KRAS inhibitors

Abstract

The present disclosure provides KRAS inhibitors. Also provided are methods of using these compounds in the treatment of cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 371,191, filed on August 11, 2022, and U.S. Provisional Application No. 63 / 483,876, filed on February 8, 2023, both of which are incorporated herein by reference in their entirety. Technical Field

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

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

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

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

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

[0007] Z is a bond, O, NR e or CR e R f , where R e and R f are independently hydrogen or C1-C3 alkyl;

[0008] R 1 is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, haloC1-C3 alkoxy, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl;

[0009] R 2 and R 3 independently selected from hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halogen, halo-C1-C3 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 and hydroxyl;

[0010] U is a bond, CH2NH, or NH;

[0011] Y is a bond, O, NR g (CR e R f ) m NR f , or CR e R f , wherein m is 1, 2, or 3, and wherein R e 、R f and R g are independently hydrogen or C1-C3 alkyl;

[0012] A is a four- to ten-membered monocyclic or bicyclic or tricyclic bridged, fused, or spirocyclic saturated, unsaturated, or partially unsaturated ring system optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring system is optionally substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, amidoC1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halogen, haloC1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo; provided that when Y is a bond, A contains at least one nitrogen atom;

[0013] R' is a halogen;

[0014] R 4 is an aryl or heteroaryl ring optionally substituted with one, two, or three substituents independently selected from the group consisting of C2-C4 alkenyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halogen, haloC1-C3 alkoxy, haloC1-C3 alkyl, nitro, and oxo;

[0015] X is O or NR 16 , where R 16 is hydrogen or C1-C3 alkyl;

[0016] R 5 Selected from hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di (C1-C3 alkyl) amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR a R bC1-C6 alkyl, wherein aryl, the aryl portion of arylC1-C6 alkyl, C3-C6 cycloalkyl, the cycloalkyl portion of C3-C6 cycloalkylC1-C6 alkyl, heteroaryl, the heteroaryl portion of heteroarylC1-C6 alkyl, heterocyclyl, the heterocyclyl portion of heterocyclylC1-C6 alkyl are optionally substituted with one, two, three, or four groups independently selected from the group consisting of 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, carboxyl, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoC1-C3 alkyl, halogen, haloC1-C3 alkoxy, haloC1-C3 alkyl, heterocyclyl, heterocyclylC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, nitro and oxo; wherein the heterocyclyl and heterocyclyl portions of heterocyclylC1-C3 alkyl are further optionally substituted with one, two, or three groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen and haloC1-C3 alkyl; or

[0017] R 5 and R 16 together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted with one, two, three, four, or five groups independently selected from the group consisting of one, two, three, or four groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; and

[0018] R a and R b One of them is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, arylC1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkylC1-C6 alkyl.

[0019] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 is a five- or six-membered aromatic ring optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0020] In certain aspects, the disclosure provides a compound having Formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is a bond.

[0021] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is NH.

[0022] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is NCH3.

[0023] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein A is a six- to ten-membered monocyclic, bicyclic, or tricyclic bridged, fused, or spirocyclic saturated ring system containing one or two nitrogen atoms.

[0024] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein A is a five- to ten-membered monocyclic, bicyclic, or tricyclic bridged, fused, or spirocyclic saturated ring system containing one or two nitrogen atoms.

[0025] In certain aspects, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein U is a bond. In certain aspects, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein U is CH2NH. In certain aspects, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein U is NH.

[0026] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein AU is selected from: in:

[0027] represents the point of attachment to the carbonyl group; and

[0028] Indicates the point of attachment to Y.

[0029] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein YAU is selected from the group consisting of: in:

[0030] represents the point of attachment to the carbonyl group; and

[0031] represents the point of attachment to the quinazoline ring.

[0032] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 It's a halogen.

[0033] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3It's a halogen.

[0034] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of isothiazolyl, pyridinyl, pyrimidinyl and thiazolyl.

[0035] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein X is O.

[0036] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from: wherein each ring is optionally substituted by 1, 2, or 3 groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halogen, halogenated C1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo.

[0037] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 is -(C1-C3 alkyl)-R 6 , where R 6 is a three- to five-membered monocyclic ring system, an eight- or nine-membered bicyclic fused saturated ring system, or a ten-membered tricyclic saturated ring system, wherein each ring system optionally contains one nitrogen atom, and wherein each ring system is optionally substituted with one or two groups independently selected from C1-C3 alkyl, halogen, and (4- to 6-membered heterocyclyl)C1-C3 alkyl; wherein the heterocyclyl portion of the (4- to 6-membered heterocyclyl)C1-C3 alkyl is further optionally substituted with a halogen group.

[0038] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 yes and Indicates the point of attachment to X.

[0039] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 yes in:

[0040] n is 0, 1, or 2;

[0041] Each R 20 is a halogen; and

[0042] Indicates the point of attachment to X.

[0043] In certain aspects, the disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

[0044] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is a monocyclic heteroaryl ring containing one, two, or three nitrogen atoms, wherein the ring is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl.

[0045] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 yes in Indicates the point of attachment to the parent molecule.

[0046] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is a C6-C ... 10 Aryl: C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, halogenated C1-C3 alkyl, hydroxy and hydroxyC1-C3 alkyl.

[0047] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is naphthyl substituted with one, two, three, four, or five substituents independently selected from C1-C3 alkyl, C2-C4 alkynyl, halogen, and hydroxy.

[0048] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is naphthyl, wherein the naphthyl is substituted with one, two, or three groups independently selected from C2-C4 alkynyl, halogen, and hydroxy.

[0049] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 yes in Indicates the point of attachment to the parent molecule.

[0050] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R' is fluoro.

[0051] In certain aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R' is chloro.

[0052] In some aspects, the present disclosure provides a compound selected from as well as or a pharmaceutically acceptable salt thereof.

[0053] In some aspects, the present disclosure provides a compound selected from:

[0054] (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;

[0055] (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;

[0056] (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;

[0057] (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;

[0058] (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-pyrrolizin-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;

[0059] (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;

[0060] (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-pyrrolizin-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;

[0061] (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;

[0062] (Z)-1-(6-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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;

[0063] (Z)-1-((1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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;

[0064] (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;

[0065] (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-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;

[0066] (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-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)amino)cyclobutyl)-2-fluoro-3-(thiazol-2-yl)acrylamide;

[0067] (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-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;

[0068] (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-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);

[0069] (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-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);

[0070] (Z)-1-(3-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-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;

[0071] (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-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-2H-4,7-cycloimidoisoindol-2-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one;

[0072] (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-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-yl)-2-fluoro-3-(thiazol-2-yl)acrylamide;

[0073] (Z)-1-((2S,5R)-4-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one;

[0074] (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);

[0075] (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);

[0076] (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;

[0077] (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;

[0078] 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;

[0079] 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;

[0080] (Z)-1-(4-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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);

[0081] (Z)-1-(4-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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);

[0082] (Z)-1-(5-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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);

[0083] (Z)-1-(5-((7M)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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);

[0084] (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;

[0085] (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;

[0086] (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;

[0087] (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;

[0088] 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;

[0089] (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;

[0090] 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;

[0091] 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;

[0092] (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;

[0093] 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;

[0094] 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;

[0095] 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;

[0096] 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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;

[0097] 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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;

[0098] 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0099] 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0100] (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;

[0101] (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;

[0102] (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

[0103] 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

[0104] 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

[0105] (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;

[0106] (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;

[0107] 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;

[0108] 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;

[0109] 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;

[0110] 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;

[0111] 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;

[0112] 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;

[0113] 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;

[0114] 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;

[0115] 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;

[0116] 2-((S)-4-(7-(8-ethylnaphth-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;

[0117] 2-((S)-4-(7-(8-ethylnaphth-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;

[0118] 2-((S)-4-(7-(8-ethylnaphth-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;

[0119] 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;

[0120] 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;

[0121] 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;

[0122] 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;

[0123] 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;

[0124] 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;

[0125] 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;

[0126] 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;

[0127] (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;

[0128] (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;

[0129] (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-pyrrolizin-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;

[0130] (Z)-1-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one;

[0131] (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;

[0132] (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;

[0133] 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0134] 2-((2S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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;

[0135] 2-((2S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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;

[0136] 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-naphthocarbonitrile;

[0137] 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-naphthocarbonitrile;

[0138] (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;

[0139] (Z)-1-((R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0140] (Z)-1-((R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one;

[0141] (Z)-1-((3R)-3-((7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0142] (Z)-1-((3R)-3-((7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one;

[0143] 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0144] 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0145] 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-((Z)-2-fluoro-3-(pyrazin-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0146] (Z)-1-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; and

[0147] (Z)-1-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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.

[0148] In some aspects, the present disclosure provides atropisomers of the compounds of any of the aforementioned aspects. In certain aspects, the compound is a stable atropisomer as described herein.

[0149] In some aspects, the present disclosure provides a pharmaceutical composition comprising the compound of any one of the aforementioned aspects or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0150] In some aspects, the present disclosure provides an oral dosage form comprising a compound according to any one of the preceding aspects, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0151] In some aspects, the present disclosure provides a method of treating a cancer expressing KRAS G12C, G12D and / or G12V mutations in a subject in need thereof, the method comprising administering to the subject a compound of any of the preceding aspects or a pharmaceutically acceptable salt thereof.

[0152] In some aspects, the present disclosure provides a method of treating a cancer expressing a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a compound of any one of the preceding aspects or a pharmaceutically acceptable salt thereof.

[0153] In some aspects, the present disclosure provides a method for treating a cancer sensitive to KRAS G12C inhibition in a subject in need thereof, the method comprising administering to the subject a compound of any one of the preceding aspects or a pharmaceutically acceptable salt thereof.

[0154] 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 one of the preceding aspects, or a pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, gastric cancer, or uterine cancer.

[0155] 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 one of the preceding aspects, or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer.

[0156] In some aspects of the method, the compound is an atropisomer of the compound of any of the preceding aspects. In certain aspects, the compound is a stable atropisomer as described herein.

[0157] 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 described 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.

[0158] In some aspects, the present disclosure provides a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting the cell with a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0159] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the inhibition of KRAS G12C.

[0160] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, for use in the treatment of a disease or disorder associated with KRAS G12C.

[0161] In another aspect, the present disclosure provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer. In some aspects, the cancer is lung cancer. In some aspects, the cancer is non-small cell lung cancer.

[0162] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for inhibiting the activity of KRAS G12C.

[0163] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for treating a disease or disorder associated with KRAS G12C. DETAILED DESCRIPTION

[0164] Unless otherwise stated, any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0165] The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise.

[0166] As used herein, the term "or" is a logical disjunction (ie, and / or) and does not indicate a mutually exclusive disjunction unless expressly indicated by the terms "or," "unless," "alternatively," and words of similar effect.

[0167] 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 compounds of formula (I), and pharmaceutically acceptable salts of two or more compounds of formula (I).

[0168] As used herein, the term "C2-C4 alkenyl" refers to a group derived from a straight or branched chain hydrocarbon containing from two to four carbon atoms and one double bond.

[0169] 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.

[0170] As used herein, the term "C1-C6 alkoxy" refers to a C1-C6 alkyl group attached to the parent molecular moiety through an oxygen atom.

[0171] 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.

[0172] As used herein, the term "C1-C6 alkoxy C1-C6 alkyl," refers to a C1-C6 alkoxy group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0173] 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.

[0174] As used herein, the term "C1-C3 alkyl" refers to a group derived from a straight-chain or branched saturated hydrocarbon containing from one to three carbon atoms.

[0175] As used herein, the term "C1-C6 alkyl" refers to a group derived from a straight-chain or branched saturated hydrocarbon containing one to six carbon atoms.

[0176] As used herein, the term (C1-C6 alkyl)amino refers to R—NH, wherein R is a C1-C6 alkyl group.

[0177] As used herein, the term "(C1-C6 alkyl)amino C1-C3 alkyl," refers to a (C1-C6 alkyl)amino group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0178] 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.

[0179] As used herein, the term "C2-C4 alkynyl" refers to a group derived from a straight or branched chain hydrocarbon containing from two to four carbon atoms and one triple bond.

[0180] As used herein, the term "amido" refers to NH2C(O)-.

[0181] As used herein, the term "amido C1-C3 alkyl" refers to an amido group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0182] As used herein, the term "amino" refers to -NH2.

[0183] 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.

[0184] As used herein, the term "aryl" refers to a phenyl group or a bicyclic fused ring system in which one or both rings are phenyl groups. The bicyclic fused ring system consists of a phenyl group fused to a four to six-membered aromatic or non-aromatic carbocyclic ring. The aryl group of the present disclosure can be attached to the parent molecular moiety through any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.

[0185] 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.

[0186] As used herein, the term "carboxyl" refers to -CO2H.

[0187] As used herein, the term "carboxy C1-C6 alkyl" refers to a C1-C6 alkyl group substituted with one, two, or three carboxyl groups.

[0188] As used herein, the term "cyano" refers to -CN.

[0189] As used herein, the term "cyano C1-C3 alkyl" refers to a C1-C3 alkyl group substituted with one, two, or three cyano groups.

[0190] As used herein, the term "C3-C4 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring system having three or four carbon atoms and zero heteroatoms.

[0191] As used herein, the term "C3-C6 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring system having three to six carbon atoms and zero heteroatoms.

[0192] As used herein, the term "C3-C6 cycloalkylC1-C6 alkyl," refers to a C3-C6 cycloalkyl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0193] As used herein, the term "di(C1-C6 alkyl)amino" refers to -NR z R z’ , where R z and R z’ are the same or different C1-C6 alkyl groups.

[0194] As used herein, the term "di(C1-C3 alkyl)amino C2-C6 alkyl" refers to -(C2-C6 alkyl)NR z R z’ , where R z and R z’ are the same or different C1-C6 alkyl groups.

[0195] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, or I.

[0196] As used herein, the term "halo C1-C3 alkoxy" refers to a C1-C3 alkoxy group substituted with one, two, or three halogen atoms.

[0197] As used herein, the term "haloC1-C3 alkyl" refers to a C1-C3 alkyl group substituted with one, two, or three halogen atoms.

[0198] As used herein, the term "halogenated C1-C6 alkyl" refers to a C1-C6 alkyl group substituted with one to six halogen atoms.

[0199] As used herein, the term "heteroaryl" refers to an aromatic five- or six-membered ring in which at least one atom is selected from N, O, and S, and the remaining atoms are carbon. The term "heteroaryl" also includes: bicyclic systems in which the heteroaryl ring is fused to a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S; and tricyclic systems in which the bicyclic system is fused to a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S. The heteroaryl group is attached to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. Representative examples of heteroaryl groups include, but are not limited to, alloxazine, benzo[1,2-d:4,5-d']bithiazole, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.

[0200] As used herein, the term "heteroaryl C1-C6 alkyl," refers to a heteroaryl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0201] As used herein, the term "heterocyclyl" refers to a five-, six-, seven-, eight-, nine-, ten-, eleven-, or twelve-membered saturated or partially unsaturated ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" also includes groups in which the heterocyclyl ring is fused to one, two, or three four- to six-membered aromatic or non-aromatic carbocyclic or monocyclic heterocyclyl groups. The term "heterocyclyl" also includes monocyclic or polycyclic heterocyclyl groups as described above, which are further substituted by one or more spirocyclic groups attached to the heterocyclyl group via a spiro carbon. Examples of heterocyclyl groups include, but are not limited to, dihydro-1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropane], hexahydro-2H-1,4-dioxa-2a1-azacyclopenta[cd]pentalenyl, hexahydropyrrolizinyl, indolinyl, morpholinyl, octahydroindolizinyl, octahydroquinolizinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thiomorpholinyl.

[0202] The term "heterocyclyl C1-C6 alkyl," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0203] As used herein, the term "hydroxy" refers to -OH.

[0204] 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.

[0205] As used herein, the term "hydroxy C1-C6 alkyl," refers to a hydroxy group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0206] As used herein, the term "NR a R b -C(O)" refers to an NR attached to the parent molecular moiety through a carbonyl group a R b group.

[0207] As used herein, the term "NR a R b -C(O)-C1-C6 alkyl" refers to an NR group attached to the parent molecular moiety through a C1-C6 alkyl group a R b -C(O)- group.

[0208] As used herein, the term "NR a R b "C1-C6 alkyl" refers to an NR group attached to the parent molecular moiety through a C1-C6 alkyl group a R b group.

[0209] As used herein, the term "nitro" refers to -NO2.

[0210] As used herein, the term "oxo" refers to =0.

[0211] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein using appropriate isotopically labeled reagents in place of unlabeled reagents that would otherwise be employed. 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 advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0212] Another aspect of the subject matter described herein is the use of the disclosed compounds as radiolabeled ligands for developing ligand binding assays or for monitoring in vivo adsorption, metabolism, distribution, receptor binding or occupancy, or compound disposition. For example, the compounds described herein can be prepared using radioisotopes, and the resulting radiolabeled compounds can be used to develop binding assays or for metabolic studies. Alternatively, and for the same purpose, the compounds described herein can be converted to a radiolabeled form by catalytic tritiation using methods known to those skilled in the art.

