14-3. 09(m,1H),3.04-2.90(m,2H),2.86-2.79(m,1H),2.54(s,3H),2.41-2 .36(m,1H),2.16-2.07(m,1H),1.89-1.81(m,2H),1.80-1.73(m,1H).

[0149] Step 3: Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (from Step 2, 320 mg, 0.536 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (168 mg, 0.54 mmol), and potassium phosphate tribasic solution (2.0 M, 0.80 mL, 1.6 mmol) were dissolved in dioxane (5 mL). The solution was purged with a stream of nitrogen for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (17 mg, 0.03 mmol) was added, and the resulting solution was heated at 100 °C for 3 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→6% MeOH / DCM) to give the desired product (243 mg, 0.34 mmol, 64% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 40 H 42 Calculated for FN6O5 705.3; Found 705.3. NMR: 1 H NMR(500MHz,CD3OD)δ 7.93(d,J=8.8Hz,1H),7.86(d,J=8.1Hz,1H),7.55(d,J=2.3Hz,1H),7.53-7.45(m,2H),7.43-7.29 (m,7H),7.25(d,J=2.5Hz,1H),5.36(s,2H),5.27-5.16(m,2H),4.56-4.50(m,1H),4.49-4.37(m,3 H),4.20-4.14(m,1H),3.80(s,1H),3.61-3.55(m,1H),3.53(s,3H),3.12-2.95(m,3H),2.85-2.78 (m,1H),2.53(s,3H),2.40-2.32(m,1H),2.15-2.08(m,1H),1.88-1.80(m,2H),1.79-1.74(m,1H).

[0150] Step 4: 2-((S)-4-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (from Step 3, 240 mg, 0.34 mmol) and palladium on carbon (10 wt%, 36 mg, 0.03 mmol) were suspended in ethanol (20 mL). Hydrogen gas was bubbled through the reaction mixture for 5 minutes. The reaction mixture was kept under a positive pressure of hydrogen (1 atm, balloon) for 2.5 hours. The reaction mixture was filtered through diatomaceous earth (Celite™), taking care not to let the filter cake dry out, and the filtrate was concentrated. The crude residue was sufficiently pure to be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 32 H 36 Calculated value of FN6O3: 571.3; Measured value: 571.2. 1 H NMR(500MHz,CD3OD)δ 7.88(d,J=8.7Hz,1H),7.85(d,J=8.2Hz,1H),7.54(d,J=2.4Hz,1H),7.52-7.45(m,2H ),7.35-7.28(m,2H),7.24(d,J=2.4Hz,1H),5.36(s,2H),4.57-4.44(m,3H),4.40-4. 33(m,1H),3.53(s,3H),3.51-3.41(m,1H),3.23-2.99(m,4H),2.88-2.79(m,1H),2.7 3-2.68(m,2H),2.54(s,3H),2.41-2.35(m,1H),2.19-2.08(m,1H),1.88-1.74(m,3H).

[0151] Step 5: 2-((S)-4-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile 2-((S)-4-(8-Fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile (from Step 4, 298 mg, 0.52 mmol) was suspended in HCl solution (4.0 M in dioxane, 2 mL, 8.0 mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was directly concentrated and further dried under high vacuum to give the desired product as the HCl salt (assuming quantitative yield). The crude material was pure enough to be used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 30 H 31 Calculated FN6O2 value 527.3; measured value 527.2. 1 H NMR(500MHz, CD3OD)δ 8.17(br d,J=8.8Hz,1H),7.78(d,J=8.2Hz,1H),7.66(br d,J=5.6Hz,1H),7.49-7.42(m,2H),7.30(d,J=2.3Hz,1H),7.27-7.22(m,1H),7.15(br d,J=3.8Hz,1H),5.22-5.09(m,2H),5.03-4.88(m,3H),4.39-4.22(m,2H),4.14-3.95(m,2H),3.83-3.77(m,1H),3 .76-3.72(m,1H),3.67-3.65(m,5H),3.61-3.55(m,2H),2.52-2.40(m,1H),2.29-2.15(m,2H),2.14-2.07(m,1H). [ka] 2-((S)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0152] Step 1: Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (85 mg, 0.20 mmol from Step 2 of Intermediate 4), 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (120 mg, 0.20 mmol), and potassium phosphate tribasic solution (2.0 M, 0.30 mL, 0.60 mmol) were dissolved in dioxane (4 mL). The solution was purged with a stream of nitrogen for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (6.5 mg, 0.01 mmol) was added, and the resulting solution was heated at 100 °C for 2.5 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→6% MeOH / DCM) to give the desired product (50 mg, 0.07 mmol, 37% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 38 H 37 Calculated for ClFN6O5 679.3; Found 679.3. 1H NMR(500MHz,CD3OD)δ 8.07(dd,J=8.2,1.1Hz,1H),7.98(d,J=8.1Hz,1H),7.86(d,J=8.7Hz,1H),7.63(dd,J=8.1,7.3Hz, 1H),7.57(dd,J=7.4,1.2Hz,1H),7.50-7.46(m,2H),7.43-7.30(m,6H),5.27-5.15(m,2H),4.57-4 .29(m,4H),4.20-4.14(m,1H),3.77-3.67(m,1H),3.61-3.49(m,1H),3.15-2.94(m,3H),2.87-2.7 9(m,1H),2.54(s,3H),2.43-2.37(m,1H),2.17-2.08(m,1H),1.88-1.82(m,2H),1.80-1.76(m,1H).

[0153] Step 2: 2-((S)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (from Step 1, 50 mg, 0.07 mmol) and palladium on carbon (10 wt%, 78 mg, 0.07 mmol) were suspended in ethanol (10 mL). Hydrogen gas was bubbled through the reaction mixture for 5 minutes. The reaction mixture was kept under positive pressure of hydrogen (1 atm, balloon) for 1.5 hours. The reaction mixture was filtered through diatomaceous earth (Celite™), taking care not to let the filter cake dry out, and the filtrate was concentrated. The crude residue was sufficiently pure to be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 30 H 31 Calculated for ClFN6O 545.2; found 545.4. [ka] 6-(6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine

[0154] To a solution of 6-bromo-4-methylpyridin-2-amine (1 g, 5.35 mmol) in DMF (20 mL) was added NaH (0.64 g, 16 mmol, 60%) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, 1-(chloromethyl)-4-methoxybenzene (2.1 g, 13.4 mmol) was added. The mixture was stirred at 0 °C for 1.5 h. TLC (on silica gel, petroleum ether:ethyl acetate = 5:1) showed the reaction was complete. The reaction was quenched with saturated NH Cl (20 mL), extracted with ethyl acetate (20 mL × 3), washed with brine (50 mL), and dried over anhydrous Na SO . The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to give 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (2 g, 4.68 mmol, 87.5% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.16(d,J=8.8Hz,4H),6.88-6.84(m,4H),6.60(s,1H),6.16(s,1H),4.64(s,4H),3.80(s,6H),2.13(s,3H). [ka] (6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid

[0155] To a solution of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (Intermediate 6A, 1000 mg, 2.34 mmol), bis(pinacolato)diboron (Intermediate 6A, 832.5 mg, 3.28 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (171 mg, 0.23 mmol) in 1,4-dioxane (20 mL) was added KOAc (459.32 mg, 4.68 mmol). The mixture was stirred at 90 °C under N for 5 h. The reaction mixture was filtered. The filtrate containing the crude product (6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid (918 mg, 2.34 mmol, crude) in 1,4-dioxane (20 mL) was used in the next step without purification. MS (ESI) m / z 393.3 [M+1] + . [ka] tert-Butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

[0156] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1 g, 3.03 mmol) and DIPEA (1.32 mL, 7.57 mmol) in THF (15 mL) was added tert-butyl piperazine-1-carboxylate (0.56 g, 3.03 mmol) under N2. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was concentrated. The residue was diluted with ethyl acetate (60 mL) and washed with water (30 mL × 2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1 to 4:1) to give tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (1.33 g, 2.77 mmol, 91.5% yield) as a yellow solid. MS (ESI) m / z 481.0 [M+3] + . 1H NMR(400MHz,CDCl3)δ 7.77(d,J=1.6Hz,1H),3.93-3.84(m,4H),3.72-3.61(m,4H),1.50(s,9H). [ka] tert-Butyl 4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate

[0157] A solution of tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (Intermediate 6C, 1000 mg, 2.08 mmol) and potassium fluoride (2420 mg, 41.65 mmol) in DMA (10 mL) was stirred at 110° C. under N for 12 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×3) and dried over anhydrous NaSO. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, petroleum ether:ethyl acetate = 20:1 to 3:1) to give tert-butyl 4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (730 mg, 1.57 mmol, 75.6% yield) as a yellow solid. MS (ESI) m / z 463.1 [M+1] + . [ka] tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate

[0158] A solution of tert-butyl 4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (Intermediate 6D, 600 mg, 1.29 mmol), (6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid (Intermediate 6B, 756 mg, 1.93 mmol), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (104 mg, 0.14 mmol), and potassium phosphate (548 mg, 2.59 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 60° C. under N for 12 minutes. The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1 to 3:1) to give tert-butyl 4-(7-(4-(bis(4-methoxybenzyl)amino)-6-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (600 mg, 0.82 mmol, 63.4% yield) as a yellow oil. MS(ESI) m / z 731.4 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.76(d,J=1.2Hz,1H),7.18(d,J=8.8Hz,4H),6.85(d,J=8.8Hz,4H),6.59(s,1H),6.37(s,1H) ),4.69(s,4H),3.98-3.87(m,4H),3.80(s,6H),3.69-3.65(m,4H),2.27(s,3H),1.51(s,9H). [ka] tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate

[0159] A solution of tert-butyl 4-(7-(4-(bis(4-methoxybenzyl)amino)-6-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (Intermediate 6E, 800 mg, 1.09 mmol), TosOH (5 mg, 0.05 mmol), and NIS (1200 mg, 5.33 mmol) in DMF (10 mL) was stirred at 25° C. for 12 hours. The reaction mixture was diluted with water (15 mL) and EtOAc (15 mL). The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1 to 3:1) to give tert-butyl-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (400 mg, 0.467 mmol, 42.7% yield) as a yellow solid. MS(ESI) m / z 857.2 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.82(d,J=1.2Hz,1H),7.17(d,J=8.4Hz,4H),6.86(d,J=8.4Hz,4H),6.48(s,1H),4.76-4.65(m,2H ),4.62-4.50(m,2H),4.01-3.92(m,4H),3.82(s,6H),3.72-3.63(m,4H),2.38(s,3H),1.52(s,9H). [ka] tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate

[0160] A mixture of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (Intermediate 6F, 400 mg, 0.4700 mmol), methyl 2,2-difluoro-2-fluorosulfonyl acetate (1345 mg, 7 mmol), and CuI (267 mg, 1.4 mmol) in DMA (10 mL) was stirred at 80° C. under N for 5 h. The reaction mixture was then cooled to room temperature, and additional CuI (267 mg, 1.4 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl acetate (1345 mg, 7 mmol) were added to the mixture. The reaction mixture was stirred at 80° C. under N for an additional 12 h. The mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with brine (30 mL × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1 to 3:1) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (270 mg, 0.34 mmol, 72.4% yield) as a yellow solid. MS (ESI) m / z 799.0 [M+1] + . [ka] tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate

[0161] To a solution of (2S)-1-methylpyrrolidin-2-ylmethanol (97.6 mg, 0.85 mmol) in THF (10 mL) was added NaH (81 mg, 2.03 mmol, 60%) at 0° C. The mixture was stirred at 0° C. for 0.5 h. tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (Intermediate 6G, 270 mg, 0.34 mmol) in THF (5 mL) was added. The mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with brine (30 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, DCM:MeOH=10:1) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (250 mg, 0.28 mmol, 82.7% yield) as a white solid. MS(ESI) m / z 894.5[M+1] + . [ka] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4(3H)-one

[0162] A mixture of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (Intermediate 6H, 250 mg, 0.28 mmol) and NaOH (224 mg, 5.59 mmol) in ethanol (30 mL) and water (10 mL) was stirred at 45 °C for 3 days. The mixture was quenched with 2 N HCl to pH = 6-7. The mixture was concentrated in vacuo to remove EtOH. The residue was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4(3H)-one (200 mg, 0.28 mmol, 98.5% yield) as a pale yellow solid. MS(ESI) m / z 726.3 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.07(s,1H),7.14(d,J=8.4Hz,4H),6.85(d,J=8.4Hz,4H),6.41(s,1H),4.98-4.65(m,4H),4.59-4.49(m,2H),3.80(s ,6H),3.55-3.38(m,1H),2.90(d,J=8.0Hz,3H),2.41(s,3H),2.31-2.21(m,2H),2.14-2.03(m,2H),1.37-1.19(m,2H). [ka] 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4(3H)-one

[0163] A solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4(3H)-one (Intermediate 6I, 300 mg, 0.4100 mmol) in TFA (10 mL, 130 mmol) was stirred at 50° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude product 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4(3H)-one (247 mg, 0.41 mmol, 99.7% yield) as a brown oil. MS (ESI) m / z: 486.1 [M+H] + . [ka] tert-Butyl 3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0164] To a solution of 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4(3H)-one (Intermediate 6J, 80 mg, 0.13 mmol) in DCM (3 mL) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (85 mg, 0.40 mmol), DIPEA (51 mg, 0.39 mmol), and BOP (192 mg, 0.43 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was diluted with water (15 mL) and then extracted with DCM (15 mL×3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (instrument: ACSWH-GX-N; column: Phenomenex Synergi C18 150x25 mm 10 μm; mobile phase: A: HO (0.1% TFA) and B: acetonitrile; gradient: B 38% to 68% linear in 10 min; flow rate: 25 mL / min; column temperature: RT; wavelength: 220 nm and 254 nm) to afford the desired tert-butyl 3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 0.037 mmol, 27.6% yield) as a yellow solid, which was used directly in the next step. MS(ESI)m / z:680.2[M+H] + . [ka] 6-(6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0165] To a solution of tert-butyl 3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 6K, 20 mg, 0.03 mmol) in DCM (1.5 mL) was added TFA (0.5 mL, 6.53 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 3 hours. The reaction mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA as additive; instrument: GX-p; column: Phenomenex Synergi C18 150 × 25 mm, 10 µm; mobile phase: A: HO (0.225% FA) and B: acetonitrile; gradient: 3% to 33% B in 10 min, linear; flow rate: 15 mL / min; column temperature: RT; wavelength: 220 nm, 254 nm) to give the desired product. The mixture of atropisomers was separated by chiral SFC (column: Cellucoat 50 × 4.6 mm ID, 3 µm; mobile phase: phase A: CO2, and phase B: IPA (0.05% DEA); gradient elution: 40% IPA (0.05% DEA) in CO2, flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar) to give two product peaks. Peak 1 product: Intermediate 6 (4.88 mg, 0.0082 mmol, 27.9% yield). MS (ESI) m / z 580.0 [M+1] + ; 1 H NMR(400MHz, methanol-d4)δ 7.89(S,1H),6.62(S,1H),4.77(br dd,J=13.6,2.8Hz,1H),4.63-4.52(m,3H),3.95-3.87(m,2H),3.76-3.69(m,2H),3.64-3.48(m,2 H),3.16-3.02(m,1H),2.96(S,3H),2.45(d,J=1.2Hz,3H),2.39-2.28(m,1H),2.13-1.93(m,7H). [ka] 6-(6-chloro-4-{2,5-diazabicyclo[2.2.2]octan-2-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] 6-(4,6-dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0166] To a solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)-pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-quinazolin-4(3H)-one (Intermediate 6I, 50 mg, 0.07 mmol) in POCl3 (1.5 mL, 16.09 mmol) was added DIEA (0.01 mL, 0.07 mmol). The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was concentrated under reduced pressure and treated with ethyl acetate (10 mL). The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 6-(4,6-dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.067 mmol, 97.5% yield) as a yellow solid. MS (ESI) m / z: 744.0 [M+H] + 。 [ka] tert-Butyl 5-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate

[0167] To a solution of 6-(4,6-dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Intermediate 7A, 40 mg, 0.05 mmol) in DMA (2 mL) was added DIEA (0.02 mL, 0.2700 mmol) and tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (31.7 mg, 0.15 mmol). The mixture was stirred at 50° C. for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel plate, dichloromethane:methanol=10:1) to give the product (40 mg, 0.044 mmol, 80.9% yield) as a colorless oil. MS (ESI) m / z: 920.3 [M+H] + . [ka] 6-(4,6-dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0168] A solution of tert-butyl 5-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Intermediate 7B, 40 mg, 0.040 mmol) in TFA (4 mL, 52.24 mmol) was stirred at 50° C. for 4 hours. The mixture was then concentrated to dryness. The residue was purified by preparative HPLC (formic acid as additive, instrument: ACSWH-GX-Q; column: Shim-pack C18 150 × 25, 10 μm; mobile phase: A: HO (0.225% FA) and B: acetonitrile; gradient: 2% to 35% B in 11 min, linear; flow rate: 25 mL / m; column temperature: RT; wavelength: 220 nm. 254 nm) to give the desired product (11.1 mg, 0.019 mmol, 44.2% yield) as a white solid. MS (ESI) m / z: 580.2 [M+H] + ; 1 H NMR(400MHz,CD3OD)δ 8.53(s,0.4H),8.05(s,1H),6.61(s,1H),4.95(br s,1H),4.68-4.49(m,2H),4.35(d,J=11.6Hz,1H),4.27-4.19(m,1H),3.62-3.33(m, 4H),2.86-2.70(m,4H),2.45(d,J=1.2Hz,3H),2.40-2.18(m,2H),2.16-1.79(m,7H). [ka] 4-(6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-7-yl)naphthalen-2-ol [ka] tert-Butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0169] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300 mg, 3.03 mmol) in dioxane (8 mL) was added DIPEA (0.476 mL, 2.72 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (193 mg, 0.908 mmol). The resulting mixture was stirred at 25 °C for 2 hours. LCMS showed the reaction was complete. The mixture was concentrated. The residue was diluted with ethyl acetate (50 mL) and washed with water (30 mL × 2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (12 g ISCO column, MeOH / DCM, 0-5%, 20 min) to give tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (415 mg, 0.82 mmol, 90% yield) as a white solid. MS (ESI) m / z 507.0 [M+1] + . 1 H NMR(499MHz,DMSO-d6)δ 8.10(d,J=1.9Hz,1H),4.38(br d,J=10.6Hz,2H),4.25(br s,2H),3.66(m,2H)1.79(m,2H),1.62(m,2H),1.47 s,9H). [ka] tert-Butyl-3-(7-bromo-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0170] To a solution of tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 8A, 415 mg, 0.820 mmol) in DMSO (6 mL) was added cesium fluoride (187 mg, 1.230 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (236 mg, 2.050 mmol). The mixture was heated to 100 °C for 2 hours. The residue was diluted with DCM (50 mL) and washed with water (30 mL × 2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (12 g ISCO column, MeOH / DCM, 0–15%, 30 min) to give tert-butyl 3-(7-bromo-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (108 mg, 0.185 mmol, 22.5% yield) as a yellow oil. MS(ESI) m / z 586.1 [M+1] + . [ka] tert-Butyl 3-[6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0171] A suspension of tert-butyl 3-(7-bromo-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 8B, 108 mg, 0.185 mmol) and NaCO in 1,4-dioxane (2954 μL) and water (739 μL) was degassed, and Pd(Ph) (42.7 mg, 0.037 mmol) was added in one portion. The mixture was again degassed and heated in a pressure vial at 95 °C for 1 h. The reaction mixture was diluted with water (10 mL) and DCM (10 mL). The mixture was extracted with DCM (10 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude tert-butyl 3-[6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, MS(ESI) m / z 857.2 [M+1] + was obtained, which was used directly in the next step. [ka] 4-(6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-7-yl)naphthalen-2-ol

[0172] To a solution of crude tert-butyl 3-[6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in DCM (4 mL) was added TFA (0.8 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by preparative HPLC using the following conditions: Column: XBridge C18, 200 mm × 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.05% trifluoroacetic acid; Gradient: 5% B hold at 0 min, 5-45% B over 20 min, then 100% B hold at 0 min; Flow rate: 20 mL / min; Column temperature: 25 °C. Fractions containing the desired product were combined and dried by centrifugal evaporation. This material was further purified by preparative HPLC using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.05% trifluoroacetic acid; Gradient: 4% B at 0 min hold, 4 to 44% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25 °C. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the desired product (22.3 mg, 0.039 mmol) as a white solid. MS (ESI) m / z 547.93 [M+1] + ; 1 H NMR(500MHz,DMSO-d6)δ 8.02(s,1H),7.82(br d,J=8.2Hz,1H),7.46(br t,J=7.5Hz,1H),7.36-7.15(m,3H),7.24(m,1H),4.63(br d,1H),4.60(m,3H),4.21(br s,2H),3.83(m,2H),2.97(m,2H),2.55(m,4H),2.28(s,1H),2.08(m,2H),1.97(m,5H). [ka] 6-(2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] (3-Bromopropoxy)(tert-butyl)dimethylsilane

