KRAS g12c inhibitors

Abstract

The present disclosure provides KRAS inhibitors of formula (I). Methods of treating cancers using the compounds are also provided.

Description

KRAS G12C INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. Provisional Application No. 63 / 606,951, filed December 6, 2023 which is incorporated by reference herein in its entirety. FIELD

[0002] The present disclosure provides KRAS inhibitors. Methods of treating cancers using the inhibitors are also provided. BACKGROUND

[0003] The KRAS oncogene is a member of the RAS family of GTPases that are involved in numerous cellular signaling processes. KRAS mutations are gain-of-function mutations that are present in up to 30% of all tumors, including as many as 90% of pancreatic cancers. KRAS serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cellular proliferation. Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRAS primary amino acid sequence comprise approximately 40% of KRAS driver mutations in lung adenocarcinoma, with a G12C transversion being the most common activating mutation. KRAS G12C mutations occur in about 13% of lung adenocarcinomas and about 3% of colorectal adenocarcinomas and are also present in cancers of the breast, bladder, cervix, ovaries, pancreas and uterus.

[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 a continued interest and effort to develop inhibitors of KRAS, particularly inhibitors of activating KRAS mutants, such as KRAS G12C.SUMMARY

[0005] The present disclosure is based, in part, on the discovery that unlike other KRAS G12C inhibitors, compounds of the disclosure target the active, KRAS G12C(ON)form of KRAS G12C protein. By inhibiting the G12CONform of KRAS, G12C, it is expected that the claimed compounds will decrease a cancer’s resistance to KRAS G12C inhibition and / or demonstrate increased potency in the clinic. Without being bound by a theory, the inhibition of G12CONform of KRAS G12C may be a result of the substituent at position 4 of the pyridopyrimidine ring in formula (I).

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

[0007] selected from the group consisting

[0008] R1is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, or three substituents independently selected from the group consisting of cyclopropyl, ethynyl, halo, hydroxy, methyl, and trifluoromethyl;

[0009] R2is heteroaryl;

[0010] R3is hydrogen or methoxy;

[0011] R4is methyl or ethyl;

[0012] R5is hydrogen or cyanomethyl; and

[0013] X is O or CH2.

[0014] In some aspects, the present disclosure provides a compound of formula (IA):or a pharmaceutically acceptable salt thereof, wherein:

[0015] R1is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, or three substituents independently selected from the group consisting of cyclopropyl, ethynyl, halo, hydroxy, methyl, and trifluoromethyl;

[0016] R2is heteroaryl;

[0017] R4is methyl or ethyl; and

[0018] R5is hydrogen or methoxy.

[0019] In some aspects, the present disclosure provides a compound of formula (IB):or a pharmaceutically acceptable salt thereof, wherein:

[0020] R1is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of ethynyl and halo;

[0021] R2is heteroaryl; and

[0022] X is O or CH2.

[0023] In some aspets, the present disclosure provides a compound of formula (IC):or a pharmaceutically acceptable salt thereof, wherein:

[0024] R1is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, or three substituents independently selected from the group consisting of ethynyl, halo, and methyl;

[0025] R2is heteroaryl; and

[0026] R3is hydrogen or cyanomethyl.

[0027] In some aspects, R1is phenyl optionally substituted with one, two, or three substituents independently selected from the group consisting of cyclopropyl, halo, and trifluoromethyl.

[0028] In some aspects, R1is naphthyl optionally substituted with one, two, or three substituents independently selected from the group consisting of ethynyl, halo, and hydroxy.

[0029] In some aspects, R1is indazolyl optionally substituted with one, two, or three halo groups.

[0030] In some aspeccts, R2is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and thazolyl.

[0031] In some aspects, the present disclosure provides a compound selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

[0032] In some aspects, the present disclosure provides a compound selected from the group consisting from the group consisting of:

[0033] (Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one;

[0034] (Z)-1-((R)-3-((7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0035] (Z)-1-((R)-3-((7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one;

[0036] 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3- (pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0037] (Z)-1-(3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyrazin-2-yl)prop-2-en-1-one;

[0038] (Z)-1-((R)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0039] (Z)-1-(4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- diazepan-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0040] (Z)-1-(4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- diazepan-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one;

[0041] (Z)-1-((R)-3-((7-(8-ethynyl-6,7-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0042] (Z)-1-((R)-3-((7-(8-ethynyl-6,7-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one;

[0043] (Z)-1-((2S,3S)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-3-yl)prop-2-en-1-one;

[0044] (Z)-1-((2R,3R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-3-yl)prop-2-en-1-one;

[0045] (Z)-1-((2S,3S)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1- one;

[0046] (Z)-1-((2R,3R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1- one;

[0047] (Z)-1-(3-(ethyl(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0048] (Z)-1-(3-(ethyl(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one;

[0049] (Z)-2-fluoro-1-((R)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxy-7-(2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one;

[0050] (Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0051] (Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one;

[0052] (Z)-2-fluoro-1-((R)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(3-methyl-2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one;

[0053] (Z)-1-((2S,3S)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one;

[0054] (Z)-1-((2R,3R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one;

[0055] (Z)-1-((2S,3S)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one;

[0056] (Z)-1-((2R,3R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one;

[0057] (Z)-1-((2R,3R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyrazin-2-yl)prop-2-en-1-one;

[0058] (Z)-1-((2S,3S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0059] (Z)-1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0060] (Z)-1-(4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one;

[0061] (Z)-1-((R)-3-((7-(2-cyclopropyl-3-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0062] (Z)-1-((R)-3-((7-(2-cyclopropyl-3-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one;

[0063] (Z)-1-((R)-3-((7-(2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0064] (Z)-1-((R)-3-((7-(2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one;

[0065] (Z)-2-fluoro-1-((R)-3-((8-fluoro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one;

[0066] (Z)-2-fluoro-1-((R)-3-((8-fluoro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridazin-2-yl)prop-2-en-1-one;

[0067] (Z)-1-((R)-3-((7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0068] (Z)-1-((R)-3-((7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one;

[0069] 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0070] 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(pyridazin-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0071] 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(pyrazin-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0072] 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0073] (Z)-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro- 3-(pyrimidin-4-yl)prop-2-en-1-one;

[0074] (Z)-N-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepan-6-yl)-2-fluoro-3-(pyridin-2-yl)acrylamide;

[0075] (Z)-N-((R)-1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan- 3-yl)-2-fluoro-3-(pyridin-2-yl)acrylamide;

[0076] (Z)-N-((R)-1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan- 3-yl)-2-fluoro-3-(pyridazin-2-yl)acrylamide;

[0077] (Z)-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;

[0078] 2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0079] 2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; and

[0080] 2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(pyridazin-2-yl)acryloyl)piperazin-2-yl)acetonitrile;

[0081] or a pharmaceutically acceptable salt thereof.

[0082] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0083] In some aspects, the present disclosure provides an oral dosage form comprising a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0084] In some aspects, the present disclosure provides a method of treating cancer expressing KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof.

[0085] In some aspects, the present disclosure provides a method of treating cancer expressing KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof.

[0086] In some aspects, the present disclosure provides a method for treating a cancer susceptible to KRAS G12C inhibition in a subject in need thereof, the method comprising administering to the subject a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof.

[0087] In some aspects, the present disclosure provides a method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof, wherein the canceris lung cancer, colorectal cancer, pancreatic cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, gastric cancer or cancer of the uterus.

[0088] In some aspects, the present disclosure provides a method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer.

[0089] In some aspects, the present disclosure provides an atropisomer of a compound of any of the prior aspects. In certain aspects, the compound is a stable atropisomer as described herein.

[0090] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0091] In some aspects, the present disclosure provides an oral dosage form comprising a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0092] In some aspects, the present disclosure provides a method of treating cancer expressing KRAS G12Cmutation in a subject in need thereof, the method comprising administering to the subject a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof.

[0093] In some aspects, the present disclosure provides a method of treating cancer expressing KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof.

[0094] In some aspects, the present disclosure provides a method for treating a cancer susceptible to KRAS G12C inhibition in a subject in need thereof, the method comprising administering to the subject a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof.

[0095] In some aspects, the present disclosure provides a method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a compound of any of the prior 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 cancer of the uterus.

[0096] In some aspects, the present disclosure provides a method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a compound of any of the prior aspects, or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer.

[0097] In some aspects of the method, the compound is an atropisomer of a compound of any of the prior aspects. In certain aspects, the compound is a stable atropisomer as described herein.

[0098] In another aspect, the present disclosure provides a method for inhibiting KRAS G12C activity in a in a cell, comprising contacting the cell with a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. In one aspect, the contacting is in vitro. In one aspect, the contacting is in vivo.

[0099] In some aspects, the present disclosure provides a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0100] 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.

[0101] In another aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRAS G12C-associated disease or disorder.

[0102] In another aspect, the present disclosure provides a use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer. In some aspects, the cancer is lung cancer. In some aspects, the cancer is non-small cell lung cancer.

[0103] In another aspect, the present disclosure provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of KRAS G12C.

[0104] In another aspect, the present disclosure provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRAS G12C-associated disease or disorder.DETAILED DESCRIPTION

[0105] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference.

[0106] Unless otherwise indicated, any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0107] The singular forms “a,” “an,” and “the” include plural referents unless the context dictates otherwise.

[0108] As used herein, the term “or” is a logical disjunction (i.e., and / or) and does not indicate an exclusive disjunction unless expressly indicated such as with the terms “either,” “unless,” “alternatively,” and words of similar effect.

[0109] As used herein, the phrase “or a pharmaceutically acceptable salt thereof” refers to at least one compound, or at least one salt of the 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 the compound of Formula (I), and two or more pharmaceutically acceptable salts of a compound of Formula (I).

[0110] The term “aryl,” as used herein, refers to a phenyl group, or a bicyclic fused ring system wherein one or both of the rings is a phenyl group. Bicyclic fused ring systems consist of a phenyl group fused to a four- to six-membered aromatic or non-aromatic carbocyclic ring. The aryl groups of the present disclosure can be attached to the parent molecular moiety through any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.

[0111] The terms “halo” and “halogen”, as used herein, refer to F, Cl, Br, or I.

[0112] The term “heteroaryl,” as used herein, refers to an aromatic five- or six-membered ring where at least one atom is selected from N, O, and S, and the remaining atoms are carbon. The term “heteroaryl” also includes bicyclic systems where a 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 where abicyclic 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 groups are attached to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. Representative examples of heteroaryl groups include, but are not limited to, alloxazine, benzo[1,2-d:4,5-d’]bisthiazole, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.

[0113] In those aspects where the term “heteroaryl,” includes bicyclic systems, an aromatic five- or six-membered ring having at least one atom selected from N, O, and S 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. In those aspects where the term “heteroaryl,” includes tricyclic systems, a bicyclic system defined in the prior sentence 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.

[0114] The term “hydroxy,” as used herein, refers to –OH.

[0115] The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include13C and14C. Isotopically-labeled compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non- labeled reagent otherwise employed. Such compounds can have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds can have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

[0116] An additional aspect of the subject matter described herein is the use of the disclosed compounds as radiolabeled ligands for development of ligand binding assays or for monitoring of in vivo adsorption, metabolism, distribution, receptor binding or occupancy, or compound disposition. For example, a compound described herein can be prepared usinga radioactive isotope and the resulting radiolabeled compound can be used to develop a binding assay or for metabolism studies. Alternatively, and for the same purpose, a compound described herein can be converted to a radiolabeled form by catalytic tritiation using methods known to those skilled in the art.

[0117] Certain compounds of the present disclosure exist as stereoisomers. It should be understood that when stereochemistry is not specified, the present disclosure encompasses all stereochemical isomeric forms, or mixtures thereof, which possess the ability inhibit KRAS G12C. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.

[0118] Certain compounds of the present disclosure exist as atropisomers. The term “atropisomers” refers to conformational stereoisomers which occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are asymmetrical (i.e., optical activity arises without requiring an asymmetric carbon center or stereocenter). Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted. Atropisomers are enantiomers (or epimers) without a single asymmetric atom.

[0119] The atropisomers can be considered stable if the barrier to interconversion is high enough to permit the atropisomers to undergo little or no interconversion at room temperature for at least a week. In some aspects the atropisomers undergo little or no interconversion at room temperature for at least a year. In some aspects, an atropisomeric compound of the disclosure does not undergo more than about 5% interconversion to its opposite atropisomer at room temperature during one week when the atropisomeric compound is in substantially pure form, which is generally a solid state. In some aspects, an atropisomeric compound of the disclosure does not undergo more than about 5% interconversion to its opposite atropisomer at room temperature (approximately 25 ºC)during one year. In some aspects, the atropisomeric compounds of the disclosure are stable enough to undergo no more than about 5% interconversion in an aqueous pharmaceutical formulation held at 0 ºC for at least one week. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of single atropisomers, and intermediate mixtures.

[0120] The energy barrier to thermal racemization of atropisomers may be determined by the steric hindrance to free rotation of one or more bonds forming a chiral axis. Certain biaryl compounds exhibit atropisomerism where rotation around an interannular bond lacking C2 symmetry is restricted. The free energy barrier for isomerization (enantiomerization) is a measure of the stability of the interannular bond with respect to rotation. Optical and thermal excitation can promote racemization of such isomers, dependent on electronic and steric factors.

[0121] Ortho-substituted biaryl compounds may exhibit this type of conformational, rotational isomerism. Such biaryls are enantiomeric, chiral atropisomers where the sp2–sp2carbon-carbon, interannular bond between the aryl rings has a sufficiently high energy barrier to prevent free rotation, and where substituents W1≠ W2and W3≠ W4render the molecule asymmetric.

[0122] The steric interaction between W1:W3, W1:W4, and / or W2:W4, W2:W3is large enough to make the planar conformation an energy maximum. Two non-planar, axially chiral enantiomers then exist as atropisomers when their interconversion is slow enough such that they can be isolated free of each other. Bold lines and dashed lines in the figures shown above indicate those moieties, or portions of the molecule, which are sterically restricted due to a rotational energy barrier. Balded moieties exist orthogonally above the plane of the page, and dashed moieties 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.

[0123] The pharmaceutical compositions of the disclosure can include one or more pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S.M. et al., J. Pharm. Sci., 66:1-19 (1977)). The salts can be obtained during the final isolation and purification of the compounds described herein, or separately be reacting a free base function of the compound with a suitable acid or by reacting an acidic group of the compound with a suitable base. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N′-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like. Pharmaceutical Compositions

[0124] In another aspect, the present disclosure provides a composition, e.g., a pharmaceutical composition, containing one or a combination of the compounds described within the present disclosure, formulated together with a pharmaceutically acceptable carrier. Pharmaceutical compositions of the disclosure also can be administered in combination therapy, i.e., combined with other agents, as described herein.