[0213] Certain compounds disclosed herein exist as stereoisomers. It should be understood that when stereochemistry is not specified, 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 a chiral center, or by preparing a mixture of enantiomeric products followed by separation, such as conversion into a mixture of diastereoisomers, followed by separation or recrystallization, chromatography techniques, or direct separation of enantiomers on a chiral chromatography column. Starting compounds of specific stereochemistry are commercially available or can be prepared and resolved by techniques known in the art.

[0214] Certain compounds of the present disclosure exist as atropisomers. The term "atropisomer" refers to a conformational stereoisomer that occurs when the rotation around a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule, and the substituents at both ends of the single bond are asymmetric (i.e., optical activity is produced without the need for an asymmetric carbon center or stereocenter). When the rotation barrier around a single bond is high enough and the interconversion between conformations is slow enough, separation and isolation of isomeric substances can be allowed. Atropisomers are enantiomers (or epimers) in the absence of a single asymmetric atom.

[0215] If the barrier to interconversion is high enough to allow little or no interconversion at room temperature for at least one week, the atropisomer can be considered stable. In some aspects, the atropisomer experiences little or no interconversion at room temperature for at least one year. In some aspects, when the atropisomer compound is in a substantially pure form (which is generally a solid state), the atropisomer compound of the present disclosure does not experience more than about 5% of the interconversion to its relative atropisomer during one week at room temperature. In some aspects, the atropisomer compound of the present disclosure does not experience more than about 5% of the interconversion to its relative atropisomer at room temperature (approximately 25 ° C) during one year. In some aspects, the atropisomer compound of the present disclosure is sufficiently stable to experience no more than about 5% of the interconversion in the aqueous pharmaceutical formulation at 0 ° C for at least one week. The chemical entity, pharmaceutical composition and method of the present invention are intended to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, single atropisomers and intermediate mixtures in optically pure forms.

[0216] The energy barrier to the thermal racemization of atropisomers can be determined by the steric hindrance to the free rotation of one or more bonds forming the chiral axis. Certain biaryl compounds exhibit atropisomerism, in which rotation around the inter-ring bond lacking C2 symmetry is restricted. The free energy barrier to isomerization (enantiomerization) is a measure of the stability of the inter-ring bond with respect to rotation. Optical and thermal excitations can promote the racemization of such isomers, depending on electronic and steric factors.

[0217] Ortho-substituted biaryl compounds can exhibit this type of conformational and rotational isomerism. Such biaryl compounds are enantiomeric and chiral atropisomers, where sp 2 -sp 2 The carbon-carbon, intercyclic bonds between the aryl rings have sufficiently high energy barriers to prevent free rotation, and wherein the substituent W 1 ≠W 2 and W 3 ≠W 4 Makes the molecule asymmetric.

[0218] W 1 :W 3 、W 1 :W 4 , and / or W 2 :W 4 、W 2 :W 3The steric interactions between the two non-planar, axially chiral enantiomers are large enough to allow the planar conformation to be at an energy maximum. When the interconversion of two non-planar, axially chiral enantiomers is slow enough so that they can freely separate from each other, then they exist as atropisomers. The bold and dotted lines in the figures shown above indicate those parts, or parts of the molecule, that are spatially restricted due to the rotational energy barrier. The bold parts exist orthogonally above the plane of the page, and the dotted parts exist orthogonally below the plane of the page. The 'flat' part of the molecule (the left ring in each of the two depicted biaryls) is in the plane of the page.

[0219] The pharmaceutical composition of the present disclosure may include one or more pharmaceutically acceptable salts." pharmaceutically acceptable salts " refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesirable toxicological effects (see, for example, Berge, SM et al., J.Pharm.Sci. [Journal of Pharmaceutical Sciences], 66: 1-19 (1977)). These salts can be obtained during the final separation and purification of compounds as described herein, or by reacting the free base functional group of the compound with a suitable acid alone, or by reacting the acidic group of the compound with a suitable base. Acid addition salts include salts derived from nontoxic inorganic acids (such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, etc.) and salts derived from nontoxic organic acids (such as aliphatic monocarboxylic acids and aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.). Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, calcium, and the like, as well as from non-toxic organic amines such as N,N′-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like. Pharmaceutical composition

[0220] In another aspect, the present disclosure provides compositions, such as pharmaceutical compositions, containing one or a combination of compounds described herein 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 as described herein.

[0221] As used herein, "pharmaceutically acceptable carriers" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In some aspects, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0222] The pharmaceutical composition of the present disclosure can be administered via one or more routes of administration using various methods known in the art. As will be appreciated by those skilled in the art, route of administration and / or pattern will vary depending on the desired result. In some aspects, the route of administration for the compound of the present disclosure includes intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal column or other parenteral routes of administration, such as by injection or infusion. As used herein, phrase "parenteral administration" means the mode of administration except enteral and topical administration, is usually administered by injection, and includes but is not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardial, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

[0223] Sterile injectable solutions can be prepared by optionally incorporating the active compound in the desired amount into a suitable solvent containing one or a combination of the above-listed ingredients, followed by sterilization microfiltration. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing an alkaline dispersion medium and the desired other ingredients from those described above. In the case of sterile powders for the preparation of sterile injectable solutions, some preparation methods are drying under reduced pressure and freeze drying (lyophilization), which produces a powder of the active ingredient plus any other desired ingredients from a previously sterile-filtered solution of the active ingredient plus any other desired ingredients.

[0224] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils, and injectable organic esters. Suitable fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin), by maintaining the desired particle size in the case of dispersions, and by the use of surfactants.

[0225] 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 as pharmaceutically active substances is known in the art. Unless any conventional media or agents are incompatible with the active compound, the use of such media or agents in the pharmaceutical compositions of the present disclosure is contemplated. Supplementary active compounds may also be incorporated into the compositions.

[0226] Therapeutic compositions typically must be sterile and stable under manufacturing and storage conditions. Compositions can be formulated as solutions or liquids with an ordered structure suitable for high drug concentrations. Supporting agents can be solvents or dispersion media containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.) and suitable mixtures thereof. For example, suitable fluidity can be maintained by using a coating (such as lecithin), by maintaining the required particle size and by using a surfactant in the case of a dispersion. In many cases, it is desirable to include an isotonic agent, for example, sugar, polyols (such as mannitol, sorbitol) or sodium chloride in the composition. The extended absorption of injectable compositions can be achieved by including in the composition an agent (for example, monostearate and gelatin) that delays absorption.

[0227] Alternatively, the compounds of the disclosure may be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.

[0228] Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, for example, tablets, lozenges, dragees, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for making pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, the pharmaceutical composition according to this disclosure can contain at least one medicament selected from sweeteners, flavorings, coloring agents, demulcents, antioxidants, and preservatives.

[0229] Tablets can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient which is suitable for the manufacture of tablets.

[0230] Aqueous suspensions can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of aqueous suspensions, including, but not limited to, suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents such as, for example, naturally occurring phospholipids such as lecithin; condensation products of alkylene oxides with fatty acids such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long-chain aliphatic alcohols such as, for example, heptadecanethenyl-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as, for example, polyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, including, but not limited to, sucrose, saccharin, and aspartame.

[0231] Oily suspensions can for example be prepared by suspending at least one compound with 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 being suspended in 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. In order to provide a delicious oily suspension, at least one sweetener and / or at least one flavoring agent already described above can be added to the oily suspension. Oily suspensions can further contain at least one preservative, including but not limited to for example antioxidants, such as butylated hydroxyanisole and alpha-tocopherol.

[0232] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersant and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersants, wetting agents, and suspending agents have been described above. Exemplary preservatives include, but are not limited to, antioxidants such as ascorbic acid. In addition, dispersible powders and granules may also contain at least one excipient, including, but not limited to, sweeteners, flavorings, and coloring agents.

[0233] The active compound can be prepared with a carrier that will prevent the rapid release of the compound, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods for preparing such formulations are patented or generally known to those skilled in the art. See, for example, Robinson, JR, ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0234] The therapeutic composition can be administered using medical devices known in the art. For example, in one aspect, the therapeutic composition of the present disclosure can be administered using a needle-free subcutaneous injection device, such as the devices disclosed in U.S. 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 that can be used in the present disclosure include: U.S. Patent No. 4,487,603, which discloses an implantable microinfusion pump for dispensing drugs at a controlled rate; U.S. Patent No. 4,486,194, which discloses a therapeutic device for administering drugs through the skin; U.S. Patent No. 4,447,233, which discloses a drug infusion pump for delivering drugs at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion device for continuous drug delivery; U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system with a multi-chamber compartment; and U.S. Patent 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.

[0235] In certain aspects, the compounds of the disclosure can be administered parenterally, i.e., by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and / or infusion.

[0236] In some aspects, the compounds of the disclosure can be administered orally, ie, via gelatin capsules, tablets, hard or soft capsules, or liquid capsules. Uses / treatments of KRAS inhibitors

[0237] Administration of the therapeutic agents described herein may include administration of a therapeutically effective amount of the therapeutic agent. As used herein, the term "therapeutically effective amount" refers to, but is not limited to, an amount of a therapeutic agent to treat a condition treatable by administering a composition comprising a KRAS inhibitor as described herein. This amount is sufficient to exhibit a detectable therapeutic or ameliorative effect. The effect may include, for example, but is not limited to, the treatment of the conditions listed herein. The precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition being treated, the advice of the treating physician, and the therapy or combination of therapies selected for administration.

[0238] For administration of the compounds described herein, dosages range from about 0.0001 to 100 mg / kg host body weight and more typically 0.01 to 40 mg / kg host body weight. Exemplary treatment regimens entail administration once a day, twice a week, three times a week, weekly, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months, or once every three to six months.

[0239] The disclosed compounds strongly inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Therefore, in another aspect, the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising any compound disclosed herein and a pharmaceutically acceptable carrier.

[0240] Ras mutations, including but not limited to KRAS mutations, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, certain aspects relate to administering the disclosed compounds (e.g., in the form of 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 compounds disclosed herein 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 myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other aspects, these compounds can be used to treat lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0241] Determining whether a tumor or cancer contains a KRAS mutation can be performed by evaluating the nucleotide sequence encoding the KRAS protein, by evaluating the amino acid sequence of the KRAS protein, or by evaluating the characteristics of a putative KRAS mutant protein. The sequence of the wild-type human KRAS protein is known in the art.

[0242] 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 aspects, KRAS mutation evaluation is performed on the sample, including by real-time PCR. In real-time PCR, a fluorescent probe specific for KRAS mutations is used. When there is a mutation, the probe binds and detects fluorescence. In some aspects, a direct sequencing method of a specific region (e.g., exon 2 and / or exon 3) in the KRAS gene is used to identify KRAS mutations. This technology will identify all possible mutations in the region sequenced.

[0243] Methods for detecting mutations in KRAS proteins are known to those skilled in the art. These methods include, but are not limited to, detecting KRAS mutants using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0244] Methods for determining whether a tumor or cancer contains a KRAS mutation can use a variety of samples. In some aspects, the sample is taken from a subject with a tumor or cancer. In some aspects, the sample is taken from a subject with a cancer or tumor. In some aspects, the sample is a fresh tumor / cancer sample. In some aspects, the sample is a frozen tumor / cancer sample. In some aspects, the sample is a formalin-fixed paraffin-embedded sample. In some aspects, the sample is processed into a cell lysate. In some aspects, the sample is processed into DNA or RNA. The present disclosure also relates to a method for treating a hyperproliferative disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.In some aspects, the methods relate to the treatment of cancers such as acute myeloid leukemia, juvenile cancers, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphomas and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory glioma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic Neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oral In some aspects, the method is directed to treating a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

[0245] In certain aspects, the present disclosure relates to a method for treating lung cancer, comprising administering an effective amount of any of the above compounds (or a pharmaceutical composition comprising the same) to a subject in need thereof. In 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 treatable with the disclosed compounds include, but are not limited to, glandular 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 the compounds according to the methods of the present disclosure include, for example, subjects who have been diagnosed with acute myeloid leukemia, acute myeloid leukemia, juvenile cancers, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchogenic carcinoma, Burkitt's lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germinal tumor, or the like. Cell tumors, primary lymphomas, cervical cancer, childhood cancers, chordomas, heart tumors, 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), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory glioma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), SCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancers. In some aspects, subjects treated with the compounds of the disclosure include subjects who have been diagnosed with a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or the prostate (e.g., benign prostatic hypertrophy (BPH)).The present disclosure further provides a method for regulating the activity of mutant KRAS protein by contacting the protein with an effective amount of a compound of the present disclosure. Regulation can be to inhibit or activate protein activity. In some aspects, the present disclosure provides a method for inhibiting protein activity by contacting a mutant KRAS protein with an effective amount of a compound of the present disclosure in a solution. In some aspects, the present disclosure provides a method for inhibiting the activity of mutant KRAS protein by contacting cells, tissues, and organs expressing a protein of interest. In some aspects, the present disclosure provides a method for inhibiting protein activity in a subject (including but not limited to rodents and mammals (e.g., humans)) by administering an effective amount of a compound of the present disclosure to the subject. In some aspects, the regulation percentage exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the inhibition percentage exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the present disclosure provides methods for 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 KRAS mutant in the cell. In some aspects, the present disclosure provides methods for 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 aspects, the present disclosure provides methods for 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 for inhibiting KRAS activity 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 aspects, 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 the activity of KRAS in the mammal. In some aspects, 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 the activity of KRAS in the human. The present disclosure provides methods for treating diseases mediated by KRAS activity in subjects in need of such treatment. The present disclosure also provides methods for combination therapy, wherein agents known to modulate other pathways, or other components of the same pathway, or even overlapping target enzyme groups are used in combination with the compounds of the present disclosure or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates or derivatives thereof. In one aspect, such therapy includes, but is not limited to, combinations of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies and radiation therapy.

[0246] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of the present disclosure. In some aspects, the chemotherapeutic agent is selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0247] The compounds described herein can be used in combination with the medicament disclosed herein or other suitable medicaments, depending on the condition being treated. Therefore, in some aspects, the one or more compounds of the present disclosure will be co-administered with other medicaments as described above. When used in combination therapy, the compound described herein and the second medicament are administered simultaneously or individually. The combined administration can include administering both medicaments simultaneously with the same dosage form, administering simultaneously with different dosage forms, and administering alone. That is, the compound described herein and any medicament described above can be formulated together with the same dosage form and administered simultaneously. Alternatively, the compound of the present disclosure and any medicament described above can be administered simultaneously, wherein the two medicaments are present in separate preparations. In another alternative, the compound of the present disclosure can be administered immediately after any of the medicaments described above, or vice versa. In some aspects of a separate administration scheme, the compound of the present disclosure and any medicament described above are administered at intervals of a few minutes, or at intervals of a few hours, or at intervals of a few days.