[0173] To a stirred solution of 3-bromopropan-1-ol (10.00 g, 71.9 mmol) in anhydrous dichloromethane (50 mL) at 0° C. under nitrogen, imidazole (4.90 g, 71.9 mmol) was added, followed by tert-butyldimethylsilyl chloride (14.10 g, 94 mmol). The reaction mixture was slowly warmed to room temperature and stirred at the same temperature for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) diluted with water (50 mL). The suspension was extracted with dichloromethane (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product residue. The residue was purified by silica gel column chromatography using 0-5% ethyl acetate in petroleum ether to give (3-bromopropoxy)(tert-butyl)dimethylsilane (8.00 g, 31.6 mmol, 43.9% yield) as a colorless oil. 1 H NMR(400MHz,CD3OD):δ 3.69(t,J=4.0Hz,2H),3.57(t,J=6.4Hz,2H),1.99-1.93(m,2H),0.87(s,9H),0.06(s,6H)ppm. [ka] 1-(tert-butyl) 2-methyl(2R,4R)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-fluoropyrrolidine-1,2-dicarboxylate

[0174] To a stirred solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (Intermediate 9A, 5.00 g, 20.22 mmol) in anhydrous THF (30 mL) was added dropwise LiHMDS (1 M in THF, 30.3 mL, 30.3 mmol) under a nitrogen atmosphere at −25° C. After the reaction mixture was stirred at the same temperature for 30 minutes, (3-bromopropoxy)(tert-butyl)dimethylsilane (7.68 g, 30.3 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 30 minutes and then slowly warmed to room temperature. The reaction mixture was quenched with saturated aqueous solution. It was diluted with ammonium chloride solution (15 mL) and then water (50 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 20-30% ethyl acetate in petroleum ether to give 1-(tert-butyl) 2-methyl(2R,4R)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-fluoropyrrolidine-1,2-dicarboxylate (7.23 g, 17.24 mmol, 85.0% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3):δ 5.18-5.03(m,1H),4.10-3.98(m,1H),3.78(s,3H),3.74-3.52(m,3H),2.48-2.23(m, 3H),2.19-1.98(m,1H),1.65(s,9H),1.48-1.44(m,2H),0.90(s,9H),0.60(s,6H)ppm. 19 F(376MHz,CD3OD):δ -172.47~-172.96(m)ppm.LCMS-ELSD(ESI)m / z:320.2[M+H-Boc] + . [ka] 1-(tert-butyl) 2-methyl (2R,4R)-4-fluoro-2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate

[0175] To a stirred solution of 1-(tert-butyl) 2-methyl(2R,4R)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-fluoropyrrolidine-1,2-dicarboxylate (Intermediate 9B, 7.00 g, 16.68 mmol) at 25° C., TBAF (1 M in THF, 16.68 mL, 16.68 mmol) was added dropwise and stirred at the same temperature for 4 hours. The reaction mixture was quenched with saturated aqueous solution. Ammonium chloride solution (90 mL) was added and diluted with ethyl acetate (100 mL). The mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude residue as a colorless oil. The crude product was purified by silica gel column chromatography using 50% ethyl acetate in petroleum ether to give 1-(tert-butyl) 2-methyl(2R,4R)-4-fluoro-2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate (4.97 g, 15.64 mmol, 94.0% yield) as a colorless oil. LCMS-ELSD (ESI) m / z: 206.2 [M+H-Boc] + . [ka] 1-(tert-butyl) 2-methyl(2R,4R)-4-fluoro-2-(3-iodopropyl)pyrrolidine-1,2-dicarboxylate

[0176] To a stirred solution of 1-(tert-butyl) 2-methyl(2R,4R)-4-fluoro-2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate (Intermediate 9C, 9.00 g, 29.5 mmol) in dichloromethane (100 mL) was added triphenylphosphine (15.50 g, 58.9 mmol) and imidazole (6.02 g, 88 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 10 minutes, followed by the addition of iodine (29.9 g, 118 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate solution (30 mL), and the suspension was extracted with dichloromethane (2 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The crude product was purified by silica gel column chromatography using 10-20% ethyl acetate in petroleum ether to give 1-(tert-butyl) 2-methyl(2R,4R)-4-fluoro-2-(3-iodopropyl)pyrrolidine-1,2-dicarboxylate (10.10 g, 24.32 mmol, 83.0% yield) as a colorless oil. LCMS-ELSD (ESI) m / z: 361.2 [M+H-Boc] + . [ka] tert-Butyl 3-(6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-(piperidin-1-yl)propan-2-yl)oxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0177] To a stirred solution of 1-(tert-butyl) 2-methyl (2R,4R)-4-fluoro-2-(3-iodopropyl)pyrrolidine-1,2-dicarboxylate (Intermediate 9D, 10.0 g, 24.08 mmol) in dichloromethane (20 mL) was added HCl in dioxane (8.03 mL, 24.08 mmol) at 25 °C, and the reaction mixture was stirred at the same temperature for 6 h. Upon complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure at room temperature to give a crude residue of methyl (2R,4R)-4-fluoro-2-(3-iodopropyl)pyrrolidine-2-carboxylate·HCl (6.5 g, 20.63 mmol, 86.0% yield), which was used directly in the next step without further purification. LCMS-ELSD (ESI) m / z: 188.2 [M+H] + . [ka] Methyl (2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate

[0178] To a stirred solution of methyl (2R,4R)-4-fluoro-2-(3-iodopropyl)pyrrolidine-2-carboxylate (Intermediate 9E, 6.5 g, 20.63 mmol) in anhydrous acetonitrile (30 mL) was added triethylamine (10 mL) at room temperature. The reaction mixture was stirred at 45 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (neutral alumina) using 40-50% ethyl acetate in petroleum ether to give methyl (2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (3.20 g, 83.0% yield) as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6):δ 5.76-5.19(m,1H),3.59(s,3H),3.25-3.16(m,1H),2.97-2.95(m,1H),2.86 -2.76(m,1H),2.68-2.51(m,2H),2.02-1.91(m,2H),1.85-1.72(m,3H)ppm.LCMS-ELSD(ESI)m / z:188.3[M+H] + . [ka] ((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol

[0179] To a stirred solution of methyl (2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (Intermediate 9F, 3.20 g, 17.09 mmol) under nitrogen at 0°C, LiAlH4 (2 M in THF, 17.09 mL, 34.2 mmol) was added dropwise over 10 min. After the addition, the reaction mixture was allowed to warm to room temperature over 30 min. The mixture was stirred at this temperature for 1 h and then quenched at 0°C with saturated aqueous ammonium chloride (5 mL). Once the effervescence ceased, anhydrous sodium sulfate was added to the reaction mixture, followed by dichloromethane (20 mL). The reaction mixture was stirred for 20 h and filtered. The filtrate was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue of ((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (2.20 g, 13.68 mmol, 80.0% yield) as a light brown oil. 1 H NMR(400MHz,CD3OD):δ 5.34-5.10(m,1H),3.51-3.29(m,3H),3.25-3.10(m,1H),3.04-2.93(m,1H),2.90-2.73( m,1H),2.71-2.59(m,1H),2.28-2.12(m,,1H),1.95-1.73(m,4H),1.68-1.66(m,1H)ppm. 19 F(376MHz,CD3OD):δ -175.69~-176.04(m)ppm.LCMS-ELSD(ESI)m / z:160.0[M+H] + . [ka] tert-Butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0180] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (3.5 g, 10.6 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2240 mg, 10.55 mmol) in THF (50 mL) was added DIEA (2.48 mL, 26.5 mmol). The mixture was stirred at 20 °C for 12 hours. LCMS showed that the reaction was complete and the desired product was detected. The reaction mixture was diluted with EtOAc (40 mL) and water (40 mL). The mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product, tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.3 g, 10.5 mmol, 98.8% yield), was used in the next step without further purification. MS (ESI) m / z: 506.9 [M+3] + . 1 H NMR(400MHz,CDCl3)δ 7.75(d,J=2.0Hz,1H),4.40(s,4H),3.78-3.51(m,2H),2.02-1.90(m,2H),1.77-1.67(m,2H),1.53(s,9H). [ka] tert-Butyl (1R,5S)-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0181] To a degassed solution of tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 9H, 1 g, 3.03 mmol) in DMA (80 mL) was added cesium fluoride (5.25 g, 34.6 mmol). The mixture was degassed with nitrogen gas for 10 minutes and heated in a sealed tube at 88 °C for 5 hours. Water (200 mL) and ethyl acetate (150 mL) were added, and the mixture was stirred for 15 minutes. The separated aqueous layer was extracted with ethyl acetate (2 × 100 mL), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The resulting residue was purified by flash column chromatography using 15-25% ethyl acetate in petroleum ether as the eluent to give tert-butyl 3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.7 g, 8.77 mmol, 63.4% yield) as a pale yellow solid. MS(ESI) m / z 489.0 [M+1] + . [ka] N,N-Bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

[0182] 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (20 g, 46.8 mmol), bis(pinacolato)diboron (35.7 g, 140 mmol), and potassium acetate (18.37 g, 187 mmol) were combined as solids and dissolved in dioxane (200 mL). Nitrogen was flushed through the solution for 20 minutes, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.9 g, 2.3 mmol) was added. The reaction mixture was heated at 100°C for 5 hours. The reaction mixture was diluted with EtOAc (200 mL) and filtered through diatomaceous earth (Celite™). The filtrate was concentrated to give the desired product (22 g, 40.7 mmol, 87% yield). [ka] tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0183] To a degassed solution of Intermediate 9I (2.00 g, 4.08 mmol) in anhydrous 1,4-dioxane (20 mL) was added potassium phosphate (1.73 g, 8.17 mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (Intermediate 9J, 5.8 g, 12.25 mmol), and PdCl(dppf) (149 mg, 0.204 mmol). The mixture was again degassed and heated at 80° C. for 48 hours. The reaction progress was monitored by LCMS. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate (40 mL), filtered through a bed of diatomaceous earth (Celite™), and concentrated in vacuo to give the crude product. The residue was purified by silica gel column chromatography using 30% ethyl acetate in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 1.74 mmol, 42% yield). 1 H NMR(400MHz,CDCl3):δ 7.76(d,J=1.6Hz,1H),7.20-7.18(d,J=8.8Hz,4H),6.86(dt,J=9.6Hz,4H),6.60(s,1H),6.38(s,1H),4.60(s,3H),4.39- 4.21(m,4H),3.63(s,6H),2.29(s,3H),1.98-1.96(m,6H),1.76-1.63(m,2H),1.49(s,9H)ppm.LCMS(ESI)m / z:757.2[M+H] + . [ka] tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8 diazabicyclo[3.2.1]octane-8-carboxylate

[0184] To a stirred solution of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 9K, 1.40 g, 1.849 mmol) in anhydrous acetonitrile (15 mL) under nitrogen at 0° C. was added N-iodosuccinimide (0.42 g, 1.849 mmol) and trifluoroacetic acid (0.028 mL, 0.370 mmol). The reaction mixture was allowed to reach room temperature over 1 h. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate (5 mL) and saturated aqueous sodium bicarbonate (4 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude residue. The crude residue was purified by silica gel column chromatography using 30% ethyl acetate in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.42 g, 1.560 mmol, 84% yield) as a pale yellow fluffy solid. LCMS (ESI) m / z: 883.3 [M+H] + . [ka] tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0185] To a stirred solution of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 9L, 1.40 g, 1.585 mmol) in anhydrous DMA (10 mL) in a sealed tube under a nitrogen atmosphere was added copper(I) iodide (0.60 g, 3.17 mmol). After degassing the reaction mixture for 10 minutes, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.91 g, 4.76 mmol) was added and the reaction mixture was heated to 90° C. for 12 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was diluted with diethyl ether (20 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with diethyl ether (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The crude product was purified by silica gel column chromatography using 30% ethyl acetate in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.85 g, 0.630 mmol, 40% yield) as a pale yellow solid. 1 H NMR(400MHz,CDCl3):δ 7.77(s,1H),7.16(d,J=8.8Hz,4H),6.87(dt,J=9.6 and 2.8Hz,4H),6.43(s,1H),4.76-4.72(m,2H),4.59-4.55(m, 2H),3.81(s,6H),2.43(s,3H),1.97-1.82(m,4H),1.97-1.82(m,4H),1.53(s,9H)ppm.LCMS(ESI)m / z:825.2[M+H] + . [ka] tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0186] To a stirred solution of ((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (Intermediate 9G, 0.23 g, 1.454 mmol) in anhydrous THF (2.1 mL) was added sodium hydride (43.6 mg, 1.091 mmol) at 0° C., and the reaction mixture was stirred at the same temperature for 30 minutes. After 30 minutes, tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 9M, 0.60 g, 0.727 mmol) dissolved in anhydrous THF (10 mL) was added dropwise to the reaction mixture, and the temperature was maintained at 0° C. The reaction mixture was stirred for the next 2 hours while warming to room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (1 mL) and diluted with ethyl acetate (5 mL). The mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product residue. The crude residue was purified over neutral alumina using 30% ethyl acetate in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (657 mg, 0.703 mmol, 97.0% yield) as a pale yellow solid. LCMS(ESI)m / z:964.3[M+H] + . [ka] 6-(2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0187] To a stirred solution of TFA (200 μL, 2.59 mmol) and triethylsilane (83 μL, 0.518 mmol) was added tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 9N, 0.50 g, 0.518 mmol) at room temperature. The reaction mixture was then stirred at 35° C. for 12 hours. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to remove most of the TFA under reduced pressure below 35° C. The residue was co-evaporated with methanol (3 × 1 mL) to remove residual TFA. The residue was neutralized with DIPEA and concentrated under reduced pressure to give the free base. The crude product was then purified by silica gel (previously neutralized with DIPEA) column chromatography using a mixture of MeOH, dichloromethane, and DIPEA (15:80:2.5) to give 6-(2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine. The atropisomers were separated by chiral SFC (column: 25 mm od × 5 mm i.d., 5 μm mobile phase: Phase A: CO and Phase B: MeOH (0.1% NHOH); gradient elution: 40% MeOH (0.1% NHOH) in CO. Flow rate: 350 mL / min; detector: UV 220 nm; column temperature: 30 °C; back pressure: 100 bar) to give two product peaks: Peak 1 (Intermediate 9-1) and Peak 2 (Intermediate 9-2).

[0188] Peak 1, Isomer 1: Intermediate 9-1 (66 mg, 33% yield). MS (ESI) m / z 624.3 [M+1]+. 1H NMR(499MHz,DMSO-d6)δ 7.88-7.76(m,1H),6.94-6.75(m,2H),6.57-6.42(m,1H),5.49-5.24(m,1H),4.36-4 .27(m,1H),4.22-4.16(m,1H),4.11(s,1H),4.07-4.01(m,1H),3.58-3.49(m,3H),3. 48-3.42(m,1H),3.01-2.92(m,1H),2.89-2.74(m,1H),2.58-2.54(m,1H),2.40-2.36 (m,3H),2.35-2.26(m,1H),1.87-1.87(m,1H),1.96-1.78(m,3H),1.71-1.57(m,5H).

[0189] Peak 2, Isomer 2: Intermediate 9-2 (58.8 mg, 29% yield). MS (ESI) m / z 624.3 [M+1]+. 1 H NMR(499MHz,DMSO-d6)δ 7.92-7.72(m,1H),6.96-6.76(m,2H),6.60-6.41(m,1H),5.52-5.23(m,1H),4.40 -4.31(m,1H),4.27-4.18(m,1H),4.15-4.04(m,2H),3.68-3.61(m,2H),3.60-3.54 (m,1H),3.53-3.46(m,1H),3.00-2.92(m,1H),2.90-2.75(m,1H),2.60-2.53(m,1H) ),2.37(d,J=1.4Hz,3H),2.36-2.27(m,1H),1.96-1.77(m,4H),1.74-1.61(m,5H). [ka] 6-(2-{[(2R,7aS)-2-Fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0190] To a stirred solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (commercially available or prepared according to the procedure described in WO 2022 / 031678, 251 mg, 1.575 mmol) in THF (5 mL) at 0° C. was added NaH (28.4 mg, 1.181 mmol), and the mixture was stirred for an additional 30 min. Then, a solution of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (650 mg, 0.788 mmol) in THF (2 mL) was added, and the mixture was allowed to warm gradually to room temperature over 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water and then brine, then dried over Na2SO4 and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography using a CombiFlash system (40 g RediSep® column, 50-60% EtOAc-petroleum ether) to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (475 mg, 0.492 mmol, 62.5% yield) as a brown solid. MS(ESI)m / z:964.2[M+H] + . [ka] 6-(2-{[(2R,7aS)-2-Fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0191] A stirred solution of TFA (190 μL, 2.462 mmol) and triethylsilane (79 μL, 0.492 mmol) was added to tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 10A, 475 mg, 0.492 mmol) at room temperature, and the resulting reaction mixture was heated to 35° C. for 24 hours. The reaction mixture was then concentrated under reduced pressure, co-distilled with toluene (twice), neutralized with DIPEA, and concentrated under reduced pressure to give a crude residue that was purified by achiral SFC followed by chiral SFC to give 6-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2 amine (isomer 1) (9 mg, 0.014 mmol, 2.93% yield) and (isomer 2) (8 mg, 0.013 mmol, 2.60% yield).

[0192] (isomer 1):MS(ESI)m / z:624.2, [M+H] + . 1H NMR(400MHz,DMSO-d6)δ=7.82(s,1H),6.84(s,2H),6.49(s,1H),5.27(d,J=45.2Hz,1H), 4.35(d,J=9.4Hz,1H),4.27(d,J=9.4Hz,1H),4.08(ABq,J=8.4Hz,2H),3.76-3.68(m,2H) ,3.59(d,J=10.1Hz,1H),3.51(d,J=10.1Hz,1H),3.10-3.00(m,3H),2.87-2.80(m,1H),2 .35(s,3H),2.14-2.10(m,1H),2.05-2.03(m,1H),2.02-1.95(m,1H),1.80-1.70(m,7H).

[0193] Preparative achiral SFC conditions: Column / dimensions: Princeton SFC Diol (250 x 4.6) mm, 5 μl; CO2%: 30%; Co-solvent%: 70% (0.2% NH3 in methanol); Flow rate: 3 mL / min; Back pressure: 100 bar; Retention time = 6.129 min.

[0194] Preparative chiral SFC conditions: Column / dimensions: Chiralcel ODH (250 x 4.6) mm, 5 u; CO2%: 30%; Co-solvent%: 70% (5 mM NH4OAc in ACN:methanol (1:1)); Flow rate: 4 mL / min; Back pressure: 100 bar; Retention time of peak-01 = 3.234 min and retention time of peak-02 = 6.862 min. [ka] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0195] The desired product was prepared in a manner similar to Intermediate 2, substituting tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as the starting material (prepared as described in WO2021106231). LCMS (ESI) m / z: [M+H] + C 32 H 32 Calculated F2N5O2 value 556.2; Measured value 556.1; 1 H NMR(500MHz,CD3OD)δ 7.87-7.83(m,2H),7.41-7.36(m,1H),7.34-7.29(m,2H),7.10(t,J=3.0Hz,1H),4.71-4.62(m,4H),4.17 -4.12(m,3H),3.89-3.79(m,4H),3.21-3.17(m,1H),3.04(S,3H),2.43-2.34(m,2H),2.20-2.00(m,6H). [ka] (5M)-6-(6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-({1-[(piperidin-1-yl)methyl]cyclopropyl}methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0196] Step 1: tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1-(Piperidin-1-ylmethyl)cyclopropyl)methanol (51 mg, 0.30 mmol) was dissolved in THF (10 mL) and sodium hydride (60% dispersion in mineral oil, 13 mg, 0.33 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The solution was cooled to 0° C. and tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.30 mmol) was added dropwise as a solution in THF (2 mL). The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with water (20 mL) and ethyl acetate (100 mL) was added. The layers were separated and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the desired product, which was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 52 H 61 Calculated for ClF4N7O5 974.4; Found 974.4.