[0125] As used herein, “pharmaceutically acceptable carrier” includes 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 can be coated in a material to protect the compound from the action of acids and other natural conditions that can inactivate the compound.

[0126] The pharmaceutical compositions of the present disclosure can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and / or mode of administration will vary depending upon the desired results. In some aspects, the routes of administrationfor compounds of the disclosure include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

[0127] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, some methods of preparation are reduced pressure drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0128] Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, and injectable organic esters. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0129] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0130] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution or as a liquidwith ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be desirable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0131] Alternatively, the compounds of the disclosure can 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.

[0132] Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparation. Exemplary oral preparations include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, a pharmaceutical composition in accordance with the disclosure can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.

[0133] A tablet can, for example, be prepared by admixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets.

[0134] An aqueous suspension can be prepared, for example, by admixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension, including, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose,` hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersingor wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example, heptadecathylene-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. An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.

[0135] Oily suspensions can, for example, be prepared by suspending at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof in either a vegetable oil, such as, for example, arachis oil, sesame oil, and coconut oil; or in mineral oil, such as, for example, liquid paraffin. An oily suspension can also contain at least one thickening agent, such as, for example, beeswax, hard paraffin, and cetyl alcohol. In order to provide a palatable oily suspension, at least one of the sweetening agents already described herein above, and / or at least one flavoring agent can be added to the oily suspension. An oily suspension can further contain at least one preservative, including, but not limited to, for example, an anti-oxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.

[0136] Dispersible powders and granules can, for example, be prepared by admixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersing and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents are already described above. Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents, flavoring agents, and coloring agents.

[0137] The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable,biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Robinson, J.R., ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0138] Therapeutic compositions can be administered with medical devices known in the art. For example, in one aspect, a therapeutic composition of the disclosure can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Patent Nos.5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556. Examples of well-known implants and modules useful in the present disclosure include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No.4,486,194, which discloses a therapeutic device for administering medication through the skin; U.S. Patent No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; 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.

[0139] In certain aspects, the compounds of the present disclosure can be administered parenterally, i.e., by injection, including, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and / or infusion.

[0140] In some aspects, the compounds of the present disclosure can be administered orally, i.e, via a gelatin capsule, tablet, hard or soft capsule, or a liquid capsule. Use of KRAS Inhibitors / Methods of Treating

[0141] Administration of a therapeutic agent described herein may include administration of a therapeutically effective amount of therapeutic agent. The term “therapeutically effective amount” as used herein refers, without limitation, to an amount of a therapeutic agent to treat a condition treatable by administration of a composition comprising theKRAS inhibitors described herein. That amount is the amount sufficient to exhibit a detectable therapeutic or ameliorative effect. The effect can include, for example and without limitation, treatment of the conditions listed herein. The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and therapeutics or combination of therapeutics selected for administration.

[0142] For administration of the compounds described herein, the dosage ranges from about 0.0001 to 100 mg / kg, and more usually 0.01 to 40 mg / kg, of the host body weight. An exemplary treatment regime entails administration once per day, bi-weekly, tri-weekly, weekly, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.

[0143] The disclosed compounds strongly inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, in another aspect the disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount a pharmaceutical composition of comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier to a subject in need thereof.

[0144] Ras mutations including but not limited to KRAS mutations have also been identified in hematological malignancies (e.g., cancers that affect blood, bone marrow and / or lymph nodes). Accordingly, certain aspects are directed to administration of a disclosed compounds (e.g., in the form of a pharmaceutical composition) to a patient in need of treatment of a hematological malignancy. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the presently disclosed compounds can be used for treatment of diseases such as Acute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronic myelogenous leukemia (CML), Acute monocytic leukemia (AMoL) and / or other leukemias. In other aspects, the compounds are useful for treatment of lymphomas such as all subtypes of Hodgkins lymphoma or non-Hodgkins lymphoma.

[0145] Determining whether a tumor or cancer comprises a KRAS mutation can be undertaken by assessing the nucleotide sequence encoding the KRAS protein, by assessing the amino acid sequence of KRAS protein, or by assessing the characteristics of a putativeKRAS mutant protein. The sequence of wild-type human KRAS proteins is known in the art.

[0146] Methods for detecting a KRAS mutation are known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some aspects, samples are evaluated for KRAS mutations including by real-time PCR. In real-time PCR, fluorescent probes specific for the KRAS mutation are used. When a mutation is present, the probe binds and fluorescence is detected. In some aspects, the KRAS mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and / or exon 3) in the KRAS gene, for example. This technique will identify all possible mutations in the region sequenced.

[0147] Methods for detecting a mutation in a KRAS protein are known by those of skill in the art. These methods include, but are not limited to, detection of a KRAS mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0148] Methods for determining whether a tumor or cancer comprises a KRAS mutation can use a variety of samples. In some aspects, the sample is taken from a subject having a tumor or cancer. In some aspects, the sample is taken from a subject having 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 to a cell lysate. In some aspects, the sample is processed to DNA or RNA. The disclosure also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said 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, said method relates to the treatment of cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers (e.g., Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer,astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative 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, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, isletcell 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 carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, 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, 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 cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Viral-Induced cancer. In some aspects, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

[0149] In certain aspects, the disclosure relates to methods for treatment of lung cancers, the methods comprise administering an effective amount of any of the above-described compound (or a pharmaceutical composition comprising the same) to a subject in need thereof. In certain aspects the lung cancer is a non-small cell lung carcinoma (NSCLC), for example adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma. In other aspects, the lung cancer is a small cell lung carcinoma. 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 compounds of the disclosure, or pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative of said compounds, according to the methods of this disclosure include, for example, subjects that have been diagnosed as having acute myeloid leukemia, acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS- related cancers (e.g., Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative 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, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (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 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 carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplasticsyndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, 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, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasalcavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Viral-Induced cancer. In some aspects subjects that are treated with the compounds of the disclosure include subjects that have been diagnosed as having a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign pro static hypertrophy (BPH)). The disclosure further provides methods of modulating a mutant KRAS protein activity by contacting the protein with an effective amount of a compound of the disclosure. Modulation can be inhibiting or activating protein activity. In some aspects, the disclosure provides methods of inhibiting protein activity by contacting the mutant KRAS protein with an effective amount of a compound of the disclosure in solution. In some aspects, the disclosure provides methods of inhibiting the mutant KRAS protein activity by contacting a cell, tissue, organ that express the protein of interest. In some aspects, the disclosure provides methods of inhibiting protein activity in a subject including but not limited to rodents and mammal (e.g., human) by administering into the subject an effective amount of a compound of the disclosure. In some aspects, the percentage modulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the percentage of inhibiting exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the disclosure provides methods of inhibiting KRAS activity in a cell by contacting said cell with an amount of a compound of the disclosure sufficient to inhibit the activity of a KRAS mutant in said cell. In some aspects, the disclosure provides methods of inhibiting mutant KRAS in a tissue bycontacting said tissue with an amount of a compound of the disclosure sufficient to inhibit the activity of mutant KRAS in said tissue. In some aspects, the disclosure provides methods of inhibiting KRAS in an organism by contacting said organism with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS in said organism. In some aspects, the disclosure provides methods of inhibiting KRAS activity in an animal by contacting said animal with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS in said animal. In some aspects, the disclosure provides methods of inhibiting KRAS including in a mammal by contacting said mammal with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS in said mammal. In some aspects, the disclosure provides methods of inhibiting KRAS activity in a human by contacting said human with an amount of a compond of the disclosure sufficient to inhibit the activity of KRAS in said human. The present disclosure provides methods of treating a disease mediated by KRAS activity in a subject in need of such treatment. The present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative thereof. In one aspect, such therapy includes but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment.

[0150] Many chemotherapeutics are presently known in the art and can be used in combination with the compounds of the disclosure. In some aspects, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti- metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

[0151] The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some aspects, the one or more compounds of the disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agentsin the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the disclosure and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present disclosure can be administered just followed by and any of the agents described above, or vice versa. In some aspects of the separate administration protocol, a compound of the disclosure and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

[0152] The compounds can be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. Any variables (e.g., numbered “R” substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the disclosure. SYNTHESIS

[0153] The aspects described herein are further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the aspects described herein, and without departing from the spirit and scope thereof, can make various changes and modifications to them to adapt to various uses and conditions. As a result, the aspects described herein are not limited by the illustrative examples set forth herein below, but rather are defined by the claims appended hereto. Abbreviations

[0154] The following abbreviations are used in the example section below and elsewhere herein: AA for ammonium acetate; BOC or Boc for tert-butoxycarbonyl; Bu for butyl; DCM for dichloromethane; DIPEA for diisopropylethylamine; DMF for N,N-dimethylformamide; DMSO for dimethylsulfoxide; Et for ethyl; EtOAc for ethyl acetate; EtOH for ethanol; h for hours; HATU for 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCl for hydrochloric acid; HMDS for hexamethyldisilazide; K3PO4for potassium phosphate; Me for methyl; MeCN or ACN for acetonitrile; MeOH for methanol; Na2SO4 for sodium sulfate; PdCl2 for palladium (II) chloride; RT or rt for room temperature or retention time (context will dictate); SFC for supercritical fluid chromatography; SiO2for silicon dioxide; TBAF for tetrabutlammonium fluoride; TEA for trimethylamine; TFA for trifluoroacetic acid; and THF for tetrahyrofuran.Example 1 (Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2- fluoro-3-(pyridazin-3-yl)prop-2-en-1-one

[0155] To a stirred solution of 7-(8-ethynyl-7-fluoronaphthalen-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 (8.5 mg, 0.015 mmol), (Z)-2-fluoro-3- (pyridazin-3-yl)acrylic acid (4.99 mg, 0.030 mmol), and 1-methylimidazole (0.018 mL, 0.223 mmol) in acetonitrile (0.5 mL) was added chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (8.3 mg, 0.030 mmol). The mixture was stirred for 15 min and was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 80% 5:95 MeCN:H2O with 10 mM AA / 20% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (8.5 mg, 0.010 mmol, 76% yield) as a brown solid. LC / MS (ESI) m / z: [M+H]+calc’d for C39H34F4N8O2723.3; found 723.6;1H NMR (500 MHz, DMSO-d6) δ 9.20 (br s, 2H), 8.30- 8.15 (m, 2H), 8.09 - 7.98 (m, 1H), 7.85 - 7.75 (m, 1H), 7.74 - 7.63 (m, 2H), 7.61 (br t, J=9.0 Hz, 1H), 7.08 (d, J=37.9 Hz, 1H), 5.43 - 4.92 (m, 2H), 4.40 - 3.95 (m, 4H), 3.92 - 3.71 (m, 2H), 3.82-3.61 (m, 1H), 3.47 (s, 3H), 3.20 - 2.65 (m, 4H), 2.45 - 2.23 (m, 2H), 2.20 - 1.96 (m, 3H), 1.87 - 1.61 (m, 3H).Example 2 (Z)-1-((R)-3-((7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2- fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0156] To a stirred solution of 7-(8-chloronaphthalen-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 (6.5 mg, 0.012 mmol), (Z)-2-fluoro-3-(pyridin-2- yl)acrylic acid (4.81 mg, 0.029 mmol), and 1-methylimidazole (0.014 mL, 0.173 mmol) in acetonitrile (0.5 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (6.46 mg, 0.023 mmol). The mixture was stirred for 15 min and was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 77% 5:95 MeCN:H2O with 10 mM AA / 23% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to afford the desired product (5.3 mg, 0.007 mmol, 63% yield) as a brown solid. LC / MS (ESI) m / z: [M+H]+calc’d for C38H35ClF3N7O2714.3; found 714.3;1H NMR (500 MHz, DMSO-d6) δ 9.26 - 9.13 (m, 1H), 8.66 - 8.55 (m, 1H), 8.22 - 8.16 (m, 1H), 8.13 - 8.03 (m, 1H), 7.94 - 7.84 (m, 1H), 7.82 - 7.76 (m, 1H), 7.75 - 7.69 (m, 1H), 7.67 - 7.59 (m, 2H), 7.58 - 7.52 (m, 1H), 7.41 - 7.31 (m, 1H), 6.80 (d, J=38.6 Hz, 1H), 5.38 - 5.09 (m, 2H), 4.31-3.87 (m, 5H), 3.45 (br s, 3H), 3.13 - 2.59 (m, 5H), 2.44 - 1.93 (m, 5H), 1.84 - 1.60 (m, 3H).Example 3 (Z)-1-((R)-3-((7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2- fluoro-3-(pyridazin-3-yl)prop-2-en-1-one

[0157] To a stirred solution of 7-(8-chloronaphthalen-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 (10.7 mg, 0.019 mmol), (Z)-2-fluoro-3-(pyridazin-3- yl)acrylic acid (6.4 mg, 0.038 mmol), and 1-methylimidazole (0.023 mL, 0.285 mmol) in acetonitrile (0.5 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (10.7 mg, 0.038 mmol). The mixture was stirred for 15 min and was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 82% 5:95 MeCN:H2O with 10 mM AA / 18% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to afford the desired product (13 mg, 0.018 mmol, 92% yield) as a brown solid; LC / MS (ESI) m / z: [M+H]+calc’d for C37H34ClF3N8O2715.2; found 715.31H NMR (500 MHz, DMSO-d6) δ 9.31 - 9.24 (m, 1H), 8.97 (br d, J=6.7 Hz, 1H), 8.73 (br d, J=6.8 Hz, 1H), 8.61 (s, 1H), 8.21 (br d, J=8.2 Hz, 1H), 8.10 (br d, J=8.1 Hz, 1H), 7.74 (br t, J=7.6 Hz, 1H), 7.67 - 7.53 (m, 3H), 6.90 (br d, J=37.5 Hz, 1H), 5.58 - 5.21 (m, 2H), 4.60 - 4.19 (m, 3H), 4.14 - 4.03 (m, 1H), 4.02 - 3.93 (m, 1H), 3.91 - 3.76 (m, 1H), 3.75 - 3.38 (m, 2H), 3.12-2.95 (m, 2H), 3.10 (s, 3H), 2.45 - 1.80 (m, 8H).2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2- yl)acryloyl)piperazin-2-yl)acetonitrile