[0248] These compounds can be prepared by methods known in the art (including those methods described below and including variations within the art technology). Some reagents and intermediates are known in the art. Other reagents and intermediates can be prepared by methods known in the art using readily available materials. Any variable used to describe the synthesis of a compound (e.g., a numbered "R" substituent) is intended only to illustrate how to prepare the compound and should not be confused with the variables used in the claims or other parts of this specification. The following methods are for illustrative purposes and are not intended to limit the scope of this disclosure. synthesis

[0249] The aspects described herein are further defined in the following examples. It should be understood that these examples are provided by way of illustration only. From the above discussion and examples, those skilled in the art can determine the essential features of the aspects described herein, and, without departing from the spirit and scope thereof, various changes and modifications can be made to adapt them to various uses and conditions. Therefore, the aspects described herein are not limited by the illustrative examples set forth below herein, but are defined by the appended claims. abbreviation

[0250] The following abbreviations are used in the Examples section below and elsewhere herein: AA for ammonium acetate; ACN for acetonitrile; BOC or Boc for tert-butyloxycarbonyl; Cbz for benzyloxycarbonyl; DCM for dichloromethane; DEA for diethylamine; DIPEA or DIEA for diisopropylethylamine; DMA for dimethylacetamide; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; dpp for 1,1'-bis(diphenylphosphino)ferrocene; Et for ethyl; EtOAc for ethyl acetate; EtOH for ethanol; h for hour; HDMS for hexamethyldisilazane; and Propanol, IPA; for minutes, min; for lithium hexamethyldisilazide, LiHDMS; for methoxymethyl, MOM; for methyl, Me; for acetonitrile, MeCN or ACN; for methanol, MeOH; for N-iodosuccinimide, NIS; for acetate, OAc; for phenyl, Ph; for p-methoxybenzyl, PMB; for room temperature or retention time, RT or rt (the context will indicate); for tosyl, Tos; for tetrabutylammonium fluoride, TBAF; for trimethylamine, TEA or Et3N; for triethylsilane, TES-H; for trifluoroacetic acid, TFA; and for tetrahydrofuran, THF. 6-Chloro-7-(8-chloronaphth-1-yl)-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline 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

[0251] (S)-tert-Butyl 4-(7-bromo-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (prepared according to the procedure found in U.S. Patent 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 tetrakistriphenylphosphine palladium(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 carried out 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 afford the desired product (33 mg, 0.05 mmol, 63% yield). LC / MS (ESI) m / z: for C 34 H 39 Calculated value of Cl2FN5O3 [M+H] + 654.2; measured value 654.2. 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

[0252] 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 min, at which time LC / MS analysis showed complete conversion to the desired mass of product. The reaction mixture was directly concentrated and used in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 29 H 31 Calculated value of Cl2FN5O3 [M+H] + 554.2; measured value 554.1. 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-fluoronaphthalene-2-ol Step 1: (1R,5S)-tert-butyl 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

[0253] 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-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (prepared according to WO 2022 / 002102, 0.25 g, 0.43 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (prepared according to WO 2022 / 002102, 0.25 g, 0.43 mmol) were added to the mixture by bubbling nitrogen. 2021 / 041671 described in the procedure preparation, 0.26g, 0.51mmol) and sodium carbonate (0.11g, 1.1mmol) in dioxane (12mL) and water (4mL) suspension degassed 15min. 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (0.03g, 0.04mmol) was added, and the red suspension was heated at 100 ° C for 24h. The dark suspension was diluted with EtOAc (20mL) and washed with water (10mL) and brine (10mL). The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→10% MeOH / DCM) to provide the desired product (110mg, 0.12mmol, 29% yield). LC / MS (ESI) m / z: for C 48 H 63 Calculated value of ClF2N5O5Si [M+H] + 890.4; measured value 890.5. Step 2: (1R,5S)-tert-butyl 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

[0254] 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 of sufficient purity to be used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 39 H 43 Calculated value of ClF2N5O5 [M+H] + 734.3; measured value 734.3. 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

[0255] (1R,5S)-tert-butyl 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 provide the desired product (60 mg, 0.095 mmol, 88% yield) as an HCl salt. LC / MS (ESI) m / z: for C 32 H 31 Calculated value of ClF2N5O5 [M+H] + 590.2; measured value 590.4. (S)-4-(8-Fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)naphthalen-2-ol Step 1: tert-Butyl 4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

[0256] 7- bromo -2,4- dichloro -8- fluoroquinazoline (250mg, 0.85mmol) is dissolved in dioxane (15ml), and DIPEA (0.44mL, 2.5mmol) is added, followed by tert-butyl piperazine -1- carboxylate (160mg, 0.85mmol). The reaction mixture is stirred at room temperature for 2h. The mixture is diluted with EtOAc (20mL) and quenched by adding NaOH solution (1.0M, 2mL). The layers are separated, and the organic phase is washed with brine (10mL). The combined aqueous layer is back extracted with EtOAc (2 × 20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue is purified by column chromatography (5 → 45% EtOAc / hexane) to provide the desired product (230mg, 0.52mmol, 61% yield) as a white solid. LC / MS (ESI) m / z: for C 17 H 20 Calculated value of BrClFN4O2 [M+H] + 445.0; Found 444.8. NMR: 1 H NMR (500MHz, CD3OD) δ7.80 (dd, J = 9.1, 1.6 Hz, 1H), 7.68 (dd, J = 9.1, 6.5 Hz, 1H), 3.99-3.93 (m, 4H), 3.69-3.63 (m, 4H), 1.49 (s, 9H). Step 2: (S)-tert-Butyl 4-(7-bromo-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0257] tert-Butyl 4-(7-bromo-2-chloro-8-fluoroquinazoline-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 solution of LiHMDS (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 provide the desired product (120 mg, 0.23 mmol, 41% yield) as a white solid. LC / MS (ESI) m / z: for C 23 H 32 Calculated value of BrFN5O3 [M+H] + 524.2; Found 524.1. NMR: 1 H NMR (500MHz, CD3OD) δ7.70 (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). Step 3: (S)-tert-Butyl 4-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0258] (S)-tert-Butyl 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 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (7.5 mg, 0.01 mmol) was added and the resulting solution was heated at 100 °C for 24 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 provide the desired product (120 mg, 0.19 mmol, 83% yield) as an off-white solid. LC / MS (ESI) m / z: for C 35 H 43 Calculated value of FN5O5 [M+H] + 632.3; Found 632.2. NMR: 1 H NMR (500MHz, CD3OD) δ7.91(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),2.5 5(s,3H),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). Step 4: (S)-4-(8-Fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)naphthalen-2-ol

[0259] (S)-tert-Butyl 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 with DCM (3×5 mL). The crude residue was further dried under high vacuum to provide the desired product as its HCl salt (assuming quantitative yield). The crude material was of sufficient purity to be used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 28 H 31 Calculated value of FN5O2 [M+H] + 488.2; measured value 488.1. 2-((S)-4-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline-4- 2-[( ...methyl-1-piperazin-2-yl)acetonitrile)] Step 1: (S)-benzyl 4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0260] 7- bromo-2,4- dichloro-8-fluoroquinazoline (500mg, 1.7mmol) is dissolved in dioxane (15ml), and DIPEA (0.89mL, 5.1mmol) is added, followed by (S) -2- (cyanomethyl) piperazine-1- benzyl carboxylate (440mg, 1.7mmol). The reaction mixture is stirred at room temperature for 2h. The mixture is diluted with EtOAc (20mL) and quenched by adding NaOH solution (1.0M, 2mL). The layers are separated, and the organic phase is washed with brine (10mL). The combined aqueous layer is back extracted with EtOAc (2 × 20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue is purified by column chromatography (5 → 50% EtOAc / hexane) to provide the desired product (760mg, 1.5mmol, 87% yield) as a white solid. LC / MS (ESI) m / z: for C 22 H 19 Calculated value of BrClFN5O2 [M+H] + 518.0; Found 517.9. NMR: 1H NMR (500MHz, CD3OD) δ7.80 (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). Step 2: (S)-benzyl 4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0261] (S) -4- (7- bromo -2- chloro -8- fluoroquinazoline -4- bases) -2- (cyanomethyl) piperazine -1- benzyl carboxylate (from step 1, 150mg, 0.29mmol) and (S) - (1- methylpyrrolidin -2- bases) methanol (100mg, 0.87mmol) are suspended in THF (8mL). A solution of LiHMDS (1.0M in THF, 0.32mL, 0.32mmol) is added dropwise, and the reaction mixture is heated at 65 DEG C for 5h. The mixture is diluted with EtOAc (20mL) and washed with water (10mL) and brine (10mL). The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude residue is purified by column chromatography (0 → 8% MeOH / DCM) to provide the desired product (139mg, 0.23mmol, 80% yield) as a white solid. LC / MS (ESI) m / z: for C 28 H 31Calculated value of BrFN6O3 [M+H]+ 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 (brdd, J = 11.0, 6.0 Hz, 1H), 4.45 (dd, J = 11.0, 5.2 Hz, 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). Step 3: (S)-benzyl 2-(cyanomethyl)-4-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0262] (S)-benzyl 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 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (17 mg, 0.03 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 provide the desired product (243 mg, 0.34 mmol, 64% yield) as an off-white solid. LC / MS (ESI) m / z: for C 40 H 42 Calculated value of FN6O5 [M+H] +705.3; Found 705.3. NMR: 1 H NMR (500MHz, CD3OD) δ7.93(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,3H),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). 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

[0263] (S)-benzyl 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 was bubbled through the reaction mixture for 5 min. The reaction mixture was maintained under positive hydrogen pressure (1 atm, balloon) for 2.5 h. The reaction mixture was filtered through diatomaceous earth (Celite), taking care not to dry the filter cake, and the filtrate was concentrated. The crude residue was of sufficient purity to be used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 32 H 36 Calculated value of FN6O3 [M+H] + 571.3; measured value 571.2. 1H NMR(500MHz,CD3OD)δ7.88(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) ,2.73-2.68(m,2H),2.54(s,3H),2.41-2.35(m,1H),2.19-2.08(m,1H),1.88-1.74(m,3H). 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

[0264] 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 provide the desired product as an HCl salt (assuming quantitative yield). The crude material was of sufficient purity to be used directly in the next step without additional purification. LC / MS (ESI) m / z: for C 30 H 31 Calculated value of FN6O2 [M+H] + 527.3; measured value 527.2. 1H NMR (500MHz, CD3OD) δ8.17(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). 2-((S)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Step 1: (S)-benzyl 2-(cyanomethyl)-4-(8-fluoro-7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0265] (S)-benzyl 4-(7-bromo-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (from Intermediate 4, Step 2, 85 mg, 0.20 mmol), 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 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (6.5 mg, 0.01 mmol) was added, and the resulting solution was heated at 100°C for 2.5 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 provide the desired product (50 mg, 0.07 mmol, 37% yield) as an off-white solid. LC / MS (ESI) m / z: for C38 H 37 Calculated value of ClFN6O5 [M+H] + 679.3; measured value 679.3. 1 H NMR (500MHz, CD3OD) δ8.07(dd,J=8.2,1.1Hz,1H),7.98(d,J=8.1Hz,1H),7.86(d,J=8.7Hz,1H),7.63(d d,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,2 H),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 -2.79(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). 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

[0266] (S)-benzyl 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 was bubbled through the reaction mixture for 5 min. The reaction mixture was maintained under positive hydrogen pressure (1 atm, balloon) for 1.5 h. The reaction mixture was passed through Celite®. TM ) was filtered, taking care not to allow the filter cake to dry, and the filtrate was concentrated. The crude residue was of sufficient purity to be used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 30 H 31 Calcd. value of ClFN6O [M+H] + 545.2; measured value 545.4. 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 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine

[0267] To a solution of 6-bromo-4-methylpyridin-2-amine (1g, 5.35mmol) in DMF (20mL) was added NaH (0.64g, 16mmol, 60%) at 0°C. The mixture was stirred at 0°C for 0.5h. 1-(chloromethyl)-4-methoxybenzene (2.1g, 13.4mmol) was then added. The mixture was stirred at 0°C for 1.5h. TLC (on silica gel, petroleum ether: ethyl acetate = 5: 1) showed that the reaction was complete. The reaction was quenched with saturated NH4Cl (20mL) and extracted with ethyl acetate (20mL × 3), washed with brine (50mL) and dried over anhydrous Na2SO4. 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 afford 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) δ7.16 (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). (6-(Bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid

[0268] 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)dichloropalladium(II) (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 N₂ 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] + . tert-Butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

[0269] 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 h. The mixture was concentrated. The residue was diluted with ethyl acetate (60 mL), 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 provide tert-butyl 4- (7-bromo-2,6-dichloro-8-fluoroquinazoline-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] + . 1 H NMR (400MHz, CDCl3) δ7.77 (d, J = 1.6Hz, 1H), 3.93-3.84 (m, 4H), 3.72-3.61 (m, 4H), 1.50 (s, 9H). tert-Butyl 4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate

[0270] By 4- (7- bromo -2,6- dichloro -8- fluoroquinazoline -4- bases) piperazine -1- tert-butyl formate (intermediate 6C, 1000mg, 2.08mmol) and potassium fluoride (2420mg, 41.65mmol) in DMA (10mL) solution under N2 at 110 DEG C stirred for 12h. The reaction mixture was quenched with water (30mL) and extracted with EtOAc (30mL × 3). The combined organic layer was washed with brine (30mL × 3) and dried over anhydrous Na2SO4. 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 provide 4- (7- bromo -6- chloro -2,8- difluoroquinazoline -4- bases) piperazine -1- tert-butyl formate (730mg, 1.57mmol, 75.6% yield) as a yellow solid. MS (ESI) m / z 463.1[M+1] + . tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate

[0271] 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 N2 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 afford 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] + ; 1H NMR (400MHz, CDCl3) δ7.76(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). 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

[0272] 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 h. 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 afford 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) δ7.82(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). 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

[0273] 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 another 12 h. The mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with brine (30 mL × 3) and dried over anhydrous Na SO 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 provide 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] + . 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

[0274] 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) was added in THF (5 mL). 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 layers were 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 afford 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] + . 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

[0275] 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 d. The mixture was quenched with 2N 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 Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford 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 light yellow solid. MS (ESI) m / z 726.3 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.07(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,2 H),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). 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

[0276] 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 afford 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] + . 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

[0277] 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 layers were 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 150 x 25 mm 10 um; mobile phase: A is HO (0.1% TFA), and B is acetonitrile; gradient: linearly B 38%-68% in 10 min; flow rate: 25 mL / min; column temperature: room temperature; 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] + . 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

[0278] 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 x 25 mm, 10 um; mobile phase: A is H2O (0.225% FA), and B is acetonitrile; gradient: linearly B 3%-33% in 10 min; flow rate: 15 mL / min; column temperature: room temperature; wavelength: 220 nm, 254 nm) to afford the desired product. The mixture of atropisomers was separated by chiral SFC (column: Cellucoat 50 x 4.6 mm ID, 3 um mobile phase: phase A is CO2, and phase B is 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 obtain 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 (400 MHz, methanol-d4) δ 7.89 (s, 1H), 6.62 (s, 1H), 4.77 (br dd, J = 13.6, 2.8 Hz, 1H), 4.63-4.52 (m, 3H), 3.95-3.87 (m, 2H), 3.76-3.69 (m, 2H), 3.64-3.48 (m, 2H), 3.16-3.02 (m, 1H), 2.96 (s, 3H), 2.45 (d, J = 1.2 Hz, 3H), 2.39-2.28 (m, 1H), 2.13-1.93 (m, 7H). 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 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

[0279] 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)-quinazoline-4(3H)-one (intermediate 6I, 50 mg, 0.07 mmol) in POCl (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×2). The combined organic layers were washed with saturated NaHCO solution (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 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] + . 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

[0280] 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 layers were 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 provide the product (40 mg, 0.044 mmol, 80.9% yield) as a colorless oil. MS (ESI) m / z: 920.3 [M+H] + . 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

[0281] 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 an additive, instrument: ACSWH-GX-Q; column: Shim-pack C18 150×25, 10 μm; mobile phase: A is H 2 O (0.225% FA), and B is acetonitrile; gradient: linearly B 2%-35% in 11 min; flow rate: 25 mL / m; column temperature: room temperature; wavelength: 220 nm, 254 nm) to provide the desired product (11.1 mg, 0.019 mmol, 44.2% yield) as a white solid. MS (ESI) m / z: 580.2 [M+H] + ; 1H NMR(400MHz,CD3OD)δ8.53(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). 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 tert-Butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0282] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300mg, 3.03mmol) in dioxane (8mL) was added DIPEA (0.476mL, 2.72mmol) and 3,8-diazabicyclo [3.2.1] octane-8-tert-butyl formate (193mg, 0.908mmol). The resulting mixture was stirred at 25°C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated. The residue was diluted with ethyl acetate (50mL) and washed with water (30mL × 2) and brine (50mL). 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 provide 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) δ8.10(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),1.47s,9H). 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

[0283] To a solution of tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-formate (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 provide 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] + . 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

[0284] By tert-butyl 3-(7-bromo-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-formate (intermediate 8B, 108 mg, 0.185 mmol) and NaCO3 suspension in 1,4-dioxane (2954 μl) and water (739 μl) degassed and Pd(Ph3)4 (42.7 mg, 0.037 mmol) was added once. The mixture was degassed again and heated at 95 ° C in a pressure vial for 1 hour. 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 afford 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] + , and used it directly in the next step. 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

[0285] 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 hour. The reaction mixture was concentrated under reduced pressure to provide a residue, which 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: hold at 5% B for 0 minutes, 5%-45% B over 20 minutes, then hold at 100% B for 0 minutes; Flow rate: 20 mL / min; Column temperature: 25° C. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via 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: 4% B for 0 minutes, 4% to 44% B over 20 minutes, then 100% B for 0 minutes; Flow rate: 20 mL / min; Column temperature: 25°C. Fractions containing the desired product were combined and dried via centrifugal evaporation to provide 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) δ8.02(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). 6-(2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolizin-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 (3-Bromopropoxy)(tert-butyl)dimethylsilane

[0286] To a stirred solution of 3-bromopropan-1-ol (10.00 g, 71.9 mmol) in anhydrous dichloromethane (50 mL) was added imidazole (4.90 g, 71.9 mmol) at 0 ° C under nitrogen, 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 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and diluted with water (50 mL). The suspension was extracted with dichloromethane (3 × 200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude residue of the product. The residue was purified by silica gel column chromatography with 0-5% ethyl acetate in petroleum ether to obtain (3-bromopropoxy) (tert-butyl) dimethylsilane (8.00 g, 31.6 mmol, 43.9% yield) as a colorless oil. 1 H NMR (400MHz, CD3OD): δ3.69 (t, J = 4.0 Hz, 2H), 3.57 (t, J = 6.4 Hz, 2H), 1.99-1.93 (m, 2H), 0.87 (s, 9H), 0.06 (s, 6H) ppm. 1-(tert-Butyl)-2-methyl (2R,4R)-2-(3-((tert-Butyldimethylsilyl)oxy)propyl)-4-fluoropyrrolidine-1,2-dicarboxylate