[0197] Step 2: (5M)-6-(6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-({1-[(piperidin-1-yl)methyl]cyclopropyl}methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine Triethylsilane (1 mL, 6.3 mmol) and TFA (2 mL, 26.0 mmol) were combined as a liquid and stirred for 30 minutes. To this solution was added tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (from Step 1, 180 mg, 0.19 mmol). The reaction mixture was heated at 40° C. for 24 hours. The reaction mixture was directly concentrated and purified by preparative HPLC to give the desired product (50 mg, 0.08 mmol, 43% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.80(d,J=1.2Hz,1H),6.83(s,2H),6.49(s,1H),4.30(d,J=12.0Hz,1H),4.27-4.23(m,2H),4.19(d,J=12.0Hz,1H),3.55-3. 40(m,4H),2.37-2.25(m,9H),1.70-1.55(m,4H),1.47-1.39(m,4H),1.38-1.29(m,2H),0.63-0.60(m,2H),0.38-0.36(m,2H). [ka] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka] [ka] Ethyl octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate

[0198] Intermediate 13A was prepared according to the procedure of Molecules 2017, 22:827, compound 25a. [ka] 1-Benzyl 4a-ethyl (4aS,7aR)-hexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate (Peak 2)

[0199] To a solution of ethyl octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (Intermediate 13A, 1.7 g, 8.62 mmol) and TEA (2.402 mL, 17.23 mmol) in THF (10 mL) was added N-(benzyloxycarbonyl)succinimide (1.718 g, 6.89 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc (15 mL) and washed with saturated aqueous sodium bicarbonate (2 × 15 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel / DCM-20% MeOH / DCM gradient from 100:0 to 50:50) to give 1-benzyl 4a-ethylhexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate (2.20 g, 6.64 mmol, 77% yield). 1-benzyl 4a-ethylhexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate (2.20 g) was subjected to SFC chiral separation. [Column: Cellulose-4 (525 cm, 5 μm) Method: CO₂ / IPA:heptane (1:3) with 0.1% ammonia hydroxide at 320 mL / min] gave the following:

[0200] Peak 1 (19B1): 1-benzyl 4a-ethylhexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate (625 mg, 1.792 mmol, 20.79% yield). LCMS (ESI) m / z: 332.3 [M+H] +LC retention time: 1.05 min (Waters Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 0.05% TFA; gradient: 2 to 98% B over 1 min, then hold at 98% B for 0.5 min; flow: 0.8 mL / min; detection: MS and UV (220 nm)). 1 H NMR(499MHz,chloroform-d)δ 7.41-7.28(m,5H),5.17(br s,2H),4.13(br d,J=6.4Hz,2H),2.86(br s,1H),2.15(br d,J=10.8Hz,1H),2.03-1.90(m,1H),1.90-1.74(m,4H),1.73-1.63(m,1H),1.58-1.42(m,3H),1.27-1.14(m,4H),0.98-0.68(m,1H).

[0201] Peak 2 (19B2): 1-benzyl 4a-ethyl (4aS,7aR)-hexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate (640 mg, 1.835 mmol, 21.29% yield). LCMS (ESI) m / z: 332.3 [M+H] + LC retention time: 1.05 min (Waters Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 0.05% TFA; gradient: 2 to 98% B over 1 min, then hold at 98% B for 0.5 min; flow: 0.8 mL / min; detection: MS and UV (220 nm)). 1 H NMR(499MHz,chloroform-d)δ 7.41-7.28(m,5H),5.17(br s,2H),4.13(br d,J=6.4Hz,2H),2.86(br s,1H),2.15(br d,J=10.8Hz,1H),2.03-1.90(m,1H),1.90-1.74(m,4H),1.73-1.63(m,1H),1.58-1.42(m,3H),1.27-1.14(m,4H),0.98-0.68(m,1H).

[0202] Peak 3 (19B3): 1-benzyl 4a-ethylhexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate (130 mg, 0.373 mmol, 4.32% yield). LCMS (ESI) m / z: 332.3 [M+H] + LC retention time: 1.05 min (Waters Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 0.05% TFA; gradient: 2 to 98% B over 1 min, then hold at 98% B for 0.5 min; flow: 0.8 mL / min; detection: MS and UV (220 nm)). 1 H NMR(499MHz,chloroform-d)δ 7.40-7.28(m,5H),5.18-5.10(m,2H),4.38(ddd,J=13.4,2.5,1.4Hz,1H),4.13-4.05(m,2H),2.88(dd,J=12.8,7.0Hz,1H),2. 79-2.67(m,2H),2.42(dt,J=13.1,2.7Hz,1H),2.28-2.14(m,2H),1.76-1.55(m,4H),1.46-1.26(m,2H),1.20(t,J=7.2Hz,3H).

[0203] Peak 4 (19B4): 1-benzyl 4a-ethylhexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate (141 mg, 0.404 mmol, 4.69% yield). LCMS (ESI) m / z: 332.3 [M+H] + LC retention time: 1.05 min (Waters Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 0.05% TFA; gradient: 2 to 98% B over 1 min, then hold at 98% B for 0.5 min; flow: 0.8 mL / min; detection: MS and UV (220 nm)). 1H NMR(499MHz,chloroform-d)δ 7.40-7.28(m,5H),5.18-5.10(m,2H),4.38(ddd,J=13.4,2.5,1.4Hz,1H),4.13-4.05(m,2H),2.88(dd,J=12.8,7.0Hz,1H),2. 79-2.67(m,2H),2.42(dt,J=13.1,2.7Hz,1H),2.28-2.14(m,2H),1.76-1.55(m,4H),1.46-1.26(m,2H),1.20(t,J=7.2Hz,3H). [ka] Ethyl (4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate

[0204] A mixture of 1-benzyl 4a-ethyl (4aS,7aR)-hexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate (Intermediate 13B2, 640 mg, 1.931 mmol) and 10% Pd-C (103 mg, 0.097 mmol) in MeOH (10 mL) was hydrogenated under 1 atmosphere of hydrogen for 18 hours. The Pd / C was filtered off, and the filtrate was concentrated to give crude ethyl (4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (385 mg, 1.854 mmol, 96% yield) as a clear oil. 1 H NMR(499MHz,chloroform-d)δ 4.17(dtt,J=10.6,7.1,3.6Hz,2H),3.57(t,J=6.1Hz,1H),2.90(ddd,J=13.0,7.7,3.7Hz,1H),2.71(ddd, J=13.0,7.0,3.6Hz,1H),2.01-1.92(m,2H),1.84-1.62(m,7H),1.60-1.40(m,2H),1.28(t,J=7.1Hz,3H). [ka] Ethyl (4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate

[0205] To a solution of ethyl (4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (Intermediate 13C, 385 mg, 1.952 mmol) and formaldehyde solution, 37 wt% in HO (176 mg, 5.85 mmol) in MeOH (5.0 mL) was added sodium cyanoborohydride (123 mg, 1.952 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated. The mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous sodium carbonate (2 × 5 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to give crude ethyl (4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (380 mg, 1.798 mmol, 92% yield). 1 H NMR (499 MHz, chloroform-d) δ 4.24-4.12 (m, 2H), 3.29 (t, J = 6.4 Hz, 1H), 2.60-2.51 (m, 1H), 2.36-2.28 (m, 3H), 2.00-1.88 (m, 2H), 1.83-1.60 (m, 8H), 1.56-1.40 (m, 1H), 1.32-1.26 (m, 3H). [ka] ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol

[0206] To a solution of ethyl (4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (Intermediate 13D, 380 mg, 1.798 mmol) in anhydrous THF (2.0 mL) was added a 1.0 M solution of lithium aluminum hydride in THF (4496 μL, 4.50 mmol), and the mixture was stirred at room temperature for 18 hours. Brine (0.3 mL) was added dropwise to the mixture. EtOAc (5.0 mL) was added to the mixture. The precipitate was filtered off, and the filtrate was concentrated to give crude ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (327 mg, 1.739 mmol, 97% yield).1 H NMR (499 MHz, chloroform-d) δ 3.69-3.62 (m, 2H), 2.87 (t, J = 7.6 Hz, 1H), 2.51 (td, J = 11.1, 3.4 Hz, 1H), 2.43-2.35 (m, 1H), 2.30 (S, 3H), 2.01-1.85 (m, 2H), 1.82-1.74 (m, 1H), 1.68-1.52 (m, 6H), 1.47-1.42 (m, 1H), 1.39-1.33 (m, 1H). [ka] tert-Butyl (1R,5S)-3-(2,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0207] Step 1: tert-butyl (1R,5S)-3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (prepared according to the procedure described in WO 2021 / 136231 A1, 42 g, 89 mmol) was dissolved in MeCN (420 mL) and DMA (63 mL). Cesium fluoride (67.6 g, 445 mmol), tetramethylammonium chloride (1.0 g, 8.9 mmol), and 18-crown-6 (2.4 g, 8.9 mmol) were added as solids. The reaction mixture was heated at 60 °C for 16 h. The reaction mixture was diluted with EtOAc (1 L) and washed with water (2 × 500 mL) and brine (500 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give the desired product (26.5 g, 58 mmol, 65% yield), which was pure enough to be used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 19 H22 Calculated value for BrF2N4O2: 455.1; Found value: 455.2.

[0208] Step 2: tert-butyl (1R,5S)-3-(2,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.0 g, 11.0 mmol) from Step 1 was dissolved in dioxane (135 mL) and water (15 mL). ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (8.4 g, 16.5 mmol) and cesium carbonate (11 g, 33 mmol) were added, and the resulting solution was flushed with nitrogen for 15 minutes. Pd(dppf)Cl (0.8 g, 1.1 mmol) was added, and the reaction mixture was heated at 100 °C for 16 hours. Water (50 mL) and EtOAc (100 mL) were added and the layers were separated. The aqueous layer was further extracted with EtOAc (2×100 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by reverse-phase HPLC to give the desired product (3.0 g, 3.9 mmol, 35% yield). LC / MS (ESI) m / z: [M+H] + C 42 H 52 Calculated F3N4O4Si value: 761.4; Found value: 761.2. [ka]

[0209] tert-Butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(2,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 13F, 45 mg, 0.06 mmol) and ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (Intermediate 13E, 10 mg, 0.06 mmol) were combined and dissolved in THF (1.0 mL). Lithium bis(trimethylsilylamide) solution (1.0 M in THF, 90 μL, 0.09 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The solution was directly concentrated and purified by preparative HPLC to give the desired product (35 mg, 0.04 mmol, 65% yield). LC / MS (ESI) m / z: [M+H] + C 52 H 70 Calculated value of F2N5O5Si: 910.5; Measured value: 910.6. [ka] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0210] tert-Butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 13F, 35 mg, 0.04 mmol) was dissolved in DCM (1.0 mL) and TFA (1.0 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was directly concentrated and resuspended in THF (100 μL). TBAF solution (1.0 M in THF, 770 μL, 0.77 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly concentrated and purified by preparative HPLC to give the desired product (9.6 mg, 0.015 mmol, 39% yield). LC / MS (ESI) m / z: [M+H] + C 36 H 38 Calculated F2N5O2 value 610.3; Measured value 610.5; 1 H NMR(500MHz,CD3OD)δ 7.85-7.81(m,1H),7.79-7.74(m,1H),7.32-7.27(m,2H),7.26-7.20(m,1H),7.09 (d,J=2.5Hz,1H),4.58-4.42(m,3H),4.38-4.27(m,1H),3.67-3.56(m,4H),3.13-2 .97(m,1H),2.85-2.71(m,1H),2.63-2.51(m,1H),2.49-2.37(m,3H),2.03-1.94(m ,1H),1.94-1.90(m,1H),1.90-1.81(m,6H),1.81-1.68(m,6H),1.63-1.55(m,1H). [ka] 6-(4-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate [ka]

[0211] ((2R,7aR)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (Intermediate 9G, 110 mg, 0.68 mmol) was dissolved in THF (5 mL) and the solution was cooled to 0° C. Sodium hydride (60 wt % dispersion in mineral oil, 27 mg, 0.68 mmol) was added portionwise as a solid and the reaction mixture was stirred for 30 minutes. tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (Intermediate 6G, 300 mg, 0.375 mmol) was added and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 2 hours, the reaction mixture was quenched with water (20 mL) and diluted with EtOAc (25 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (25 mL). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography on neutral alumina (70% EtOAc / hexanes) to give the desired product (200 mg, 44% yield). LC / MS (ESI) m / z: [M+H] + C 48 H 54 Calculated for ClF5N7O5: 938.4; Found: 938.2. [ka] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one [ka]

[0212] tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (Intermediate 14A, 8.8 g, 9.38 mmol) was dissolved in EtOH (30 mL) and sodium hydroxide (11.2 g, 28 mmol) was added as a solid. The reaction mixture was heated at 80° C. for 36 h. The reaction mixture was concentrated directly and the crude material was dissolved in water (80 mL) and extracted with EtOAc (3×150 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The crude residue was purified by reverse-phase column chromatography (55% MeCN in water) to give the product as a mixture of atrop isomers. The material was further purified by chiral SFC to give the desired isomer (retention time = 4.72 min, 1.2 g, 1.56 mmol, 17% yield) and a second isomer (retention time = 5.85 min, 1.3 g, 1.69 mmol, 18% yield). LC / MS (ESI) m / z: [M+H] + C 39 H 38 F 25 Calculated N5O4 770.2; Measured 770.2. [ka] 6-(4-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0213] Step 1: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 60 mg, 0.08 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (52 mg, 0.12 mmol) were combined and dissolved in acetonitrile (4 mL). Triethylamine (10 μL, 0.08 mmol) was added, followed by tert-butyl 3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (35 mg, 0.16 mmol). The reaction mixture was heated at 35° C. for 10 hours. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2×10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (60→100% EtOAc / hexanes) to give the desired product (65 mg, 0.06 mmol, 73% yield). LC / MS (ESI) m / z: [M+H] + C 51 H58 Calculated value for ClF5N7O5: 978.4, measured value: 977.8.

[0214] Step 2: 6-(4-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (from Step 1, 60 mg, 0.06 mmol) was dissolved in TFA (1.5 mL), and triethylsilane (1 μL, 0.006 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40° C. for 16 h. The crude mixture was directly purified by preparative HPLC to give the desired product (17 mg, 0.02 mmol, 39% yield). LC / MS (ESI) m / z: [M+H] + C 30 H 34 ClF5N7O calculated value 638.2, found value 638.8; 1 H NMR(400MHz,CD3OD)δ 8.05-7.81(m,1H),6.63(S,1H),5.49-5.25(m,1H),4.72(br dd,J=8.6,13.6Hz,2H),4.57-4.41(m,2H),3.85(ddd,J=3.3,6.7,14.0Hz,2H),3.67-3.47(m,3H),3.31-3.23(m,2H),3.19-3.1 1(m,1H),3.09-2.94(m,2H),2.69-2.54(m,1H),2.47(d,J=1.4Hz,2H),2.32-2.19(m,1H),2.17-2.01(m,6H),1.99-1.87(m,3H). [ka] 6-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0215] Step 1: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 60 mg, 0.08 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (52 mg, 0.12 mmol) were combined and dissolved in acetonitrile (4 mL). Triethylamine (10 μL, 0.08 mmol) was added, followed by tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (19 mg, 0.10 mmol). The reaction mixture was heated at 35° C. for 10 hours. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2×10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (40→100% EtOAc / hexanes) to give the desired product (60 mg, 0.06 mmol, 75% yield). LC / MS (ESI) m / z: [M+H] + C49 H 54 Calculated value for ClF5N7O5: 950.4, Measured value: 950.2

[0216] Step 2: 6-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (from Step 1, 60 mg, 0.06 mmol) was dissolved in TFA (1.5 mL), and triethylsilane (1 μL, 0.006 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40° C. for 16 h. The crude mixture was directly purified by preparative HPLC to give the desired product as its TFA salt (14 mg, 0.02 mmol, 31% yield). LC / MS (ESI) m / z: [M+H] + C 28 H 30 Calculated value of ClF5N7O 610.2, found value 610.2; 1 H NMR(400MHz,CD3OD)δ 8.38(d,J=1.60Hz,1H),6.66(S,1H),5.49-5.60(m,1H),4.87-4.88(m,4H),4.62-4.81(m,5H),3.91-4.12(m,1H),3.69-3.7 8(m,1H),3.50-3.50(m,1H),3.09-3.18(m,1H),2.69-2.76(m,1H),2.48-2.48(m,5H),2.29-2.48(m,3H),2.03-2.06(m,1H). [ka] tert-Butyl (1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0217] Step 1: tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (commercially available or prepared according to the procedure described in WO 2022 / 031678, 2.0 g, 12.6 mmol) was dissolved in THF (60 mL) and the solution was cooled to 0 °C. Sodium hydride (60 wt% dispersion in mineral oil, 0.9 g, 22.8 mmol) was added portionwise as a solid and the reaction mixture was stirred for 30 minutes. tert-Butyl (1R,5S)-3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (prepared according to the procedure described in WO 2021 / 136231 A1, 5.2 g, 11.4 mmol) was added and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 24 hours, the reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and diluted with EtOAc (75 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 x 75 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by trituration with diethyl ether to give the desired product (5.0 g, 8.2 mmol, 72% yield). LC / MS (ESI) m / z: [M+H] + C 27 H 35Calculated value for BrF2N5O3: 594.2; Found value: 594.2; 1 H NMR(400MHz,DMSO-d6)δ 7.73(d,J=1.20Hz,1H),7.46(d,J=6.40Hz,1H),5.21-5.35(m,1H),4.23-4.29(m,5H),4.10(d,J=10.40Hz,1H),4.02(d,J=10.00Hz,1H),2 .00(t,J=12.40Hz,2H),3.01-3.10(m,2H),2.12(d,J=Hz,1H),2.13-2.00(m,2H),1.75-1.85(m,6H),1.67(t,J=8.40Hz,2H),1.46(S,9H).

[0218] Step 2: tert-butyl (1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (from Step 1, 100 mg, 0.17 mmol) was dissolved in dioxane (2 mL) and water (0.5 mL). 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (63 mg, 0.22 mmol) and cesium carbonate (164 mg, 0.51 mmol) were added, and the resulting solution was flushed with nitrogen for 15 minutes. Pd(dppf)Cl2 (12 mg, 0.02 mmol) was added, and the reaction mixture was heated at 100 °C for 5 hours. Water (5 mL) and EtOAc (5 mL) were added and the layers were separated. The aqueous layer was further extracted with EtOAc (2 x 5 mL) and the combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (40% EtOAc / hexanes) to give the desired product (70 mg, 0.09 mmol, 56% yield). LC / MS (ESI) m / z: [M+H]+ C 37 H 41 Calculated value for ClF2N5O3: 676.3; Found value: 676.3.

[0219] Step 3: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline tert-Butyl (1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (from Step 2, 70 mg, 0.1 mmol) was dissolved in DCM (2 mL) and HCl solution (4.0 M in dioxane, 0.13 mL, 0.52 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was directly concentrated and the crude residue was purified by reverse-phase HPLC to give the desired product as its TFA salt (26 mg, 0.04 mmol, 35%). LC / MS (ESI) m / z: [M+H] + C 32 H 33 Calculated for ClF2N5O 576.2; found 576.3. [ka] 6-(6-chloro-4-((2R,5S)-2,5-dimethylpiperazin-1-yl)-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0220] The desired product was prepared using procedures similar to those described herein using the appropriate starting materials. 1H NMR(400MHz, CD3OD)δ 7.96(S,1H),6.54(S,1H),5.49-5.62(m,1H),4.50-4.61(m,2H),4.40-4.49(m,1H),3.80-3.76(m,8H),3.51-3.52(m,2H),3 .25-3.21(m,1H),3.15-3.20(m,2H),2.36-2.50(m,2H),2.15-2.36(m,1H),1.37(q,J=6.80Hz,3H),1.29(q,J=6.80Hz,3H). [ka] (1R,4R)-2-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-amine [ka]

[0221] Step 1: tert-butyl ((1R,4R)-2-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-yl)carbamate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 50 mg, 0.07 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (57 mg, 0.13 mmol) were combined and dissolved in acetonitrile (5 mL). Triethylamine (20 μL, 0.13 mmol) was added, followed by tert-butyl ((1R,4R)-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (14 mg, 0.07 mmol). The reaction mixture was heated at 40° C. for 12 h. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2×10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 50 H 56 Calculated value for ClF5N7O5: 964.4, measured value: 963.8.

[0222] Step 2: (1R,4R)-2-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-amine tert-Butyl ((1R,4R)-2-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (from Step 1, 80 mg, 0.08 mmol) was dissolved in TFA (1.5 mL), and triethylsilane (10 μL, 0.06 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40° C. for 12 h. The crude mixture was directly purified by preparative HPLC to give the desired product (19 mg, 0.03 mmol, 33% yield). LC / MS(ESI)m / z:[M+H] + C 29 H 32 ClF5N7O calculated value 624.2, found value 624.2; 1 H NMR(400MHz,CDCl3)δ 7.79-7.64(m,1H),6.44-6.28(m,1H),5.38-5.17(m,1H),4.92(br d,J=1.3Hz,1H),4.85-4.72(m,2H),4.33(d,J=10.3Hz,1H),4.25-4.16(m,1H),3.87(br dd,J=2.6,9.4Hz,1H),3.60-3.36(m,2H),3.28-3.06(m,1H),2.80(d,J=10.3Hz,1H),2.72-2.54(m,3 H),2.47-2.29(m,4H),2.23-2.09(m,7H),2.00(S,4H),1.94-1.81(m,3H),1.82-1.69(m,3H),1.62(br d,J=9.5Hz,2H). [ka] 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0223] Step 1: tert-butyl 5-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 50 mg, 0.07 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (43 mg, 0.10 mmol) were combined and dissolved in acetonitrile (2 mL). Triethylamine (14 μL, 0.10 mmol) was added, followed by tert-butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (15 mg, 0.07 mmol). The reaction mixture was heated at 40° C. for 12 hours. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 51 H 58 Calculated value for ClF5N7O5: 978.4, measured value: 978.2.