[0158] 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (25 mg, 0.043 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (22 mg, 0.13 mmol) were combined as solids and dissolved in DMF (500 μL).1-methylimidazole (20 μL, 0.26 mmol) was added followed by chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (36 mg, 0.13 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 100% 5:95 MeCN:H2O with 10 mM AA / 0% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (20.2 mg, 0.028 mmol, 64% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C41H36F3N8O2729.3; found 729.3;1H NMR (500 MHz, DMSO-d6) δ 9.10 - 8.99 (m, 1H), 8.68 - 8.61 (m, 1H), 8.03 - 7.95 (m, 1H), 7.92 - 7.85 (m, 1H), 7.85 - 7.76 (m, 1H), 7.50 - 7.44 (m, 1H), 7.42 - 7.33 (m, 2H), 7.24 - 7.14 (m, 1H), 6.63 (d, J=38.6 Hz, 1H), 5.27 (d, J=55.0 Hz, 1H), 5.08 - 4.81 (m, 1H), 4.52 - 4.32 (m, 1H), 4.27 - 3.76 (m, 6H), 3.14 - 2.98 (m, 4H), 2.86 - 2.78 (m, 1H), 2.15 - 1.95 (m, 3H), 1.87 - 1.73 (m, 3H), 1.50 - 1.38 (m, 3H).Example 5 (Z)-1-(3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1- yl)-2-fluoro-3-(pyrazin-2-yl)prop-2-en-1-one

[0159] 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-(2-methylpyrrolidin-3-yl)pyrido[4,3- d]pyrimidin-4-amine (152 mg, 0.259 mmol) and (Z)-2-fluoro-3-(pyrazin-2-yl)acrylic acid (87 mg, 0.518 mmol) were combined as solids and dissolved in MeCN (1.5 mL). 1- methylimidazole (210 μL, 2.6 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (145 mg, 0.520 mmol). The reaction mixture was stirred for 5 min and was directly purified by preparative SFC (column: ES Green Sep Diol 1.8 uM, 30 mm x 150 mm, 5 μm particles; flow rate: 90 mL / min; column temperature: 35 °C; isocratic: 80% CO2:20% MeOH with 0.1% NH4OH) to provide the desired product as a mixture of two C4 cis-diastereomers. The mixture of cis isomers was further purified by preparative SFC (column: Chiralcel OD-H, 30 mm x 250 mm, 5 μm particles; flow rate: 90.5 mL / min; column temperature: 35 °C; isocratic: 55% CO2:45% EtOH with 0.1% diethylamine) to provide the title compound (38 mg, 0.052 mmol, 20% yield).1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J=2.2 Hz, 1H), 8.97 (s, 1H), 8.77 - 8.71 (m, 1H), 8.61 (s, 1H), 8.22 (s, 2H), 7.75 - 7.65 (m, 2H), 7.62 (s, 1H), 6.94 (br d, J=35.9 Hz, 1H), 5.43 - 4.76 (m, 2H), 4.10 (s, 3H), 3.74 – 3.45 (m, 3H) 3.63 (s, 1H), 3.33 (under H2O peak, s, 3H), 3.13 - 2.84 (m, 3H), 2.19 - 1.59 (m, 8H), 1.20 – 1.14 (m, 3H).Example 6 (Z)-1-((R)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2- fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0160] 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-2-methylpiperazin-1-yl)pyrido[4,3- d]pyrimidine (5 mg, 8.73 µmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (4.4 mg, 0.026 mmol) were combined as solids and dissolved in DMF (450 μL).1-methylimidazole (4 μL, 0.05 mmol) was added followed by chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (7.4 mg, 0.03 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 70% 5:95 MeCN:H2O with 10 mM AA / 30% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (4.4 mg, 6.10 µmol, 70% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C40H36F4N7O2722.3; found 722.3; 1H NMR (500 MHz, DMSO-d6) δ 9.18 - 8.97 (m, 1H), 8.68 - 8.58 (m, 1H), 8.25 - 8.15 (m, 2H), 7.92 - 7.85 (m, 1H), 7.80 - 7.76 (m, 1H), 7.72 - 7.63 (m, 2H), 7.62 - 7.54 (m, 1H), 7.40 - 7.32 (m, 1H), 6.70 - 6.52 (m, 1H), 5.25 (d, J=54.2 Hz, 1H), 5.08 - 4.79 (m, 1H), 4.51 - 4.29 (m, 1H), 4.25 - 3.53 (m, 6H), 3.18 - 2.96 (m, 4H), 2.90 - 2.72 (m, 1H), 2.15 - 1.91 (m, 3H), 1.89 - 1.67 (m, 4H), 1.50 - 1.37 (m, 3H).Example 7 (Z)-1-(4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-diazepan-1-yl)-2-fluoro-3- (pyridin-2-yl)prop-2-en-1-one

[0161] 4-(1,4-diazepan-1-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (5 mg, 8.73 µmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (4.4 mg, 0.026 mmol) were combined as solids and dissolved in DMF (500 μL).1-methylimidazole (4 μL, 0.052 mmol) was added followed by chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (7.4 mg, 0.026 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 78% 5:95 MeCN:H2O with 10 mM AA / 22% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (4.4 mg, 6.10 µmol, 70% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C40H36F4N7O2722.3; found 722.3; 1H NMR (500 MHz, DMSO-d6) δ 9.21 - 9.02 (m, 1H), 8.58 (br d, J=3.5 Hz, 1H), 8.23 - 8.13 (m, 2H), 7.89 - 7.80 (m, 1H), 7.73 - 7.54 (m, 4H), 7.38 - 7.31 (m, 1H), 6.37 (d, J=40.9 Hz, 1H), 5.33 - 5.04 (m, 1H), 4.45 - 3.57 (m, 10H), 3.09 - 2.88 (m, 4H), 2.83 - 2.71 (m, 1H), 2.30 - 1.86 (m, 5H), 1.85 - 1.59 (m, 3H).Example 8 (Z)-1-(4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-diazepan-1-yl)-2-fluoro-3- (pyrimidin-2-yl)prop-2-en-1-one

[0162] 4-(1,4-diazepan-1-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (5 mg, 8.73 µmol) were combined as solids and dissolved in DMF (500 μL). 1- methylimidazole (4 μL, 0.052 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (7.4 mg, 0.026 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 82% 5:95 MeCN:H2O with 10 mM AA / 18% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (3.4 mg, 4.5 µmol, 51% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C39H35F4N8O2723.3; found 723.3;1H NMR (500 MHz, DMSO-d6) δ 9.19 - 9.05 (m, 1H), 8.83 (br d, J=4.7 Hz, 2H), 8.26 - 8.15 (m, 2H), 7.74 - 7.56 (m, 3H), 7.41 (t, J=4.7 Hz, 1H), 6.36 (d, J=34.9 Hz, 1H), 5.33 - 5.09 (m, 1H), 4.52 - 3.46 (m, 10H), 3.12 - 2.92 (m, 3H), 2.84 - 2.68 (m, 1H), 2.32 - 1.61 (m, 9H).Example 9 (Z)-1-((R)-3-((7-(8-ethynyl-6,7-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0163] 7-(8-ethynyl-6,7-difluoronaphthalen-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 (5 mg, 8.47 µmol) and (Z)-2-fluoro-3-(pyridin-2- yl)acrylic acid (4.2 mg, 0.025 mmol) were combined as solids and dissolved in DMF (400 μL).1-methylimidazole (4.1 μL, 0.051 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (7.3 mg, 0.025 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 71% 5:95 MeCN:H2O with 10 mM AA / 29% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (3.8 mg, 4.9 µmol, 58% yield); LC / MS (ESI) m / z: [M+H]+calc’d for C40H35F5N7O2740.3; found 740.5;1H NMR (500 MHz, DMSO-d6) δ 9.22 - 9.14 (m, 1H), 8.70 - 8.59 (m, 1H), 8.29 - 8.20 (m, 1H), 8.15 (br d, J=7.9 Hz, 1H), 7.88 (br d, J=6.7 Hz, 1H), 7.83 - 7.71 (m, 2H), 7.65 (br d, J=7.2 Hz, 1H), 7.45 - 7.33 (m, 1H), 6.80 (d, J=38.6 Hz, 1H), 5.38 - 5.05 (m, 2H), 4.32 - 3.99 (m, 4H), 3.99 - 3.42 (m, 5H), 3.12 - 2.91 (m, 4H), 2.85 - 2.71 (m, 1H), 2.44 - 2.24 (m, 2H), 2.16 - 1.89 (m, 3H), 1.85 - 1.63 (m, 3H).Example 10 (Z)-1-((R)-3-((7-(8-ethynyl-6,7-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one

[0164] 7-(8-ethynyl-6,7-difluoronaphthalen-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 (5 mg, 8.47 µmol) and (Z)-2-fluoro-3-(pyrimidin-2- yl)acrylic acid (4.2 mg, 0.025 mmol) were combined as solids and dissolved in DMF (400 μL).1-methylimidazole (4.1 μL, 0.051 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (7.3 mg, 0.025 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 76% 5:95 MeCN:H2O with 10 mM AA / 24% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (1.3 mg, 1.8 µmol, 26% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C39H34F5N8O2741.3; found 741.1;1H NMR (500 MHz, DMSO-d6) δ 9.24 - 9.12 (m, 1H), 8.90 - 8.80 (m, 2H), 8.28 - 8.19 (m, 1H), 8.19 - 8.13 (m, 1H), 7.78 - 7.69 (m, 1H), 7.67 - 7.59 (m, 1H), 7.52 - 7.28 (m, 1H), 6.78 (d, J=33.9 Hz, 1H), 5.38 - 5.05 (m, 2H), 4.32 - 3.99 (m, 4H), 3.99 - 3.42 (m, 5H), 3.12 - 2.91 (m, 4H), 2.85 - 2.71 (m, 1H), 2.44 - 2.24 (m, 2H), 2.16 - 1.89 (m, 3H), 1.85 - 1.63 (m, 3H).(Z)-1-((2S,3S)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-3-yl)prop-2-en-1-one and (Z)-1-((2R,3R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-3-yl)prop-2-en-1-one

[0165] 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(methyl(2-methylpyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol (40 mg, 0.066 mmol) were combined as solids and dissolved in DMF (660 μL). 1-methylimidazole (32 μL, 0.40 mmol) was added followed by chloro- N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (56 mg, 0.20 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; columntemperature: 25 °C; gradient: 79% 5:95 MeCN:H2O with 10 mM AA / 21% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product as a mixture of two C4 cis-diastereomers. The mixture of cis isomers was further purified by preparative SFC (column: Chiralcel OD-H, 30 mm x 250 mm, 5 μm particles; flow rate: 100 mL / min; column temperature: 50 °C; isocratic: 60% CO2:40% MeOH with 20 mM ammonia) to provide both title isomers.

[0166] Example 11 (first eluting, ): 6.4 mg, 8.4 μmol, 13% yield. LC / MS (ESI) m / z: [M+H]+calc’d for C41H38F4N7O3752.3; found 752.3;1H NMR (500 MHz, DMSO-d6) δ 9.24 (br s, 1H), 8.64 (br d, J=3.5 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.91 - 7.84 (m, 1H), 7.82 - 7.74 (m, 1H), 7.50 - 7.42 (m, 1H), 7.41 - 7.35 (m, 2H), 7.23 - 7.15 (m, 1H), 6.83 (d, J=37.9 Hz, 1H), 5.40 - 4.77 (m, 3H), 4.20 - 3.52 (m, 9H), 3.19 - 2.64 (m, 4H), 2.45 - 2.29 (m, 1H), 2.02 (br s, 3H), 1.77 (s, 3H), 1.25 - 1.05 (m, 3H).

[0167] Example 12 (second eluting, ): 5.3 mg, 6.7 μmol, 10% yield; LC / MS (ESI) m / z: [M+H]+calc’d for C41H38F4N7O3752.3; found 752.3;1H NMR (500 MHz, DMSO-d6) δ 9.26 - 9.20 (m, 1H), 8.64 (br s, 1H), 7.99 - 7.92 (m, 1H), 7.91 - 7.84 (m, 1H), 7.82 - 7.74 (m, 1H), 7.48 - 7.41 (m, 1H), 7.38 (br s, 2H), 7.22 - 7.17 (m, 1H), 6.83 (d, J=37.5 Hz, 1H), 5.41 - 4.76 (m, 3H), 4.26 - 3.53 (m, 9H), 2.88 (s, 4H), 2.43 - 2.28 (m, 1H), 2.20 - 1.84 (m, 3H), 1.72 (s, 3H), 1.25 - 1.05 (m, 3H).(Z)-1-((2S,3S)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one and (Z)-1-((2R,3R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one

[0168] 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(methyl(2-methylpyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol (40 mg, 0.066 mmol) and (Z)-2-fluoro-3-(pyridazin-2-yl)acrylic acid (34 mg, 0.20 mmol) were combined as solids and dissolved in DMF (660 μL). 1- methylimidazole (32 μL, 0.40 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (56 mg, 0.20 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 84% 5:95 MeCN:H2O with 10 mM AA / 16% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product as a mixture of two C4 cis-diastereomers. The mixture of cis isomers was further purified by preparative SFC (column: Chiralcel OD-H, 30 mm x 250 mm, 5 μm particles; flow rate: 100 mL / min; column temperature: 50 °C; isocratic: 60% CO2:40% MeOH with 20 mM ammonia) to provide both title isomers.

[0169] Example 13 (first eluting, ): This material was isolated as the bis-TFA salt.

[0170] 5.2 mg, 5.1 μmol, 7.7% yield; LC / MS (ESI) m / z: [M+H]+calc’d for C40H37F4N8O3 753.3; found 753.3;1H NMR (500 MHz, DMSO-d6) δ 9.31 (d, J=2.2 Hz, 1H), 9.23 - 9.15(m, 1H), 8.07 - 8.00 (m, 1H), 7.99 - 7.94 (m, 1H), 7.85 - 7.74 (m, 1H), 7.50 - 7.43 (m, 1H), 7.40 (br s, 1H), 7.19 (br s, 1H), 7.07 (d, J=37.5 Hz, 1H), 5.66 - 5.39 (m, 1H), 5.25 - 4.83 (m, 2H), 4.71 - 3.14 (m, 12H), 2.45 - 1.83 (m, 8H), 1.24 - 1.07 (m, 3H).