[0287] To a stirred solution of (2S, 4R)-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (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. The reaction mixture was stirred at the same temperature for 30 min, and then (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 min and then slowly warmed to room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (15 mL) and then diluted with water (50 mL). The mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 20%-30% ethyl acetate in petroleum ether to afford 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): δ5.18-5.03(m,1H),4.10-3.98(m,1H),3.78(s,3H),3.74-3.52(m,3H),2.4 8-2.23(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 to -172.96(m)ppm. LCMS-ELSD(ESI)m / z:320.2[M+H-Boc] + . 1-(tert-Butyl)2-methyl (2R,4R)-4-fluoro-2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate

[0288] To a stirred solution of (2R, 4R)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (Intermediate 9B, 7.00 g, 16.68 mmol) was added TBAF (1 M in THF, 16.68 mL, 16.68 mmol) dropwise at 25 ° C and stirred at the same temperature for 4 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (90 mL) 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 obtain a crude residue as a colorless oil. The crude product was purified by silica gel column chromatography using 50% ethyl acetate in petroleum ether to afford 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] + . 1-(tert-Butyl)2-methyl (2R,4R)-4-fluoro-2-(3-iodopropyl)pyrrolidine-1,2-dicarboxylate

[0289] To a stirred solution of (2R, 4R)-4-fluoro-2-(3-hydroxypropyl) pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (intermediate 9C, 9.00g, 29.5mmol) in dichloromethane (100mL) was added triphenylphosphine (15.50g, 58.9mmol), imidazole (6.02g, 88mmol) at 0°C, and the reaction mixture was stirred at the same temperature for 10min, followed by the addition of iodine (29.9g, 118mmol). The reaction mixture was stirred at room temperature for 12h. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate solution (30mL) and the suspension was extracted with dichloromethane (2×200mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. This crude product was purified by silica gel column chromatography using 10%-20% ethyl acetate in petroleum ether to afford 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] + . 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

[0290] To a stirred solution of (2R,4R)-4-fluoro-2-(3-iodopropyl)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (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. When the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure at room temperature to obtain the crude residue of (2R,4R)-4-fluoro-2-(3-iodopropyl)pyrrolidine-2-carboxylic acid methyl ester HCl (6.5 g, 20.63 mmol, 86.0% yield), which was used as is in the next step without any further purification. LCMS-ELSD (ESI) m / z: 188.2 [M+H] + . (2R,7aR)-2-Fluorotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester

[0291] To a stirred solution of (2R, 4R)-4-fluoro-2-(3-iodopropyl)pyrrolidine-2-formic acid methyl ester (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 h. The reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was purified by column chromatography (aluminum oxide-neutral) using 40%-50% ethyl acetate in petroleum ether to obtain (2R, 7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a (5H)-formic acid methyl ester (3.20 g, 83.0% yield) as a light yellow oil. 1 H NMR (400MHz, DMSO-d6): δ5.76-5.19(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] + . ((2R,7aR)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol

[0292] To a stirred solution of (2R,7aR)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-methyl carboxylate (intermediate 9F, 3.20 g, 17.09 mmol) was added dropwise LiAlH4 (2M in THF, 17.09 mL, 34.2 mmol) at 0 ° C over 10 min under nitrogen. After addition, the reaction mixture was warmed to room temperature within 30 min. The mixture was stirred at this temperature for 1 h and then quenched with saturated aqueous ammonium chloride solution (5 mL) at 0 ° C. Once bubbling stopped, anhydrous sodium sulfate was added to the reaction mixture, followed by dichloromethane (20 mL). The reaction mixture was stirred for 20 min and filtered. The filtrate was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude residue of ((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (2.20 g, 13.68 mmol, 80.0% yield) as a light brown oil. 1 H NMR (400MHz, CD3OD): δ5.34-5.10(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 to -176.04(m)ppm. LCMS-ELSD(ESI)m / z:160.0[M+H] + . tert-Butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0293] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (3.5g, 10.6mmol) and 3,8-diazabicyclo [3.2.1] octane-8-tert-butyl formate (2240mg, 10.55mmol) in THF (50mL) was added DIEA (2.48mL, 26.5mmol). The mixture was stirred at 20°C for 12h. LCMS showed that the reaction was complete and the desired product was detected. The reaction mixture was diluted with EtOAc (40mL) and water (40mL). The mixture was extracted with EtOAc (40mL × 3). The combined organic layer was washed with brine (100mL), 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 purification. MS (ESI) m / z: 506.9 [M+3] + . 1 H NMR (400MHz, CDCl3) δ7.75 (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). tert-Butyl (1R,5S)-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0294] To a degassed solution of 3-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-tert-butyl formate (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 for 10 min and heated at 88 ° C for 5 h in a sealed tube. Water (200 mL) and ethyl acetate (150 mL) were added and stirred for 15 min. The separated aqueous layer was extracted with ethyl acetate (2 × 100 mL) and the combined organic layer was dried over anhydrous Na SO dried, filtered and concentrated. The resulting residue was purified by flash column chromatography using 15%-25% ethyl acetate in petroleum ether as eluent to provide 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 light yellow solid. MS (ESI) m / z 489.0 [M+1]+ . N,N-Bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

[0295] 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 bubbled through the solution for 20 min, and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (1.9 g, 2.3 mmol) was added and the reaction mixture was heated at 100 °C for 5 h. The reaction mixture was diluted with EtOAc (200 mL) and filtered through Celite®. TM The filtrate was concentrated to afford the desired product (22 g, 40.7 mmol, 87% yield). 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

[0296] 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), PdCl2(dppf) (149 mg, 0.204 mmol). The mixture was degassed again and heated at 80 ° C for 48 h. The reaction progress was monitored by LCMS. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate (40 mL), and filtered through Celite®. TM ) bed and concentrated in vacuo to provide a crude product. The residue was purified by silica gel column chromatography using 30% ethyl acetate in petroleum ether to obtain 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). 1H NMR (400MHz, CDCl3): δ7.76(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] + . 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

[0297] 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) was added N-iodosuccinimide (0.42 g, 1.849 mmol) and trifluoroacetic acid (0.028 mL, 0.370 mmol) at 0 ° C under nitrogen. The reaction mixture was allowed to reach room temperature over one hour. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate solution (5 mL) and saturated aqueous sodium bicarbonate solution (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 obtain a crude residue. The crude residue was purified by silica gel column chromatography using 30% ethyl acetate in petroleum ether to afford 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 light yellow fluffy solid. LCMS (ESI) m / z: 883.3 [M+H] + . 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

[0298] 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) was added copper (I) iodide (0.60 g, 3.17 mmol) in a sealed tube under nitrogen. The reaction mixture was degassed for 10 min, then 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 h. The reaction progress was monitored by LCMS. The reaction mixture was diluted with ether (20 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with ether (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. The crude product was purified by silica gel column chromatography using 30% ethyl acetate in petroleum ether to obtain 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): δ7.77 (s, 1H), 7.16 (d, J = 8.8Hz, 4H), 6.87 (dt, J = 9.6 and 2.8Hz, 4H), 6.43 (s, 1H), 4.76-4.7 2(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] + . 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-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0299] To a stirred solution of ((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 min. After 30 min, 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 while maintaining the temperature at 0° C. The reaction mixture is stirred for another 2h, and the reaction mixture is warmed to room temperature. The reaction mixture is quenched with saturated aqueous ammonium chloride solution (1mL) and diluted with ethyl acetate (5mL). The mixture is extracted with ethyl acetate (3×5mL). The combined organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude residue of the product. The crude residue is purified using 30% ethyl acetate in petroleum ether on neutral alumina to obtain 3- (7- (6- (bis (4- methoxybenzyl) amino) -4- methyl -3- (trifluoromethyl) pyridin-2-yl) -6- chloro- 8- fluoro- 2- (( (2R, 7aR) -2- fluorotetrahydro -1H- pyrrolizine -7a (5H) -yl) methoxy) quinazoline -4-yl) -3,8- diazabicyclo [3.2.1] octane -8- tert-butyl formate (657mg, 0.703mmol, 97.0% yield) as a light yellow solid. LCMS (ESI) m / z: 964.3 [M+H] + . 6-(2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolizin-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

[0300] 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-pyrrolazin-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 h. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure and below 35 °C to remove most of the TFA. The residue was co-evaporated with methanol (3×1 mL) to remove any remaining TFA. The residue is neutralized with DIPEA and concentrated under reduced pressure to obtain free alkali.Then the crude product is purified by a mixture of MeOH, dichloromethane and DIPEA (15:80:2.5) using silica gel (neutralized with DIPEA in advance) column chromatography to obtain 6-(2-{[(2R, 7aR)-2-fluoro-hexahydro-1H-pyrrolizine-7a-yl] methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octane-3-yl}-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine. The atropisomers were separated by chiral SFC (column: OD 25×5 mm ID, 5 um. Mobile phase: phase A is CO2, and phase B is MeOH (0.1% NH4OH); gradient elution: 40% MeOH (0.1% NH4OH) in CO2; flow rate: 350 mL / min; detector: UV 220 nm; column temperature: 30°C; back pressure: 100 bar) to obtain two product peaks: Peak 1 (Intermediate 9-1) and Peak 2 (Intermediate 9-2).

[0301] Peak 1, Isomer 1: Intermediate 9-1 (66 mg, 33% yield). MS (ESI) m / z 624.3 [M+1] +. 1H NMR(499MHz, DMSO-d6)δ7.88-7.76(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),3.58-3.4 9(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).

[0302] 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)δ7.92-7.72(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). 6-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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 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-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0303] To a stirred solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) was added NaH (28.4 mg, 1.181 mmol) at 0°C and the mixture was stirred for an additional 30 minutes. 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 gradually warmed to room temperature over a period of 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with water, then with salt water, and then dried over Na 2 SO 4 and concentrated under reduced pressure to provide a crude residue which was purified by silica gel column chromatography using a CombiFlash instrument (40 g The product was purified by column chromatography (50% to 60% EtOAc-petroleum ether) to afford 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-pyrrolazin-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) + . 6-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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

[0304]

[0146] 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-pyrrolazin-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 h. The reaction mixture was then concentrated under reduced pressure, co-distilled with toluene (twice), neutralized with DIPEA and concentrated under reduced pressure to afford a crude residue, which was purified by achiral SFC followed by chiral SFC to afford 6-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolazin-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).

[0305] (Isomer 1): MS (ESI) m / z: 624.2, [M+H] + . 1 H 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).

[0306] Preparative achiral SFC conditions: column / size: Princeton SFC Diol (250X 4.6) mm, 5u; CO2%: 30%; co-solvent%: 70% (0.2% NH3 in methanol); flow rate: 3 mL / min; back pressure: 100 bar; retention time = 6.129 min.

[0307] Preparative chiral SFC conditions: column / size: Chiralcel ODH (250X 4.6) mm, 5u; 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. 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-fluoronaphthalene-2-ol

[0308] In a similar manner to Intermediate 2, the desired product was prepared starting from (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-carboxylic acid tert-butyl ester (prepared as described in WO 2021106231). LCMS (ESI) m / z: for C 32 H 32 Calculated value of F2N5O2 [M+H] + 556.2; measured value 556.1; 1 H NMR (500MHz, CD3OD) δ7.87-7.83(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). (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 Step 1: (1R,5S)-tert-butyl 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

[0309] (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 h. The solution was cooled to 0 ° C and (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-carboxylic acid tert-butyl ester (250 mg, 0.30 mmol) was added dropwise in THF (2 mL) as a solution. The reaction mixture was stirred at 0 ° C for 1 h. 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 afford the desired product, which was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 52 H 61 Calculated value of ClF4N7O5 [M+H] + 974.4; measured value 974.4. 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 liquids and stirred for 30 min. 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 h. The reaction mixture was directly concentrated and purified by preparative HPLC to afford the desired product (50 mg, 0.08 mmol, 43% yield) as a white solid.1 H NMR (400MHz, DMSO-d6) δ7.80(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,1 H),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). 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 Octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylic acid ethyl ester

[0310] Intermediate 13A was prepared according to the procedure in Molecules 2017, 22: 827, compound 25a. (4aS,7aR)-1-benzyl 4a-ethyl hexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate (peak 2)

[0311] 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 x 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 100:0 to 50:50 gradient) to produce hexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylic acid 1-benzyl 4a-ethyl ester (2.20 g, 6.64 mmol, 77% yield). Hexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylic acid 1-benzyl 4a-ethyl ester (2.20 g) was subjected to SFC chiral separation. [Column: Cellulose-4 (5×25 cm, 5 μm) Method = CO 2 / IPA with 0.1% ammonium hydroxide: heptane (1:3). 320 mL / min] to provide:

[0312] Peak 1 (19B1): 1-benzyl 4a-ethyl hexahydro-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 x 50 mm, 1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 0.05% TFA; gradient: 2%-98% B over 1 minute, then hold at 98% B for 0.5 minute; flow rate: 0.8 mL / min; detection: MS and UV (220 nm).). 1 H NMR (499MHz, chloroform-d) δ7.41-7.28(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).

[0313] Peak 2 (19B2): (4aS,7aR)-hexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylic acid 1-benzyl 4a-ethyl ester (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 x 50 mm, 1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 0.05% TFA; gradient: 2%-98% B over 1 minute, then hold at 98% B for 0.5 minute; flow rate: 0.8 mL / min; detection: MS and UV (220 nm).). 1 H NMR (499MHz, chloroform-d) δ7.41-7.28(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).

[0314] Peak 3 (19B3): 1-benzyl 4a-ethyl hexahydro-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 x 50 mm, 1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 0.05% TFA; gradient: 2%-98% B over 1 minute, then hold at 98% B for 0.5 minute; flow rate: 0.8 mL / min; detection: MS and UV (220 nm).). 1H NMR (499 MHz, CHLOROFORM-d) δ 7.40-7.28 (m, 5H), 5.18-5.10 (m, 2H), 4.38 (ddd, J = 13.4, 2.5, 1.4 Hz, 1H), 4.13-4.05 (m, 2H), 2.88 (dd, J = 12.8, 7.0 Hz, 1H), 2.79-2.67 (m, 2H), 2.42 (dt, J = 13.1, 2.7 Hz, 1H), 2.28-2.14 (m, 2H), 1.76-1.55 (m, 4H), 1.46-1.26 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H).

[0315] Peak 4 (19B4): 1-benzyl 4a-ethyl hexahydro-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 x 50 mm, 1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 0.05% TFA; gradient: 2%-98% B over 1 minute, then hold at 98% B for 0.5 minute; flow rate: 0.8 mL / min; detection: MS and UV (220 nm).). 1 H NMR (499 MHz, CHLOROFORM-d) δ 7.40-7.28 (m, 5H), 5.18-5.10 (m, 2H), 4.38 (ddd, J = 13.4, 2.5, 1.4 Hz, 1H), 4.13-4.05 (m, 2H), 2.88 (dd, J = 12.8, 7.0 Hz, 1H), 2.79-2.67 (m, 2H), 2.42 (dt, J = 13.1, 2.7 Hz, 1H), 2.28-2.14 (m, 2H), 1.76-1.55 (m, 4H), 1.46-1.26 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H). (4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylic acid ethyl ester

[0316] A mixture of (4aS,7aR)-1-benzyl 4a-ethyl 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 atm of hydrogen for 18 h. The Pd / C was filtered off, and the filtrate was concentrated to afford crude (4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (385 mg, 1.854 mmol, 96% yield) as a clear oil. 1 H NMR (499 MHz, CHLOROFORM-d) δ 4.17 (dtt, J = 10.6, 7.1, 3.6 Hz, 2H), 3.57 (t, J = 6.1 Hz, 1H), 2.90 (ddd, J = 13.0, 7.7, 3.7 Hz, 1H), 2.71 (ddd, J = 13.0, 7.0, 3.6 Hz, 1H), 2.01-1.92 (m, 2H), 1.84-1.62 (m, 7H), 1.60-1.40 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). (4aS,7aR)-1-Methyloctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylic acid ethyl ester

[0317] To a solution of (4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylic acid ethyl ester (Intermediate 13C, 385 mg, 1.952 mmol) and formaldehyde solution (37 wt.% in H2O) (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 hours. The mixture was then concentrated. The mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous sodium carbonate solution (2×5 mL). The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated to provide crude (4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylic acid ethyl ester (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). ((4aS,7aR)-1-Methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol

[0318] To a solution of (4aS, 7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylic acid ethyl ester (intermediate 13D, 380 mg, 1.798 mmol) in anhydrous THF (2.0 mL) was added a solution of 1.0 M lithium aluminum hydride solution in THF (4496 μl, 4.50 mmol), and the mixture was stirred at room temperature for 18 hours. Salt water (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 provide a crude product ((4aS, 7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol (327 mg, 1.739 mmol, 97% yield). 1 HNMR (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). 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 Step 1: (1R,5S)-tert-butyl 3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0319] (1R, 5S) -3- (7- bromo -2- chloro -8- fluoroquinazoline -4- bases) -3,8- diazabicyclo [3.2.1] octane -8- tert-butyl carboxylate (42g, 89mmol, prepared according to the procedure described in WO 2021 / 136231 A1) was dissolved in MeCN (420mL) and DMA (63mL). Cesium fluoride (67.6g, 445mmol), tetramethylammonium chloride (1.0g, 8.9mmol) and 18- crown ether -6 (2.4g, 8.9mmol) were added as solids. The reaction mixture was heated at 60 ° C for 16h. The reaction mixture was diluted with EtOAc (1L) and washed with water (2 × 500mL) and brine (500mL). The organic phase was dried over sodium sulfate, filtered and concentrated to afford the desired product (26.5 g, 58 mmol, 65% yield) which was sufficiently pure to be used in the next step without additional purification. LC / MS (ESI) m / z: for C 19 H 22 Calculated value of BrF2N4O2 [M+H] + 455.1; measured value 455.2. Step 2: (1R,5S)-tert-butyl 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

[0320] Tert-butyl (1R,5S)-3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (from Step 1, 5.0 g, 11.0 mmol) 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 sparged with nitrogen for 15 min. Pd(dppf)Cl2 (0.8 g, 1.1 mmol) was added, and the reaction mixture was heated at 100°C for 16 h. 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 provide the desired product (3.0 g, 3.9 mmol, 35% yield); LC / MS (ESI) m / z: for C 42 H 52Calculated value of F3N4O4Si [M+H] + 761.4; measured value 761.2. 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

[0321] 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 h. The solution was directly concentrated and purified by preparative HPLC to afford the desired product (35 mg, 0.04 mmol, 65% yield); LC / MS (ESI) m / z: for C 52 H 70 Calculated value of F2N5O5Si [M+H] + 910.5; measured value 910.6. 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

[0322] 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 min. 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 h. The reaction mixture was directly concentrated and purified by preparative HPLC to afford the desired product (9.6 mg, 0.015 mmol, 39% yield); LC / MS (ESI) m / z: for C 36 H 38 Calculated value of F2N5O2 [M+H] + 610.3; measured value 610.5; 1 H NMR (500MHz, CD3OD) δ7.85-7.81(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,4 H),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). 6-(4-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0323] ((2R, 7aR) -2- fluorotetrahydro -1H- pyrrolazine -7a (5H) -yl) methanol (intermediate 9G, 110mg, 0.68mmol) was dissolved in THF (5mL), and the solution was cooled to 0 ° C. Sodium hydride (60wt% dispersion in mineral oil, 27mg, 0.68mmol) was added portionwise as a solid, and the reaction mixture was stirred for 30min. 4- (7- (6- (bis (4- methoxybenzyl) amino) -4- methyl -3- (trifluoromethyl) pyridin-2-yl) -6- chloro-2,8- difluoroquinazoline -4-yl) piperazine -1- tert-butyl carboxylate (intermediate 6G, 300mg, 0.375mmol) was added, and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 2h, the reaction mixture was quenched with water (20mL) and diluted with EtOAc (25mL). 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 / hexane) to provide the desired product (200 mg, 44% yield). LC / MS (ESI) m / z: for C 48 H 54 Calculated value of ClF5N7O5 [M+H] + 938.4; measured value 938.2. 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one

[0324] 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-pyrrolazin-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 directly concentrated, and the crude material was taken up in water (80 mL) and extracted with EtOAc (3 x 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 afford the product as a mixture of atropisomers. The material was further purified by chiral SFC to afford the desired isomer (retention time = 4.72 min, 1.2 g, 1.56 mmol, 17% yield) and the second isomer (retention time = 5.85 min, 1.3 g, 1.69 mmol, 18% yield). LC / MS (ESI) m / z: for C 39 H 38 F 25 Calculated value of N5O4 [M+H] + 770.2; measured value 770.2. 6-(4-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate

[0325] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 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 purified by column chromatography (60 → 100% EtOAc / hexane) to provide the desired product (65 mg, 0.06 mmol, 73% yield); LC / MS (ESI) m / z: for C 51 H 58 Calculated value of ClF5N7O5 [M+H] + 978.4, measured value 977.8. Step 2: 6-(4-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0326] 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-pyrrolazin-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 afford the desired product (17 mg, 0.02 mmol, 39% yield). LC / MS (ESI) m / z: for C 30 H 34 Calcd. value of ClF5N7O [M+H] + 638.2, measured value 638.8; 1H NMR (400MHz, CD3OD) δ8.05-7.81(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). 6-(4-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0327] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 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 purified by column chromatography (40 → 100% EtOAc / hexane) to provide the desired product (60 mg, 0.06 mmol, 75% yield). LC / MS (ESI) m / z: for C 49 H 54 Calculated value of ClF5N7O5 [M+H] + 950.4, measured value 950.2 Step 2: 6-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0328] 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-pyrrolazin-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 afford the desired product (14 mg, 0.02 mmol, 31% yield) as its TFA salt; LC / MS (ESI) m / z: for C 28 H 30 Calcd. value of ClF5N7O [M+H] + 610.2, measured value 610.2; 1H NMR (400MHz, CD3OD) δ8.38 (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) ,3.69-3.78(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). tert-Butyl (1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: (1R,5S)-tert-butyl 3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0329] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-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 min. (1R,5S)-3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5.2 g, 11.4 mmol, prepared according to the procedure described in WO 2021 / 136231 A1) was added and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 24h, the reaction mixture was quenched with saturated ammonium chloride solution (50mL) and diluted with EtOAc (75mL). Each layer was separated, and the aqueous phase was further extracted with EtOAc (2 × 75mL). The combined organic phase was washed with brine (50mL), dried over sodium sulfate, filtered and concentrated. The crude residue was purified by grinding with ether to provide the desired product (5.0g, 8.2mmol, 72% yield). LC / MS (ESI) m / z: for C 27 H35 Calculated value of BrF2N5O3 [M+H] + 594.2; measured value 594.2; 1 H NMR (400MHz, DMSO-d6) δ7.73(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). Step 2: (1R,5S)-tert-butyl 3-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0330] Tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 sparged with nitrogen for 15 min. Pd(dppf)Cl2 (12 mg, 0.02 mmol) was added, and the reaction mixture was heated at 100°C for 5 h. Water (5 mL) and EtOAc (5 mL) were added and the layers were separated. The aqueous layer was further extracted with EtOAc (2 × 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 / hexane) to provide the desired product (70 mg, 0.09 mmol, 56% yield); LC / MS (ESI) m / z: for C 37 H 41 Calculated value of ClF2N5O3 [M+H] + 676.3; measured value 676.3. 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-pyrrolazin-7a(5H)-yl)methoxy)quinazoline

[0331] tert-Butyl (1R,5S)-3-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 afford the desired product (26 mg, 0.04 mmol, 35%) as its TFA salt. LC / MS (ESI) m / z: for C 32 H 33 Calcd. value of ClF2N5O [M+H] + 576.2; measured value 576.3. 6-(6-chloro-4-((2R,5S)-2,5-dimethylpiperazin-1-yl)-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0332] The desired products were prepared using procedures analogous to those described herein using appropriate starting materials. 1 H NMR(400MHz,CD3OD)δ7.96(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),3.51-3.5 2(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). (1R,4R)-2-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-amine 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-yl)carbamate

[0333] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 50 H 56 Calculated value of ClF5N7O5 [M+H] + 964.4, measured value 963.8. 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-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptan-4-amine

[0334] 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptane-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 afford the desired product (19 mg, 0.03 mmol, 33% yield). LC / MS (ESI) m / z: for C 29 H 32 Calcd. value of ClF5N7O [M+H] + 624.2, measured value 624.2; 1 H NMR (400MHz, CDCl3) δ7.79-7.64(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). 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine 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

[0335] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 51 H 58 Calculated value of ClF5N7O5 [M+H] + 978.4, measured value 978.2. Step 2: 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0336] 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-pyrrolazin-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 afford the desired product (23 mg, 0.04 mmol, 68% yield). LC / MS (ESI) m / z: for C 30 H 34 Calcd. value of ClF5N7O [M+H] + 638.2, measured value 638.2; 1 H NMR(400MHz,CD3OD)δ7.93(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). 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate

[0337] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 50 H 57 Calculated value of ClF5N7O5 [M+H] + 964.4, measured value 964.2. Step 2: 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0338] 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-pyrrolazin-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 afford the desired product (28 mg, 0.04 mmol, 70% yield) as its TFA salt. LC / MS (ESI) m / z: for C 29 H 32 Calcd. value of ClF5N7O [M+H] + 624.2, measured value 624.2; 1H NMR (400MHz, CD3OD) δ8.19 (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). 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((3aR,4S,7R,7aS)-octahydro-1H-4,7-cycloiminoisoindol-8-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine Step 1: (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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-2H-4,7-cycloimidoisoindole-2-carboxylic acid tert-butyl ester

[0339] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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-cycloimidoisoindole-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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 52 H 58 Calculated value of ClF5N7O5 [M+H] +990.4, measured value 990.0. Step 2: 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((3aR,4S,7R,7aS)-octahydro-1H-4,7-cycloiminoisoindol-8-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0340] 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-2H-4,7-cycloimidoisoindole-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 afford the desired product (13 mg, 0.02 mmol, 24% yield). LC / MS (ESI) m / z: for C 31 H 34 Calcd. value of ClF5N7O [M+H] + 650.2, measured value 649.8; 1 H NMR (400MHz, CDCl3) δ7.70-7.57(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). 6-(4-(3,7-diazabicyclo[4.2.0]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,7-diazabicyclo[4.2.0]octane-7-carboxylate

[0341] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 50 H 56 Calculated value of ClF5N7O5 [M+H] + 964.4, measured value 964.2. Step 2: 6-(4-(3,7-diazabicyclo[4.2.0]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0342] 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-pyrrolazin-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 afford the desired product (12 mg, 0.02 mmol, 33% yield). LC / MS (ESI) m / z: for C 29 H 32 Calcd. value of ClF5N7O [M+H] + 624.2, measured value 624.2; 1 H NMR (400MHz, CD3OD) δ8.07-8.09(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). (1s,3S)-N1-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)cyclobutane-1,3-diamine 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)amino)cyclobutyl)carbamate

[0343] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 48 H 54 Calculated value of ClF5N7O5 [M+H] + 938.4, measured value 938.4. 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-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)cyclobutane-1,3-diamine

[0344] 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-pyrrolazin-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 afford the desired product (17 mg, 0.03 mmol, 34% yield) as an AcOH salt. LC / MS (ESI) m / z: for C 27 H 30 Calculated value of ClF5N7O5 [M+H] + 598.2, measured value 598.2. 1H 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). 6-(4-(3,6-diazabicyclo[3.2.0]heptane-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate

[0345] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 49 H 54 Calculated value of ClF5N7O5 [M+H] + 950.4, measured value 950.4. Step 2: 6-(4-(3,6-diazabicyclo[3.2.0]heptan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0346] 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-pyrrolazin-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 afford the desired product (17 mg, 0.03 mmol, 41% yield). LC / MS (ESI) m / z: for C 28 H 30 Calculated value of ClF5N7O5 [M+H] + 610.2, measured value 610.2; 1HNMR (400MHz, CD3OD) δ8.22-8.23(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). 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine 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-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[0347] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 50 H 56 Calculated value of ClF5N7O5 [M+H] + 964.4, measured value 964.4. Step 2: 6-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,6-diazaspiro[3.4]octan-6-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0348] 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-pyrrolazin-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 afford the desired product (8 mg, 0.01 mmol, 20% yield) as a formate salt. LC / MS (ESI) m / z: for C 29 H 32 Calculated value of ClF5N7O5 [M+H] + 624.2, measured value 624.2. (Z)-2-Fluoro-3-(thiazol-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate

[0349] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (1.1g, 4.5mmol) is dissolved in THF (25mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 0.18g, 4.5mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and thiazole-2-carboxaldehyde (0.51g, 4.5mmol) is added. The reaction mixture is allowed to warm to room temperature and stir for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (20mL). The solution is diluted with water (20mL) and EtOAc (150mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×50mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→60% acetone / hexanes) to afford ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate (10:1 E / Z, as obtained by 11H NMR, 620 mg, 3.1 mmol, 68% yield). LC / MS (ESI) m / z: calculated for C8H9FNO2S [M+H] + 202.0; measured value 202.2; 1 H NMR (500MHz, CDCl3) δ7.94 (d, J = 3.2 Hz, 1H), 7.52 (d, J = 3.2 Hz, 1H), 7.34 (d, J = 22.2 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(thiazol-2-yl)acrylate

[0350] (E) -2- fluoro- 3- (thiazol-2-yl) ethyl acrylate (620 mg, 3.1 mmol) was dissolved in toluene (15 mL) and iodine (39 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 ° C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to provide (Z) -2- fluoro- 3- (thiazol-2-yl) ethyl acrylate (509 mg, 2.5 mmol, 82% yield). LC / MS (ESI) m / z: calculated for C8H9FNO2S [M + H] + 202.0; Measured value 202.0; 1 HNMR (500MHz, CDCl3) δ7.96 (dd, J=3.2, 2.6Hz, 1H), 7.57 (d, J=3.2Hz, 1H), 7.43 (dd, J=33.3, 0.8Hz, 1H), 4.38 (q, J=7.2Hz, 2H), 1.39 (t, J=7.1Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid

[0351] (Z) -2- fluoro -3- (thiazol-2-yl) ethyl acrylate (510mg, 2.5mmol) was dissolved in MeOH (15mL). The solution was cooled to 0°C and sodium hydroxide solution (1.0M, 2.5mL, 2.5mmol) was added. The reaction mixture was stirred for 5h. The solution was concentrated to remove methanol. Additional water (1.5mL) was added and the aqueous solution was cooled to 0°C. HCl solution (1.0M, 2.5mL, 2.5mmol) was added dropwise. After 10min, a white solid precipitated out. The solid was collected by filtration and washed with MeCN. The solid was dried under vacuum to provide (Z) -2- fluoro -3- (thiazol-2-yl) acrylic acid (337mg, 1.9mmol, 77% yield) as a white solid. LC / MS (ESI) m / z: calculated for C6H5FNO2S [M+H] + 174.0; measured value 173.8; 1 HNMR (500MHz, DMSO-d6) δ8.04 (s, 2H), 7.29 (d, J = 34.5Hz, 1H). (Z)-2-Fluoro-3-(pyrimidin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate

[0352] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (1.6g, 6.6mmol) is dissolved in THF (50mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 0.26g, 6.6mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and pyrimidine-2-carboxaldehyde (0.71g, 6.6mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (20mL). The solution is diluted with water (20mL) and EtOAc (150mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×50mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→90% EtOAc / hexanes) to provide ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate (5:1 E / Z, as judged by 1H NMR, 592 mg, 3.0 mmol, 46% yield). LC / MS (ESI) m / z: for C9H 10 Calculated value of FN2O2 [M+H] + 197.2; measured value 197.1; 1H NMR (500MHz, CDCl3) δ 8.70 (d, J = 4.9 Hz, 2H), 7.18 (t, J = 4.9 Hz, 1H), 6.77 (d, J = 17.5 Hz, 1H), 4.28 (q, J = 7.2 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate

[0353] (E) -2-fluoro-3- (pyrimidin-2-yl) ethyl acrylate (592 mg, 3.0 mmol) was dissolved in toluene (15 mL) and iodine (38 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 ° C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to provide (Z) -2-fluoro-3- (pyrimidin-2-yl) ethyl acrylate (253 mg, 1.3 mmol, 43% yield). LC / MS (ESI) m / z: for C9H 10 Calculated value of FN2O2 [M+H] + 197.2; measured value 196.6; 1 H NMR (500MHz, CDCl3) δ 8.83 (d, J = 4.9 Hz, 2H), 7.21 (t, J = 4.9 Hz, 1H), 7.13 (d, J = 30.8 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylic acid

[0354] (Z) -2- fluoro -3- (pyrimidin-2-yl) ethyl 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 h. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added and the aqueous solution was cooled to 0 ° C. HCl solution (1.0 M, 2.5 mL, 2.5 mmol) was added dropwise. After 10 min, a white solid precipitated. The solid was collected by filtration and dried under vacuum to provide (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: calculated for C7H6FN2O2 [M + H] + 169.1; measured value 168.8; 1H NMR (500MHz, DMSO-d6) δ 8.90 (d, J = 4.9 Hz, 2H), 7.46 (t, J = 4.9 Hz, 1H), 6.94 (d, J = 31.5 Hz, 1H). (Z)-2-Fluoro-3-(pyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate

[0355] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (1.5g, 6.2mmol) is dissolved in THF (31mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 0.25g, 6.2mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and pyridine carboxaldehyde (0.66g, 6.2mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (15mL). The solution is diluted with water (20mL) and EtOAc (100mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×50mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to afford ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate (3:1 E / Z mixture, as obtained by 1 1H NMR, 910 mg, 4.6 mmol, 75% yield). LC / MS (ESI) m / z: for C 10 H 11 Calculated value of FNO2 [M+H] + 196.1; Found 196.1; Reported E isomer: 1 H NMR (500MHz, CDCl3) δ8.59 (dd, J=4.9, 1.8Hz, 1H), 7.67 (ddd, J=7.9, 7.6, 1.8Hz, 1H), 7.56 (d, J=7.9Hz, 1H), 7.21 (dd, J=7.6, 4.9Hz, 1H), 6.90 (d, J=20.4Hz, 1H), 4.25 (q, J=7.2Hz, 2H), 1.23 (t, J=7.1Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate

[0356] (E) -2- fluoro- 3- (pyridin-2-yl) ethyl acrylate (420 mg, 2.1 mmol) was dissolved in toluene (10 mL) and iodine (27 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 ° C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to provide (Z) -2- fluoro- 3- (pyridin-2-yl) ethyl acrylate (240 mg, 1.2 mmol, 58% yield). LC / MS (ESI) m / z: for C 10 H 11 Calculated value of FNO2 [M+H] + 196.1; measured value 196.1; 1 H NMR (500MHz, CDCl3) δ8.66(ddd,J=5.0,1.8,0.8Hz,1H),7.88(ddd,J=8.0,1.2,0.8Hz,1H),7.75(ddd,J=8.0,7.8,1 .8Hz, 1H), 7.25 (ddd, J=7.8, 5.0, 1.2Hz, 1H), 7.14 (d, J=34.9Hz, 1H), 4.36 (q, J=7.2Hz, 2H), 1.38 (t, J=7.2Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid

[0357] (Z) -2- fluoro -3- (pyridin-2-yl) ethyl acrylate (415 mg, 2.1 mmol) was dissolved in MeOH (15 mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0 M, 2.1 mL, 2.1 mmol) was added. The reaction mixture was stirred for 5 h. The solution was concentrated to remove methanol. Additional water (2.0 mL) was added and the aqueous solution was cooled to 0 ° C. HCl solution (1.0 M, 2.1 mL, 2.1 mmol) was added dropwise. After 10 min, a white solid precipitated. The solid was collected by filtration and washed with Et2O. The solid was dried under vacuum to provide (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: calculated for C8H7FNO2 [M+H] + 168.0; measured value 167.8. 1HNMR(500MHz,DMSO-d6)δ8.66(ddd,J=4.8,1.8,0.8Hz,1H),7.89(ddd,J=8.0,7.5,1.8Hz,1H) ,7.81(ddd,J=8.0,1.1,0.8Hz,1H),7.40(dd,J=7.5,4.8,1.1Hz,1H),6.97(d,J=35.3Hz,1H). 2-((S)-4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile Step 1: (S)-benzyl 4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0358] 7- bromo-2,4- dichloro-8-fluoroquinazoline (500mg, 1.7mmol) is dissolved in dioxane (15ml), and DIPEA (0.89mL, 5.1mmol) is added, followed by (S) -2- (cyanomethyl) piperazine-1- benzyl carboxylate (440mg, 1.7mmol). The reaction mixture is stirred at room temperature for 2h. The mixture is diluted with EtOAc (20mL) and quenched by adding NaOH solution (1.0M, 2mL). The layers are separated, and the organic phase is washed with brine (10mL). The combined aqueous layer is back extracted with EtOAc (2 × 20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue is purified by column chromatography (5 → 50% EtOAc / hexane) to provide the desired product (760mg, 1.5mmol, 87% yield) as a white solid. LC / MS (ESI) m / z: for C 22 H 19 Calculated value of BrClFN5O2 [M+H] + 518.0; Found 517.9; NMR: 1H NMR (500MHz, CD3OD) δ7.80 (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). Step 2: (S)-benzyl 4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0359] By (S) -4- (7- bromo -2- chloro -8- fluoroquinazoline -4- bases) -2- (cyanomethyl) piperazine -1- benzyl carboxylate (from step 1, 250mg, 0.48mmol) and ((2R, 7aS) -2- fluorotetrahydro -1H- pyrrolizine -7a (5H) -yl) methanol, HCl salt (commercially available, or according to the procedure described in WO 2022 / 031678 prepared, 104mg, 0.53mmol) suspended in THF (8mL). A solution of LiHMDS (1.0M in THF, 1.1mL, 1.1mmol) was added dropwise, and the reaction mixture was heated at 65 ° C for 16h. The mixture was diluted with EtOAc (20mL) and washed with water (10mL) and brine (10mL). The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→8% MeOH / DCM) to afford the desired product (184 mg, 0.29 mmol, 60% yield) as a white solid. LC / MS (ESI) m / z: for C 30 H 32 Calculated value of BrF2N6O3 [M+H] + 641.2; measured value 641.1. Step 3: (S)-benzyl 2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate

[0360] (S)-benzyl 4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (from step 2, 80 mg, 0.125 mmol), 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 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (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 provide the desired product (51 mg, 0.07 mmol, 55% yield) as an off-white solid. LC / MS (ESI) m / z: for C 42 H 43 Calculated value of F2N6O5 [M+H] + 749.3; measured value 749.3. Step 4: 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0361] (S)-benzyl 2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 was bubbled through the reaction mixture for 5 min. The reaction mixture was maintained under positive hydrogen pressure (1 atm, balloon) for 2 h. The reaction mixture was passed through Celite®. TM ) was filtered, taking care not to allow the filter cake to dry, and the filtrate was concentrated. The crude residue was of sufficient purity to be used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 34 H 37 Calculated value of F2N6O3 [M+H] +615.3; measured value 615.2. Step 5: 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0362] 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 afford the desired product as an HCl salt (assuming quantitative yield). The crude material was of sufficient purity to be used directly in the next step without additional purification. LC / MS (ESI) m / z: for C 32 H 33 Calculated value of F2N6O2 [M+H] + 571.3; measured value 571.2. 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Step 1: (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0363] (S)-benzyl 4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (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 provide the desired product (78 mg, 0.11 mmol, 49% yield) as an off-white solid. LC / MS (ESI) m / z: for C 40 H 38 Calculated value of ClF2N6O5 [M+H] + 723.3; measured value 723.2. Step 2: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0364] (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 was bubbled through the reaction mixture for 5 min. The reaction mixture was maintained under positive hydrogen pressure (1 atm, balloon) for 2 h. The reaction mixture was passed through Celite®. TM ) was filtered, taking care not to allow the filter cake to dry, and the filtrate was concentrated. The crude residue was of sufficient purity to be used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 32 H 33 Calcd. for ClF2N6O [M+H] + 589.3; measured value 589.2. (1S,4S)-2-[(7M)-2-{[(2R,7aR)-2-Fluoro-hexahydro-1H-pyrrolizin-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 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

[0365] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 of sufficient purity to be used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 50 H 56 Calculated value of ClF5N7O5 [M+H] + 964.4, measured value 963.8. 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

[0366] By N-[(1S, 4S)-2-[(7M)-2-{[(2R, 7aR)-2-fluoro-hexahydro-1H-pyrrolazin-7a-yl] methoxy}-7-(6-{bis[(4-methoxyphenyl) methyl] amino}-4-methyl-3-(trifluoromethyl) pyridin-2-yl)-6-chloro-8-fluoroquinazoline-4-yl]-2-azabicyclo[2.2.1] heptane-4-yl] tert-butyl 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 provide the desired product (15 mg, 0.02 mmol, 37% yield). LC / MS (ESI) m / z: for C 29 H 32 Calcd. value of ClF5N7O [M+H] + 624.2, measured value 624.1; 1 H NMR (400MHz, CD3OD) δ7.91-7.63(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). (1R,4R,7R)-2-[(7M)-2-{[(2R,7aR)-2-Fluoro-hexahydro-1H-pyrrolizin-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 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

[0367] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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 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 purified by column chromatography on neutral alumina (45% EtOAc / hexane) to provide the desired product (52 mg, 0.05 mmol, 81% yield). LC / MS (ESI) m / z: for C 50 H 56 Calculated value of ClF5N7O5 [M+H] + 964.4, measured value 964.5. Step 2: (1R,4R,7R)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolizin-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

[0368] Tert-butyl N-[(1R,4R,7R)-2-[(7M)-2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolazin-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 afford the desired product (26 mg, 0.035 mmol, 64% yield) as a TFA salt. LC / MS (ESI) m / z: for C 29 H 32 Calcd. value of ClF5N7O [M+H] + 624.2, measured value 624.2; 1 H NMR(400MHz,CD3OD)δ8.07(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,1H),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). (5M)-6-(4,6-dichloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0369] 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 (240 μL, 3.3 mmol) was added followed by one drop 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 with toluene (3×2 mL) to afford the desired product (brown solid) as the HCl salt (assuming quantitative yield). LC / MS (ESI) m / z: for C 37 H 36 Calculated value of Cl2F4N5O3 [M+H] + 744.2; measured value 744.1. 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

[0370] 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-(piperazine-2-yl)acetonitrile 2HCl 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 min. Triethylsilane (80 μL, 0.5 mmol), TFA (500 μL) and a drop of water (about 10 μL) were then added to the solution. The reaction mixture was heated at 50°C for 16 h. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm×200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25° C.; gradient: 87% 5:95 MeCN: HO with 10 mM AA / 13% 95:5 MeCN: HO with 10 mM AA→100% 95:5 MeCN: HO with 10 mM AA; λ=220 nm) to provide the desired product (7.5 mg, 0.013 mmol, 25% yield) and the nitrile hydrolysis product (8.7 mg, 0.014 mmol, 28% yield). LC / MS (ESI) m / z: for C 27 H 30 Calcd. value of ClF4N8O [M+H] + 593.2; found 593.2 [expected]; and LC / MS (ESI) m / z: for C 27 H 31 Calculated value of ClF4N8O2 [M+H] + 611.2; Found 611.4 [hydrolysis]; 1 H NMR (600 MHz, DMSO-d6) δ 7.83 (s, 1H), 6.85 (s, 2H), 6.49 (s, 1H), 4.39 (dd, J = 10.8, 4.5 Hz, 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) [expected] and 1H NMR(600MHz,DMSO-d6)δ7.85(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]. (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

[0371] By 6-(4,6-dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine, HCl salt (intermediate 32, 35 mg, 0.045 mmol) and ((1S, 4S)-2-azabicyclo [2.2.1] heptane-4-yl) tert-butyl carbamate (intermediate 37, 11 mg, 0.054 mmol) merge and be suspended in DCM (500 μ L).DIPEA (40 μ L, 0.22 mmol) is added, and the reaction mixture is heated at 50 ° C for 30 min.Then triethylsilane (29 μ L, 0.18 mmol), TFA (500 μ L) and a drop of water (about 10 μ L) are added to the solution.The reaction mixture is heated at 50 ° C for 16 h. The reaction mixture was directly concentrated, and the crude residue was azeotroped with toluene (3 x 1 mL) to afford the desired product as a TFA salt, which was used directly in the next step without additional purification. LC / MS (ESI) m / z: for C 27 H 31 Calcd. value of ClF4N7O [M+H] + 580.0; measured value 580.3. (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

[0372] By 6-(4,6-dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine, HCl salt (intermediate 32, 35 mg, 0.045 mmol) and ((1R, 4R, 7R)-2-azabicyclo [2.2.1] heptane-7-yl) tert-butyl carbamate (11 mg, 0.054 mmol) are combined and suspended in DCM (500 μ L). DIPEA (40 μ L, 0.22 mmol) is added, and the reaction mixture is heated at 50 ° C for 30 min. Then triethylsilane (29 μ L, 0.18 mmol), TFA (500 μ L) and a drop of water (about 10 μ L) are added to the solution. The reaction mixture is heated at 50 ° C for 16 h. The reaction mixture was directly concentrated, and the crude residue was azeotroped with toluene (3 x 1 mL) to afford the desired product as a TFA salt, which was used directly in the next step without additional purification. LC / MS (ESI) m / z: for C 27 H 31 Calcd. value of ClF4N7O [M+H] + 580.0; measured value 580.1. (Z)-2-Fluoro-3-(6-methylpyridin-2-yl)acrylic acid Step 1: Ethyl (Z)-2-fluoro-3-(6-methylpyridin-2-yl)acrylate

[0373] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and 6-methylpyridine-2-carboxaldehyde (125mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). The layers are separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by HPLC (column: Xbridge C18, 5 μm particles; gradient: 5:95 MeCN:H 2 O with 0.05% TFA→95:5 MeCN:H 2 O with 0.05% TFA; λ=220 nm) to afford the desired product (31 mg, 0.15 mmol, 14% yield); LC / MS (ESI) m / z: for C 11 H 13 Calculated value of FNO2 [M+H] + 210.1; measured value 209.7; 1 H NMR (500MHz, CDCl3) δ7.71(d,J=7.8Hz,1H),7.63(t,J=7.8Hz,1H),7.10(d,J=7.8Hz,1 H), 7.11 (d, J = 35.2Hz, 1H), 4.34 (q, J = 7.2Hz, 2H), 2.56 (s, 3H), 1.36 (t, J = 7.2Hz, 3H). Step 2: (Z)-2-Fluoro-3-(6-methylpyridin-2-yl)acrylic acid

[0374] (Z) -2-fluoro-3- (6-methylpyridin-4-yl) ethyl acrylate (31 mg, 0.15 mmol) was dissolved in MeOH (1.5 mL) and sodium hydroxide solution (1.0 M, 150 μL, 0.15 mmol) was added dropwise. The mixture was stirred for 2 h. The reaction mixture was concentrated, diluted with water (1 mL), and hydrochloric acid solution (1.0 M, 150 μL, 0.14 mmol) was added. The solution was lyophilized and the crude material was used without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: calculated for C9H9FNO2 [M+H] + 182.1; measured value 182.1; 1H NMR (500MHz, DMSO-d6) δ7.80 (t, J = 7.7Hz, 1H), 7.65 (d, J = 7.7Hz, 1H), 7.29 (d, J = 7.7Hz, 1H), 6.94 (d, J = 35.4Hz, 1H), 2.50 (s, 3H). tert-Butyl ((1S,4S)-2-azabicyclo[2.2.1]heptane-4-yl)carbamate Step 1: tert-Butyl ((1S,4S)-2-benzyl-2-azabicyclo[2.2.1]heptan-4-yl)carbamate

[0375] (1S, 4S) -2-benzyl -2- azabicyclo [2.2.1] heptane -4- amine (commercially available, or can also be prepared by following the procedure described in U.S. Patent 8,476,295B2) (20.2g, 100mmol) was dissolved in water (150mL). The solution was cooled to 0 ° C, and solid NaOH (about 24g) was added portionwise until the pH of the solution was about 14. A solution of di-tert-butyl dicarbonate (26.2g, 120mmol) in DCM (300mL) was added, and the resulting solution was stirred for 1h. The layers were separated, and the aqueous layer was further extracted with DCM (2 × 100mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude residue was recrystallized from hot heptane to provide the desired product (24.7g, 82mmol, 82% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.49-7.15(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). Step 2: tert-Butyl ((1S,4S)-2-azabicyclo[2.2.1]heptane-4-yl)carbamate

[0376] Tert-butyl ((1S, 4S)-2-benzyl-2-azabicyclo[2.2.1]heptane-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 was bubbled through the solution for 5 min and the reaction mixture was kept under a hydrogen atmosphere for 16 h. The reaction mixture was filtered through Celite 1 and filtered. TM) was filtered, and the solution was concentrated to afford the desired product (11 g, 52 mmol, 92% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ5.09(br s,1H),3.92-3.58(m,2H),1.95(br s,1H),2.03-1.66(m,6H),1.30(s,9H). 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 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

[0377] (S)-benzyl 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 bubbled through the solution for 15 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride ((dtbpf)PdCl) (11 mg, 0.017 mmol) 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 provide the desired product (159 mg, 0.245 mmol, 73% yield) as an off-white solid. LC / MS (ESI) m / z: for C 36 H 38 Calculated value of FN8O3 [M+H] + 649.3; measured value 649.3; 1H NMR (500MHz, CD3OD) δ7.94(d,J=8.6Hz,1H),7.60(d,J=5.2Hz,1H),7.55(d,J=8.6Hz,1H),7.4 4-7.29(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). 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

[0378] 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 was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 h. The solution was filtered through Celite TM Filtration through a pad of 4% HCl and concentration afforded the desired product, which was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 28 H 32 Calculated value of FN8O [M+H] + 515.3; measured value 515.2; 1H NMR (500MHz, CD3OD) δ7.90(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,1H),3.36-3.32(m,1H),3.24-2.99(m,5H),2.85-2.79(m,1H),2.72(dd,J=6.3,2.6 Hz,2H),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). 2-((2S)-4-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile 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

[0379] (S)-benzyl 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 bubbled through the solution for 15 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride ((dtbpf)PdCl) (11 mg, 0.017 mmol) 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 → 10% MeOH / DCM with 5% NH4OH) to provide the desired product (160 mg, 0.25 mmol, 76% yield) as an off-white solid. LC / MS (ESI) m / z: for C 34H 35 Calculated value of F2N6O4 [M+H] + 629.3; measured value 629.4; 1 H NMR(500MHz,CD3OD)δ7.82(d,J=8.7Hz,1H),7.44-7.29(m,6H),7.28-7.23(m,1H),6.77(d,J=8.2 Hz,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),4.49-4.4 3(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). 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