[0224] Step 2: 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine tert-Butyl 5-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (from Step 1, 50 mg, 0.05 mmol) was dissolved in TFA (1.5 mL), and triethylsilane (10 μL, 0.06 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40° C. for 16 h. The crude mixture was directly purified by preparative HPLC to give the desired product (23 mg, 0.04 mmol, 68% yield). LC / MS (ESI) m / z: [M+H] + C 30 H 34 ClF5N7O calculated value 638.2, found value 638.2; 1 H NMR(400MHz,CD3OD)δ 7.93(S,1H),6.63(S,1H),5.28-5.49(m,1H),4.36-4.44(m,2H),4.08-4.19(m,2H),3.70-3.90(m,3H),3.41- 3.48(m,2H),3.13-3.33(m,2H),3.13-3.16(m,2H),2.79-2.82(m,2H),2.47-2.47(m,3H),1.93-2.05(m,9H). [ka] 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0225] Step 1: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 50 mg, 0.07 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (43 mg, 0.10 mmol) were combined and dissolved in acetonitrile (2 mL). Triethylamine (14 μL, 0.10 mmol) was added, followed by tert-butyl hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (17 mg, 0.08 mmol). The reaction mixture was heated at 40° C. for 12 hours. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 50 H 57 Calculated value for ClF5N7O5: 964.4, measured value: 964.2.

[0226] Step 2: 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (from Step 1, 52 mg, 0.054 mmol) was dissolved in TFA (1.5 mL), and triethylsilane (10 μL, 0.06 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40° C. for 16 h. The crude mixture was directly purified by preparative HPLC to give the desired product as its TFA salt (28 mg, 0.04 mmol, 70% yield). LC / MS(ESI)m / z:[M+H] + C 29 H 32 ClF5N7O calculated value 624.2, found value 624.2; 1 H NMR(400MHz,CD3OD)δ 8.19(d,J=2.00Hz,1H),6.66(S,1H),5.40-5.59(m,2H),4.70-4.85(m,2H),4.32-4.50(m,3H), 4.05-4.05(m,1H),3.50-3.56(m,5H),2.68-2.80(m,1H),2.46-2.53(m,9H),2.28-2.43(m,3H). [ka] 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,4S,7R,7aS)-octahydro-1H-4,7-epiminoisoindol-8-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0227] Step 1: tert-butyl (3aR,4S,7R,7aS)-8-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-2H-4,7-epiminoisoindole-2-carboxylate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 50 mg, 0.07 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (57 mg, 0.13 mmol) were combined and dissolved in acetonitrile (5 mL). Triethylamine (18 μL, 0.13 mmol) was added, followed by tert-butyl (3aR,4S,7R,7aS)-octahydro-2H-4,7-epiminoisoindole-2-carboxylate (15 mg, 0.07 mmol). The reaction mixture was heated at 40° C. for 12 h. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2×10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 52 H 58 Calculated value for ClF5N7O5: 990.4, measured value: 990.0.

[0228] Step 2: 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,4S,7R,7aS)-octahydro-1H-4,7-epiminoisoindol-8-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine tert-Butyl (3aR,4S,7R,7aS)-8-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-2H-4,7-epiminoisoindole-2-carboxylate (from Step 1, 80 mg, 0.08 mmol) was dissolved in TFA (1.5 mL), and triethylsilane (10 μL, 0.06 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40° C. for 16 h. The crude mixture was directly purified by preparative HPLC to give the desired product (13 mg, 0.02 mmol, 24% yield). LC / MS(ESI)m / z:[M+H] + C 31 H 34 Calculated value of ClF5N7O: 650.2, found value: 649.8; 1 H NMR(400MHz,CDCl3)δ 7.70-7.57(m,1H),6.40(S,1H),5.43-5.16(m,2H),4.74(br S,3H),4.40-4.13(m,2H),3.53-3.33(m,1H),3.15-2.98(m,3H),2.95-2.77(m,3H),2.75-2.69(m,1H),2.67 -2.53(m,2H),2.41(d,J=1.5Hz,2H),2.17-2.07(m,2H),2.00(S,2H),1.90-1.84(m,1H),1.94-1.62(m,2H). [ka] 6-(4-(3,7-diazabicyclo[4.2.0]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0229] Step 1: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,7-diazabicyclo[4.2.0]octane-7-carboxylate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 50 mg, 0.07 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (43 mg, 0.10 mmol) were combined and dissolved in acetonitrile (5 mL). Triethylamine (14 μL, 0.10 mmol) was added, followed by tert-butyl 3,7-diazabicyclo[4.2.0]octane-7-carboxylate (17 mg, 0.08 mmol). The reaction mixture was heated at 40° C. for 12 hours. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 50 H 56Calculated value for ClF5N7O5: 964.4, measured value: 964.2.

[0230] Step 2: 6-(4-(3,7-diazabicyclo[4.2.0]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,7-diazabicyclo[4.2.0]octane-7-carboxylate (from Step 1, 54 mg, 0.06 mmol) was dissolved in TFA (1.5 mL) and triethylsilane (10 μL, 0.06 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40° C. for 16 h. The crude mixture was directly purified by preparative HPLC to give the desired product (12 mg, 0.02 mmol, 33% yield). LC / MS (ESI) m / z: [M+H] + C 29 H 32 ClF5N7O calculated value 624.2, found value 624.2; 1 H NMR(400MHz,CD3OD)δ 8.07-8.09(m,1H),6.63(d,J=0.80Hz,1H),5.31-5.44(m,1H),4.70-4.90(m,1H),4.37-4.50(m,3H),3.94-4.17(m,4H) ),3.32-3.35(m,2H),3.19-3.22(m,1H),2.86-2.89(m,2H),2.38-2.55(m,5H),2.16-2.19(m,1H),1.95-2.03(m,4H). [ka] (1S,3S)-N1-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)cyclobutane-1,3-diamine [ka]

[0231] Step 1: tert-butyl ((1S,3s)-3-((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)amino)cyclobutyl)carbamate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 70 mg, 0.09 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (60 mg, 0.14 mmol) were combined and dissolved in acetonitrile (5 mL). Triethylamine (20 μL, 0.14 mmol) was added, followed by tert-butyl ((1S,3s)-3-aminocyclobutyl)carbamate (17 mg, 0.09 mmol). The reaction mixture was heated at 40° C. for 12 hours. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 48 H 54 Calculated value for ClF5N7O5: 938.4, measured value: 938.4.

[0232] Step 2: (1S,3S)—N1-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)cyclobutane-1,3-diamine tert-Butyl ((1S,3s)-3-((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)amino)cyclobutyl)carbamate (73 mg, 0.078 mmol) was dissolved in TFA (1.5 mL), and triethylsilane (10 μL, 0.06 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40° C. for 16 h. The crude mixture was directly purified by preparative HPLC to give the desired product as the AcOH salt (17 mg, 0.03 mmol, 34% yield). LC / MS (ESI) m / z: [M+H] + C 27 H 30 Calculated value for ClF5N7O5: 598.2, Measured value: 598.2. 1 H NMR (400MHz, CD3OD) δ8.26-8.03(m, 1H), 6.62(s, 1H), 5.59-5.23(m, 1H), 4.56-4.06 (m, 4H), 3.64-3.54(m, 1H), 3.54-3.47(m, 1H), 3.24-3.14(m, 1H), 3.09-2.93(m, 3H) , 2.87(td, J=5.5, 11.0Hz, 1H), 2.64-2.52(m, 1H), 2.47(d, J=1.4Hz, 3H), 2.34-2.20 (m, 2H), 2.19-2.09(m, 1H), 2.08-1.97(m, 3H), 1.96-1.95(m, 3H), 1.92-1.82(m, 1H). [ka] 6-(4-(3,6-diazabicyclo[3.2.0]heptan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0233] Step 1: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 60 mg, 0.08 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (52 mg, 0.12 mmol) were combined and dissolved in acetonitrile (5 mL). Triethylamine (17 μL, 0.12 mmol) was added, followed by tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (31 mg, 0.16 mmol). The reaction mixture was heated at 40° C. for 12 hours. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 49 H 54Calculated value for ClF5N7O5: 950.4, Measured value: 950.4.

[0234] Step 2: 6-(4-(3,6-diazabicyclo[3.2.0]heptan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (from Step 1, 60 mg, 0.063 mmol) was dissolved in TFA (1.5 mL) and triethylsilane (10 μL, 0.06 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40° C. for 16 h. The crude mixture was directly purified by preparative HPLC to give the desired product (17 mg, 0.03 mmol, 41% yield). LC / MS (ESI) m / z: [M+H] + C 28 H 30 Calculated value of ClF5N7O5: 610.2, Measured value: 610.2; 1 H NMR(400MHz,CD3OD)δ 8.22-8.23(m,1H),6.63(S,1H),5.37(d,J=52.80Hz,1H),4.64-4.72(m,1H),4.42-4.50(m,2H),3.95-4.09(m,3H), 3.50-3.55(m,3H),3.15-3.23(m,2H),2.88-2.89(m,1H),2.47-2.51(m,3H),2.09-2.21(m,4H),1.93-2.00(m,4H). [ka] 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0235] Step 1: tert-butyl 6-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 50 mg, 0.07 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (29 mg, 0.07 mmol) were combined and dissolved in acetonitrile (5 mL). Triethylamine (10 μL, 0.07 mmol) was added, followed by tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (13.78 mg, 0.07 mmol). The reaction mixture was heated at 40° C. for 12 hours. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 50 H 56 Calculated value for ClF5N7O5: 964.4, measured value: 964.4.

[0236] Step 2: 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine tert-Butyl 6-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (from Step 1, 50 mg, 0.052 mmol) was dissolved in TFA (1.5 mL) and triethylsilane (10 μL, 0.06 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40° C. for 16 h. The crude mixture was directly purified by preparative HPLC to give the desired product as the formate salt (8 mg, 0.01 mmol, 20% yield). LC / MS (ESI) m / z: [M+H] + C 29 H 32 Calculated value for ClF5N7O5: 624.2, measured value: 624.2. [ka] (Z)-2-Fluoro-3-(thiazol-2-yl)acrylic acid

[0237] Step 1: Preparation of ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (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 portionwise as a solid. The reaction mixture was stirred for 10 minutes, and thiazole-2-carbaldehyde (0.51 g, 4.5 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The solution was diluted with water (20 mL) and EtOAc (150 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→60% acetone / hexanes) to give ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate ( 1 10:1 E / Z as determined by H NMR, 620 mg, 3.1 mmol, 68% yield. LC / MS (ESI) m / z: [M+H] + Calculated value of C8H9FNO2S: 202.0; Found value: 202.2; 1 H NMR(500MHz,CDCl3)δ 7.94(d,J=3.2Hz,1H),7.52(d,J=3.2Hz,1H),7.34(d,J=22.2Hz,1H),4.43(q,J=7.2Hz,2H),1.41(t,J=7.2Hz,3H).

[0238] Step 2: Preparation of ethyl (Z)-2-fluoro-3-(thiazol-2-yl)acrylate Ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate (620 mg, 3.1 mmol) was dissolved in toluene (15 mL) and iodine (39 mg, 0.15 mmol) was added. The reaction mixture was heated at 100° C. for 7 days. The solution was concentrated and purified by column chromatography (0→100% EtOAc / hexanes) to give ethyl (Z)-2-fluoro-3-(thiazol-2-yl)acrylate (509 mg, 2.5 mmol, 82% yield). LC / MS (ESI) m / z: [M+H] +Calculated value of C8H9FNO2S: 202.0; Found value: 202.0; 1 H NMR(500MHz,CDCl3)δ 7.96(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).

[0239] Step 3: Preparation of (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(thiazol-2-yl)acrylate (510 mg, 2.5 mmol) was dissolved in MeOH (15 mL). The solution was cooled to 0° C., and sodium hydroxide solution (1.0 M, 2.5 mL, 2.5 mmol) was added. The reaction mixture was stirred for 5 hours. The solution was concentrated to remove methanol. Additional water (1.5 mL) was added, and the aqueous solution was cooled to 0° C. HCl solution (1.0 M, 2.5 mL, 2.5 mmol) was added dropwise. After 10 minutes, a white solid precipitated. The solid was collected by filtration and washed with MeCN. The solid was dried under vacuum to give (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (337 mg, 1.9 mmol, 77% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated value of C6H5FNO2S: 174.0; Found value: 173.8; 1 H NMR(500MHz,DMSO-d6)δ 8.04(S,2H),7.29(d,J=34.5Hz,1H). [ka] (Z)-2-Fluoro-3-(pyrimidin-2-yl)acrylic acid

[0240] Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-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 portionwise as a solid. The reaction mixture was stirred for 10 minutes, and pyrimidine-2-carbaldehyde (0.71 g, 6.6 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The solution was diluted with water (20 mL) and EtOAc (150 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→90% EtOAc / hexanes) to give ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate (5:1 E / Z as judged by H NMR, 592 mg, 3.0 mmol, 46% yield). LC / MS (ESI) m / z: [M+H] + C9H 10 Calculated FN2O2 197.2; Measured 197.1; 1 H NMR(500MHz,CDCl3)δ 8.70(d,J=4.9Hz,2H),7.18(t,J=4.9Hz,1H),6.77(d,J=17.5Hz,1H),4.28(q,J=7.2Hz,3H),1.39(t,J=7.2Hz,3H).

[0241] Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate Ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate (592 mg, 3.0 mmol) was dissolved in toluene (15 mL) and iodine (38 mg, 0.15 mmol) was added. The reaction mixture was heated at 100° C. for 7 days. The solution was concentrated and purified by column chromatography (0→100% EtOAc / hexanes) to give ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate (253 mg, 1.3 mmol, 43% yield). LC / MS (ESI) m / z: [M+H] + C9H 10Calculated FN2O2 197.2; Measured 196.6; 1 H NMR(500MHz,CDCl3)δ 8.83(d,J=4.9Hz,2H),7.21(t,J=4.9Hz,1H),7.13(d,J=30.8Hz,1H),4.38(q,J=7.2Hz,2H),1.39(t,J=7.2Hz,3H).

[0242] Step 3: Preparation of (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate (253 mg, 1.3 mmol) was dissolved in MeOH (10 mL). The solution was cooled to 0° C., and sodium hydroxide solution (1.0 M, 1.3 mL, 1.3 mmol) was added. The reaction mixture was stirred for 2 hours. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added, and the aqueous solution was cooled to 0° C. HCl solution (1.0 M, 2.5 mL, 2.5 mmol) was added dropwise. After 10 minutes, a white solid precipitated. The solid was collected by filtration and dried under vacuum to give (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylic acid (190 mg, 1.1 mmol, 88% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated value for C7H6FN2O2: 169.1; Found value: 168.8; 1 H NMR(500MHz,DMSO-d6)δ 8.90(d,J=4.9Hz,2H),7.46(t,J=4.9Hz,1H),6.94(d,J=31.5Hz,1H). [ka] (Z)-2-Fluoro-3-(pyridin-2-yl)acrylic acid

[0243] Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1.5 g, 6.2 mmol) was dissolved in THF (31 mL). The solution was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.2 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes, and picolinaldehyde (0.66 g, 6.2 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (15 mL). The solution was diluted with water (20 mL) and EtOAc (100 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to give ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate ( 1 A 3:1 E / Z mixture was obtained, 910 mg, 4.6 mmol, 75% yield, as determined by H NMR. LC / MS (ESI) m / z: [M+H] + C 10 H 11 Calculated for FNO2 196.1; Found 196.1; E isomer reported: 1 H NMR(500MHz,CDCl3)δ 8.59(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).

[0244] Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate Ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate (420 mg, 2.1 mmol) was dissolved in toluene (10 mL) and iodine (27 mg, 0.15 mmol) was added. The reaction mixture was heated at 100° C. for 7 days. The solution was concentrated and purified by column chromatography (0→100% EtOAc / hexanes) to give ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate (240 mg, 1.2 mmol, 58% yield). LC / MS (ESI) m / z: [M+H] + C 10 H 11 Calculated FNO2 196.1; Measured 196.1; 1 H NMR(500MHz,CDCl3)δ 8.66(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).

[0245] Step 3: Preparation of (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate (415 mg, 2.1 mmol) was dissolved in MeOH (15 mL). The solution was cooled to 0° C., and sodium hydroxide solution (1.0 M, 2.1 mL, 2.1 mmol) was added. The reaction mixture was stirred for 5 hours. The solution was concentrated to remove methanol. Additional water (2.0 mL) was added, and the aqueous solution was cooled to 0° C. HCl solution (1.0 M, 2.1 mL, 2.1 mmol) was added dropwise. After 10 minutes, a white solid precipitated. The solid was collected by filtration and washed with EtO. The solid was dried under vacuum to give (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (235 mg, 1.4 mmol, 66% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated for C8H7FNO2 168.0; found 167.8. 1H NMR(500MHz,DMSO-d6)δ 8.66(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). [ka] 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0246] Step 1: Benzyl (S)-4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate 7-Bromo-2,4-dichloro-8-fluoroquinazoline (500 mg, 1.7 mmol) was dissolved in dioxane (15 mL) and DIPEA (0.89 mL, 5.1 mmol) was added, followed by benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylate (440 mg, 1.7 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (20 mL) and quenched by the addition of NaOH solution (1.0 M, 2 mL). The layers were separated and the organic phase was washed with brine (10 mL). The combined aqueous layers were back-extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (5 → 50% EtOAc / hexanes) to give the desired product (760 mg, 1.5 mmol, 87% yield) as a white solid. LC / MS(ESI)m / z:[M+H] + C 22 H 19Calculated for BrClFN5O2 518.0; Found 517.9; NMR: 1 H NMR(500MHz,CD3OD)δ 7.80(dd,J=9.1,1.5Hz,1H),7.68(dd,J=9.1,6.5Hz,1H),7.45-7.28(m,5H),5.24-5.12(m,2H),4.79-4.71(m,1H), 4.50-4.34(m,2H),4.14-4.08(m,1H),3.81-3.70(m,1H),3.69-3.61(m,1H),3.59-3.46(m,1H),3.04-2.88(m,2H).

[0247] Step 2: Benzyl (S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (from Step 1, 250 mg, 0.48 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, HCl salt (commercially available or prepared according to the procedure described in WO 2022 / 031678, 104 mg, 0.53 mmol) were suspended in THF (8 mL). A solution of LiHMDS (1.0 M in THF, 1.1 mL, 1.1 mmol) was added dropwise, and the reaction mixture was heated at 65 °C for 16 h. The mixture was diluted with EtOAc (20 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→8% MeOH / DCM) to give the desired product (184 mg, 0.29 mmol, 60% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + C 30 H 32 Calculated value for BrF2N6O3: 641.2; Found: 641.1.

[0248] Step 3: Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (80 mg, 0.125 mmol from Step 2), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (39 mg, 0.125 mmol), and potassium phosphate tribasic solution (2.0 M, 0.19 mL, 0.375 mmol) were dissolved in dioxane (2 mL). The solution was purged with a stream of nitrogen for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (4 mg, 0.006 mmol) was added, and the resulting solution was heated at 100°C for 3 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→6% MeOH / DCM) to give the desired product (51 mg, 0.07 mmol, 55% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 42 H 43 Calculated value of F2N6O5: 749.3; Found value: 749.3.

[0249] Step 4: 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate (from Step 3, 50 mg, 0.07 mmol) and palladium on carbon (10 wt%, 36 mg, 0.03 mmol) were suspended in ethanol (10 mL). Hydrogen gas was bubbled through the reaction mixture for 5 minutes. The reaction mixture was maintained under a positive pressure of hydrogen (1 atm, balloon) for 2 hours. The reaction mixture was filtered through diatomaceous earth (Celite™), taking care not to allow the filter cake to dry out, and the filtrate was concentrated. The crude residue was sufficiently pure to be used directly in the next step without further purification (assuming quantitative yield). LC / MS(ESI)m / z:[M+H] + C 34 H 37 Calculated value of F2N6O3: 615.3; Measured value: 615.2.

[0250] Step 5: 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile (from step 4, 37 mg, 0.06 mmol) was suspended in HCl solution (4.0 M in dioxane, 0.5 mL, 2.0 mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was directly concentrated and further dried under high vacuum to give the desired product as the HCl salt (assuming quantitative yield). The crude material was pure enough to be used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 32 H 33 Calculated F2N6O2 value: 571.3; Measured value: 571.2. [ka] 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0251] Step 1: Benzyl (S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (140 mg, 0.22 mmol), 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (63 mg, 0.22 mmol), and potassium phosphate tribasic solution (2.0 M, 0.33 mL, 0.66 mmol) were dissolved in dioxane (2 mL). The solution was purged with a stream of nitrogen for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (7 mg, 0.01 mmol) was added, and the resulting solution was heated at 100°C for 3 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→6% MeOH / DCM) to give the desired product (78 mg, 0.11 mmol, 49% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 40 H 38Calculated value for ClF2N6O5: 723.3; Found value: 723.2.