[0171] Example 14: (second eluting, ): 6.6 mg, 8.5 μmol, 13% yield; LC / MS (ESI) m / z: [M+H]+calc’d for C40H37F4N8O3753.3; found 753.3;1H NMR (500 MHz, DMSO-d6) δ 9.23 (s, 1H), 9.20 - 9.16 (m, 1H), 8.06 - 7.98 (m, 1H), 7.97 - 7.91 (m, 1H), 7.82 - 7.74 (m, 1H), 7.48 - 7.41 (m, 1H), 7.38 (br s, 1H), 7.21 - 7.16 (m, 1H), 7.07 (d, J=37.6 Hz, 1H), 5.39 - 4.74 (m, 3H), 4.30 - 3.40 (m, 9H), 3.14 - 2.57 (m, 4H), 2.45 - 2.32 (m, 1H), 2.10 (s, 3H), 1.87 - 1.65 (m, 3H), 1.24 - 1.11 (m, 3H).(Z)-1-(3-(ethyl(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2-fluoro- 3-(pyridin-2-yl)prop-2-en-1-one

[0172] N-ethyl-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-(pyrrolidin-3-yl)pyrido[4,3- d]pyrimidin-4-amine (7 mg, 0.012 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (5.98 mg, 0.036 mmol) were combined as solids and dissolved in DMF (300 μL). 1- methylimidazole (6 μL, 0.072 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (10 mg, 0.036 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 71% 5:95 MeCN:H2O with 10 mM AA / 29% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (5.3 mg, 7.0 µmol, 59% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C38H38F3N8O2695.3; found 695.3;1H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.69 - 8.62 (m, 1H), 7.95 -7.86 (m, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.36 - 7.26 (m, 2H), 7.04 (d, J=7.6 Hz, 1H), 6.66 (d, J=39.0 Hz, 1H), 5.28 (d, J=54.8 Hz, 1H), 4.99 - 4.85 (m, 1H), 4.56 - 4.41 (m, 2H), 4.16 (d, J=10.4 Hz, 1H), 4.08 (d, J=10.4 Hz, 1H), 4.24 - 4.01 (m, 1H), 3.88 - 3.70 (m, 2H), 3.19 - 3.16 (m, 1H), 3.14 - 3.01 (m, 5H), 2.87 - 2.80 (m, 1H), 2.15 - 1.97 (m, 3H), 1.88 - 1.72 (m, 4H), 0.77 (br d, J=8.3 Hz, 2H), 0.63 (br d, J=4.2 Hz, 2H).(Z)-1-(3-(ethyl(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2-fluoro- 3-(pyridazin-3-yl)prop-2-en-1-one

[0173] N-ethyl-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-(pyrrolidin-3-yl)pyrido[4,3- d]pyrimidin-4-amine (10 mg, 0.017 mmol) and (Z)-2-fluoro-3-(pyridazin -2-yl)acrylic acid (8.6 mg, 0.055 mmol) were combined as solids and dissolved in DMF (300 μL). 1- methylimidazole (8.2 μL, 0.10 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (14 mg, 0.051 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 78% 5:95 MeCN:H2O with 10 mM AA / 22% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (3.2 mg, 4.2 µmol, 24% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C42H37F4N8O2737.3; found 737.0;1H NMR (500 MHz, DMSO-d6) δ 9.21 - 9.15 (m, 1H), 9.06 (s, 1H), 8.25 - 8.16 (m, 2H), 8.08 - 7.99 (m, 1H), 7.81 - 7.73 (m, 1H), 7.72 - 7.62 (m, 2H), 7.62 - 7.54 (m, 1H), 7.11 - 6.99 (m, 1H), 5.34 - 5.15 (m, 1H), 5.13 - 5.02 (m, 1H), 4.39 - 3.77 (m, 8H), 3.11 - 2.92 (m, 4H), 2.83 - 2.71 (m, 1H), 2.45 - 2.32 (m, 2H), 2.14 - 1.90 (m, 3H), 1.80 - 1.61 (m, 3H), 1.46 - 1.35 (m, 3H).(Z)-2-fluoro-1-((R)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-5-methoxy-7-(2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one

[0174] 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5- methoxy-N-methyl-N-((R)-pyrrolidin-3-yl)-7-(2-(trifluoromethyl)phenyl)pyrido[4,3- d]pyrimidin-4-amine (7 mg, 0.012 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (6.07 mg, 0.036 mmol) were combined as solids and dissolved in DMF (300 μL). 1- methylimidazole (5.8 μL, 0.07 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (10 mg, 0.036 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 69% 5:95 MeCN:H2O with 10 mM AA / 31% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (5.3 mg, 6.9 µmol, 57% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C36H36F6N7O3728.3; found 728.3;1H NMR (500 MHz, DMSO-d6) δ 8.62 (br s, 1H), 7.95 - 7.70 (m, 5H), 7.63 (br s, 1H), 7.39 - 7.31 (m, 1H), 6.78 (d, J=37.2 Hz, 1H), 5.35 - 5.10 (m, 1H), 4.95 - 4.83 (m, 1H), 4.25 - 3.98 (m, 3H), 3.95 (s, 3H), 3.84 - 3.53 (m, 3H), 3.15 - 2.91 (m, 6H), 2.84 - 2.69 (m, 1H), 2.37 - 2.19 (m, 2H), 2.16 - 1.90 (m, 3H), 1.85 - 1.62 (m, 3H).(Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0175] 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-N-methyl-N-((R)-pyrrolidin-3- yl)pyrido[4,3-d]pyrimidin-4-amine (7 mg, 0.012 mmol) and (Z)-2-fluoro-3-(pyridin-2- yl)acrylic acid (5.82 mg, 0.035 mmol) were combined as solids and dissolved in DMF (300 μL). 1-methylimidazole (5.6 μL, 0.07 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (9.8 mg, 0.035 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 68% 5:95 MeCN:H2O with 10 mM AA / 32% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (5.4 mg, 7.1 µmol, 62% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C41H38F4N7O3752.3; found 752.1;1H NMR (500 MHz, DMSO-d6) δ 8.62 (br s, 1H), 8.25 - 8.13 (m, 2H), 7.92 - 7.83 (m, 1H), 7.81 - 7.73 (m, 1H), 7.72 - 7.65 (m, 2H), 7.58 (br t, J=9.0 Hz, 1H), 7.40 - 7.33 (m, 1H), 6.79 (d, J=37.5 Hz, 1H), 5.34 - 5.10 (m, 1H), 5.03 - 4.87 (m, 1H), 4.30 - 3.93 (m, 4H), 3.89 (br s, 3H), 3.84 - 3.67 (m, 4H), 3.58 - 3.44 (m, 2H), 3.13 - 2.88 (m, 6H), 2.86 - 2.66 (m, 1H), 2.42 - 2.19 (m, 2H), 2.15 - 1.87 (m, 3H).(Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one

[0176] 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-N-methyl-N-((R)-pyrrolidin-3- yl)pyrido[4,3-d]pyrimidin-4-amine (7 mg, 0.012 mmol) and (Z)-2-fluoro-3-(pyridazin-2- yl)acrylic acid (5.9 mg, 0.035 mmol) were combined as solids and dissolved in DMF (300 μL). 1-methylimidazole (5.6 μL, 0.07 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (9.8 mg, 0.035 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 74% 5:95 MeCN:H2O with 10 mM AA / 26% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (4.3 mg, 5.5 µmol, 47% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C40H37F4N8O3753.3; found 753.3;1H NMR (500 MHz, DMSO-d6) δ 9.18 (br s, 1H), 8.23 - 8.15 (m, 2H), 8.06 - 7.99 (m, 1H), 7.81 - 7.74 (m, 1H), 7.73 - 7.64 (m, 2H), 7.59 (br t, J=8.8 Hz, 1H), 7.05 (d, J=37.5 Hz, 1H), 5.39 - 5.11 (m, 1H), 5.06 - 4.87 (m, 1H), 4.34 - 3.96 (m, 4H), 3.90 (br s, 3H), 3.86 - 3.42 (m, 3H), 3.14 - 2.91 (m, 6H), 2.85 - 2.67 (m, 1H), 2.43 - 2.19 (m, 2H), 2.14 - 1.90 (m, 3H), 1.84 - 1.58 (m, 3H).(Z)-2-fluoro-1-((R)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-methyl-2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one

[0177] 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N- methyl-7-(3-methyl-2-(trifluoromethyl)phenyl)-N-((R)-pyrrolidin-3-yl)pyrido[4,3- d]pyrimidin-4-amine (7 mg, 0.012 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (6.2 mg, 0.037 mmol) were combined as solids and dissolved in DMF (300 μL). 1- methylimidazole (6 μL, 0.075 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (10.5 mg, 0.037 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 75% 5:95 MeCN:H2O with 10 mM AA / 25% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (4.8 mg, 6.60 µmol, 53% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C36H36F6N7O2712.3; found 712.1;1H NMR (500 MHz, DMSO-d6) δ 9.19 (br s, 1H), 8.62 (br s, 1H), 7.93 - 7.82 (m, 1H), 7.81 - 7.72 (m, 1H), 7.69 - 7.62 (m, 1H), 7.61 - 7.55 (m, 1H), 7.40 - 7.33 (m, 1H), 7.33 - 7.27 (m, 1H), 6.79 (d, J=37.8 Hz, 1H), 5.37 - 5.12 (m, 2H), 4.29 - 3.72 (m, 4H), 3.62 - 3.45 (m, 4H), 3.11 - 2.90 (m, 4H), 2.84 - 2.70 (m, 1H), 2.55 (s, 3H), 2.38 - 2.23 (m, 2H), 2.16 - 1.90 (m, 3H), 1.81 - 1.65 (m, 3H).(Z)-1-((2S,3S)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1- yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one and (Z)-1-((2R,3R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1- yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one

[0178] To a stirred solution of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-(2-methylpyrrolidin-3- yl)pyrido[4,3-d]pyrimidin-4-amine (34 mg, 0.060 mmol), (Z)-2-fluoro-3-(pyridazin-3- yl)acrylic acid (20.2 mg, 0.120 mmol), and 1-methylimidazole (0.048 mL, 0.600 mmol) in acetonitrile (1 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (34 mg, 0.120 mmol). The mixture was stirred for 15 min and was purified by by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 82% 5:95MeCN:H2O with 10 mM AA / 18% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm). Further purification by preparative SFC (column: Chiralcel OD-H, 30 mm x 250 mm, 5 μm particles; flow rate: 100 mL / min; column temperature: 40 °C; isocratic: 50% CO2:50% MeOH with 0.1% NH4OH) provided both title isomers.

[0179] Example 21: (first eluting, ): 3.0 mg, 4 μmol, 7% yield; LC / MS (ESI) m / z: [M+H]+calc’d for C40H37F3N8O2719.3; found 719.3;1H NMR (500 MHz, DMSO-d6) δ 9.32 (br d, J=3.4 Hz, 1H), 9.25 - 9.17 (m, 1H), 8.16 (br dd, J=12.4, 8.2 Hz, 2H), 8.08 - 8.00 (m, 1H), 7.80 (dt, J=8.7, 4.5 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.65 - 7.54 (m, 2H), 7.09 (d, J=37.5 Hz, 1H), 5.69-5.37 (m, 1H), 5.22 - 4.80 (m, 3H), 4.61 - 4.30 (m, 2H), 4.15 - 4.01 (m, 2H), 3.79 - 3.69 (m, 1H), 3.66 (br s, 3H), 2.75 - 2.62 (m, 3H), 2.45 - 2.29 (m, 3H), 2.21 - 1.70 (m, 5H), 1.34 - 0.82 (m, 3H)

[0180] Example 22: (second eluting, ):3.0 mg, 4 μmol, 7% yield; LC / MS (ESI) m / z: [M+H]+calc’d for C40H37F3N8O2719.3; found 719.3;1H NMR (500 MHz, DMSO-d6) δ 9.33 - 9.27 (m, 1H), 9.21 (br d, J=5.1 Hz, 1H), 8.16 (br dd, J=12.0, 8.1 Hz, 2H), 8.04 (br d, J=8.7 Hz, 1H), 7.85 - 7.77 (m, 1H), 7.76 - 7.68 (m, 2H), 7.65 - 7.51 (m, 2H), 7.12 (d, J=37.6 Hz 1H), 5.51 - 5.26 (m, 1H), 5.21 - 5.07 (m, 1H), 5.04 - 4.77 (m, 2H), 4.48 - 4.15 (m, 2H), 4.02 - 3.81 (m, 1H), 3.75 (br d, J=18.7 Hz, 1H), 3.64 (br d, J=5.0 Hz, 1H), 3.59 - 3.37 (m, 1H), 3.24 (under water peak, s, 3H), 3.07 - 2.79 (m, 1H), 2.93-2.64 (s, 2H), 2.46 – 2.36 (m, 1H), 2.33 -1.65 (m, 8 H), 1.27 - 1.06 (m, 3H).(Z)-1-((2S,3S)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1- yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one and (Z)-1-((2R,3R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1- yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one

[0181] To a stirred solution of -(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-(2- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (34 mg, 0.058 mmol), (Z)-2- fluoro-3-(pyridazin-3-yl)acrylic acid (19.50 mg, 0.116 mmol), and 1-methylimidazole (0.046 mL, 0.580 mmol) in acetonitrile (1 mL) was added chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (33 mg, 0.116 mmol). The mixture was stirred for 15 min and was purified by by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 81% 5:95 MeCN:H2O with 10 mM AA / 19% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm). Further purification by preparative SFC (column: Chiralcel OD-H, 30 mm x 250 mm, 5 μm particles; flow rate: 100 mL / min; column temperature: 40 °C; isocratic: 65% CO2:35% MeOH with 0.1% NH4OH) provided both title isomers.

[0182] Example 23: (first eluting, ): 8 mg, 10 μmol, 17% yield; LC / MS (ESI) m / z: [M+H]+calc’d for C40H36F4N8O2737.3; found 737.2;1H NMR (500 MHz, DMSO-d6) δ 9.28 (br d, J=4.0 Hz, 1H), 9.20 (br d, J=4.7 Hz, 1H), 8.28 - 8.16 (m, 2H), 8.04 (br d, J=8.8 Hz, 1H), 7.80 (br dd, J=8.6, 4.8 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.61 (t, J=9.0 Hz, 1H), 7.09 (d, J=37.4Hz,1H), 5.49 - 5.23 (m, 1H), 5.22 - 5.04 (m, 1H), 5.01 - 4.81 (m, 1H), 4.41-4.17 (m, 2H), 4.00 - 3.72 (m, 2H), 3.68-3.63 (m, 2H), 3.45 (s, 3H), 3.13 - 2.59 (m, 3H), 2.43 - 1.35 (m, 8H), 1.26 - 1.07 (m, 3H).