[0380] 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 was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 h. The solution was filtered through a Celite 100 column. TM Filtration through a pad of 4% HCl and concentration afforded the desired product, which was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 26 H 29 Calculated value of F2N6O2 [M+H] + 495.2; measured value 495.2; 1H NMR(500MHz,CD3OD)δ7.77(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). 2-((S)-4-(7-(8-ethylnaphth-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile 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

[0381] (S)-benzyl 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 bubbled through the solution for 15 min. [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride ((dtbpf)PdCl) (3.8 mg, 5.9 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 provide the desired product (60 mg, 0.07 mmol, 62% yield) as an off-white solid. LC / MS (ESI) m / z: for C 49H 58 Calculated value of FN6O3Si [M+H] + 825.4; measured value 825.8; 1 H NMR(500MHz,CD3OD)δ8.05-8.00(m,2H),7.88-7.83(m,1H),7.80-7.76(m,1H),7.63- 7.58(m,1H),7.54-7.49(m,1H),7.45-7.34(m,7H),5.27-5.10(m,3H),4.65-4.29(m,6 H),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). 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

[0382] (S)-benzyl 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 additional purification. LC / MS (ESI) m / z: for C 40 H 38 Calculated value of FN6O3 [M+H] + 669.3; measured value 669.5. Step 3: Preparation of 2-((S)-4-(7-(8-ethylnaphth-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0383] (S)-benzyl 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 was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 h. The solution was filtered through a Celite 100 column. TM Filtration through a pad of 4% HCl and concentration afforded the desired product, which was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 32 H 36 Calculated value of FN6O [M+H] + 539.3; measured value 539.2. 2-((S)-4-(7-(5-chloro-2-methoxyphenyl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile 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

[0384] (S)-benzyl 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 bubbled through the solution for 15 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride ((dtbpf)PdCl) (3.8 mg, 5.8 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 provide the desired product (55 mg, 0.08 mmol, 71% yield) as an off-white solid. LC / MS (ESI) m / z: for C 35 H 37 Calculated value of ClFN6O4 [M+H] + 659.3; measured value 659.4; 1 H NMR(500MHz,CD3OD)δ7.82(d,J=8.3Hz,1H),7.43-7.28(m,8H),7.13(d,J=8.9Hz,1H),5.2 6-5.15(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,3H),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). 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

[0385] (S)-benzyl 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 was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 h. The solution was filtered through Celite TM Filtration through a pad of 4% HCl and concentration afforded the desired product, which was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 27 H 31 Calculated value of ClFN6O2 [M+H] + 525.2; measured value 525.4; 1 H NMR(500MHz,CD3OD)δ7.77(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,1 H),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 ),2.72-2.68(m,2H),2.54(s,3H),2.40-2.35(m,1H),2.16-2.09(m,1H),1.86-1.77(m,3H). 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 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

[0386] (S)-benzyl 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 bubbled through the solution for 15 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride ((dtbpf)PdCl) (4.1 mg, 6.3 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 provide the desired product (67 mg, 0.09 mmol, 75% yield) as an off-white solid. LC / MS (ESI) m / z: for C 35 H 34 Calculated value of ClF4N6O4 [M+H] + 713.2; measured value 713.5; 1 H NMR (500MHz, CD3OD) δ7.91(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). 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

[0387] (S)-benzyl 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 was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 h. The solution was filtered through a Celite 100 column. TM Filtration through a pad of 4% HCl and concentration afforded the desired product, which was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 27 H 28 Calculated value of ClF4N6O2 [M+H] + 579.2; measured value 579.2. (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

[0388] 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. To this solution was added triethylsilane (29 μl, 0.18 mmol) and TFA (0.5 mL), and the resulting mixture was maintained at 40° C. for an additional 16 h. The reaction mixture was directly concentrated, and the crude residue was azeotroped with toluene (3 x 1 mL) to afford the desired product as a crude oil, which was used directly in the next step without additional purification. LC / MS (ESI) m / z: for C 27 H 31 Calcd. value of ClF4N7O [M+H] + 580.2; measured value 580.3. (S)-2-(4-(7-(8-chloronaphth-1-yl)-8-fluoro-2-((1-(3-methoxypropyl)piperidin-4-yl)oxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Step 1: Preparation of (S)-benzyl 4-(7-bromo-8-fluoro-2-((1-(3-methoxypropyl)piperidin-4-yl)oxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0389] (S) -4- (7- bromo -2- chloro -8- fluoroquinazoline -4- bases) -2- (cyanomethyl) piperazine -1- formate (120 mg, 0.23 mmol) and 1- (3- methoxypropyl) piperidine -4- alcohol (40 mg, 0.23 mmol) are dissolved in THF (5 mL), and LiHMDS solution (1.0 M in THF, 0.5 mL, 0.5 mmol) is added dropwise. The resulting solution is stirred at room temperature for 24 h. The reaction mixture is quenched with water (5 mL) and EtOAc (10 mL). Each layer is separated, and the organic phase is further washed with salt water (5 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue is purified by column chromatography (0 → 8% MeOH / with 5% NH4OH in DCM) to provide the desired product (81 mg, 0.12 mmol, 53% yield) as a light yellow solid. LC / MS (ESI) m / z: for C 31 H 36 Calculated value of BrFN6O4 [M+H] + 655.2; measured value 655.4; 1 H NMR (500MHz, CD3OD) δ7.73(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). Step 2: Preparation of (S)-benzyl 4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-(3-methoxypropyl)piperidin-4-yl)oxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0390] (S)-benzyl 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 bubbled through the solution for 15 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride ((dtbpf)PdCl) (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 provide the desired product (30 mg, 0.04 mmol, % yield) as an off-white solid. LC / MS (ESI) m / z: for C 41 H 33 Calculated value of ClFN6O4 [M+H] + 737.3; measured value 737.2. 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

[0391] (S)-benzyl 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 was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 h. The solution was filtered through Celite TM Filtration through a pad of 4% HCl and concentration afforded the desired product, which was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C33 H 37 Calculated value of ClFN6O2 [M+H] + 603.2; measured value 603.5; 1 H NMR (500MHz, CD3OD) δ7.99 (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,J=15.3,2.6Hz,2H),4.15(t,J=6.8Hz,1H),3.52-3.38(m,3H),3.36-3.34(m,2H),3.24-3.08(m,2H),3.07-2.96(m,2H),2.93-2.81(m, 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). 2-((2S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile Step 1: Preparation of benzyl (2S)-2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazine-1-carboxylate

[0392] (S)-benzyl 4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 bubbled through the solution for 15 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride ((dtbpf)PdCl) (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 provide the desired product (39 mg, 0.06 mmol, 52% yield) as an off-white solid. LC / MS (ESI) m / z: for C 38 H 39 Calculated value of F2N8O3 [M+H] + 693.3; measured value 693.5; 1 H NMR(500MHz,CD3OD)δ7.94(d,J=8.2Hz,1H),7.61-7.58(m,1H),7.55(d,J=8.8Hz,1H),7.42- 7.32(m,7H),5.31(d,J=56.4Hz,1H),5.22-5.17(m,2H),4.60-4.53(m,2H),4.50-4.41(m,2H) ,4.33-4.23(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,1 H),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). Step 2: Preparation of 2-((2S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0393] Benzyl (2S)-2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 h. The solution was filtered through Celite TM Filtration through a pad of 4% HCl and concentration afforded the desired product, which was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 30 H 33 Calculated for F2N8O [M+H] + 559.3; measured value 559.4; 1 H NMR (500MHz, CD3OD) δ7.90(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),4.35-4.31(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). 8-(4-((S)-3-(cyanomethyl)piperazin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-naphthocarbonitrile Step 1: Preparation of (S)-benzyl 2-(cyanomethyl)-4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0394] (S)-benzyl 2-(cyanomethyl)-4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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-naphthocarbonitrile (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 bubbled through the solution for 15 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride ((dtbpf)PdCl2) (3.6 mg, 5.5 μmol) was added as a solid and the reaction mixture was heated at 100°C for 2h. 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 provide the desired product (35 mg, 0.05 mmol, 45% yield) as an off-white solid. LC / MS (ESI) m / z: for C 41 H 38 Calculated for F2N7O3 [M+H] + 714.3; measured value 714.3. Step 2: Preparation of 8-(4-((S)-3-(cyanomethyl)piperazin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-naphthocarbonitrile

[0395] (S)-benzyl 2-(cyanomethyl)-4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 h. The solution was filtered through Celite TM Filtration through a pad of 4% HCl and concentration afforded the desired product, which was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 33 H 32 Calculated for F2N7O [M+H] +559.3; measured value 559.4. 8-(4-((S)-3-(cyanomethyl)piperazin-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-1-naphthocarbonitrile Step 1: Preparation of (S)-benzyl 2-(cyanomethyl)-4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0396] (S)-benzyl 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 bubbled through the solution for 15 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride ((dtbpf)PdCl) (3.8 mg, 5.9 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 provide the desired product (40 mg, 0.06 mmol, 51% yield) as an off-white solid. LC / MS (ESI) m / z: for C 39 H 37 Calculated value of FN7O3 [M+H] + 670.3; measured value 670.5. 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-naphthocarbonitrile

[0397] (S)-benzyl 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 was bubbled through the solution and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 1.5 h. The solution was filtered through a Celite 100 column. TM Filtration through a pad of 4% HCl and concentration afforded the desired product, which was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 31 H 31 Calculated value of FN7O [M+H] + 536.3; measured value 536.4. 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 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

[0398] 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, 0.55 mL, 1.1 mmol) was added, and nitrogen was bubbled through the solution for 15 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride ((dtbpf)PdCl2) (11.8 mg, 0.018 mmol) 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 provide the desired product (60 mg, 0.08 mmol, 22% yield) as an off-white solid. LC / MS (ESI) m / z: for C 37 H 45 Calculated for F2N7O5S [M+H] + 738.3; measured value 738.6. 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

[0399] 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 phases were 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×100 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25° C.; gradient: 100% 5:95 MeCN: HO with 10 mM AA / 0% 95:5 MeCN: HO with 10 mM AA→100% 95:5 MeCN: HO with 10 mM AA; λ=220 nm) to afford the desired product (30 mg, 0.05 mmol, 58% yield) as a white solid. LC / MS (ESI) m / z: for C 32 H 38 Calcd. for F2N7O3S [M+H] + 638.3; measured value 638.4; 1 H NMR (600MHz, methanol-d4) δ7.80(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(brs,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). 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

[0400] 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'-tetramethylformamidinium hexafluorophosphate (7 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 5 min. 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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 40 H 42 Calculated for F3N8O4S [M+H] + 786.3; measured value 786.3. 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)naphthalen-2-ol Step 1: Preparation of 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol

[0401] By (1R, 5S) -3- (7- (8- ethynyl -7- fluoro -3- (methoxymethoxy) naphthalen-1-yl) -8- fluoro -2- (( (2R, 7aS) -2- fluorotetrahydro -1H- pyrrolizine -7a (5H) -yl) methoxy) quinazoline -4-yl) -3, 8- diazabicyclo [3.2.1] octane -8- tert-butyl carboxylate (prepared according to the procedure described in WO 2022 / 061251, 430 mg, 0.58 mmol) was dissolved in THF (6 mL) and 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 absorbed 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 another 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 provide the desired product (256 mg, 0.23 mmol, 40% yield); LC / MS (ESI) m / z: for C 30 H 27 Calculated value of F3N3O4 [M+H] + 550.2; measured value 550.1; 1 H NMR (600MHz, DMSO-d6) δ8.12-8.04(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). 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0402] 7-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 additional purification. LC / MS (ESI) m / z: for C 39 H 43 Calcd. for F3N5O5 [M+H]+ 718.3; found 718.2. Step 3: Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)naphthalen-2-ol

[0403] Tert-butyl 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 h. The solution was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm×200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25° C.; gradient: 94% 5:95 MeCN: HO with 0.1% TFA / 6% 95:5 MeCN: HO with 0.1% TFA→100% 95:5 MeCN: HO with 0.1% TFA; λ=220 nm) to afford the desired product (21.1 mg, 0.03 mmol, 73% yield) as a bis-TFA salt. LC / MS (ESI) m / z: for C 32 H 31 Calculated value [M+H]+ for F3N5O2: 574.2; found: 574.3; 1H NMR(500MHz,DMSO-d6)δ9.21-9.03(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=5 2.2Hz,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),3.4 2-3.27(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). 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)quinazolin-4-amine Step 1: Preparation of (R)-tert-butyl 3-((7-bromo-2-chloro-8-fluoroquinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0404] 7- bromo -2,4- dichloro -8- fluoroquinazoline (450mg, 1.52mmol) was suspended in DCM (5mL) and the mixture was cooled to 0 ° C. DIPEA (0.40mL, 2.28mmol) was added, followed by (R) -3- (methylamino) pyrrolidine -1- tert-butyl carboxylate (335mg, 1.67mmol), and the solution was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2h, then directly concentrated and used in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 18 H 22 Calculated value of BrClFN4O2 [M+H] + 459.1; measured value 459.0. Step 2: Preparation of (R)-tert-butyl 3-((7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0405] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (242 mg, 1.52 mmol) was dissolved in THF (5.0 mL) and LiHMDS solution (1.0 M in THF, 3.8 mL, 3.8 mmol) was added dropwise. After stirring for 5 min, (R)-tert-butyl 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.

[0406] The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (0→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (500 mg, 0.858 mmol, 56.4% yield over two steps). LC / MS (ESI) m / z: for C 26 H 35 Calculated value of BrClF2N5O3 [M+H] + 582.2; measured value 582.2; 1 H NMR (500MHz, CDCl3) δ7.53 (dd, J=9.0, 1.5Hz, 1H), 7.32 (dd, J=9.0, 6.3Hz, 1H), 5.2 7(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). Step 3: Preparation of (R)-tert-butyl 3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0407] (S)-tert-Butyl 3-((7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 methanesulfonic acid (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (cataCXium A Palladacycle Gen3) (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 carried out three times. Degassed dioxane (2 mL) was added and the reaction mixture was heated at 100 ° C for 2 h. The solution was directly concentrated and the crude residue was purified by column chromatography (0 → 10% MeOH / DCM) to provide the desired product (65 mg, 0.080 mmol, 93% yield). LC / MS (ESI) m / z: for C 47 H 62 Calculated value of F2N5O3Si [M+H] + 810.5; measured value 810.9; 1 H NMR(500MHz,CD3OD)δ8.04-8.00(m,2H),7.98-7.91(m,1H),7.79-7.76(m,1H),7.64-7.58( m,1H),7.54-7.48(m,1H),7.46-7.41(m,1H),7.37-7.28(m,1H),5.32(d,J=55.4Hz,1H),4.4 1-4.14(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). Step 4: Preparation of (R)-tert-butyl 3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0408] (S)-tert-Butyl 3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 38 H 42 Calculated value of F2N5O3 [M+H] + 654.3, measured value 654.4. Step 5: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0409] (S)-tert-Butyl 3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro-tetrahydro-1H-pyrrolazin-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 HCl solution (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 directly concentrated and the crude residue was evaporated from DCM (2×5 mL) to afford the desired product (40 mg, 0.068 mmol, 92% yield over two steps) as its HCl salt. LC / MS (ESI) m / z: for C 33 H 34 Calculated for F2N5O [M+H] + 554.3; measured value 554.2. 7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)quinazolin-4-amine 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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0410] (S)-tert-Butyl 3-((7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 methanesulfonic acid (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (cataCXium A Palladacycle Gen3) (3.1 mg, 4.3 μmol) were combined as solids in a microwave vial. The bottle was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out three times. Degassed dioxane (2mL) was added and the reaction mixture was heated at 100 ° C for 2h. The solution was directly concentrated, and the crude residue was purified by column chromatography (0 → 8% MeOH / DCM) to provide the desired product (51mg, 0.067mmol, 79% yield). LC / MS (ESI) m / z: for C 39 H 49 Calculated value of ClF2N7O4 [M+H] + 752.3; measured value 752.3. Step 2: Preparation of 7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)quinazolin-4-amine

[0411] (3S)-tert-Butyl 3-((7-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 HCl solution (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 directly concentrated and the crude residue was evaporated from DCM (2×5 mL) to afford the desired product (30 mg, 0.046 mmol, 69% yield) as its HCl salt. LC / MS (ESI) m / z: for C 29 H 33 Calcd. value of ClF2N7O [M+H] + 568.2; measured value 568.2. 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)quinazoline Step 1: Preparation of (S)-tert-butyl 4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate

[0412] 7- bromo -2,4- dichloro -8- fluoroquinazoline (500mg, 1.69mmol) was dissolved in dioxane (15mL). DIPEA (0.9mL, 5.1mmol) was added dropwise, followed by dropwise addition of (S) -3- methylpiperazine -1- tert-butyl formate (340mg, 1.69mmol). The reaction mixture was stirred at room temperature for 2h. The solution was concentrated, and the crude residue was purified by column chromatography (5 → 50% EtOAc / hexane) to provide the desired product (701mg, 1.53mmol, 90% yield) as a white solid. LC / MS (ESI) m / z: for C 18 H 22 Calculated value of BrClFN4O2 [M+H] + 459.1; measured value 459.1; 1H NMR (500MHz, CDCl3) δ7.53 (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). Step 2: Preparation of (S)-tert-butyl 4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate

[0413] (S)-tert-Butyl 4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (500 mg, 1.09 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 / hexanes with 5% Et3N) to provide the desired product (415 mg, 0.71 mmol, 66% yield) as a yellow solid. LC / MS (ESI) m / z: for C 26 H 35 Calculated value of BrF2N5O3 [M+H] + 582.2; measured value 582.1; 1 H NMR (500MHz, CD3OD) δ7.63 (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),4.23-4.1 5(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),3.0 6-2.96(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). Step 3: Preparation of (S)-tert-butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate

[0414] (S)-tert-Butyl 4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 methanesulfonic acid (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct [cataCXiumA Palladacycle Gen.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. The process was carried out 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 provide the desired product (190 mg, 0.024 mmol, 91% yield). LC / MS (ESI) m / z: for C 47 H 62 Calculated value of F2N5O3Si [M+H] + 810.5; measured value 810.3; 1HNMR(500MHz,CD3OD)δ8.07-7.98(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),7.37-7.30(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),3.84-3.58(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). Step 4: Preparation of (S)-tert-butyl 4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate

[0415] (S)-tert-Butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 38 H 42 Calculated value of F2N5O3 [M+H] + 654.3; measured value 654.5. Step 5: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)quinazoline

[0416] (S)-tert-Butyl 4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (140 mg, 0.214 mmol) was dissolved in dioxane (1.0 mL) and HCl solution (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 directly concentrated, and the crude residue was evaporated from DCM (2×5 mL) to afford the desired product as its HCl salt (assuming quantitative yield). LC / MS (ESI) m / z: for C 33 H 34 Calculated for F2N5O [M+H] + 554.3; measured value 554.2. 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile Step 1: Preparation of (S)-benzyl 4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0417] 7- bromo -2,4- dichloro -8- fluoroquinazoline (500mg, 1.69mmol) was dissolved in dioxane (15mL). DIPEA (0.9mL, 5.1mmol) was added dropwise, followed by dropwise addition of (S) -2- (cyanomethyl) piperazine -1- tert-butyl benzyl carboxylate (438mg, 1.69mmol). The reaction mixture was stirred at room temperature for 2h. The solution was concentrated, and the crude residue was purified by column chromatography (5 → 50% EtOAc / hexane) to provide the desired product (790mg, 1.53mmol, 90% yield) as a white solid. LC / MS (ESI) m / z: for C 22 H 19 Calculated value of BrClFN5O2 [M+H] + 518.0; measured value 518.1; 1H NMR (500MHz, CD3OD) δ7.81 (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). Step 2: Preparation of (S)-benzyl 4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0418] (S)-4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)-piperazine-1-carboxylic acid benzyl ester (120 mg, 0.23 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 / hexanes with 5% Et3N) to provide the desired product (90 mg, 0.14 mmol, 61% yield) as a yellow solid. LC / MS (ESI) m / z: for C 30 H 32 Calculated value of BrF2N6O3 [M+H] + 641.2; measured value 641.3; 1H NMR (500MHz, CD3OD) δ7.72 (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). Step 3: Preparation of 2-((S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0419] (S)-benzyl 4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 directly concentrated and the residue was evaporated from DCM (3×5 mL). The crude material was used directly in the next step without additional purification. LC / MS (ESI) m / z: for C 22 H 26 Calcd. value of BrF2N6O [M+H] + 507.1; measured value 507.1. Step 4: Preparation of (S)-tert-butyl 4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0420] 2-((S)-4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 h. The solution was concentrated and the crude residue was directly purified by column chromatography (0→8% MeOH / DCM) to afford the desired product (85 mg, 0.140 mmol, 65% yield) as a yellow solid. LC / MS (ESI) m / z: for C 27 H 34 Calculated value of BrF2N6O3 [M+H] + 607.1; measured value 607.3; 1 HNMR(500MHz,CD3OD)δ7.73(dd,J=9.0,1.6Hz,1H),7.48(dd,J=9.0,6.4Hz,1H),5.3 0(d,J=53.3Hz,1H),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). Step 5: Preparation of tert-butyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate

[0421] (S)-tert-Butyl 4-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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]palladium(II) dichloride (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 at 100 ° C in a microwave for 2 h. The reaction mixture was directly concentrated and the crude residue was purified by column chromatography (0→8% MeOH / DCM) to provide the desired product (190 mg, 0.024 mmol, 91% yield). LC / MS (ESI) m / z: for C 48 H 61 Calculated value of F2N6O3Si [M+H] + 835.4; measured value 835.4; 1 H NMR(500MHz,CD3OD)δ8.07-7.99(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,1H),7.46-7.39(m,1H),7.39-7.33(m,1H),5.30(d,J=53.3Hz,1H),4.78-4.69(m,1 H),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) ,2.47-2.12(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). Step 6: Preparation of (S)-tert-butyl 2-(cyanomethyl)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0422] (S)-tert-Butyl 2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 39 H 41 Calculated value of F2N6O3 [M+H] + 679.3; measured value 679.3. Step 7: Preparation of 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0423] (S)-tert-Butyl 2-(cyanomethyl)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (40 mg, 0.059 mmol) was dissolved in dioxane (1.0 mL) and HCl solution (4.0 M in dioxane, 1.0 mL, 4.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. The solution was directly concentrated and the crude residue was evaporated from DCM (3×5 mL) to afford the desired product as its HCl salt (assuming quantitative yield). LC / MS (ESI) m / z: for C 34 H 33 Calculated for F2N6O [M+H] + 579.3; measured value 579.4. (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

[0424] 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'-tetramethylformamidinium hexafluorophosphate (35 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 5 min. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm×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 afford the desired product (8 mg, 0.009 mmol, 34% yield) as a bis-TFA salt as an off-white solid, which is a mixture of two atropisomers. LC / MS (ESI) m / z: for C 35 H 33 Calcd. value of Cl2F2N6O2S [M+H] + 709.2; Found 709.0. NMR: Spectrum is a mixture of atropisomers; water peak suppression method used. 1 H NMR (500MHz, DMSO-d6) δ8.24-8.18(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). (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

[0425] 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'-tetramethylformamidinium hexafluorophosphate (35 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 5 min. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm×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 afford the desired product as a mixture of two atropisomers as a bis-TFA salt (5.8 mg, 0.006 mmol, 25% yield). LC / MS (ESI) m / z: for C 36 H 34 Calculated value of Cl2F2N7O2 [M+H] + 704.2; Found 704.1. NMR: Spectrum is a mixture of atropisomers; water peak suppression method used. 1H NMR(500MHz,DMSO-d6)δ8.89(d,J=4.9Hz,2H),8.24-8.19(m,1H),8.13-8.09(m,1H),7.97-7.89(m,1H),7.77-7.7 2(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). (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

[0426] 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'-tetramethylformamidinium hexafluorophosphate (35 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 5 min. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm×200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25° C.; gradient: 81% 5:95 MeCN:H 2 O with 0.1% TFA / 19% 95:5 MeCN:H 2 O with 0.1% TFA→100% 95:5 MeCN:H 2 O with 0.1% TFA; λ=220 nm) to afford 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% CO 2 :20% MeOH with 0.1% NH 4 OH; λ=254 nm) provided the desired compound as a bis-TFA salt, a single atropisomer with unknown absolute stereochemistry (1.3 mg, 0.001 mmol, 6% yield). LC / MS (ESI) m / z: for C 37 H 35 Calculated value of Cl2F2N6O2 [M+H] + 702.9; measured value 702.9. (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

[0427] (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'-tetramethylformamidinium hexafluorophosphate (7.3 mg, 0.026 mmol). The reaction mixture was stirred at room temperature for 5 min. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm×200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25° C.; gradient: 77% 5:95 MeCN: HO with 10 mM AA / 23% 95:5 MeCN: HO with 10 mM AA→100% 95:5 MeCN: HO with 10 mM AA; λ=220 nm) to afford the desired product as a single atropisomer (2.7 mg, 0.004 mmol, 72% yield). LC / MS (ESI) m / z: for C 35 H 35 Calculated value of ClF5N8O2 [M+H] + 729.2; Found 729.1. NMR: using water peak suppression method 1 H NMR (500MHz, DMSO-d6) δ8.66(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). (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-pyrrolizin-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

[0428] (5M)-6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-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'-tetramethylformamidinium hexafluorophosphate (7 mg, 0.026 mmol). The reaction mixture was stirred at room temperature for 5 min. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm×200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25° C.; gradient: 74% 5:95 MeCN: HO with 10 mM AA / 26% 95:5 MeCN: HO with 10 mM AA→100% 95:5 MeCN: HO with 10 mM AA; λ=220 nm) to afford the desired product (3.5 mg, 0.005 mmol, 94% yield) as a single atropisomer. LC / MS (ESI) m / z: for C 37 H 36 Calculated value of ClF6N8O2 [M+H] + 773.3; found 773.1. NMR: using water peak suppression method; 1H NMR (500MHz, DMSO-d6) δ8.66(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). (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

[0429] (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'-tetramethylformamidinium hexafluorophosphate (7.3 mg, 0.026 mmol). The reaction mixture was stirred at room temperature for 5 min. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm×200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25° C.; gradient: 74% 5:95 MeCN: HO with 10 mM AA / 26% 95:5 MeCN: HO with 10 mM AA→100% 95:5 MeCN: HO with 10 mM AA; λ=220 nm) to afford the desired product (1.1 mg, 0.001 mmol, 29% yield). LC / MS (ESI) m / z: for C 35 H 35 Calculated value of ClF5N8O2 [M+H]+ 729.2; Found 729.1. NMR: The presence of a diastereomer (C4 amine) complicates the spectrum; use the water peak suppression method. 1 H NMR (500MHz, DMSO-d6) δ8.66-8.62(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). (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-pyrrolizin-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

[0430] (5M)-6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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'-tetramethylformamidinium hexafluorophosphate (7 mg, 0.026 mmol). The reaction mixture was stirred at room temperature for 5 min. The reaction mixture was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm×200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25° C.; gradient: 72% 5:95 MeCN: HO with 10 mM AA / 28% 95:5 MeCN: HO with 10 mM AA→100% 95:5 MeCN: HO with 10 mM AA; λ=220 nm) to afford the desired product (1.4 mg, 0.002 mmol, 38% yield). LC / MS (ESI) m / z: for C 37 H 36 Calculated value of ClF6N8O2 [M+H] + 773.2; Found 773.2. NMR: using water peak suppression method 1 H NMR (500MHz, DMSO-d6) δ8.66(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-...

Claims

1. A compound having formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is a bond, O, NR e or CR e R f , where R e and R f are independently hydrogen or C1-C3 alkyl; R 1 is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, haloC1-C3 alkoxy, haloC1-C3 alkyl, hydroxyl, and hydroxyC1-C3 alkyl; R 2 and R 3 independently selected from hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halogen, halogenated C1-C3 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 and hydroxyl; U is a bond, CH2NH, or NH; Y is a bond, O, NR g (CR e R f ) m NR f , or CR e R f , wherein m is 1, 2, or 3, and wherein R e , R f and R g are independently hydrogen or C1-C3 alkyl; A is a four- to ten-membered monocyclic or bicyclic or tricyclic bridged, fused, or spirocyclic saturated, unsaturated, or partially unsaturated ring system optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring system is optionally substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, amidoC1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halogen, haloC1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo; provided that when Y is a bond, A contains at least one nitrogen atom; R' is a halogen; R 4 is an aryl or heteroaryl ring optionally substituted with one, two, or three substituents independently selected from the group consisting of C2-C4 alkenyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halogen, haloC1-C3 alkoxy, haloC1-C3 alkyl, nitro, and oxo; X is O or NR 16 , where R 16 is hydrogen or C1-C3 alkyl; R 5 is selected from hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di(C1-C3 alkyl)amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR a R b C1-C6 alkyl, wherein the aryl, the aryl portion of the arylC1-C6 alkyl, the C3-C6 cycloalkyl, the cycloalkyl portion of the C3-C6 cycloalkylC1-C6 alkyl, the heteroaryl, the heteroaryl portion of the heteroarylC1-C6 alkyl, the heterocyclyl, the heterocyclyl portion of the heterocyclylC1-C6 alkyl is optionally substituted by one, two, three, or four groups independently selected from the following: C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)aminoC1-C6 alkyl C3 alkyl, amino, aminoC1-C3 alkyl, carboxyl, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoC1-C3 alkyl, halogen, haloC1-C3 alkoxy, haloC1-C3 alkyl, heterocyclyl, heterocyclylC1-C3 alkyl, hydroxyl, hydroxyC1-C3 alkyl, nitro and oxo; wherein the heterocyclyl and the heterocyclyl C1-C3 alkyl moieties are further optionally substituted with one, two, or three groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen and haloC1-C3 alkyl; or R 5 and R 16 together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted by one, two, three, four, or five groups independently selected from: one, two, three, or four groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxyl and hydroxyC1-C3 alkyl; and R a and R b One of them is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, arylC1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkylC1-C6 alkyl.

2. The compound according to claim 1, wherein R 4 is a five- or six-membered aromatic ring optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen and sulfur.

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

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

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: Y is NCH3.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: A is a five- to ten-membered monocyclic, bicyclic or tricyclic bridged, fused, or spirocyclic saturated ring system containing one or two nitrogen atoms.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or 6, wherein: AU is selected from the group consisting of: in represents the point of attachment to the carbonyl group; and Indicates the point of attachment to Y.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 4 or 5, wherein: YAU is selected from the group consisting of: in: represents the point of attachment to the carbonyl group; and Indicates the point of attachment to the quinazoline ring.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: R 2 It's a halogen.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 3 It's a halogen.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: R 4 is selected from the group consisting of isothiazolyl, pyridyl, pyrimidinyl and thiazolyl.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: X is O.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: R 5 Selected from the group consisting of: Wherein each ring is optionally substituted by 1, 2, or 3 groups independently selected from the following: C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halogen, halogenated C1-C3 alkyl, hydroxyl, hydroxyC1-C3 alkyl and oxo.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: R 5 is -(C1-C3 alkyl)-R 6 , where R 6 is a three- to five-membered monocyclic ring system, an eight- or nine-membered bicyclic fused saturated ring system, or a ten-membered tricyclic saturated ring system, wherein each ring system optionally contains one nitrogen atom, and wherein each ring system is optionally substituted by one or two groups independently selected from C1-C3 alkyl, halogen and (4- to 6-membered heterocyclyl)C1-C3 alkyl; wherein the heterocyclyl portion of the (4- to 6-membered heterocyclyl)C1-C3 alkyl is further optionally substituted by a halogen group.

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

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

17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein: Z is the key.

18. The compound according to any one of claims 1 to 17, wherein R 1 is a monocyclic heteroaryl ring containing one, two, or three nitrogen atoms, wherein the ring is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, haloC1-C3 alkyl, hydroxyl, and hydroxyC1-C3 alkyl.

19. The compound according to any one of claims 1 to 18, wherein R 1 yes in Indicates the point of attachment to the parent molecule.

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

21. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 and 20, wherein: R 1 is naphthyl substituted with one, two, three, four, or five substituents independently selected from C1-C3 alkyl, C2-C4 alkynyl, halogen and hydroxy.

22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, 20 and 21, wherein: R 1 is naphthyl, wherein the naphthyl is substituted with one, two, or three groups independently selected from C2-C4 alkynyl, halogen and hydroxy.

23. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 17 and 20 to 22, wherein: R 1 yes in Indicates the point of attachment to the parent molecule.

24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein: R' is fluorine.

25. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein: R' is chlorine.

26. A compound selected from the group consisting of: as well as or a pharmaceutically acceptable salt thereof.

27. A compound selected from the group consisting of: (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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolazin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.2.0]heptane-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-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.2.0]heptane-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-pyrrolizin-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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)octahydro-2H-4,7-cycloimidoisoindol-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-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-azabicyclo[2.2.1]heptane-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-pyrrolizin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl]-2-azabicyclo[2.2.1]heptane-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-ethylnaphth-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-ethylnaphth-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-ethylnaphth-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]heptane-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-pyrrolizin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-naphthocarbonitrile; 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-naphthocarbonitrile; (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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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-pyrrolazin-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.

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

29. An oral dosage form 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. A method of treating a cancer expressing KRAS G12C, G12D and / or G12V mutations in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

31. A method of treating a cancer expressing a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

32. A method for treating a cancer sensitive to KRAS G12C inhibition in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

33. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound as described in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein: The cancer is lung cancer, colorectal cancer, pancreatic cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, stomach cancer, or uterine cancer.

34. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound as described in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein: The cancer is non-small cell lung cancer.

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