[0252] Step 2: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (Step 1, 58 mg, 0.08 mmol) and palladium on carbon (10 wt%, 36 mg, 0.03 mmol) were suspended in ethanol (10 mL). Hydrogen gas was bubbled through the reaction mixture for 5 minutes. The reaction mixture was maintained under a positive pressure of hydrogen (1 atm, balloon) for 2 hours. The reaction mixture was filtered through diatomaceous earth (Celite™), taking care not to allow the filter cake to dry out, and the filtrate was concentrated. The crude residue was sufficiently pure to be used directly in the next step without further purification (assuming quantitative yield). LC / MS(ESI)m / z:[M+H] + C 32 H 33 Calculated value for ClF2N6O: 589.3; Found: 589.2. [ka] (1S,4S)-2-[(7M)-2-{[(2R,7aR)-2-Fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-4-amine [ka]

[0253] Step 1: tert-butyl N-[(1S,4S)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-4-yl]carbamate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 50 mg, 0.065 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (57 mg, 0.13 mmol) were combined and dissolved in acetonitrile (5 mL). Triethylamine (18 μL, 0.13 mmol) was added, followed by tert-butyl ((1S,4S)-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (14 mg, 0.065 mmol). The reaction mixture was heated at 40° C. for 12 h. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2×10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was sufficiently pure to be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 50 H 56 Calculated value for ClF5N7O5: 964.4, measured value: 963.8.

[0254] Step 2: (1S,4S)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-4-amine tert-Butyl N-[(1S,4S)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-4-yl]carbamate (from Step 1, 70 mg, 0.06 mmol) was dissolved in TFA (1.5 mL), and triethylsilane (10 μL, 0.06 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40° C. for 12 h. The crude mixture was directly purified by preparative HPLC to give the desired product (15 mg, 0.02 mmol, 37% yield). LC / MS(ESI)m / z:[M+H] + C 29 H 32 ClF5N7O calculated value 624.2, found value 624.1; 1 H NMR(400MHz,CD3OD)δ 7.91-7.63(m,1H),6.48(S,1H),5.52-5.25(m,1H),5.14-4.99(m,1H),4.89(br S,1H),4.45(d,J=10.5Hz,1H),4.31-4.21(m,1H),3.95(br d,J=8.8Hz,1H),3.72-3.47(m,1H),3.25-3.14(m,1H),3.04-2.95(m,1H),2.79-2.59(m,2H),2.5 0(S,2H),2.20(dt,J=6.4,12.9Hz,1H),2.13-2.06(m,4H),2.07-1.94(m,8H),1.86-1.71(m,4H). [ka] (1R,4R,7R)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-7-amine [ka]

[0255] Step 1: tert-butyl N-[(1R,4R,7R)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate 14B, 50 mg, 0.065 mmol) and benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (43 mg, 0.10 mmol) were combined and dissolved in acetonitrile (2 mL). Triethylamine (14 μL, 0.10 mmol) was added, followed by tert-butyl ((7R)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate (17 mg, 0.08 mmol). The reaction mixture was heated at 40° C. for 16 hours. Water (10 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography on neutral alumina (45% EtOAc / hexanes) to give the desired product (52 mg, 0.05 mmol, 81% yield). LC / MS (ESI) m / z: [M+H] + C 50 H 56 Calculated value for ClF5N7O5: 964.4, measured value: 964.5.

[0256] Step 2: (1R,4R,7R)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-7-amine tert-Butyl N-[(1R,4R,7R)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-7-yl]carbamate (from Step 1, 52 mg, 0.05 mmol) was dissolved in TFA (1.5 mL), and triethylsilane (1 μL, 0.006 mmol) and water (0.05 mL) were added. The reaction mixture was heated at 40 °C for 12 h. The crude mixture was directly purified by preparative HPLC to give the desired product as a TFA salt (26 mg, 0.035 mmol, 64% yield). LC / MS (ESI) m / z: [M+H] + C 29 H 32 ClF5N7O calculated value 624.2, found value 624.2; 1 H NMR(400MHz,CD3OD)δ 8.07(S,1H),6.65(S,1H),5.45-5.58(m,1H),5.19(S,1H),4.79-4.81(m,3H),4.38-4.97(m,1H),3.99-4.09(m,1 H),3.33-3.81(m,4H),2.90-3.00(m,1H),2.61-2.82(m,1H),2.47-2.59(m,5H),2.09(m,6H),1.82-1.90(m,1H). [ka] (5M)-6-(4,6-dichloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0257] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4(3H)-one (Intermediate 6I, 240 mg, 0.33 mmol) was dissolved in DCM (1.6 mL) and thionyl chloride was added (240 μL, 3.3 mmol), followed by dropwise addition of DMF (approximately 10 μL). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was directly concentrated and the crude product was azeotroped from toluene (3×2 mL) to give the desired product as a brown solid (assuming quantitative yield) as the HCl salt. LC / MS (ESI) m / z: [M+H] + C 37 H 36 Calculated value for Cl2F4N5O3: 744.2; Found value: 744.1. [ka] 2-[(2S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]piperazin-2-yl]acetonitrile and 2-[(2S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]piperazin-2-yl]acetamide [ka]

[0258] 6-(4,6-Dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine, HCl salt (Intermediate 32, 40 mg, 0.05 mmol) and (S)-2-(piperazin-2-yl)acetonitrile, diHCl salt (15 mg, 0.08 mmol) were combined and suspended in DCM (500 μL). DIPEA (45 μL, 0.26 mmol) was added, and the reaction mixture was heated at 50° C. for 30 minutes. To the solution was then added triethylsilane (80 μL, 0.5 mmol), TFA (500 μL), and a drop of water (approximately 10 μL). The reaction mixture was heated at 50° C. for 16 hours. 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: 87% 5:95 MeCN:10 mM AA in HO / 13% 95:5 MeCN:10 mM AA in HO → 100% 95:5 MeCN:10 mM AA in HO; λ = 220 nm) to give the desired product (7.5 mg, 0.013 mmol, 25% yield) along with the nitrile hydrolysis product (8.7 mg, 0.014 mmol, 28% yield). LC / MS (ESI) m / z: [M+H] + C 27 H 30 Calculated for ClF4N8O: 593.2; Found: 593.2 [desired]; and LC / MS (ESI) m / z: [M+H] + C 27 H 31 Calculated value for ClF4N8O2: 611.2; Found value: 611.4 [hydrolysis]; 1 H NMR(600MHz,DMSO-d6)δ 7.83(s,1H),6.85(s,2H),6.49(s,1H),4.39(dd,J=10.8,4.5Hz,1H),4.24-4.09(m,3H),3.27-3 .21(m,2H),3.10-3.00(m,3H),2.97-2.86(m,2H),2.75-2.70(m,2H),2.60-2.54(m,1H),2.37(br s, 3H), 2.35 (s, 3H), 2.20-2.14 (m, 1H), 1.96-1.90 (m, 1H), 1.71-1.61 (m, 3H) [desired] and1 H NMR(600MHz,DMSO-d6)δ 7.85(s,1H),7.43-7.43(m,1H),7.41(br s,1H),6.89-6.83(m,3H),6.49(s,1H),4.39(dd,J=10.6,4.5Hz,1H),4.24(br d,J=12.7Hz,1H),4.20-4.11(m,2H),3.17(br t,J=11.7Hz,1H),3.09(br d,J=5.8Hz,1H),3.01(br d,J=11.8Hz,1H),2.98-2.93(m,2H),2.91-2.85(m,1H),2.60-2.54(m,1H),2.37(br s,3H),2.36(br s,3H),2.23-2.14(m,3H),1.97-1.91(m,1H),1.71-1.60(m,3H)[hydrolysis]. [ka] (1S,4S)-2-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-4-amine [ka]

[0259] 6-(4,6-Dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine, HCl salt (Intermediate 32, 35 mg, 0.045 mmol) and tert-butyl ((1S,4S)-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (Intermediate 37, 11 mg, 0.054 mmol) were combined and suspended in DCM (500 μL). (40 μL, 0.22 mmol) was added and the reaction mixture was heated at 50° C. for 30 min. To the solution was then added triethylsilane (29 μL, 0.18 mmol), TFA (500 μL), and a drop of water (approximately 10 μL). The reaction mixture was heated at 50° C. for 16 h. The reaction mixture was directly concentrated and the crude residue was azeotroped from toluene (3×1 mL) to give the desired product as the TFA salt, which was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 27 H 31 Calculated for ClF4N7O 580.0; found 580.3. [ka] (1R,4R,7R)-2-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-7-amine [ka]

[0260] 6-(4,6-Dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine, HCl salt (Intermediate 32, 35 mg, 0.045 mmol) and tert-butyl ((1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate (11 mg, 0.054 mmol) were combined and suspended in DCM (500 μL). DIPEA (4 HCl (0.0 μL, 0.22 mmol) was added and the reaction mixture was heated at 50° C. for 30 min. To the solution was then added triethylsilane (29 μL, 0.18 mmol), TFA (500 μL), and a drop of water (approximately 10 μL). The reaction mixture was heated at 50° C. for 16 h. The reaction mixture was directly concentrated and the crude residue was azeotroped from toluene (3×1 mL) to give the desired product as the TFA salt, which was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 27 H 31 Calculated value for ClF4N7O: 580.0; found value: 580.1. [ka] (Z)-2-Fluoro-3-(6-methylpyridin-2-yl)acrylic acid

[0261] Step 1: Ethyl (Z)-2-fluoro-3-(6-methylpyridin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes, and 6-methylpyridine-2-carbaldehyde (125 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by HPLC (column: Xbridge C18, 5 μm particles; gradient: 5:95 MeCN:HO with 0.05% TFA to 95:5 MeCN:HO with 0.05% TFA; λ = 220 nm) to give the desired product (31 mg, 0.15 mmol, 14% yield). LC / MS (ESI) m / z: [M+H] + C 11 H 13 Calculated FNO2 210.1; measured 209.7; 1 H NMR(500MHz,CDCl3)δ 7.71(d,J=7.8Hz,1H),7.63(t,J=7.8Hz,1H),7.10(d,J=7.8Hz,1H),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).

[0262] Step 2: (Z)-2-Fluoro-3-(6-methylpyridin-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(6-methylpyridin-4-yl)acrylate (31 mg, 0.15 mmol) was dissolved in MeOH (1.5 mL) and sodium hydroxide solution (1.0 M, 150 μL, 0.15 mmol) was added dropwise. The mixture was stirred for 2 hours. 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 further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + Calculated value for C9H9FNO2: 182.1; Found value: 182.1; 1 H NMR(500MHz,DMSO-d6)δ 7.80(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). [ka] tert-Butyl ((1S,4S)-2-azabicyclo[2.2.1]heptan-4-yl)carbamate [ka]

[0263] Step 1: tert-butyl ((1S,4S)-2-benzyl-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (1S,4S)-2-Benzyl-2-azabicyclo[2.2.1]heptan-4-amine (commercially available or can be prepared according to the procedure described in U.S. Pat. No. 8,476,295 B2) (20.2 g, 100 mmol) was dissolved in water (150 mL). The solution was cooled to 0° C., and solid NaOH (approximately 24 g) was added portionwise until the pH of the solution reached approximately 14. A solution of di-tert-butyl dicarbonate (26.2 g, 120 mmol) in DCM (300 mL) was added, and the resulting solution was stirred for 1 h. The layers were separated, and the aqueous layer was further extracted with DCM (2×100 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude residue was recrystallized from hot heptane to give the desired product (24.7 g, 82 mmol, 82% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.49-7.15(m,5H),4.94-4.67(m,1H),3.87-3.59(m,2H),3.26-3.17(m,1H),3.10- 2.85(m,1H),2.64-2.30(m,1H),2.16-19.2(m,2H),1.88-1.58(m,4H),1.43(s,9H).

[0264] Step 2: tert-butyl ((1S,4S)-2-azabicyclo[2.2.1]heptan-4-yl)carbamate tert-Butyl ((1S,4S)-2-benzyl-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (17 g, 56 mmol) was dissolved in MeOH (250 mL) and palladium hydroxide on carbon (20 wt%, 1.7 g) was added as a solid. Hydrogen gas was bubbled through the solution for 5 minutes, and the reaction mixture was maintained under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth (Celite™), and the solution was concentrated to give the desired product (11 g, 52 mmol, 92% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 5.09(br s,1H),3.92-3.58(m,2H),1.95(br s,1H),2.03-1.66(m,6H),1.30(s,9H). [ka] 2-((2S)-4-(8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0265] Step 1: Preparation of benzyl (2S)-2-(cyanomethyl)-4-(8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (200 mg, 0.335 mmol) and (5-methyl-1H-indazol-4-yl)boronic acid (59 mg, 0.335 mmol) were combined as solids and dissolved in dioxane (4 mL). Potassium phosphate solution (2.0 M, 0.5 mL, 1.0 mmol) was added, and nitrogen was flushed through the solution for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), (dtbpf)PdCl2, (11 mg, 0.017 mmol) was added as a solid, and the reaction mixture was heated at 100 °C for 2 hours. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (5 mL) and brine (5 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0-8% MeOH / DCM with 5% NH4OH) to give the desired product (159 mg, 0.245 mmol, 73% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 36 H 38 Calculated value of FN8O3: 649.3; Measured value: 649.3; 1H NMR(500MHz,CD3OD)δ 7.94(d,J=8.6Hz,1H),7.60(d,J=5.2Hz,1H),7.55(d,J=8.6Hz,1H),7.44-7.29(m,7H), 5.27-5.16(m,2H),4.83-4.74(m,3H),4.56-4.51(m,1H),4.49-4.38(m,3H),4.20-4.12( m,1H),3.78-3.69(m,1H),3.66-3.51(m,2H),3.12-2.94(m,3H),2.85-2.77(m,1H),2.53 (S,1H),2.42-2.34(m,1H),2.30(d,J=3.1Hz,3H),2.17-2.06(m,1H),1.86-1.73(m,3H).

[0266] Step 2: Preparation of 2-((2S)-4-(8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (2S)-2-(cyanomethyl)-4-(8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (150 mg, 0.23 mmol) was dissolved in EtOH (20 mL) and palladium on carbon (10 wt%, 246 mg, 0.23 mmol) was added. Hydrogen gas was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 hours. The solution was filtered through a Celite™ pad and concentrated to give the desired product, which could be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 28 H 32 Calculated FN8O value 515.3; measured value 515.2; 1H NMR(500MHz,CD3OD)δ 7.90(d,J=8.3Hz,1H),7.61(d,J=3.3Hz,1H),7.54(d,J=8.7Hz,1H),7.41(d,J=8.7Hz, 1H),7.31(dd,J=8.3,6.6Hz,1H),4.58-4.45(m,3H),4.42-4.34(m,1H),3.51-3.42(m,1 H),3.36-3.32(m,1H),3.24-2.99(m,5H),2.85-2.79(m,1H),2.72(dd,J=6.3,2.6Hz,2 H),2.54(S,3H),2.41-2.34(m,1H),2.30(S,3H),2.17-2.08(m,1H),1.89-1.76(m,3H). [ka] 2-((2S)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0267] Step 1: Preparation of benzyl (2S)-2-(cyanomethyl)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (200 mg, 0.335 mmol) and (2-fluoro-6-hydroxyphenyl)boronic acid (52 mg, 0.335 mmol) were combined as solids and dissolved in dioxane (4 mL). Potassium phosphate solution (2.0 M, 0.5 mL, 1.0 mmol) was added, and nitrogen was flushed through the solution for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), (dtbpf)PdCl2, (11 mg, 0.017 mmol) was added as a solid, and the reaction mixture was heated at 100 °C for 2 hours. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (5 mL) and brine (5 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0->10% MeOH / DCM with 5% NH4OH) to give the desired product (160 mg, 0.25 mmol, 76% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 34 H 35 Calculated F2N6O4 value 629.3; Measured value 629.4; 1 H NMR(500MHz,CD3OD)δ 7.82(d,J=8.7Hz,1H),7.44-7.29(m,6H),7.28-7.23(m,1H),6.77(d,J=8.2Hz,1H),6.70(t, J=8.7Hz,1H),5.25-5.16(m,2H),4.82-4.77(m,2H),4.56-4.49(m,1H),4.49-4.43(m,1H),4 .43-4.35(m,2H),4.19-4.09(m,1H),3.73-3.61(m,1H),3.61-3.42(m,2H),3.13-2.95(m,2H ),2.87-2.79(m,1H),2.54(S,3H),2.40-2.32(m,1H),2.18-2.07(m,1H),1.88-1.73(m,3H).

[0268] Step 2: Preparation of 2-((2S)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (2S)-2-(cyanomethyl)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (200 mg, 0.32 mmol) was dissolved in EtOH (20 mL) and palladium on carbon (10 wt%, 340 mg, 0.32 mmol) was added. Hydrogen gas was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 hours. The solution was filtered through a Celite™ pad and concentrated to give the desired product, which could be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 26 H 29 Calculated F2N6O2 495.2; Measured 495.2; 1 H NMR(500MHz,CD3OD)δ 7.77(d,J=8.7Hz,1H),7.31-7.22(m,2H),6.76(d,J=8.2Hz,1H),6.73-6.66(m,1H) ),4.56-4.50(m,1H),4.50-4.40(m,2H),4.36-4.30(m,1H),3.46-3.38(m,1H),3. 30-3.26(m,1H),3.19-3.07(m,3H),3.06-2.98(m,1H),2.85-2.77(m,1H),2.73-2 .67(m,2H),2.54(S,3H),2.43-2.32(m,1H),2.18-2.05(m,1H),1.90-1.72(m,3H). [ka] 2-((S)-4-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0269] Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (70 mg, 0.12 mmol) and (8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)boronic acid (41 mg, 0.12 mmol) were combined as solids and dissolved in dioxane (4 mL). Potassium phosphate solution (2.0 M, 0.18 mL, 0.35 mmol) was added, and nitrogen was flushed through the solution for 15 minutes. [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), (dtbpf)PdCl2, (3.8 mg, 5.9 μmol) was added as a solid, and the reaction mixture was heated at 100 °C for 2 hours. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (5 mL) and brine (5 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0-8% MeOH / DCM with 5% NH4OH) to give the desired product (60 mg, 0.07 mmol, 62% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 49 H 58 Calculated value of FN6O3Si: 825.4; Measured value: 825.8; 1H NMR(500MHz,CD3OD)δ 8.05-8.00(m,2H),7.88-7.83(m,1H),7.80-7.76(m,1H),7.63-7.58(m,1H),7.5 4-7.49(m,1H),7.45-7.34(m,7H),5.27-5.10(m,3H),4.65-4.29(m,6H),4.52-4 .28(m,3H),3.83-3.60(m,1H),3.56-3.37(m,1H),3.20-2.89(m,4H),2.51-2.41 (m,1H),2.22(S,1H),1.89-1.75(m,3H),0.90-0.85(m,18H),0.62-0.45(m,3H).

[0270] Step 2: Preparation of benzyl (S)-2-(cyanomethyl)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate (50 mg, 0.061 mmol) was dissolved in DMF (4 mL) and CsF (28 mg, 0.18 mmol) was added. The suspension was heated at 60° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 mL) and brine (5 mL). The layers were separated and the organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 40 H 38 Calculated value of FN6O3: 669.3; measured value: 669.5.

[0271] Step 3: Preparation of 2-((S)-4-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-2-(cyanomethyl)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (50 mg, 0.075 mmol) was dissolved in EtOH (10 mL) and palladium on carbon (10 wt%, 80 mg, 0.075 mmol) was added. Hydrogen gas was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 hours. The solution was filtered through a Celite™ pad and concentrated to give the desired product, which could be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 32 H 36 Calculated FN6O 539.3; Measured 539.2. [ka] 2-((S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0272] Step 1: Preparation of benzyl (S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (70 mg, 0.117 mmol) and (5-chloro-2-methoxyphenyl)boronic acid (21.84 mg, 0.117 mmol) were combined as solids and dissolved in dioxane (4 mL). Potassium phosphate solution (2.0 M, 0.18 mL, 1.0 mmol) was added, and nitrogen was flushed through the solution for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), (dtbpf)PdCl2, (3.8 mg, 5.8 μmol) was added as a solid, and the reaction mixture was heated at 100 °C for 2 hours. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (5 mL) and brine (5 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0-8% MeOH / DCM with 5% NH4OH) to give the desired product (55 mg, 0.08 mmol, 71% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 35 H 37 Calculated value of ClFN6O4: 659.3; Found value: 659.4; 1 H NMR(500MHz,CD3OD)δ 7.82(d,J=8.3Hz,1H),7.43-7.28(m,8H),7.13(d,J=8.9Hz,1H),5.26-5.15(m,2H),4 .80-4.76(m,2H),4.62-4.49(m,2H),4.46-4.35(m,2H),4.17-4.11(m,1H),3.80(S,3 H),3.73-3.68(m,1H),3.60-3.48(m,1H),3.18-3.13(m,1H),3.06-2.96(m,2H),2.92 -2.86(m,1H),2.57(S,3H),2.48-2.42(m,1H),2.16-2.12(m,1H),1.89-1.78(m,3H).