[0183] Example 24: (second eluting, ): 3 mg, 4 μmol, 8% yield; LC / MS (ESI) m / z: [M+H]+calc’d for C40H36F4N8O2737.3; found 737.1;1H NMR (500 MHz, DMSO-d6) δ 9.27 (br d, J=4.5 Hz, 1H), 9.20 (br d, J=4.1 Hz, 1H), 8.27 - 8.17 (m, 2H), 8.08 - 7.99 (m, 1H), 7.82 - 7.75 (m, 1H), 7.74 - 7.63 (m, 2H), 7.61 (t, J=9.0 Hz, 1H), 7.09 (d, J=37.6Hz , 1H), 5.47 - 5.20 (m, 1H), 5.19-5.02 (m, 1H), 5.01 - 4.76 (m, 1H), 4.31 - 4.17 (m, 1H), 4.09 (br d, J=15.5 Hz, 2H), 3.85 - 3.69 (m, 2H), 3.62 (s, 3H), 3.17 (s, 1H), 3.13 - 2.65 (m, 3H), 2.45 - 1.57 (m, 8H), 1.30 - 1.13 (m, 3H).(Z)-1-((2R,3R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1- yl)-2-fluoro-3-(pyrazin-2-yl)prop-2-en-1-one

[0184] To a stirred solution of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-(2-methylpyrrolidin-3- yl)pyrido[4,3-d]pyrimidin-4-amine (34.1 mg, 0.060 mmol), (Z)-2-fluoro-3-(pyrazin-2- yl)acrylic acid (20.18 mg, 0.120 mmol), and 1-methylimidazole (0.048 mL, 0.600 mmol) in acetonitrile (1 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (34 mg, 0.120 mmol). The mixture was stirred for 15 min and was purified by by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 77% 5:95 MeCN:H2O with 10 mM AA / 23% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm). Further purification by preparative SFC (column: Chiralpak IH, 21 mm x 250 mm, 5 μm particles; flow rate: 75 mL / min; columntemperature: 40 °C; isocratic: 70% CO2:30% MeOH with 0.1% NH4OH) provided the desired product (first eluting, 7.5 mg, 0.01 mmol, 17% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C40H37F3N8O2719.3; found 719.2;1H NMR (500 MHz, DMSO-d6) δ 9.26 (br d, J=3.8 Hz, 1H), 8.96 (s, 1H), 8.73 (br s, 1H), 8.61 (s, 1H), 8.15 (dd, J=11.4, 8.2 Hz, 2H), 7.80 - 7.67 (m, 2H), 7.66 - 7.50 (m, 2H), 6.93 (d, J=37.5 Hz 1H), 5.41 - 4.75 (m, 4H), 4.27 - 4.16 (m, 1H), 4.13 - 3.87 (m, 3H), 3.78-3.71 (m, 1H), 3.17 (s, 3H), 3.12 - 2.76 (m, 2H), 2.72 - 2.59 (m, 1H), 2.47 - 2.31 (m, 1H), 2.23 - 1.57 (m, 7H), 1.15 - 1.09 (m, 3H).(Z)-1-((2S,3S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one and (Z)-1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0185] To a stirred solution of 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-(2- methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (34 mg, 0.058 mmol), (Z)-2- fluoro-3-(pyridin-2-yl)acrylic acid (19.40 mg, 0.116 mmol), and 1-methylimidazole (0.046 mL, 0.580 mmol) in acetonitrile (1 mL) was added chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (33 mg, 0.116 mmol). The mixture was stirred for 15 min and was purified by by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 72% 5:95 MeCN:H2O with 10 mM AA / 28% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm). Further purification by preparative SFC (column: Chiralpak IH, 21 mm x 250 mm, 5 μm particles; flow rate: 75 mL / min; column temperature: 40 °C; isocratic: 80% CO2:20% MeOH with 0.1% NH4OH) provided both title isomers.

[0186] Example 26: (first eluting, ): 6 mg, 8 μmol, 14% yield; LC / MS (ESI) m / z: [M+H]+calc’d for C41H37F4N7O2736.2; found 736.3;1H NMR (500 MHz, DMSO-d6) δ 9.33 - 9.21 (m, 1H), 8.65 (br d, J=3.8 Hz, 1H), 8.28 - 8.14 (m, 2H), 7.94 - 7.87 (m, 1H), 7.83 - 7.75 (m, 1H), 7.73 - 7.65 (m, 2H), 7.61 (br t, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.83 (d, J=38.2 Hz 1H) 5.48 - 4.70 (m, 3H), 4.34 - 3.67 (m, 4H), 3.65 - 3.40 (m, 2H), 3.18 (s, 3H), 3.09 - 2.58 (m, 3H), 2.24 - 1.35 (m, 8H), 1.16 - 1.09 (m, 3H).

[0187] Example 27: (second eluting, ): 7 mg, 9 μmol, 15% yield; LC / MS (ESI) m / z: [M+H]+calc’d for C41H37F4N7O2736.2; found 736.2;1H NMR (500 MHz, DMSO-d6) δ 9.25 (br d, J=3.9 Hz, 1H), 8.64 (br d, J=4.8 Hz, 1H), 8.27 - 8.12 (m, 2H), 7.94 - 7.83 (m, 1H), 7.77 (br d, J=8.3 Hz, 1H), 7.73 - 7.63 (m, 2H), 7.60 (br t, J=9.0 Hz, 1H), 7.38 (br t, J=6.4 Hz, 1H), 6.82 (d, J=38.1 Hz 1H), 5.44 - 4.73 (m, 3H), 4.25 - 3.83 (m, 4H), 3.79 - 3.25 (m, 2H), 3.17 (s, 3H), 3.11 - 2.62 (m, 3H), 2.19 - 1.26 (m, 8H), 1.16 - 1.07 (m, 3H).(Z)-1-(4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridazin- 2-yl)prop-2-en-1-one

[0188] 7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine (12 mg, 0.022 mmol) and (Z)-2-fluoro-3-(pyridazin-3-yl)acrylic acid (3.6 mg, 0.022 mmol) were combined as solids and dissolved in DMF (400 μL).1-methylimidazole (17 μL, 0.22 mmol) was added followed by chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (6.1 mg, 0.022 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 100% 5:95 MeCN:H2O with 0.1% TFA / 0% 95:5 MeCN:H2O with 0.1% TFA → 100% 95:5 MeCN:H2O with 0.1% TFA; λ = 220 nm) to provide the desired product as its bis TFA salt (4.4 mg, 5.0 μmol, 23% yield).LC / MS (ESI) m / z: [M+H]+calc’d for C34H32ClF3N10O2705.2; found 705.2.(Z)-1-((R)-3-((7-(2-cyclopropyl-3-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2- fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0189] 7-(2-cyclopropyl-3-fluorophenyl)-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 (7 mg, 0.013 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (6.5 mg, 0.039 mmol) were combined as solids and dissolved in DMF (400 μL).1-methylimidazole (6 μL, 0.078 mmol) was added followed by chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (10.9 mg, 0.039 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 74% 5:95 MeCN:H2O with 10 mM AA / 26% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (5.3 mg, 7.7 µmol, 59% yield); LC / MS (ESI) m / z: [M+H]+calc’d for C37H38F4N7O2688.3; found 688.2; 1H NMR (500 MHz, DMSO-d6) δ 9.23 (br s, 1H), 8.65 - 8.58 (m, 1H), 7.94 - 7.83 (m, 1H), 7.81 - 7.73 (m, 1H), 7.43 - 7.33 (m, 2H), 7.31 - 7.20 (m, 2H), 6.79 (d, J=37.5 Hz, 1H), 5.36 - 5.10 (m, 2H), 4.28 - 3.73 (m, 4H), 3.62 - 3.42 (m, 5H), 3.12 - 2.92 (m, 3H), 2.84 - 2.70 (m, 1H), 2.42 - 2.25 (m, 2H), 2.16 - 1.89 (m, 3H), 1.77 - 1.63 (m, 3H), 0.83 (br t, J=6.1 Hz, 1H), 0.69 - 0.56 (m, 2H), 0.28 (br s, 2H).(Z)-1-((R)-3-((7-(2-cyclopropyl-3-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2- fluoro-3-(pyridazin-2-yl)prop-2-en-1-one

[0190] 7-(2-cyclopropyl-3-fluorophenyl)-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 (7 mg, 0.013 mmol) and (Z)-2-fluoro-3-(pyridazin-2-yl)acrylic acid (6.6 mg, 0.039 mmol) were combined as solids and dissolved in DMF (400 μL).1-methylimidazole (6 μL, 0.078 mmol) was added followed by chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (10.9 mg, 0.039 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 74% 5:95 MeCN:H2O with 10 mM AA / 26% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (5.3 mg, 7.7 µmol, 59% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C36H37F4N8O2689.3; found 689.2; 1H NMR (500 MHz, DMSO-d6) δ 9.22 (br s, 1H), 9.19 - 9.13 (m, 1H), 8.07 - 7.98 (m, 1H), 7.80 - 7.72 (m, 1H), 7.42 - 7.35 (m, 1H), 7.23 (br s, 2H), 7.04 (d, J=37.2 Hz, 1H), 5.38 - 5.11 (m, 2H), 4.31 - 3.76 (m, 4H), 3.66 - 3.43 (m, 5H), 3.14 - 2.91 (m, 3H), 2.84 - 2.68 (m, 1H), 2.42 - 2.22 (m, 2H), 2.16 - 1.89 (m, 3H), 1.78 - 1.63 (m, 3H), 0.86 - 0.78 (m, 1H), 0.61 (br s, 2H), 0.27 (br s, 2H).(Z)-1-((R)-3-((7-(2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3- (pyridin-2-yl)prop-2-en-1-one

[0191] 7-(2-cyclopropylphenyl)-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 (7 mg, 0.013 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (6.7 mg, 0.040 mmol) were combined as solids and dissolved in DMF (400 μL).1-methylimidazole (6 μL, 0.081 mmol) was added followed by chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (11.3 mg, 0.040 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 79% 5:95 MeCN:H2O with 10 mM AA / 21% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (7.3 mg, 10.9 µmol, 81% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C37H39F3N7O2670.3; found 670.3; 1H NMR (500 MHz, DMSO-d6) δ 9.26 (br s, 1H), 8.67 - 8.58 (m, 1H), 7.92 - 7.82 (m, 1H), 7.81 - 7.73 (m, 1H), 7.42 - 7.25 (m, 4H), 7.03 (br d, J=7.9 Hz, 1H), 6.80 (d, J=38.0 Hz, 1H), 5.42 - 5.16 (m, 2H), 4.32 - 3.71 (m, 5H), 3.66 - 3.38 (m, 4H), 3.38 - 3.00 (m, 2H), 2.96 - 2.73 (m, 1H), 2.43 - 2.22 (m, 3H), 2.21 - 1.95 (m, 3H), 1.89 - 1.75 (m, 4H), 0.80 - 0.73 (m, 2H), 0.60 (br s, 2H).(Z)-1-((R)-3-((7-(2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3- (pyridazin-2-yl)prop-2-en-1-one

[0192] 7-(2-cyclopropylphenyl)-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 (7 mg, 0.013 mmol) and (Z)-2-fluoro-3-(pyridazin-2-yl)acrylic acid (6.8 mg, 0.040 mmol) were combined as solids and dissolved in DMF (400 μL).1-methylimidazole (6 μL, 0.081 mmol) was added followed by chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (11.3 mg, 0.040 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 80% 5:95 MeCN:H2O with 10 mM AA / 20% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (6.6 mg, 9.8 µmol, 73% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C36H38F3N8O2671.3; found 671.2; 1H NMR (500 MHz, DMSO-d6) δ 9.28 - 9.24 (m, 1H), 9.21 - 9.16 (m, 1H), 8.09 - 7.97 (m, 1H), 7.81 - 7.73 (m, 1H), 7.42 - 7.36 (m, 1H), 7.35 - 7.24 (m, 2H), 7.10 - 7.00 (m, 1H), 7.05 (d, J=37.2 Hz, 1H), 5.37 - 5.16 (m, 2H), 4.33 - 3.76 (m, 5H), 3.68 - 3.28 (m, 4H), 3.22 - 2.97 (m, 2H), 2.88 - 2.73 (m, 1H), 2.42 - 2.22 (m, 3H), 2.20 - 1.94 (m, 3H), 1.90 - 1.75 (m, 4H), 0.80 - 0.73 (m, 2H), 0.60 (br s, 2H).(Z)-2-fluoro-1-((R)-3-((8-fluoro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one

[0193] 8-fluoro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-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 (7 mg, 0.012 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (6.2 mg, 0.037 mmol) were combined as solids and dissolved in DMF (400 μL). 1- methylimidazole (6 μL, 0.074 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (10.4 mg, 0.037 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 73% 5:95 MeCN:H2O with 10 mM AA / 27% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (5.5 mg, 7.67 µmol, 62% yield); LC / MS (ESI) m / z: [M+H]+calc’d for C35H33F7N7O2716.3; found 716.2;1H NMR (500 MHz, DMSO-d6) δ 9.22 (br s, 1H), 8.65 - 8.59 (m, 1H), 7.91 - 7.83 (m, 2H), 7.81 - 7.74 (m, 1H), 7.70 - 7.64 (m, 1H), 7.45 - 7.33 (m, 2H), 6.79 (d, J=37.8 Hz, 1H), 5.40 - 5.17 (m, 2H), 4.00 (br d, J=4.1 Hz, 5H), 3.66 - 3.39 (m, 4H), 3.16 (br d, J=4.3 Hz, 3H), 2.95 - 2.78 (m, 1H), 2.40 - 2.23 (m, 2H), 2.20 - 1.92 (m, 3H), 1.90 - 1.63 (m, 3H).(Z)-2-fluoro-1-((R)-3-((8-fluoro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridazin-2-yl)prop-2-en-1-one