[0273] Step 2: Preparation of 2-((S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (60 mg, 0.09 mmol) was dissolved in EtOH (15 mL) and palladium on carbon (10 wt%, 97 mg, 0.09 mmol) was added. Hydrogen gas was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 hours. The solution was filtered through a Celite™ pad and concentrated to give the desired product, which could be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 27 H 31 Calculated value of ClFN6O2: 525.2; Found value: 525.4; 1 H NMR(500MHz,CD3OD)δ 7.77(d,J=8.5Hz,1H),7.42(dd,J=8.9,2.5Hz,1H),7.31(d,J=2.5Hz,1H),7.26(dd,J =8.5,6.6Hz,1H),7.12(d,J=8.9Hz,1H),4.54-4.41(m,4H),4.37-4.29(m,1H),3.80(S ,3H),3.46-3.40(m,1H),3.19-3.10(m,3H),3.05-2.99(m,1H),2.84-2.78(m,2H),2.7 2-2.68(m,2H),2.54(S,3H),2.40-2.35(m,1H),2.16-2.09(m,1H),1.86-1.77(m,3H). [ka] 2-((S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0274] Step 1: Preparation of benzyl (S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (75 mg, 0.126 mmol) and (5-chloro-2-(trifluoromethoxy)phenyl)boronic acid (30 mg, 0.126 mmol) were combined as solids and dissolved in dioxane (4 mL). Potassium phosphate solution (2.0 M, 0.19 mL, 1.0 mmol) was added, and nitrogen was flushed through the solution for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), (dtbpf)PdCl2, (4.1 mg, 6.3 μmol) was added as a solid, and the reaction mixture was heated at 100 °C for 2 hours. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (5 mL) and brine (5 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0-8% MeOH / DCM with 5% NH4OH) to give the desired product (67 mg, 0.09 mmol, 75% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 35 H 34 Calculated value for ClF4N6O4: 713.2; Found value: 713.5; 1H NMR(500MHz,CD3OD)δ 7.91(d,J=8.7Hz,1H),7.61-7.57(m,1H),7.51-7.48(m,1H),7.42-7.29(m,5H),5.25-5.13(m,2H),4.78-4.72(m,1H),4.57(br S,3H),4.54-4.46(m,2H),4.43-4.31(m,2H),4.19-4.10(m,1H),3.74-3.66(m,1H),3.60-3.53(m,1H),3.20-3.12( m,1H),3.09-2.93(m,2H),2.91-2.81(m,1H),2.56(S,3H),2.48-2.37(m,1H),2.20-2.06(m,1H),1.93-1.75(m,3H).

[0275] Step 2: Preparation of 2-((S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (65 mg, 0.09 mmol) was dissolved in EtOH (15 mL) and palladium on carbon (10 wt%, 97 mg, 0.09 mmol) was added. Hydrogen gas was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 hours. The solution was filtered through a Celite™ pad and concentrated to give the desired product, which could be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 27 H 28 Calculated for ClF4N6O2 579.2; Found 579.2. [ka] (1S,4S)-2-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-amine [ka]

[0276] 6-((R)-4,6-Dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine, HCl (35 mg, 0.045 mmol), and tert-butyl ((1S,4S)-2-azabicyclo[2.2.1]heptan-4-yl)carbamate (11.42 mg, 0.054 mmol) were combined and suspended in DCM (0.5 mL). DIPEA (39 μL, 0.22 mmol) was added, and the reaction mixture was heated at 40° C. for 15 min. Triethylsilane (29 μL, 0.18 mmol) and TFA (0.5 mL) were added to the solution, and the resulting mixture was maintained at 40° C. for an additional 16 h. The reaction mixture was concentrated directly and the crude residue was azeotroped from toluene (3 x 1 mL) to give the desired product as a crude oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 27 H 31 Calculated for ClF4N7O 580.2; found 580.3. [ka] (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(3-methoxypropyl)piperidin-4-yl)oxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0277] Step 1: Preparation of benzyl (S)-4-(7-bromo-8-fluoro-2-((1-(3-methoxypropyl)piperidin-4-yl)oxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (S)-4-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (120 mg, 0.23 mmol) and 1-(3-methoxypropyl)piperidin-4-ol (40 mg, 0.23 mmol) were dissolved in THF (5 mL) and a LiHMDS solution (1.0 M in THF, 0.5 mL, 0.5 mmol) was added dropwise. The resulting solution was stirred at room temperature for 24 h. The reaction mixture was quenched with water (5 mL) and EtOAc (10 mL). The layers were separated, and the organic phase was further washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→8% MeOH / DCM with 5% NH4OH) to give the desired product (81 mg, 0.12 mmol, 53% yield) as a pale yellow solid. LC / MS(ESI)m / z:[M+H] + C 31 H 36 Calculated value for BrFN6O4: 655.2; Found value: 655.4; 1 H NMR(500MHz,CD3OD)δ 7.73(d,J=9.3Hz,1H),7.49(dd,J=9.3,6.3Hz,1H),7.44-7.30(m,5H),5.27-5.08(m,3H),4.68-4.55(m,2H),4.33(br d,J=4.5Hz,2H),3.68(S,2H),3.62-3.50(m,2H),3.50-3.43(m,3H),3.30(br S,1H),3.10-2.94(m,2H),2.94-2.74(m,2H),2.57-2.43(m,2H),2.29-2.08(m,2H),1.99-1.88(m,2H),1.87-1.73(m,2H),1.73-1.60(m,2H). [ka] Step 2: Preparation of benzyl (S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(3-methoxypropyl)piperidin-4-yl)oxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0278] Benzyl (S)-4-(7-bromo-8-fluoro-2-((1-(3-methoxypropyl)piperidin-4-yl)oxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (80 mg, 0.12 mmol) and 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (35 mg, 0.12 mmol) were combined as solids and dissolved in dioxane (2 mL). Potassium phosphate solution (2.0 M, 0.18 mL, 1.0 mmol) was added, and nitrogen was flushed through the solution for 15 minutes. [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), (dtbpf)PdCl2, (4.0 mg, 6.1 μmol) was added as a solid, and the reaction mixture was heated at 100 °C for 12 h. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (5 mL) and brine (5 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→8% MeOH / DCM with 5% NH4OH) to give the desired product (30 mg, 0.04 mmol, % yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 41 H 33 Calculated for ClFN6O4 737.3; found 737.2.

[0279] Step 3: Preparation of (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(3-methoxypropyl)piperidin-4-yl)oxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(3-methoxypropyl)piperidin-4-yl)oxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (30 mg, 0.04 mmol) was dissolved in EtOH (10 mL) and palladium on carbon (10 wt%, 43 mg, 0.04 mmol) was added. Hydrogen gas was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 hours. The solution was filtered through a Celite™ pad and concentrated to give the desired product, which could be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 33 H 37 Calculated value of ClFN6O2: 603.2; Measured value: 603.5; 1 H NMR(500MHz,CD3OD)δ 7.99(d,J=7.7Hz,1H),7.85(br d,J=8.9Hz,2H)7.77(d,J=8.0Hz,2H),7.55-7.40(m,1H),7.37-7.24(m,2H),5.29-5.19(m,1H),4.63(br S,1H),4.29(br dd. 2H),2.80-2.65(m,2H),2.55-2.41(m,1H),2.39-2.28(m,2H),2.23-2 .11(m,1H),1.99-1.88(m,2H),1.86-1.65(m,2H),1.42-1.23(m,2H). [ka] 2-((2S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0280] Step 1: Preparation of benzyl (2S)-2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (70 mg, 0.11 mmol) and (5-methyl-1H-indazol-4-yl)boronic acid (19 mg, 0.11 mmol) were combined as solids and dissolved in dioxane (2 mL). Potassium phosphate solution (2.0 M, 0.16 mL, 0.33 mmol) was added, and nitrogen was flushed through the solution for 15 minutes. [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), (dtbpf)PdCl2, (4.0 mg, 6.1 μmol) was added as a solid, and the reaction mixture was heated at 100 °C for 12 h. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (5 mL) and brine (5 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→8% MeOH / DCM with 5% NH4OH) to give the desired product (39 mg, 0.06 mmol, 52% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 38 H 39 Calculated F2N8O3 value 693.3; Measured value 693.5; 1H NMR(500MHz,CD3OD)δ 7.94(d,J=8.2Hz,1H),7.61-7.58(m,1H),7.55(d,J=8.8Hz,1H),7.42-7.32(m,7H),5.3 1(d,J=56.4Hz,1H),5.22-5.17(m,2H),4.60-4.53(m,2H),4.50-4.41(m,2H),4.33-4.2 3(m,2H),4.18-4.12(m,2H),3.78-3.69(m,1H),3.63-3.50(m,2H),3.47-3.41(m,1H),3 .21-3.14(m,2H),3.06(S,4H),2.27-2.12(m,3H),2.03-1.95(m,2H),1.94-1.87(m,1H).

[0281] Step 2: Preparation of 2-((2S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (2S)-2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazine-1-carboxylate (39 mg, 0.056 mmol) was dissolved in EtOH (10 mL) and palladium on carbon (10 wt%, 59 mg, 0.056 mmol) was added. Hydrogen gas was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 hours. The solution was filtered through a Celite™ pad and concentrated to give the desired product, which could be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 30 H 33 Calculated F2N8O value 559.3; Measured value 559.4; 1H NMR(500MHz,CD3OD)δ 7.90(d,J=8.9Hz,1H),7.60(d,J=3.9Hz,1H),7.55(d,J=8.8Hz,1H),7.41(d,J=8.5Hz,1H),7.31 (ddd,J=8.6,6.5,1.9Hz,1H),5.31(d,J=55.8Hz,1H),4.59-4.51(m,1H),4.41-4.35(m,1H),4.3 5-4.31(m,1H),4.28-4.24(m,1H),4.13(t,J=6.7Hz,1H),3.53-3.43(m,2H),3.27-3.10(m,8H), 3.06-2.98(m,3H),2.42-2.32(m,1H),2.23-2.13(m,2H),2.01-1.95(m,2H),1.94-1.85(m,1H). [ka] 8-(4-((S)-3-(cyanomethyl)piperazin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-naphthonitrile [ka]

[0282] Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate Benzyl (S)-2-(cyanomethyl)-4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (70 mg, 0.11 mmol) and 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (31 mg, 0.11 mmol) were combined as solids and dissolved in dioxane (2 mL). Potassium phosphate solution (2.0 M, 0.16 mL, 0.33 mmol) was added, and nitrogen was flushed through the solution for 15 minutes. [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), (dtbpf)PdCl2, (3.6 mg, 5.5 μmol) was added as a solid, and the reaction mixture was heated at 100 °C for 2 h. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (5 mL) and brine (5 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→8% MeOH / DCM with 5% NH4OH) to give the desired product (35 mg, 0.05 mmol, 45% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 41 H 38 Calculated F2N7O3 714.3; Found 714.3.

[0283] Step 2: Preparation of 8-(4-((S)-3-(cyanomethyl)piperazin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-naphthonitrile Benzyl (S)-2-(cyanomethyl)-4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (30 mg, 0.04 mmol) was dissolved in EtOH (10 mL) and palladium on carbon (10 wt%, 45 mg, 0.04 mmol) was added. Hydrogen gas was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 hours. The solution was filtered through a Celite™ pad and concentrated to give the desired product, which could be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 33 H 32 Calculated value of F2N7O 559.3; measured value 559.4. [ka] 8-(4-((S)-3-(cyanomethyl)piperazin-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-1-naphthonitrile [ka]

[0284] Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (70 mg, 0.12 mmol) and (8-cyanonaphthalen-1-yl)boronic acid (23 mg, 0.12 mmol) were combined as solids and dissolved in dioxane (4 mL). Potassium phosphate solution (2.0 M, 0.18 mL, 0.35 mmol) was added, and nitrogen was flushed through the solution for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), (dtbpf)PdCl2, (3.8 mg, 5.9 μmol) was added as a solid, and the reaction mixture was heated at 100 °C for 2 hours. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (5 mL) and brine (5 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0-8% MeOH / DCM with 5% NH4OH) to give the desired product (40 mg, 0.06 mmol, 51% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 39 H 37 Calculated value of FN7O3: 670.3; measured value: 670.5.

[0285] Step 2: Preparation of 8-(4-((S)-3-(cyanomethyl)piperazin-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-1-naphthonitrile Benzyl (S)-2-(cyanomethyl)-4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (40 mg, 0.06 mmol) was dissolved in EtOH (10 mL) and palladium on carbon (10 wt%, 64 mg, 0.04 mmol) was added. Hydrogen gas was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 hours. The solution was filtered through a Celite™ pad and concentrated to give the desired product, which could be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 31 H 31 Calculated value of FN7O: 536.3; measured value: 536.4. [ka] tert-Butyl (7-fluoro-4-(8-fluoro-4-((1R,5S)-8-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate [ka]

[0286] Step 1: Preparation of tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.36 mmol) and (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (113 mg, 0.36 mmol) were combined as solids and dissolved in dioxane (5 mL). Potassium phosphate solution (2.0 M, 0 0.55 mL, 1.1 mmol) was added and nitrogen was flushed through the solution for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), (dtbpf)PdCl2, (11.8 mg, 0.018 mmol) was added as a solid and the reaction mixture was heated at 100 °C for 2 hours. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (5 mL) and brine (5 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→8% MeOH / DCM with 5% NH4OH) to give the desired product (60 mg, 0.08 mmol, 22% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 37 H 45 Calculated value of F2N7O5S: 738.3; measured value: 738.6.

[0287] Step 2: Preparation of tert-butyl (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate tert-Butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.08 mmol) was dissolved in DCM (5 mL) and zinc bromide (37 mg, 0.16 mmol) was added in one portion. The resulting suspension was heated at 40° C. for 3 h. Water (10 mL) was added to quench the reaction and the mixture was stirred for 10 min. EtOAc (10 mL) was added and the layers were separated. The combined organic phase was further washed with water (10 mL) and brine (10 mL), 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: 20 mL / min; Column temperature: 25 °C; Gradient: 100% 5:95 MeCN:10 mM AA in HO / 0% 95:5 MeCN:10 mM AA in HO → 100% 95:5 MeCN:10 mM AA in HO; λ = 220 nm) to give the desired product as a white solid (30 mg, 0.05 mmol, 58% yield). LC / MS (ESI) m / z: [M+H] + C 32 H 38 Calculated value of F2N7O3S: 638.3; Measured value: 638.4; 1 H NMR (600MHz, methanol-d4)δ 7.80(d,J=8.7Hz,1H),7.52(dd,J=8.3,5.4Hz,1H),7.46(dd,J=8.5,6.7Hz,1H),7.17(t,J=8.7Hz,1H),4.54(br S,1H),4.53(br S,1H),4.51(br d,J=13.3Hz,2H),3.67(br S,2H),3.62(br d,J=12.7Hz,2H),3.16-3.07(m,1H),2.70(S,3H),2.67-2.60(m,1H),2.25-2.17(m,1H),1.97-1.92(m,5H),1.90-1.82(m,5H),1.56(S,9H). [ka]

[0288] Step 3: Preparation of tert-butyl (7-fluoro-4-(8-fluoro-4-((1R,5S)-8-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate tert-Butyl (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate (30 mg, 0.05 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (8 mg, 0.05 mmol) were combined as solids and dissolved in DMF (1.0 mL). 1-Methylimidazole (40 μL, 0.5 mmol) was added, followed by chloro-N,N,N′,N′-tetramethylformamidium hexafluorophosphate (7 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 5 minutes. EtOAc (10 mL) and water (10 mL) were added and the layers were separated. The organic phase was washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 40 H 42 Calculated value of F3N8O4S 786.3; measured value 786.3. [ka] 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)naphthalen-2-ol [ka]

[0289] Step 1: Preparation of 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol tert-Butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (prepared by the procedure described in WO 2022 / 061251, 430 mg, 0.58 mmol) was dissolved in THF (6 mL) and a TBAF solution (1.0 M in THF, 0.58 mL, 0.58 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 5 minutes and concentrated. The residue was dissolved in EtOH (6 mL) and sodium hydroxide solution (1.0 M, 1.7 mL, 1.7 mmol) was added. The reaction mixture was heated at 60° C. for 16 h and at 70° C. for an additional 16 h. EtOAc (10 mL) and water (10 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×5 mL). The combined organic phases were washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→10% MeOH / DCM) to give the desired product (256 mg, 0.23 mmol, 40% yield). LC / MS (ESI) m / z: [M+H]+C 30 H 27 Calculated value for F3N3O4: 550.2; Measured value: 550.1; 1H NMR(600MHz,DMSO-d6)δ 8.12-8.04(m,1H),7.82(br d,J=8.0Hz,1H),7.69(br s,1H),7.53(br t,J=8.8Hz,1H),7.31-7.22(m,2H),5.44-5.22(m,2H),5.31(d,J=56.7Hz,1H),4.23- 4.07(m,2H),4.02(s,1H),3.44(s,3H),3.40-3.23(m,1H),3.25-3.01(m,3H),2.84(br d,J=5.8Hz,1H),2.24-1.94(m,3H),1.89-1.76(m,3H). [ka]

[0290] Step 2: Preparation of tert-butyl 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate 7-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (20 mg, 0.04 mmol) was dissolved in MeCN (0.5 mL). tert-Butyl piperazine-1-carboxylate (14 mg, 0.07 mmol) and DIPEA (0.03 mL, 0.18 mmol) were added and the reaction mixture was heated at 60° C. for 1 h. The solution was concentrated and the crude residue was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H]+C 39 H 43 Calculated for F3N5O5 718.3; found 718.2.

[0291] Step 3: Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)naphthalen-2-ol tert-Butyl 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (26 mg, 0.04 mmol) was dissolved in dioxane (0.5 mL) and methanol (0.5 mL). HCl solution (4.0 M in dioxane, 0.1 mL, 0.4 mmol) was added dropwise, and the reaction mixture was stirred for 2 hours. The solution 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: 94% 5:95 MeCN:0.1% TFA in HO / 6% 95:5 MeCN:0.1% TFA in HO → 100% 95:5 MeCN:0.1% TFA in HO; λ = 220 nm) to give the desired product as the bis-TFA salt (21.1 mg, 0.03 mmol, 73% yield). LC / MS (ESI) m / z: [M+H]+ C 32 H 31 Calculated F3N5O2 value 574.2; Measured value 574.3; 1 H NMR(500MHz,DMSO-d6)δ 9.21-9.03(m,1H),8.01-7.93(m,1H),7.86(d,J=8.4Hz,1H),7.47(t,J=9.0Hz,1H),7. 38(d,J=2.3Hz,1H),7.37-7.33(m,1H),7.09(d,J=2.3Hz,1H),5.56(d,J=52.2Hz,1H), 4.65-4.54(m,2H),4.00-3.91(m,4H),3.88-3.72(m,3H),3.53-3.42(m,5H),3.42-3.2 7(m,1H),2.66-2.52(m,3H),2.38-2.28(m,1H),2.25-2.12(m,2H),2.10-1.97(m,1H). [ka] 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)quinazolin-4-amine [ka]

[0292] Step 1: Preparation of tert-butyl (R)-3-((7-bromo-2-chloro-8-fluoroquinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate 7-Bromo-2,4-dichloro-8-fluoroquinazoline (450 mg, 1.52 mmol) was suspended in DCM (5 mL) and cooled to 0 °C. DIPEA (0.40 mL, 2.28 mmol) was added, followed by tert-butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate (335 mg, 1.67 mmol), and the solution was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2 hours, then directly concentrated and used in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 18 H 22 Calculated for BrClFN4O2 459.1; found 459.0. [ka]

[0293] Step 2: Preparation of tert-butyl (R)-3-((7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (242 mg, 1.52 mmol) was dissolved in THF (5.0 mL) and a LiHMDS solution (1.0 M in THF, 3.8 mL, 3.8 mmol) was added dropwise. After stirring for 5 min, tert-butyl (R)-3-((7-bromo-2-chloro-8-fluoroquinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (700 mg, 1.52 mmol) was added as a solid, and the reaction mixture was heated at 65° C. for 48 h.

[0294] The reaction mixture was directly concentrated and the crude residue was purified by column chromatography (0->100% EtOAc + 5% EtN / hexanes) to give the desired product (500 mg, 0.858 mmol, 56.4% yield over two steps). LC / MS (ESI) m / z: [M+H] + C 26 H 35 Calculated value for BrClF2N5O3: 582.2; Found value: 582.2; 1 H NMR (500 MHz, CDCl3) δ 7.53(dd,J=9.0,1.5Hz,1H),7.32(dd,J=9.0,6.3Hz,1H),5.27(d,J=53.8Hz, 1H),5.13-5.04(m,1H),4.26(d,J=10.3Hz,1H),4.15(d,J=10.3Hz,1H),3.88- 3.79(m,1H),3.72-3.56(m,1H),3.50-3.30(m,2H),3.28-3.14(m,3H),3.24( S,3H),3.00-2.93(m,1H),2.29-2.10(m,5H),1.98-1.83(m,3H),1.48(S,9H). [ka]

[0295] Step 3: Preparation of tert-butyl (R)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate tert-Butyl (S)-3-((7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (50 mg, 0.086 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (37 mg, 0.086 mmol), and methanesulfonate(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (cataCXium A Palladacyclegen3) (3.1 mg, 4.3 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (2 mL) was added and the reaction mixture was heated at 100° C. for 2 hours. The solution was directly concentrated and the crude residue was purified by column chromatography (0→10% MeOH / DCM) to give the desired product (65 mg, 0.080 mmol, 93% yield). LC / MS (ESI) m / z: [M+H] + C 47 H 62 Calculated value of F2N5O3Si: 810.5; Measured value: 810.9; 1H NMR(500MHz,CD3OD)δ 8.04-8.00(m,2H),7.98-7.91(m,1H),7.79-7.76(m,1H),7.64-7.58(m,1H),7.54-7.4 8(m,1H),7.46-7.41(m,1H),7.37-7.28(m,1H),5.32(d,J=55.4Hz,1H),4.41-4.14(m, 2H),3.97-3.60(m,2H),3.51-3.42(m,3H),3.09-2.98(m,2H),2.51-2.12(m,6H),2.09 -1.85(m,4H),1.50(S,9H),1.49-1.48(m,3H),0.95-0.86(m,18H),0.63-0.52(m,3H). [ka]

[0296] Step 4: Preparation of tert-butyl (R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate tert-Butyl (S)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (60 mg, 0.074 mmol) was dissolved in DMF (2 mL) and cesium fluoride (34 mg, 0.22 mmol) was added as a solid. The mixture was heated at 60° C. for 1 h. The suspension was cooled to room temperature and diluted with EtOAc (5 mL) and water (5 mL). The layers were separated and the organic phase was further washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS(ESI)m / z:[M+H] + C 38 H 42Calculated value of F2N5O3: 654.3, measured value: 654.4. [ka]

[0297] Step 5: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine tert-Butyl (S)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro-tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (48 mg, 0.073 mmol) was dissolved in DMF (0.5 mL) and a solution of HCl (4.0 M in dioxane, 0.25 mL, 1.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The solution was concentrated directly and the crude residue was evaporated from DCM (2 × 5 mL) to give the desired product as its HCl salt (40 mg, 0.068 mmol, 92% yield over two steps). LC / MS (ESI) m / z: [M+H] + C 33 H 34 Calculated value of F2N5O: 554.3; measured value: 554.2. [ka] 7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)quinazolin-4-amine [ka]

[0298] Step 1: Preparation of tert-butyl (3R)-3-((7-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate tert-Butyl (S)-3-((7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (50 mg, 0.086 mmol), 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (commercially available, 32 mg, 0.086 mmol), and methanesulfonate (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (cataCXium A Palladacyclegen 3) (3.1 mg, 4.3 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (2 mL) was added and the reaction mixture was heated at 100° C. for 2 h. The solution was concentrated directly and the crude residue was purified by column chromatography (0→8% MeOH / DCM) to give the desired product (51 mg, 0.067 mmol, 79% yield). LC / MS (ESI) m / z: [M+H] + C 39 H 49 Calculated for ClF2N7O4 752.3; found 752.3. [ka]

[0299] Step 2: Preparation of 7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)quinazolin-4-amine tert-Butyl (3S)-3-((7-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (51 mg, 0.067 mmol) was dissolved in dioxane (0.5 mL) and a solution of HCl (4.0 M in dioxane, 0.25 mL, 1.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The solution was concentrated directly and the crude residue was evaporated from DCM (2 × 5 mL) to give the desired product as its HCl salt (30 mg, 0.046 mmol, 69% yield). LC / MS (ESI) m / z: [M+H] + C 29 H 33 Calculated for ClF2N7O 568.2; found 568.2. [ka] 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)quinazoline [ka]

[0300] Step 1: Preparation of tert-butyl (S)-4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate 7-Bromo-2,4-dichloro-8-fluoroquinazoline (500 mg, 1.69 mmol) was dissolved in dioxane (15 mL). DIPEA (0.9 mL, 5.1 mmol) was added dropwise, followed by tert-butyl (S)-3-methylpiperazine-1-carboxylate (340 mg, 1.69 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated, and the crude residue was purified by column chromatography (5->50% EtOAc / hexanes) to give the desired product (701 mg, 1.53 mmol, 90% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + C 18 H 22 Calculated value of BrClFN4O2: 459.1; Found value: 459.1; 1 H NMR(500MHz,CDCl3)δ 7.53(dd,J=9.1,6.1Hz,1H),7.45(dd,J=9.1,0.7Hz,1H),4.65(S,1H),4.30-3.82 (m,3H),3.69-3.53(m,1H),3.37-2.86(m,2H),1.49(S,9H),1.44(d,J=6.8Hz,3H). [ka]

[0301] Step 2: Preparation of tert-butyl (S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate tert-Butyl (S)-4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (500 mg, 1.09 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, HCl salt (234 mg, 1.20 mmol) were dissolved in THF (12 mL) and LiHMDS solution (1.0 M in THF, 2.4 mL, 2.4 mmol) was added dropwise. The reaction mixture was heated at 65° C. for 16 h. The solution was partially concentrated and the crude residue was purified by column chromatography (50→100% EtOAc and 5% EtN / hexanes) to give the desired product (415 mg, 0.71 mmol, 66% yield) as a yellow solid. LC / MS (ESI) m / z: [M+H] + C 26 H 35 Calculated value for BrF2N5O3: 582.2; Found value: 582.1; 1 H NMR(500MHz,CD3OD)δ 7.63(dd,J=9.0,1.3Hz,1H),7.46(dd,J=9.0,6.4Hz,1H),5.30(d,J=54.6Hz,1H),4. 79-4.69(m,1H),4.27(d,J=10.5Hz,1H),4.20(d,J=10.5Hz,1H),4.23-4.15(m,1H),4 .14-4.03(m,1H),3.94-3.87(m,1H),3.69-3.58(m,1H),3.30-3.13(m,5H),3.06-2. 96(m,1H),2.39-2.09(m,3H),2.02-1.85(m,3H),1.49(S,9H),1.40(d,J=6.7Hz,3H). [ka]

[0302] Step 3: Preparation of tert-butyl (S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate tert-Butyl (S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (150 mg, 0.258 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (112 mg, 0.26 mmol), and methanesulfonate(diadamantyl-n-butylphosphino)-2′-amino-1,1′-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium A Palladacyclegen.3] (9.4 mg, 0.013 mmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (2 mL) and potassium phosphate solution (2.0 M in water, 390 μL, 0.77 mmol) were added, and the reaction mixture was heated in a microwave at 100° C. for 2 h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (0→10% MeOH / DCM) to give the desired product (190 mg, 0.024 mmol, 91% yield). LC / MS (ESI) m / z: [M+H] + C 47 H 62 Calculated value of F2N5O3Si: 810.5; Measured value: 810.3; 1H NMR(500MHz,CD3OD)δ 8.07-7.98(m,2H),7.80-7.69(m,2H),7.64-7.58(m,1H),7.54-7.48(m,1H),7.45-7.39(m,1H),7.3 7-7.30(m,1H),5.30(d,J=55.0Hz,1H),4.96-4.87(m,1H),4.34-4.07(m,4H),4.00-3.91(m,1H),3.8 4-3.58(m,1H),3.28-3.13(m,5H),3.07-2.97(m,1H),2.40-2.12(m,3H),2.10-1.93(m,3H),1.54(d, J=6.7Hz,1.5H),1.52-1.49(m,9H),1.37(d,J=6.6Hz,1.5H),0.93-0.85(m,18H),0.59-0.50(m,3H). [ka]

[0303] Step 4: Preparation of tert-butyl (S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate tert-Butyl (S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (190 mg, 0.235 mmol) was dissolved in DMF (3 mL) and cesium fluoride (107 mg, 0.70 mmol) was added as a solid. The mixture was heated at 60° C. for 1 h. The suspension was cooled to room temperature and diluted with EtOAc (10 mL) and water (5 mL). The layers were separated and the organic phase was further washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS(ESI)m / z:[M+H] + C 38 H42 Calculated F2N5O3 654.3; Found 654.5. [ka]

[0304] Step 5: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)quinazoline tert-Butyl (S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (140 mg, 0.214 mmol) was dissolved in dioxane (1.0 mL) and a solution of HCl (4.0 M in dioxane, 0.25 mL, 1.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The solution was concentrated directly and the crude residue was evaporated from DCM (2 × 5 mL) to give the desired product as its HCl salt (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 33 H 34 Calculated value of F2N5O: 554.3; measured value: 554.2. [ka] 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile [ka]

[0305] Step 1: Preparation of benzyl (S)-4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate 7-Bromo-2,4-dichloro-8-fluoroquinazoline (500 mg, 1.69 mmol) was dissolved in dioxane (15 mL). DIPEA (0.9 mL, 5.1 mmol) was added dropwise, followed by tert-butyl benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylate (438 mg, 1.69 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated, and the crude residue was purified by column chromatography (5->50% EtOAc / hexanes) to give the desired product (790 mg, 1.53 mmol, 90% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + C 22 H 19 Calculated value of BrClFN5O2: 518.0; Found value: 518.1; 1 H NMR(500MHz,CD3OD)δ 7.81(dd,J=9.2,1.5Hz,1H),7.69(dd,J=9.2,6.4Hz,1H),7.44-7.29(m,5H),5.24-5.14(m,2H),4.79-4.73(m,1H), 4.50-4.34(m,2H),4.15-4.08(m,1H),3.84-3.71(m,1H),3.70-3.61(m,1H),3.59-3.47(m,1H),3.05-2.88(m,2H). [ka]

[0306] Step 2: Preparation of benzyl (S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate Benzyl (S)-4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)-piperazine-1-carboxylate (120 mg, 0.23 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, HCl salt (50 mg, 0.25 mmol) were dissolved in THF (5 mL) and LiHMDS solution (1.0 M in THF, 0.51 mL, 0.51 mmol) was added dropwise. The reaction mixture was heated at 65° C. for 16 h. The solution was partially concentrated and the crude residue was purified by column chromatography (50→100% EtOAc and 5% EtN / hexanes) to give the desired product (90 mg, 0.14 mmol, 61% yield) as a yellow solid. LC / MS (ESI) m / z: [M+H] + C 30 H 32 Calculated value for BrF2N6O3: 641.2; Found value: 641.3; 1 H NMR (500 MHz, CD3OD) δ 7.72(dd,J=9.0,1.4Hz,1H),7.48(dd,J=9.0,6.4Hz,1H),7.41-7.32(m,5H),5 .30(d,J=54.0Hz,1H),5.18(S,2H),4.79-4.71(m,1H),4.44-4.30(m,2H),4.28 (d,J=10.4Hz,1H),4.23(d,J=10.4Hz,1H),3.73-3.66(m,1H),3.56-3.49(m,2H ),3.26-3.14(m,4H),3.06-2.94(m,3H),2.39-2.09(m,3H),2.02-1.85(m,3H). [ka]

[0307] Step 3: Preparation of 2-((S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.156 mmol) was placed in a microwave vial and DCM (1 mL) and TFA (0.25 mL) were added. The reaction mixture was heated in a microwave at 90° C. for 3 h. The solution was concentrated directly and the residue was evaporated from DCM (3×5 mL). The crude material was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 22 H 26 Calculated for BrF2N6O 507.1; found 507.1. [ka]

[0308] Step 4: Preparation of tert-butyl (S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate 2-((S)-4-(7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile (110 mg, 0.217 mmol) was dissolved in DCM (15 mL) and triethylamine (0.09 mL, 0.65 mmol) was added, followed by di-tert-butyl dicarbonate (0.08 mL, 0.325 mmol). The reaction mixture was stirred at room temperature for 4 hours. The solution was concentrated and the crude residue was directly purified by column chromatography (0→8% MeOH / DCM) to give the desired product (85 mg, 0.140 mmol, 65% yield) as a yellow solid. LC / MS (ESI) m / z: [M+H] + C 27 H 34 Calculated value for BrF2N6O3: 607.1; Found value: 607.3; 1H NMR (500 MHz, CD3OD) δ 7.73(dd,J=9.0,1.6Hz,1H),7.48(dd,J=9.0,6.4Hz,1H),5.30(d,J=53.3Hz,1 H),4.73-4.63(m,1H),4.47-4.32(m,2H),4.29(d,J=10.4Hz,1H),4.23(d,J=10 .4Hz,1H),4.08-3.98(m,1H),3.67-3.59(m,1H),3.56-3.43(m,2H),3.27-3.14 (m,4H),3.06-2.84(m,3H),2.37-2.11(m,3H),2.03-1.87(m,3H),1.51(S,9H). [ka]

[0309] Step 5: Preparation of tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate tert-Butyl (S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (70 mg, 0.115 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (50 mg, 0.12 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (3.8 mg, 5.8 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (5 mL) and potassium phosphate solution (2.0 M in water, 170 μL, 0.35 mmol) were added, and the reaction mixture was heated in a microwave at 100° C. for 2 h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (0→8% MeOH / DCM) to give the desired product (190 mg, 0.024 mmol, 91% yield). LC / MS (ESI) m / z: [M+H] + C 48 H 61 Calculated value of F2N6O3Si: 835.4; Measured value: 835.4; 1 H NMR(500MHz,CD3OD)δ 8.07-7.99(m,2H),7.88-7.82(m,1H),7.80-7.75(m,1H),7.63-7.58(m,1H),7.54-7.48(m,1 H),7.46-7.39(m,1H),7.39-7.33(m,1H),5.30(d,J=53.3Hz,1H),4.78-4.69(m,1H),4.56-4 .34(m,2H),4.34-4.02(m,4H),3.48-3.37(m,1H),3.27-3.13(m,4H),3.11-2.85(m,3H),2.4 7-2.12(m,3H),2.04-1.87(m,3H),1.55-1.49(m,9H),0.92-0.84(m,18H),0.61-0.51(m,3H). [ka]

[0310] Step 6: Preparation of tert-butyl (S)-2-(cyanomethyl)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate tert-Butyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate (50 mg, 0.060 mmol) was dissolved in DMF (3 mL) and cesium fluoride (27 mg, 0.18 mmol) was added as a solid. The mixture was heated at 60° C. for 2 h. The suspension was cooled to room temperature and diluted with EtOAc (10 mL) and water (5 mL). The layers were separated and the organic phase was further washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS(ESI)m / z:[M+H] + C 39 H 41 Calculated F2N6O3 679.3; Found 679.3. [ka]

[0311] Step 7: Preparation of 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile tert-Butyl (S)-2-(cyanomethyl)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (40 mg, 0.059 mmol) was dissolved in dioxane (1.0 mL) and a solution of HCl (4.0 M in dioxane, 1.0 mL, 4.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated directly and the crude residue was evaporated from DCM (3 × 5 mL) to give the desired product as its HCl salt (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 34 H 33 Calculated value of F2N6O 579.3; measured value 579.4. [ka] (Z)-1-((3S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one

[0312] 6-Chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline (Intermediate 1, 14 mg, 0.025 mmol) and (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (Intermediate 25, 22 mg, 0.13 mmol) were combined as solids and dissolved in DMF (0.4 mL). 1-Methylimidazole (20 μL, 0.25 mmol) was added, followed by chloro-N,N,N'N'-tetramethylformamidium hexafluorophosphate (35 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 5 minutes. 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:HO with 0.1% TFA / 28% 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 the bis-TFA salt (8 mg, 0.009 mmol, 34% yield) as an off-white solid, a mixture of two atropisomers. LC / MS (ESI) m / z: [M+H] + C 35 H 33 Calculated for Cl2F2N6O2S 709.2; found 709.0. NMR: spectrum is a mixture of atropisomers; water suppression was used 1H NMR(500MHz,DMSO-d6)δ 8.24-8.18(m,1H),8.15-8.07(m,1H),8.04-7.98(m,2H),7.98-7.85(m,1H),7.77-7.71(m,1H),7 .71-7.63(m,1H),7.63-7.54(m,1H),7.54-7.43(m,1H),7.10(d,J=37.6Hz,1H),4.93-4.80(m,1H ),4.77-4.69(m,1H),4.65-4.55(m,1H),4.35-4.11(m,2H),3.88-3.56(m,2H),2.98-2.92(m,3H) ,2.86-2.75(m,1H),2.31-2.22(m,1H),2.10-2.02(m,1H),1.98-1.85(m,2H),1.45-1.33(m,3H). [ka] (Z)-1-((3S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one