[0194] 8-fluoro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-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 (7 mg, 0.012 mmol) and (Z)-2-fluoro-3-(pyridazin-2-yl)acrylic acid (6.2 mg, 0.037 mmol) were combined as solids and dissolved in DMF (400 μL). 1- methylimidazole (6 μL, 0.074 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (10.4 mg, 0.037 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 80% 5:95 MeCN:H2O with 10 mM AA / 20% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (5.3 mg, 7.4 µmol, 60% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C34H32F7N8O2717.3; found 717.2;1H NMR (500 MHz, DMSO-d6) δ 9.25 - 9.20 (m, 1H), 9.20 - 9.15 (m, 1H), 8.03 (br dd, J=11.8, 9.2 Hz, 1H), 7.88 (br d, J=6.1 Hz, 1H), 7.77 (br d, J=5.1 Hz, 1H), 7.71 - 7.63 (m, 1H), 7.46 - 7.38 (m, 1H), 7.04 (d, J=37.0 Hz, 1H), 5.36 - 5.14 (m, 2H), 4.30 - 3.75 (m, 5H), 3.67 - 3.29 (m, 4H), 3.12 - 2.92 (m, 3H), 2.75 (br s, 1H), 2.27 (br d, J=7.6 Hz, 2H), 2.16 - 1.89 (m, 3H), 1.87 - 1.68 (m, 3H).(Z)-1-((R)-3-((7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2- fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0195] 7-(3-chloro-2-(trifluoromethyl)phenyl)-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 (7 mg, 0.012 mmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (6.0 mg, 0.036 mmol) were combined as solids and dissolved in DMF (400 μL). 1- methylimidazole (6 μL, 0.072 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (10.1 mg, 0.036 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 70% 5:95 MeCN:H2O with 10 mM AA / 30% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (2.9 mg, 4.0 µmol, 33% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C35H33ClF6N7O2732.2; found 732.2;1H NMR (500 MHz, DMSO-d6) δ 9.21 (br s, 1H), 8.62 (br s, 1H), 7.93 - 7.72 (m, 4H), 7.51 (br d, J=7.1 Hz, 1H), 7.40 - 7.31 (m, 1H), 6.79 (d, J=37.8 Hz, 1H), 5.34 - 5.12 (m, 2H), 4.28 - 3.73 (m, 4H), 3.66 - 3.29 (m, 5H), 3.13 - 2.91 (m, 3H), 2.85 - 2.67 (m, 1H), 2.41 - 2.25 (m, 2H), 2.15 - 1.89 (m, 3H), 1.86 - 1.69 (m, 3H).(Z)-1-((R)-3-((7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2- fluoro-3-(pyridazin-2-yl)prop-2-en-1-one

[0196] 7-(3-chloro-2-(trifluoromethyl)phenyl)-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 (7 mg, 0.012 mmol) and (Z)-2-fluoro-3-(pyridazin-2-yl)acrylic acid (6.1 mg, 0.036 mmol) were combined as solids and dissolved in DMF (400 μL). 1- methylimidazole (6 μL, 0.072 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (10.1 mg, 0.036 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 78% 5:95 MeCN:H2O with 10 mM AA / 22% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (3.3 mg, 4.3 µmol, 36% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C34H32ClF6N8O2 733.2; found 733.2;1H NMR (500 MHz, DMSO-d6) δ 9.24 - 9.20 (m, 1H), 9.20 - 9.15 (m, 1H), 8.08 - 7.98 (m, 1H), 7.94 - 7.87 (m, 1H), 7.85 - 7.71 (m, 2H), 7.58 - 7.47 (m, 1H), 7.04 (d, J=37.6 Hz, 1H), 5.36 - 5.13 (m, 2H), 4.30 - 3.76 (m, 5H), 3.67 - 3.29 (m, 4H), 3.11 - 2.93 (m, 3H), 2.86 - 2.71 (m, 1H), 2.28 (br s, 2H), 2.15 - 1.91 (m, 3H), 1.86 - 1.67 (m, 3H).2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2- yl)acryloyl)piperazin-2-yl)acetonitrile

[0197] 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile (15 mg, 0.025 mmol) and (Z)-2-fluoro-3-(pyridin-2- yl)acrylic acid (4.2 mg, 0.025 mmol) were combined as solids and dissolved in DMF (400 μL). 1-methylimidazole (20 μL, 0.25 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (7.1 mg, 0.025 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 83% 5:95 MeCN:H2O with 10 mM AA / 17% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (4.3 mg, 5.7 µmol, 22% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C37H35ClF3N10O2 743.3; found 743.2;1H NMR (500 MHz, DMSO-d6) δ 13.34 (br s, 1H), 9.29 - 9.20 (m, 1H), 8.68 - 8.59 (m, 1H), 7.94 - 7.84 (m, 1H), 7.83 - 7.75 (m, 1H), 7.72 - 7.64 (m, 2H), 7.42 - 7.33 (m, 1H), 6.64 (d, J=38.4 Hz, 1H), 5.26 (d, J=53.6 Hz, 1H), 4.99 - 4.79 (m, 1H), 4.66 - 4.42 (m, 2H), 4.23 - 4.05 (m, 2H), 4.04 - 3.85 (m, 1H), 3.35 - 2.74 (m, 6H), 2.55 - 2.51 (m, 3H), 2.30 - 2.23 (m, 1H), 2.18 - 1.95 (m, 4H), 1.91 - 1.71 (m, 4H).2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridazin-2- yl)acryloyl)piperazin-2-yl)acetonitrile

[0198] 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile (15 mg, 0.025 mmol) and (Z)-2-fluoro-3-(pyridazin-2- yl)acrylic acid (4.3 mg, 0.025 mmol) were combined as solids and dissolved in DMF (400 μL). 1-methylimidazole (20 μL, 0.25 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (7.1 mg, 0.025 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 88% 5:95 MeCN:H2O with 10 mM AA / 12% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (2.8 mg, 3.7 µmol, 14% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C36H34ClF3N11O2 744.3; found 744.2;1H NMR (500 MHz, DMSO-d6) δ 13.33 (br s, 1H), 9.32 - 9.23 (m, 1H), 9.22 - 9.11 (m, 1H), 8.10 - 7.99 (m, 1H), 7.83 - 7.76 (m, 1H), 7.72 - 7.61 (m, 2H), 6.91 (d, J=38.1 Hz, 1H), 5.27 (d, J=53.6 Hz, 1H), 5.03 - 4.80 (m, 1H), 4.65 - 4.39 (m, 2H), 4.23 - 3.88 (m, 3H), 3.41 - 2.75 (m, 6H), 2.53 (s, 3H), 2.32 - 2.22 (m, 1H), 2.18 - 1.93 (m, 4H), 1.90 - 1.71 (m, 4H).2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyrazin-2- yl)acryloyl)piperazin-2-yl)acetonitrile

[0199] 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile (15 mg, 0.025 mmol) and (Z)-2-fluoro-3-(pyrazin-2- yl)acrylic acid (4.3 mg, 0.025 mmol) were combined as solids and dissolved in DMF (400 μL). 1-methylimidazole (20 μL, 0.25 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (7.1 mg, 0.025 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 88% 5:95 MeCN:H2O with 10 mM AA / 12% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (3.2 mg, 4.3 µmol, 16% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C36H34ClF3N11O2744.3; found 744.1;1H NMR (500 MHz, DMSO-d6) δ 13.37 (br s, 1H), 9.29 - 9.20 (m, 1H), 8.98 - 8.93 (m, 1H), 8.75 - 8.69 (m, 1H), 8.63 - 8.56 (m, 1H), 7.71 - 7.63 (m, 2H), 6.72 (d, J=39.3 Hz, 1H), 5.28 (d, J=54.2 Hz, 1H), 5.00 - 4.83 (m, 1H), 4.68 - 4.42 (m, 2H), 4.29 - 3.80 (m, 3H), 3.38 - 2.71 (m, 6H), 2.52 (s, 3H), 2.29 - 2.22 (m, 1H), 2.19 - 1.96 (m, 4H), 1.88 - 1.70 (m, 4H).2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2- yl)acryloyl)piperazin-2-yl)acetonitrile

[0200] 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile (15 mg, 0.025 mmol) and (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (4.4 mg, 0.025 mmol) were combined as solids and dissolved in DMF (400 μL). 1- methylimidazole (20 μL, 0.25 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (7.1 mg, 0.025 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 83% 5:95 MeCN:H2O with 10 mM AA / 17% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (2.5 mg, 3.3 µmol, 12% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C35H33ClF3N10O2S 749.2; found 749.1;1H NMR (500 MHz, DMSO-d6) δ 13.33 (br s, 1H), 9.30 - 9.17 (m, 1H), 8.04 - 7.92 (m, 2H), 7.73 - 7.63 (m, 2H), 7.09 (d, J=37.5 Hz, 1H), 5.26 (d, J=54.5 Hz, 1H), 5.02 - 4.75 (m, 1H), 4.67 - 4.43 (m, 2H), 4.27 - 3.80 (m, 3H), 3.39 - 2.69 (m, 6H), 2.52 (s, 3H), 2.33 - 2.22 (m, 1H), 2.14 - 1.62 (m, 8H).(Z)-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyrimidin-4-yl)prop- 2-en-1-one

[0201] To a stirred solution of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3- d]pyrimidine (8 mg, 0.015 mmol), (Z)-2-fluoro-3-(pyrimidin-4-yl)acrylic acid (5 mg, 0.030 mmol), and 1-methylimidazole (0.018 mL, 0.222 mmol) in acetonitrile (0.5 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (8 mg, 0.030 mmol). The mixture was stirred for 15 min and was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 81% 5:95 MeCN:H2O with 10 mM AA / 19% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (4.4 mg, 0.006 mmol, 42% yield) as a brown solid. LC / MS (ESI) m / z: [M+H]+calc’d for C38H33F3N8O2691.3; found 691.2;1H NMR (500 MHz, DMSO-d6) δ 9.27 - 9.19 (m, 1H), 9.13 - 9.04 (m, 1H), 8.88 (d, J=5.3 Hz, 1H), 8.20 - 8.06 (m, 2H), 7.80 (dd, J=5.3, 1.5 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.63 - 7.46 (m, 2H), 6.59 (d, J=37.5 Hz, 1H), 5.81 - 5.48 (m, 1H), 5.46 - 5.16 (m, 2H), 4.27 - 3.73 (m, 6H), 3.74 - 3.73 (m, 1H), 3.65 (s, 1H), 3.62 (br d, J=5.8 Hz, 1H), 3.41 - 3.30 (m, 1H), 3.21 - 2.96 (m, 2H), 2.88 - 2.75 (m, 1H), 2.17 - 1.64 (m, 6H).(Z)-N-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)-2-fluoro-3- (pyridin-2-yl)acrylamide

[0202] To a stirred solution of (S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepan-6-amine (6 mg, 10.4 mmol), (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (3.5 mg, 0.021 mmol), and 1-methylimidazole (0.012 mL, 0.155 mmol) in acetonitrile (0.5 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (6 mg, 0.021 mmol). The mixture was stirred for 15 min and was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 85% 5:95 MeCN:H2O with 10 mM AA / 15% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (3.6 mg, 0.005 mmol, 48% yield) as a brown solid.

[0203] LC / MS (ESI) m / z: [M+H]+calc’d for C40H36F3N7O3720.3; found 720.3;1H NMR (500 MHz, DMSO-d6) δ 9.25 - 9.09 (m, 1H), 8.93 - 8.78 (m, 1H), 8.73 - 8.72 (m, 1H), 8.71 - 8.61 (m, 1H), 8.20 - 8.09 (m, 1H), 7.95 - 7.84 (m, 1H), 7.80 - 7.66 (m, 2H), 7.65 - 7.50 (m, 1H), 7.43 - 7.32 (m, 1H), 7.26 - 7.18 (m, 1H), 6.97 - 6.77 (d, J=36.6 Hz, 1H), 5.56 - 5.08 (m, 2H), 4.62 - 4.40 (m, 1H), 4.36 - 3.45 (m, 9H), 3.30 - 2.62 (m, 5H), 2.22 - 1.32 (m, 6H).(Z)-N-((R)-1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)-2-fluoro-3-(pyridin-2- yl)acrylamide

[0204] (R)-1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-amine (5 mg, 8.79 µmol) and (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (4.4 mg, 0.026 mmol) were combined as solids and dissolved in DMF (400 μL).1-methylimidazole (4 μL, 0.053 mmol) was added followed by chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (7.4 mg, 0.026 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 76% 5:95 MeCN:H2O with 10 mM AA / 24% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (3.6 mg, 5.0 µmol, 56% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C41H39F3N7O2718.3; found 718.2; 1H NMR (500 MHz, DMSO-d6) δ 9.22 - 9.10 (m, 1H), 8.86 (br s, 1H), 8.64 (br d, J=1.9 Hz, 1H), 8.18 - 8.08 (m, 2H), 7.93 - 7.84 (m, 1H), 7.81 - 7.73 (m, 1H), 7.73 - 7.64 (m, 2H), 7.63 - 7.51 (m, 2H), 7.42 - 7.33 (m, 1H), 6.90 (d, J=37.5 Hz, 1H), 5.33 - 5.08 (m, 1H), 4.06 (br s, 6H), 3.83 - 3.39 (m, 2H), 2.99 (br d, J=13.5 Hz, 3H), 2.80 - 2.68 (m, 1H), 2.16 - 1.85 (m, 7H), 1.79 - 1.38 (m, 5H).(Z)-N-((R)-1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)-2-fluoro-3-(pyridazin-2- yl)acrylamide

[0205] R)-1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-amine (5 mg, 8.79 µmol) and (Z)-2-fluoro-3-(pyridazin-2-yl)acrylic acid (4.4 mg, 0.026 mmol) were combined as solids and dissolved in DMF (400 μL).1-methylimidazole (4 μL, 0.053 mmol) was added followed by chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (7.4 mg, 0.026 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 80% 5:95 MeCN:H2O with 10 mM AA / 20% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (3.7 mg, 5.1 µmol, 57% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C40H38F3N8O2719.3; found 719.3; 1H NMR (500 MHz, DMSO-d6) δ 9.26 - 9.10 (m, 2H), 9.04 - 8.95 (m, 1H), 8.20 - 8.09 (m, 2H), 8.07 - 7.98 (m, 1H), 7.84 - 7.75 (m, 1H), 7.74 - 7.63 (m, 2H), 7.63 - 7.48 (m, 2H), 7.15 (d, J=36.9 Hz, 1H), 5.37 - 5.06 (m, 1H), 4.05 (s, 6H), 3.85 - 3.68 (m, 1H), 3.12 - 2.87 (m, 3H), 2.81 - 2.64 (m, 1H), 2.19 - 1.87 (m, 7H), 1.83 - 1.56 (m, 5H), 1.55 - 1.38 (m, 1H).(Z)-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2- fluoro-3-(pyridin-2-yl)prop-2-en-1-one

[0206] To a stirred solution of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(octahydro-4H-pyrrolo[3,2- b]pyridin-4-yl)pyrido[4,3-d]pyrimidine (3.4 mg, 5.9 mmol), (Z)-2-fluoro-3-(pyridin-2- yl)acrylic acid (2 mg, 0.012 mmol), and 1-methylimidazole (7 mL, 0.088 mmol) in acetonitrile (0.3 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (3 mg, 0.012 mmol). The mixture was stirred for 15 min and was purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 75% 5:95 MeCN:H2O with 10 mM AA / 25% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (3 mg, 0.004 mmol, 70% yield) as a brown solid. LC / MS (ESI) m / z: [M+H]+calc’d for C42H38F3N7O2730.3; found 730.2;1H NMR (500 MHz, DMSO-d6) δ 9.10 - 8.96 (m, 1H), 8.64 (s, 1H), 8.19 - 8.09 (m, 2H), 7.92 - 7.84 (m, 1H), 7.80 - 7.68 (m, 3H), 7.64 - 7.52 (m, 2H), 7.37 (s, 1H), 6.82 (d, J=37.7 Hz, 1H), 5.39 - 4.98 (m, 2H), 4.52 - 4.24 (m, 2H), 4.22 - 3.86 (m, 3H), 3.77 - 3.47 (m, 2H), 3.16 - 2.97 (m, 2H), 2.78 (br d, J=5.0 Hz, 1H), 2.67 - 2.58 (m, 1H), 2.43 - 2.18 (m, 3H), 2.18 - 1.95 (m, 3H), 1.88 - 1.60 (m, 6H).2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2- yl)acryloyl)piperazin-2-yl)acetonitrile