[0313] 6-Chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline (Intermediate 1, 14 mg, 0.025 mmol) and (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylic acid (Intermediate 26, 22 mg, 0.13 mmol) were combined as solids and dissolved in DMF (0.4 mL). 1-Methylimidazole (20 μL, 0.25 mmol) was added, followed by chloro-N,N,N',N'-tetramethylformamidium hexafluorophosphate (35 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 5 minutes. 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: 77% 5:95 MeCN:HO with 0.1% TFA / 23% 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 the bis-TFA salt as a mixture of two atropisomers (5.8 mg, 0.006 mmol, 25% yield). LC / MS (ESI) m / z: [M+H] + C 36 H 34 Calculated for Cl2F2N7O2 704.2; found 704.1. NMR: spectrum is a mixture of atropisomers; water suppression was used 1H NMR(500MHz,DMSO-d6)δ 8.89(d,J=4.9Hz,2H),8.24-8.19(m,1H),8.13-8.09(m,1H),7.97-7.89(m,1H),7.77-7.72(m,1H),7.68-7. 64(m,1H),7.58-7.58(m,1H),7.59-7.54(m,1H),7.51-7.47(m,1H),7.45(t,J=4.9Hz,1H),6.61(d,J=35.2Hz ,1H),4.96-4.80(m,1H),4.79-4.69(m,1H),4.66-4.55(m,1H),4.39-4.04(m,3H),3.89-3.75(m,2H),3.00- 2.91(m,3H),2.87-2.79(m,1H),2.30-2.21(m,1H),2.10-2.06(m,1H),1.99-1.86(m,2H),1.44-1.35(m,3H). [ka] (Z)-1-((3S)-4-(6-chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0314] 6-Chloro-7-(8-chloronaphthalen-1-yl)-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline (Intermediate 1, 14 mg, 0.025 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (Intermediate 27, 22 mg, 0.13 mmol) were combined as solids and dissolved in DMF (0.4 mL). 1-Methylimidazole (20 μL, 0.25 mmol) was added, followed by chloro-N,N,N',N'-tetramethylformamidium hexafluorophosphate (35 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was purified directly by reverse-phase HPLC (Column: Xbridge C18, 19 mm × 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25 °C; Gradient: 81% 5:95 MeCN:HO with 0.1% TFA / 19% 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 mixture of atropisomers. A second purification using chiral SFC (column: Chiralcel OD-H, 30 mm x 250 mm, 5 μm particles; flow rate: 100 mL / min; column temperature: 40 °C, isocratic: 80% CO2:20% MeOH with 0.1% NH4OH; λ = 254 nm) gave the desired compound, a single atropisomer of unknown absolute stereochemistry as the bis-TFA salt (1.3 mg, 0.001 mmol, 6% yield). LC / MS (ESI) m / z: [M+H] + C 37 H 35 Calculated for Cl2F2N6O2 702.9; Found 702.9. [ka] (Z)-1-((1R,5S)-3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0315] (5M)-6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Intermediate 6, 3 mg, 0.005 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (Intermediate 27, 4 mg, 0.026 mmol) were combined as solids and dissolved in DMF (0.3 mL). 1-Methylimidazole (4 μL, 0.05 mmol) was added, followed by chloro-N,N,N′,N′-tetramethylformamidium hexafluorophosphate (7.3 mg, 0.026 mmol). The reaction mixture was stirred at room temperature for 5 minutes. 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: 77% 5:95 MeCN:10 mM AA in HO / 23% 95:5 MeCN:10 mM AA in HO → 100% 95:5 MeCN:10 mM AA in HO; λ = 220 nm) to give the desired product as a single atromisome (2.7 mg, 0.004 mmol, 72% yield). LC / MS (ESI) m / z: [M+H] + C 35 H 35 Calculated for ClF5N8O2: 729.2; Found: 729.1. NMR: Water suppression method used 1H NMR(500MHz,DMSO-d6)δ 8.66(d,J=5.0Hz,1H),7.90(dd,J=8.0,7.0Hz,1H),7.87(S,1H),7.81(d,J=8.0Hz,1H),7.39(dd,J=7.0,5.0Hz,1H),6.83(br S,2H),6.81(d,J=37.8Hz,1H),6.49(S,1H),4.82-4.73(m,2H),4.61-4.51(m,1H),4.45-4.36(m,2H),4.29- 4.16(m,1H),3.87-3.56(m,1H),3.44-3.35(m,1H),2.47-2.24(m,6H),2.04-1.82(m,4H),1.81-1.63(m,4H). [ka] (Z)-1-((1R,5S)-3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0316] (5M)-6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Intermediate 9, 3 mg, 0.005 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (Intermediate 27, 4 mg, 0.026 mmol) were combined as solids and dissolved in DMF (0.3 mL). 1-Methylimidazole (4 μL, 0.05 mmol) was added, followed by chloro-N,N,N',N'-tetramethylformamidium hexafluorophosphate (7 mg, 0.026 mmol). The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was purified directly by reverse-phase HPLC (Column: Xbridge C18, 19 mm × 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25 °C; Gradient: 74% 5:95 MeCN:10 mM AA in HO / 26% 95:5 MeCN:10 mM AA in HO → 100% 95:5 MeCN:10 mM AA in HO; λ = 220 nm) to give the desired product as a single atropisomer (3.5 mg, 0.005 mmol, 94% yield). LC / MS (ESI) m / z: [M+H] + C 37 H 36 Calculated for ClF6N8O2 773.3; found 773.1. NMR: Water suppression method used; 1 H NMR(500MHz,DMSO-d6)δ 8.66(d,J=5.0Hz,1H),7.90(dd,J=8.0,7.0Hz,1H),7.89(S,1H),7.81(d,J=8.0Hz,1H),7.39(dd,J=7.0,5.0Hz,1H),6.84(br S,1H),6.82(d,J=37.9Hz,1H),6.50(S,1H),5.56-5.33(m,1H),4.85-4.73(m,2H),4.66- 4.50(m,1H),4.47-4.28(m,1H),3.86-3.54(m,1H),2.40-2.34(m,3H),2.23-1.71(m,8H). [ka] (Z)-1-(5-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0317] (5M)-6-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Intermediate 7, 3 mg, 0.005 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (Intermediate 27, 4 mg, 0.026 mmol) were combined as solids and dissolved in DMF (0.3 mL). 1-Methylimidazole (4 μL, 0.05 mmol) was added, followed by chloro-N,N,N′,N′-tetramethylformamidium hexafluorophosphate (7.3 mg, 0.026 mmol). The reaction mixture was stirred at room temperature for 5 minutes. 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: 74% 5:95 MeCN:10 mM AA in HO / 26% 95:5 MeCN:10 mM AA in HO → 100% 95:5 MeCN:10 mM AA in HO; λ = 220 nm) to give the desired product (1.1 mg, 0.001 mmol, 29% yield). LC / MS (ESI) m / z: [M+H] + C 35 H 35 Calculated for ClF5N8O2 729.2; found 729.1. NMR: The spectrum is complicated by the presence of a diastereomer (C4 amine); water suppression was used. 1H NMR(500MHz,DMSO-d6)δ 8.66-8.62(m,1H),8.09-8.01(m,1H),7.91-7.85(m,1H),7.78(br d,J=8.0Hz,1H),7.38(br d,J=4.4Hz,1H),6.85(br S,2H),6.61(d,J=39.0Hz,1H),6.49(S,1H),5.13-4.98(m,1H),4.69-4.43(m,3H),4.26-4.15(m,1H),4.09-4.01(m,1 H),3.88-3.81(m,1H),3.74-3.65(m,1H),2.40-2.32(m,3H),2.29-2.03(m,3H),1.99-1.92(m,2H),1.89-1.70(m,3H). [ka] (Z)-1-((1R,5S)-3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0318] (5M)-6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Intermediate 10, 3 mg, 0.005 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (Intermediate 27, 4 mg, 0.026 mmol) were combined as solids and dissolved in DMF (0.3 mL). 1-Methylimidazole (4 μL, 0.055 mmol) was added, followed by chloro-N,N,N',N'-tetramethylformamidium hexafluorophosphate (7 mg, 0.026 mmol). The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was purified directly by reverse-phase HPLC (column: Xbridge C18, 19 mm × 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 72% 5:95 MeCN:10 mM AA in HO / 28% 95:5 MeCN:10 mM AA in HO → 100% 95:5 MeCN:10 mM AA in HO; λ = 220 nm) to give the desired product (1.4 mg, 0.002 mmol, 38% yield). LC / MS (ESI) m / z: [M+H] + C 37 H 36 Calculated for ClF6N8O2: 773.2; Found: 773.2. NMR: Water suppression method used 1H NMR(500MHz,DMSO-d6)δ 8.66(d,J=5.3Hz,1H),7.91(dd,J=7.8,7.0Hz,1H),7.91(br S,1H),7.81(d,J=7.9Hz,1H),7.39(dd,J=7.1,5.3Hz,1H),6.83(br S,2H),6.82(d,J=37.9Hz,1H),6.50(S,1H),5.63-5.43(m,1H),4.85-4.75(m,2H),4.71-4.57(m,1H),4.55-4.35(m,2H),3.87- 3.53(m,1H),2.48-2.41(m,2H),2.40-2.34(m,3H),2.33-2.23(m,1H),2.22-2.06(m,2H),2.05-1.81(m,4H),1.79-1.69(m,1H). [ka] (Z)-1-((1R,5S)-3-(6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0319] 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (Intermediate 8, 3 mg, 0.005 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (Intermediate 27, 4.6 mg, 0.027 mmol) were combined as solids and dissolved in DMF (0.3 mL). 1-Methylimidazole (4 μL, 0.25 mmol) was added, followed by chloro-N,N,N′,N′-tetramethylf...

Claims

1. Compound of formula (I): 【Chemistry 1】 (In the formula, Z is bond, O, NR ｅ or CR ｅ R ｆ And here, R ｅ and R ｆ These are, independently, hydrogen or C １ -C ３ It is alkyl; R １ is aryl or heteroaryl, where the aryl and the heteroaryl are each independently selected from 1, 2, 3, 4 or 5 substituents selected from C １ -C ３ alkoxy, C １ -C ３ alkyl, C ２ -C ４ alkenyl, C ２ -C ４ alkynyl, amino, amino C １ -C ３ alkyl, cyano, C ３ -C ４ cycloalkyl, halo, halo C １ -C ３ alkoxy, halo C １ -C ３ alkyl, hydroxy and hydroxy C １ -C ３ alkyl, and may be substituted with 1, 2, 3, 4 or 5 substituents; R ２ and R ３ These are, independently, hydrogen and C １ -C ３ Alkoxy, C １ -C ３ Alkyl, cyano, halo, halo C １ -C ３ Alkyl, -C(O)NH ２ , -C(O)NH(C １ -C ３ Alkyl), -C(O)N(C １ -C ３ Alkyl) ２ and selected from hydroxy; U is a bond, CH ２ NH, or NH; Y is bond, O, NR ｇ (CR ｅ R ｆ ) ｍ , NR ｆ or CR ｅ R ｆ Here, m is 1, 2, or 3, and R ｅ , R ｆ and R ｇ These are, independently, hydrogen or C １ -C ３ It is alkyl; A is a 4- to 10-membered monocyclic, bicyclic, or tricyclic bridging, condensed, or spirocyclic saturated, unsaturated, or partially unsaturated ring system which may contain one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring system is C １ -C ３ Alkoxy, C １ -C ３ Alkoxy C １ -C ３ Alkyl, C １ -C ３ Alkyl amide C １ -C ３ Alkyl, cyano, cyano C １ -C ３ alkyl, halo, halo C １ -C ３ Alkyl, amino, amino C １ -C ３ Alkyl, hydroxy, hydroxy C １ -C ３ It may be substituted with one, two, or three groups independently selected from alkyl and oxo groups, provided that if Y is a bond, A contains at least one nitrogen atom; R' is a halo; R ４ C ２ -C ４ Alkenil, C １ -C ３ Alkyl, cyano, cyano C １ -C ３ alkyl, halo, halo C １ -C ３ Alkoxy, Halo C １ -C ３ An aryl ring or heteroaryl ring which may be substituted with one, two, or three substituents independently selected from alkyl, nitro, and oxo; X is O or NR １６ And here, R １６ is hydrogen or C １ -C ３ It is alkyl; R ５ is hydrogen, C １ -C ６ -alkoxy C １ -C ６ -alkyl, C １ -C ６ -alkyl, aryl, aryl C １ -C ６ -alkyl, carboxy C １ -C ６ -alkyl, C ３ -C ６ -cycloalkyl, C ３ -C ６ -cycloalkyl C １ -C ６ -alkyl, di(C １ -C ３ -alkyl)amino C ２ -C ６ -alkyl, halo C １ -C ６ -alkyl, heteroaryl, heteroaryl C １ -C ６ -alkyl, heterocyclyl, heterocyclyl C １ -C ６ -alkyl, hydroxy C １ -C ６ -alkyl, NR ａ R ｂ -C(O)-C １ -C ６ -alkyl), NR ａ R ｂ C １ -C ６ is selected from alkyl, and the aryl, the aryl C １ -C ６ -alkyl aryl moiety, the C ３ -C ６ -cycloalkyl, the C ３ -C ６ -cycloalkyl C １ -C ６ -alkyl cycloalkyl moiety, the heteroaryl, the heteroaryl C １ -C ６ -alkyl heteroaryl moiety, the heterocyclyl, the heterocyclyl C １ -C ６ -alkyl heterocyclyl moiety is C １ -C ３ Alkoxy, C １ -C ３ Alkoxy C １ -C ３ Alkyl, C １ -C ３ Alkyl, (C １ -C ６ Alkyl)amino, (C １ -C ６ Alkyl) Amino C １ -C ３ Alkyl, amino, amino C １ -C ３ Alkyl, carboxy, cyano, di(C) １ -C ６ Alkyl)amino, di(C) １ -C ６ Alkyl) Amino C １ -C ３ alkyl, halo, halo C １ -C ３ Alkoxy, Halo C １ -C ３ Alkyl, heterocyclyl, heterocyclyl C １ -C ３ Alkyl, hydroxy, hydroxy C １ -C ３ The heterocyclyl and the heterocyclyl C may be substituted with one, two, three, or four groups independently selected from alkyl, nitro, and oxo; where the heterocyclyl and the heterocyclyl C １ -C ３ The heterocyclyl portion of the alkyl group is C １ -C ３ Alkoxy, C １ -C ３ Alkyl, Halo, and Halo C １ -C ３ It may be further substituted with one, two, or three groups independently selected from the alkyl group; or R ５ and R １６ Along with the nitrogen atom to which they are bonded, C １ -C ３ Alkoxy, C １ -C ３ Alkoxy C １ -C ３ Alkyl, C １ -C ３ Alkyl, amino, amino C １ -C ３ Alkyl, hydroxy, and hydroxy C １ -C ３ Forms a heterocyclic group which may be substituted with 1, 2, 3, 4, or 5 groups independently selected from 1, 2, 3, or 4 groups independently selected from the alkyl; R ａ and R ｂ One of them is hydrogen and C １ -C ３ Selected from alkyl, the other is hydrogen, C １ -C ３ Alkyl, C １ -C ３ Alkoxycarbonyl, C １ -C ３ Alkylcarbonyl, aryl C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl and C ３ -C ６ Cycloalkyl C １ -C ６ (Selected from alkyl groups) or a pharmaceutically acceptable salt thereof.

2. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a five-membered or six-membered aromatic ring that may contain one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

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

5. Y is NCH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a 5- to 10-membered monocyclic, bicyclic, or tricyclic bridged, condensed, or spirocyclic saturated ring system containing one or two nitrogen atoms.

7. A-U: 【Chemistry 2】 Selected from the group consisting of, in the formula, 【Transformation 3】 However, this represents a bond point to the carbonyl group; and 【Chemistry 4】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the bond site to Y is represented.

8. Y-A-U: 【Transformation 5】 Selected from the group consisting of, in the formula, 【Transformation 6】 However, this represents a bond point to the carbonyl group; and 【Transformation 7】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the bond site to the quinazoline ring is represented.

9. R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a halo.

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

11. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is selected from isothiazolyl, pyridinyl, pyrimidinyl, and thiazolyl.

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

13. R ５ but: 【Transformation 8】 Selected from the group consisting of, where each ring is C １ -C ３ Alkoxy, C １ -C ３ Alkoxy C １ -C ３ Alkyl, C １ -C ３ alkyl, benzyl, halo, halo C １ -C ３ Alkyl, hydroxy, hydroxy C １ -C ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one, two, or three groups independently selected from alkyl and oxo groups.

14. R ５ However, -(C １ -C ３ Alkyl)-R ６ And R ６ However, the ring system is a monocyclic ring system with 3 to 5 members, a bicyclic condensed saturated ring system with 8 or 9 members, or a tricyclic saturated ring system with 10 members, and each ring system may contain one nitrogen atom, and each ring system is C １ -C ３ Alkyl, halo, and (4- to 6-membered heterocyclyl) C １ -C ３ The alkyl group may be substituted with one or two groups independently selected; the (4- to 6-membered heterocyclyl) C １ -C ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the alkyl heterocyclyl portion may be further substituted with a halo group.

15. R ５ but 【Chemistry 9】 And, 【Chemistry 10】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the bond site to X is represented.

16. R ５ but 【Chemistry 11】 And in the formula, n is 0, 1, or 2; Each R ２０ However, it is a halo; and 【Chemistry 12】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the bond site to X is represented.

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

18. R １ However, it is a monocyclic heteroaryl ring containing 1, 2, or 3 nitrogen atoms, and the ring is C １ -C ３ Alkoxy, C １ -C ３ Alkyl, C ２ -C ４ Alkenil, C ２ -C ４ Alkinyl, Amino, Amino C １ -C ３ Alkyl, cyano, C ３ -C ４ Cycloalkyl, Halo, Halo C １ -C ３ Alkyl, hydroxy, and hydroxy C １ -C ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one, two, three, four, or five substituents independently selected from alkyl.

19. R １ but, 【Chemistry 13】 And in the formula, 【Chemistry 14】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which exhibits a bonding site to the parent molecule.

20. R １ However, C １ -C ３ Alkoxy, C １ -C ３ Alkyl, C ２ -C ４ Alkenil, C ２ -C ４ Alkinyl, Amino, Amino C １ -C ３ Alkyl, cyano, C ３ -C ４ Cycloalkyl, Halo, Halo C １ -C ３ Alkyl, hydroxy, and hydroxy C １ -C ３ C may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl. ６ -C １０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an aryl compound.

21. R １ However, C １ -C ３ Alkyl, C ２ -C ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the naphthyl is substituted with one, two, three, four, or five substituents independently selected from alkynyl, halo, and hydroxyl.

22. R １ is naphthyl, and the naphthyl is C ２ -C ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one, two, or three groups independently selected from alkynyl, halo, and hydroxyl.

23. R １ but, 【Chemistry 15】 And in the formula, 【Chemistry 16】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which exhibits a bonding site to the parent molecule.

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

25. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R' is chloro.

26. below: 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

27. below: (Z)-1-((3S)-4-(6-chloro-7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((3S)-4-(6-chloro-7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-((3S)-4-(6-chloro-7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(5-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(6-chloro-8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(6-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-((1-(piperidine-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-N-((1S,3s)-3-(((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)amino)cyclobutyl)-2-fluoro-3-(thiazole-2-yl)acrylamide; (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-9-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.2.0]heptan-6-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one (isomer 1); (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.2.0]heptan-6-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one (isomer 2); (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,7-diazabicyclo[4.2.0]octan-7-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((3aR,4S,7R,7aS)-8-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-2H-4,7-epiminoisoindole-2-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-N-((1R,4R)-2-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-yl)-2-fluoro-3-(thiazole-2-yl)acrylamide; (Z)-1-((2S,5R)-4-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-2,5-dimethylpiperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (2Z)-1-{3-[6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl}-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one (isomer 1); (2Z)-1-{3-[6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl}-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one (isomer 2); (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; 2-((S)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)-4-(8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)-4-(8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; (Z)-1-(4-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one (isomer 1); (Z)-1-(4-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one (isomer 2); (Z)-1-(5-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one (isomer 1); (Z)-1-(5-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one (isomer 2); (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (S,Z)-2-fluoro-1-(4-(8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-((1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-1-yl)-3-(pyridine-2-yl)propa-2-en-1-one; (S,Z)-2-fluoro-1-(4-(8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-((1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-1-yl)-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; 2-((S)-1-((Z)-2-fluoro-3-(pyrimidine-2-yl)acryloyl)-4-(8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; (S,Z)-2-fluoro-1-(4-(8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-((1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-1-yl)-3-(pyrimidine-2-yl)propa-2-en-1-one; 2-((S)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)-4-(8-fluoro-7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(6-methylpyridine-2-yl)acryloyl)-4-(8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(6-methylpyridine-2-yl)propa-2-en-1-one; 2-((S)-1-((Z)-2-fluoro-3-(6-methylpyridine-2-yl)acryloyl)-4-(8-fluoro-7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)-4-(8-fluoro-7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(pyrimidine-2-yl)acryloyl)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalene-1-yl)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalene-1-yl)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrimidine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(pyrimidine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; (2Z)-N-[(1S,4S)-2-[(7M)-2-{[(2R,7aR)-2-fluorohexahydro-1H-pyrrolidine-7a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl]-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-4-yl]-2-fluoro-3-(pyridine-2-yl)propaneamide; (2Z)-N-({1-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-4-yl]piperidine-4-yl}methyl)-2-fluoro-3-(pyridine-2-yl)propa-2-enamide; (2Z)-N-[(1R,4R,7R)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl]-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-7-yl]-2-fluoro-3-(pyridine-2-yl)propaneamide; 2-[(2S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazolin-4-yl]-1-[(2Z)-2-fluoro-3-(thiazole-2-yl)propa-2-enoyl]piperazine-2-yl]acetonitrile; 2-[(2S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-4-yl]-1-[(2Z)-2-fluoro-3-(thiazole-2-yl)propa-2-enoyl]piperazine-2-yl]acetamide; (2Z)-N-[(1S,4S)-2-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-4-yl]-2-fluoro-3-(thiazole-2-yl)propa-2-enamide; (2Z)-N-[(1R,4R,7R)-2-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazolin-4-yl]-2-azabicyclo[2.2.1]heptan-7-yl]-2-fluoro-3-(1,3-thiazole-2-yl)propa-2-enamide; 2-((2S)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)-4-(8-fluoro-7-(5-methyl-1H-indazole-4-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)-4-(8-fluoro-7-(5-methyl-1H-indazole-4-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyrimidine-2-yl)acryloyl)-4-(8-fluoro-7-(5-methyl-1H-indazole-4-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyrimidine-2-yl)acryloyl)-4-(8-fluoro-7-(5-methyl-1H-indazole-4-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyridazin-2-yl)acryloyl)-4-(8-fluoro-7-(5-methyl-1H-indazole-4-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyrimidine-2-yl)acryloyl)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((2S)-1-((Z)-2-fluoro-3-(pyridazin-2-yl)acryloyl)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethylnaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(pyrazine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethylnaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethylnaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrimidine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(piperazine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrimidine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(5-chloro-2-(trifluoromethoxy)phenyl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(pyrazine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; (Z)-N-((1S,4S)-2-(7M-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-yl)-2-fluoro-3-(thiazole-2-yl)acrylamide; (Z)-1-((1R,6S)-3-(7M-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((1R,6S)-3-(7M-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)piperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (S,Z)-2-(4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-((1-(3-methoxypropyl)piperidine-4-yl)oxy)quinazoline-4-yl)-1-(2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; (S,Z)-2-(4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-((1-(3-methoxypropyl)piperidine-4-yl)oxy)quinazolin-4-yl)-1-(2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((2S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazole-4-yl)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((2S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazole-4-yl)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 8-(4-((S)-3-(cyanomethyl)-4-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-7-yl)-1-naphthonitrile; 8-(4-((S)-3-(cyanomethyl)-4-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-7-yl)-1-naphthonitrile; (Z)-1-((1R,5S)-3-(7-(2-amino-7-fluorobenzo[d]thiazole-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((3R)-3-((7-(5-chloro-6-methyl-1H-indazole-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((3R)-3-((7-(5-chloro-6-methyl-1H-indazole-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; 2-((S)-4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-1-((Z)-2-fluoro-3-(pyrazine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; (Z)-1-((S)-4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; and (Z)-1-((S)-4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

29. An oral formulation comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

30. The pharmaceutical composition according to claim 28 for treating cancer expressing KRAS G12C, G12D and / or G12V mutations.

31. The pharmaceutical composition according to claim 28 for treating cancer expressing the KRAS G12C mutation.

32. The pharmaceutical composition according to claim 28 for treating cancer sensitive to KRAS G12C inhibition.

33. A pharmaceutical composition according to claim 28 for treating cancer, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, stomach cancer, or uterine cancer.

34. A pharmaceutical composition according to claim 28 for treating cancer, wherein the cancer is non-small cell lung cancer.

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