[0207] 2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile (10 mg, 0.017 mmol) and (Z)-2-fluoro-3-(pyridin-2- yl)acrylic acid (8.4 mg, 0.050 mmol) were combined as solids and dissolved in DMF (400 μL). 1-methylimidazole (8 μL, 0.1 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (14 mg, 0.050 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 79% 5:95 MeCN:H2O with 10 mM AA / 21% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (10.4 mg, 0.014 mmol, 83% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C41H35F4N8O2747.3; found 747.1;1H NMR (500 MHz, DMSO-d6) δ 9.18 - 9.05 (m, 1H), 8.64 (br d, J=3.7 Hz, 1H), 8.26 - 8.14 (m, 2H), 7.93 - 7.84 (m, 1H), 7.82 - 7.74 (m, 1H), 7.74 - 7.63 (m, 2H), 7.62 - 7.53 (m, 1H), 7.43 - 7.29 (m, 1H), 6.64 (d, J=37.9 Hz, 1H), 5.27 (d, J=54.0 Hz, 1H), 5.02 - 4.79 (m, 1H), 4.61 - 4.31 (m, 2H), 4.24 - 4.02 (m, 2H), 4.00 - 3.90 (m, 1H), 3.89 - 3.52 (m, 5H), 3.19 - 2.94 (m, 4H), 2.87 - 2.74 (m, 1H), 2.19 - 1.94 (m, 3H), 1.87 - 1.68 (m, 3H).2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2- yl)acryloyl)piperazin-2-yl)acetonitrile

[0208] 2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile (10 mg, 0.017 mmol) and (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (8.7 mg, 0.050 mmol) were combined as solids and dissolved in DMF (400 μL). 1- methylimidazole (8 μL, 0.1 mmol) was added followed by chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate (14 mg, 0.050 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 78% 5:95 MeCN:H2O with 10 mM AA / 22% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (12.1 mg, 0.016 mmol, 94% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C39H33F4N8O2S 753.2; found 753.2;1H NMR (500 MHz, DMSO-d6) δ 9.18 - 9.06 (m, 1H), 8.26 - 8.16 (m, 2H), 8.04 - 7.96 (m, 2H), 7.73 - 7.63 (m, 2H), 7.62 - 7.55 (m, 1H), 7.09 (d, J=37.5 Hz, 1H), 5.27 (d, J=54.1 Hz, 1H), 4.98 - 4.80 (m, 1H), 4.58 - 4.34 (m, 2H), 4.27 - 3.40 (m, 9H), 3.17 - 2.96 (m, 4H), 2.87 - 2.78 (m, 1H), 2.18 - 1.93 (m, 3H), 1.86 - 1.73 (m, 3H).2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridazin-2- yl)acryloyl)piperazin-2-yl)acetonitrile

[0209] 2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile (10 mg, 0.017 mmol) were combined as solids and dissolved in DMF (400 μL). 1-methylimidazole (8 μL, 0.1 mmol) was added followed by chloro- N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (14 mg, 0.050 mmol). The reaction mixture was stirred for 5 min and was directly purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C; gradient: 83% 5:95 MeCN:H2O with 10 mM AA / 17% 95:5 MeCN:H2O with 10 mM AA → 100% 95:5 MeCN:H2O with 10 mM AA; λ = 220 nm) to provide the desired product (8.2 mg, 0.011 mmol, 64% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C40H34F4N9O2748.3; found 748.2;1H NMR (500 MHz, DMSO-d6) δ 9.23 - 9.17 (m, 1H), 9.16 - 9.09 (m, 1H), 8.25 - 8.17 (m, 2H), 8.05 (br d, J=8.2 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.73 - 7.64 (m, 2H), 7.59 (td, J=9.0, 2.7 Hz, 1H), 6.91 (d, J=38.5 Hz, 1H), 5.27 (d, J=54.6 Hz, 1H), 5.01 - 4.86 (m, 1H), 4.57 - 4.34 (m, 2H), 4.28 - 3.41 (m, 8H), 3.20 - 2.97 (m, 4H), 2.86 - 2.76 (m, 1H), 2.16 - 1.96 (m, 3H), 1.87 - 1.72 (m, 3H). Preparation of Intermediates: LCMS-Method A:

[0210] Linear gradient of 20% to 98% solvent B over 1.5 minutes with 0.5-minute hold at 98% B and followed by 0.1-minute gradient to 20% B and a 0.5-minute hold at 20% B.

[0211] Solvent A :5mM Ammonium formate pH 3.3: ACN (98:02)

[0212] Solvent B: ACN: Buffer (98:02)

[0213] Flow Rate: 1.0 ml / min

[0214] Column: Aquity Uplc BEH C18 (50 x 3.0) mm, 1.7μm.

[0215] Ultraviolet ("UV") visualization at 220 nanometers ("nm"). LCMS-Method B:

[0216] Linear gradient of 20% to 98% solvent B over 1.5 minutes with 0.5-minute hold at 98% B and followed by 0.1-minute gradient to 20% B and a 0.5-minute hold at 20% B.

[0217] Solvent A: 0.1% TFA in H2O

[0218] Solvent B: 0.1% TFA in ACN

[0219] Flow Rate: 0.7 ml / min

[0220] Column: Aquity BEH C18 (50 x 3.0) mm, 1.7μm.

[0221] Ultraviolet ("UV") visualization at 220 nanometers ("nm"). LCMS-Method C:

[0222] Linear gradient of 20% to 100% solvent B over 4 minutes with 0.6-minute hold at 100% B and followed by 0.1-minute gradient to 20% B and a 0.3-minute hold at 20% B

[0223] Solvent A: 5mM Ammonium formate pH 3.3: ACN (98:02)

[0224] Solvent B: ACN: Buffer (98:02)

[0225] Flow Rate: 1.0 ml / min

[0226] Column: Kinetex XB - C18 (75 x 3.0) mm, 2.6μm

[0227] Ultraviolet ("UV") visualization at 220 nanometers ("nm"). LCMS-Method D:

[0228] Linear gradient of 20% to 98% solvent B over 4 minutes with 0.6-minute hold at 100% B and followed by 0.1-minute gradient to 20% B and a 0.3-minute hold at 20% B.

[0229] Solvent A: 0.1% TFA in H2O

[0230] Solvent B: 0.1% TFA in ACN

[0231] Flow Rate: 0.7 ml / min

[0232] Column: Aquity BEH C18 (75 x 3.0) mm, 1.7μm.

[0233] Ultraviolet ("UV") visualization at 220 nanometers ("nm").LCMS-Method E:

[0234] Linear gradient of 5% to 95% solvent B over 2.5 minutes with 1.5-minute hold at 95% B and followed by 0.3-minute gradient to 5% B and a 0.7-minute hold at 5% B.

[0235] Solvent A: 10mM AA in H2O

[0236] Solvent B: ACN

[0237] Flow Rate: 1.0 ml / min

[0238] Column: Aquity BEH C18 (75 x 3.0) mm, 1.7μm.

[0239] Ultraviolet ("UV") visualization at 220 nanometers ("nm"). LCMS-Method F:

[0240] Linear gradient of 0% to 100% solvent B over 2 minutes with 0.5-minute hold at 100% B

[0241] Solvent A: 0.05% TFA in ACN:H2O (5:95)

[0242] Solvent B: 0.05% TFA in ACN:H2O (95:5)

[0243] Flow Rate: 1.0 ml / min

[0244] Column: Aquity BEH C18 (75 x 3.0) mm, 1.7μm.

[0245] Ultraviolet ("UV") visualization at 220 nanometers ("nm"). LCMS-Method G:

[0246] Linear gradient of 0% to 100% solvent B over 2 minutes with 0.5-minute hold at 100% B

[0247] Solvent A: 10 mM NH4OAc in ACN:H2O (5:95)

[0248] Solvent B: 10 mM NH44OAc in ACN:H2O (95:5)

[0249] Flow Rate: 1.0 ml / min

[0250] Column: Aquity BEH C18 (75 x 3.0) mm, 1.7μm.

[0251] Ultraviolet ("UV") visualization at 220 nanometers ("nm"). GCMS-Method H:

[0252] Chromatographic column: HP-5ms (30m x 320μm x 0.25μm) Column length 30m, internal diameter 0.32 Mm, thickness 0.25 μm;

[0253] Spit ratio: 75:1;

[0254] Inlet temperature: 230 °C; Carrier gas: He;

[0255] Oven temp: 120°C hold time 1min;

[0256] Detector temperature: 300 °C; Column flow 2mL / min; Air flow 400 mL / min; H2flow 40 mL / min.

[0257] Heating schedule: 120 °C hold time 1 min; Then raise to 300°C with the speed of 40 °C / min and hold for 9.5 min.

[0258] Source temperature: 230 °C. SFC-Method I:

[0259] Chiral column: Chiralpak AD-H (250 x 4.6) mm 5μ.

[0260] Eluent: 0.2% NH3in ACN:MeOH (50:50); Flow rate : 3.0 mL / min; Co-Solvent : 45.0 %

[0261] Make up Pump Flow: 0.5 mL / min

[0262] Oven-A Temperature: 40 °C

[0263] Oven A Column Position: 1

[0264] BPR Pressure: 100.0 bar

[0265] BPR Temperature: 50 °C Scheme 1: Method for Preparing Vinyl IntermdiatesScheme 2: Alternative Method for Preparing Vinyl Intermediates(Z)-2-fluoro-3-(thiazol-2-yl)acrylic acidStep 1: Preparation of ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate

[0266] Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1.1 g, 4.5 mmol) was dissolved in THF (25 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 0.18 g, 4.5 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 min and thiazole-2-carbaldehyde (0.51 g, 4.5 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The mixture was quenched by addition of satruated aqueous ammonium chloride solution (20 mL). The solution was diluted with water (20 mL) and EtOAc (150 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatogrpahy (0 → 60% acetone / hexanes) to provide ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate (10:1 E / Z as judged by1H NMR, 620 mg, 3.1 mmol, 68% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C8H9FNO2S 202.0; found 202.2; 1H NMR (500 MHz, CDCl3) δ 7.94 (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

[0267] Ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate (620 mg, 3.1 mmol) was dissolved in toluene (15 mL) and iodine (39 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexanes) to provide ethyl (Z)-2-fluoro-3-(thiazol-2- yl)acrylate (509 mg, 2.5 mmol, 82% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C8H9FNO2S 202.0; found 202.0;1H NMR (500 MHz, CDCl3) δ 7.96 (dd, J=3.2, 2.6 Hz, 1H), 7.57 (d, J=3.2 Hz, 1H), 7.43 (dd, J=33.3, 0.8 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid

[0268] Ethyl (Z)-2-fluoro-3-(thiazol-2-yl)acrylate (510 mg, 2.5 mmol) was dissolved in MeOH (15 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 2.5 mL, 2.5 mmol) was added. The reaction mixture was stirred for 5 h. The solution was concentrated to remove the methanol. Additional water (1.5 mL) was added and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 2.5 mL, 2.5 mmol) was added dropwise. After 10 min, a white solid precipitated. The solid was collected by filtration andwas washed with MeCN. The solid was dried under vacuum to provide (Z)-2-fluoro-3- (thiazol-2-yl)acrylic acid (337 mg, 1.9 mmol, 77% yield) as a white solid. LC / MS (ESI) m / z: [M+H]+calc’d for C6H5FNO2S 174.0; found 173.8;1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 2H), 7.29 (d, J=34.5 Hz, 1H).Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate

[0269] Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1.5 g, 6.2 mmol) was dissolved in THF (31 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.2 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 min and picolinaldehyde (0.66 g, 6.2 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The mixture was quenched by addition of satruated aqueous ammonium chloride solution (15 mL). The solution was diluted with water (20 mL) and EtOAc (100 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatogrpahy (0 → 100% EtOAc / hexanes) to provide ethyl (E)-2- fluoro-3-(pyridin-2-yl)acrylate (3:1 E / Z mixture as judged by1H NMR, 910 mg, 4.6 mmol, 75% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C10H11FNO2 196.1; found 196.1; E isomer reported:1H NMR (500 MHz, CDCl3) δ 8.59 (dd, J=4.9, 1.8 Hz, 1H), 7.67 (ddd, J=7.9, 7.6, 1.8 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.21 (dd, J=7.6, 4.9 Hz, 1H), 6.90 (d, J=20.4 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate

[0270] Ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate (420 mg, 2.1 mmol) was dissolved in toluene (10 mL) and iodine (27 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexanes) to provide ethyl (Z)-2-fluoro-3-(pyridin-2- yl)acrylate (240 mg, 1.2 mmol, 58% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C10H11FNO2196.1; found 196.1;1H NMR (500 MHz, CDCl3) δ 8.66 (ddd, J=5.0, 1.8, 0.8Hz, 1H), 7.88 (ddd, J=8.0, 1.2, 0.8 Hz, 1H), 7.75 (ddd, J=8.0, 7.8, 1.8 Hz, 1H), 7.25 (ddd, J=7.8, 5.0, 1.2 Hz, 1H), 7.14 (d, J=34.9 Hz, 1H), 4.36 (q, J=7.2 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid

[0271] Ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate (415 mg, 2.1 mmol) was dissolved in MeOH (15 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 2.1 mL, 2.1 mmol) was added. The reaction mixture was stirred for 5 h. The solution was concentrated to remove the 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 was 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: [M+H]+calc’d for C8H7FNO2168.0; found 167.8.1H NMR (500 MHz, DMSO-d6) δ 8.66 (ddd, J=4.8, 1.8, 0.8 Hz, 1H), 7.89 (ddd, J=8.0, 7.5, 1.8 Hz, 1H), 7.81 (ddd, J=8.0, 1.1, 0.8 Hz, 1H), 7.40 (dd, J=7.5, 4.8, 1.1 Hz, 1H), 6.97 (d, J=35.3 Hz, 1H).(Z)-2-fluoro-3-(pyrimidin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate

[0272] Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1.6 g, 6.6 mmol) was dissolved in THF (50 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 0.26 g, 6.6 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 min and pyrimidine-2-carbaldehyde (0.71 g, 6.6 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The mixture was quenched by addition of satruated aqueous ammonium chloride solution (20 mL). The solution was diluted with water (20 mL) and EtOAc (150 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatogrpahy (0 → 90% EtOAc / hexanes) to provide ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate (5:1 E / Z as judged by1H NMR, 592 mg, 3.0mmol, 46% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C9H10FN2O2197.2; found 197.1; 1H NMR (500 MHz, 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, 2H), 1.39 (t, J=7.2 Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate

[0273] Ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate (592 mg, 3.0 mmol) was dissolved in toluene (15 mL) and iodine (38 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexanes) to provide ethyl (Z)-2-fluoro-3-(pyrimidin- 2-yl)acrylate (253 mg, 1.3 mmol, 43% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C9H10FN2O2197.2; found 196.6;1H NMR (500 MHz, CDCl3) δ 8.83 (d, J=4.9 Hz, 2H), 7.21 (t, J=4.9 Hz, 1H), 7.13 (d, J=30.8 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylic acid

[0274] Ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate (253 mg, 1.3 mmol) was dissolved in MeOH (10 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 1.3 mL, 1.3 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove the 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: [M+H]+calc’d for C7H6FN2O2169.1; found 168.8;1H NMR (500 MHz, DMSO-d6) δ 8.90 (d, J=4.9 Hz, 2H), 7.46 (t, J=4.9 Hz, 1H), 6.94 (d, J=31.5 Hz, 1H).(Z)-2-fluoro-3-(pyridazin-3-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyridazin-3-yl)acrylate

[0275] Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineraloil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 min and pyridazine-3-carbaldehyde (110 mg, 1.0 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The mixture was quenched by addition of satruated aqueous ammonium chloride solution (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatogrpahy (0 → 100% EtOAc / hexanes) to provide ethyl (E)-2-fluoro-3-(pyridazin-3-yl)acrylate (3:1 E / Z as judged by1H NMR, 168 mg, 0.60 mmol, 60% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C9H10N2O2197.1; found 196.8; 1H NMR (500 MHz, CDCl3) δ 9.11 (dd, J=5.0, 1.7 Hz, 1H), 7.91 (dd, J=8.6, 1.7 Hz, 1H), 7.47 (dd, J=8.6, 5.0 Hz, 1H), 7.15 (d, J=19.9 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H). Step 2: Preparation of ethyl (Z)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate

[0276] Ethyl (E)-2-fluoro-3-(pyridazin-3-yl)acrylate (98 mg, 0.5 mmol) was dissolved in toluene (2 mL) and iodine (12 mg, 0.05 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexanes) to provide ethyl (Z)-3-(4-bromothiazol-2- yl)-2-fluoroacrylate (58 mg, 0.30 mmol, 59% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C9H10N2O2197.1; found 196.8;1H NMR (500 MHz, CDCl3) δ 9.12 (dd, J=4.9, 1.6 Hz, 1H), 8.06 (dd, J=8.7, 1.6 Hz, 1H), 7.54 (dd, J=8.7, 4.9 Hz, 1H), 7.45 (d, J=34.7 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(pyridazin-3-yl)acrylic acid

[0277] Ethyl (Z)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate (55 mg, 0.28 mmol) was dissolved in MeOH (2 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 0.28 mL, 0.28 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove the methanol. Additional water (1 mL) was added and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.28 mL, 0.28 mmol) was added dropwise. The solution was frozen and directly lyophilized to provide (Z)-2-fluoro- 3-(pyridazin-3-yl)acrylic acid as a white solid (quantitative yield assumed). LC / MS (ESI) m / z: [M+H]+calc’d for C7H6FN2O2169.0; found 168.8;1H NMR (500 MHz, DMSO-d6) δ9.21 (dd, J=4.9, 1.6 Hz, 1H), 8.06 (dd, J=8.6, 1.6 Hz, 1H), 7.80 (dd, J=8.6, 4.9 Hz, 1H), 7.22 (d, J=34.7 Hz, 1H).Acrylic acid intermediate 5 (Z)-2-fluoro-3-(pyrazin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyrazin-2-yl)acrylate

[0278] Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1.7 g, 7.0 mmol) was dissolved in THF (35 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 280 mg, 7.0 mmol) was added portion wise as a solid. The reaction mixture was stirred for 10 min and pyrazine-2-carbaldehyde (750 mg, 7.0 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The mixture was quenched by addition of saturated aqueous ammonium chloride solution (50 mL). The solution was diluted with water (50 mL) and EtOAc (100 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0 → 100% EtOAc / hexanes) to provide the desired product (6:1 E / Z as judged by1H NMR, 930 mg, 4.8 mmol, 68% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C9H10FN2O2197.1; found 197.0; E isomer reported:1H NMR (500 MHz, CDCl3) δ 8.78 (d, J=1.4 Hz, 1H), 8.56 (dd, J=2.5, 1.4 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 6.86 (d, J=19.1 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyrazin-2-yl)acrylate

[0279] Ethyl (E)-2-fluoro-3-(pyrazin-2-yl)acrylate (930 mg, 4.8 mmol) was dissolved in toluene (50 mL) and iodine (240 mg, 0.95 mmol) was added. The reaction mixture was heated at 100 °C for 6 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexanes) to provide the desired product (710 mg, 3.6 mmol, 76% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C9H10FN2O2197.1; found 197.0; 1H NMR (500 MHz, CDCl3) δ 9.10 (d, J=1.5 Hz, 1H), 8.63 (dd, J=2.5, 1.5 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 7.10 (d, J=35.2 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).Step 3: Preparation of (Z)-2-fluoro-3-(pyrazin-2-yl)acrylic acid

[0280] Ethyl (Z)-2-fluoro-3-(pyrazin-2-yl)acrylate (710 mg, 3.6 mmol) was dissolved in MeOH (25 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 3.6 mL, 3.6 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove the methanol. The resulting aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 3.6 mL, 3.6 mmol) was added dropwise, and a precipitate formed. After stirring 10 min, the precipitate was collected by filtration and dried under vacuum to provide the desired product (570 mg, 3.4 mmol, 94% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C7H6FN2O2169.0; found 169.0;1H NMR (500 MHz, DMSO-d6) δ 8.98 (d, J=1.1 Hz, 1H), 8.75 (dd, J=2.4, 1.1 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H), 7.05 (d, J=34.9 Hz, 1H).(Z)-2-fluoro-3-(pyrimidin-4-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(pyrimidin-4-yl)acrylate

[0281] Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1.1 g, 4.6 mmol) was dissolved in THF (11 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 185 mg, 4.6 mmol) was added portion wise as a solid. The reaction mixture was stirred for 10 min and pyrimidin-4-carbaldehyde (250 mg, 1.0 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The mixture was quenched by addition of saturated aqueous ammonium chloride solution (20 mL). The solution was diluted with water (20 mL) and EtOAc (10 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0 → 15% acetone / hexanes) to provide the desired product (40 mg, 0.2 mmol, 9% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C9H10FN2O2197.1; found 197.0;1H NMR (500 MHz, CDCl3) δ 9.27 (d, J=1.3 Hz, 1H), 8.82 (d, J=5.4 Hz, 1H), 7.79 (dd, J=5.3, 1.5 Hz, 1H), 7.03 (d, J=33.9 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).Step 2: Preparation of (Z)-2-fluoro-3-(pyrimidin-4-yl)acrylic acid

[0282] Ethyl (Z)-2-fluoro-3-(pyrimidin-4-yl)acrylate (20 mg, 0.1 mmol) was dissolved in MeOH (1 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 0.1 mL, 0.1 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove the methanol. The resulting aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.1 mL, 0.1 mmol) was added dropwise. The solution was frozen and directly lyophilized to provide the desired product, sodium chloride adduct (quantitative yield assumed). LC / MS (ESI) m / z: [M+H]+calc’d for C7H6FN2O2169.0; found 169.0. No 1H NMR reported for this product? Intermediate 1:

[0283] Step 1: Preparation of tert-butyl (R)-3-((2-nitrophenyl)sulfonamido)pyrrolidine-1- carboxylate: To a stirred solution of tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (4.0 g, 21.48 mmol) in THF (10 mL) were added TEA (2.99 mL, 21.48 mmol) and 2- nitrobenzenesulfonyl chloride (4.76 g, 21.48 mmol) at 0 °C. The reaction mixture was allowed to warm to room temeperature and was stirred for 1h. The reaction mixture was^quenched with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuum. The crude residue was purified by column chromatography (Biotage, SiO2, eluted with 15% ethyl acetate in petroleum ether) to provide the desired product (7.0 g, 85% yield). MS (M-1) m / z: 370.1 [M-H]-. LC retention time 2.35 min [Method C].

[0284] Step 2: Preparation of tert-butyl (R)-3-((N-ethyl-2- nitrophenyl)sulfonamido)pyrrolidine-1-carboxylate: To a stirred solution of tert-butyl (R)- 3-((2-nitrophenyl)sulfonamido)pyrrolidine-1-carboxylate (7.0 g, 18.85 mmol) in DMF (15 mL) were added K2CO3 (7.81 g, 56.5 mmol) and iodoethane (7.62 mL, 94 mmol). The reaction mixture was allowed to stir at room temperature for 16h. After completion, the reaction mixture was^quenched with water (70 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layer was washed with brine (70 mL), dried over anhydrousNa2SO4, filtered, and the filtrate was concentrated in vacuum. The crude residue was purified by column chromatography (Biotage, SiO2, eluted with 10% ethyl acetate in petroleum ether) to provide the desired product (7.0 g, 17.17 mmol, 91% yield). MS (M-1) m / z: 399.2 [M-H]-. LC retention time 0.79 min [Method A].

[0285] Step 3: Preparation of tert-butyl (R)-3-(ethylamino)pyrrolidine-1-carboxylate: To a stirred solution of tert-butyl (R)-3-((N-ethyl-2-nitrophenyl)sulfonamido)pyrrolidine-1- carboxylate (4.0 g, 10.01 mmol) in DMF (30 mL) were added TEA (16.75 mL, 120 mmol) and Thioglycolic acid (8.35 mL, 120 mmol). The reaction mixture was stirred at room temperature for 16h. After completion, the reaction mixture was^quenched with water (70 mL) and extracted with ethyl acetate (2 x 70 mL). The combined organic layer was washed with saturated sodium bicarbonate (50 mL) followed by brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuum to provide the desired product, which was used directly in the next step, without additional purification. MS (M+1) m / z: 215.2 [M+H]+. LC retention time 0.36 min [Method C]. Intermediate 2:

[0286] Step 1: Preparation of tert-butyl (R)-3-((2,7-dichloro-8-fluoro-5- methoxypyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate: To a stirred solution of 2,4,7-trichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine (1 g, 3.54 mmol) in DCM (40 mL)) was added DIPEA (1.855 mL, 10.62 mmol), tert-butyl (R)-3- (methylamino)pyrrolidine-1-carboxylate (0.709 g, 3.54 mmol) at -40 °C dropwise over 5 min. The reaction mixture was stirred for 30 min at this temperature. After completion, the reaction mixture was quenched with cold water (20 mL) and extracted with DCM (2 x 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure to provie the desired product (1.4 g, 3.19 mmol, 86 % yield) as semi solid. MS (M+1) m / z: 447.2 [M+H]+. LC retention time 1.72min [Method A].

[0287] Step 2: Preparation of tert-butyl (R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidine-1-carboxylate: To a stirred solution of tert-butyl (R)-3-((2,7- dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1- carboxylate (1.4 g, 3.19 mmol) in acetonitrile (25 mL) was added DIPEA (1.761 mL, 10.08 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.803 g, 5.04 mmol) at room temperature. The reaction mixture was stirred for over night at 90 °C. After completion, the reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude residue was stirred with petroleum ether (50 mL) for 30 min and filtered, obtained solid was dried under vacuum to provide the desired product (1.5 g, 2.425 mmol, 72% yield) as off white solid. MS (M+1) m / z: 570.0 [M+H]+. LC retention time 2.8 min [Method C].

[0288] The following intermediates (Intermediates 3-6) were prepared in a similar manner to the preparation of Intermediate 2.Table 1: IntermediatesIntermediate 7:

[0289] Step1: Preparation of 1-bromo-2-cyclopropyl-3-fluorobenzene: To a stirred solution of 1-bromo-3-fluoro-2-iodobenzene (1.0 g, 3.32 mmol) in 1,4-Dioxane (15 mL) were added 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.234 g, 13.29 mmol), 2 M aqueous solution of K3PO4(4.99 mL, 9.97 mmol) and PdCl2(dppf) (0.243 g, 0.332 mmol) and the reaction mixture was degassed under N2 for 5 min, then stirred at 100 °C for 48h. After completion, the reaction mixture was quenched with water (50 mL), and extracted with ethyl acetate (2 x 70 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuum. The crude residue was purified by column chromatography (Biotage, SiO2, eluted with 1% ethyl acetate in petroleum ether) to provide the desired product (0.46 g, 2.176 mmol, 34% yield). GCMS (M) m / z: 215.0 [M]+. GC retention time 4.35 min [Method F].

[0290] Step 2: Preparation of 2-(2-cyclopropyl-3-fluorophenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane: To a stirred solution of 1-bromo-2-cyclopropyl-3-fluorobenzene (460 mg, 2.176 mmol) in 1,4-dioxane (10 mL) were added bis(pinacolato)diboron (bispin) (1.105 g, 4.35 mmol), potassium acetate (0.641 g, 6.53 mmol) and PdCl2(dppf) (0.159 g, 0.218 mmol) and reaction was degassed with N2 for 10 min, and stirred at 100 °C for 16h. After completion, the reaction mixture was^quenched with water (30 mL), and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (Biotage, SiO2with 2% ethyl acetate in petroleum ether) to provide the desired product (360 mg, 1.389 mmol, 33% yield). GCMS. MS (M) m / z: 262.0 [M+H]+. GCMS retention time 6.07 min [Method H].

[0291] The following intermediate 8 was prepared in a similar manner to the preparation of Intermediate 7.Intermediate 9:

[0292] Step 1: Preparation of tert-butyl (R)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-7-(8-((triisopropylsilyl)ethynyl)naphthalen- 1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate: To a stirred solution of tert-butyl (R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidine-1-carboxylate (200 mg, 0.351 mmol), triisopropyl((8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (229 mg, 0.527 mmol) in 1,4-dioxane (5 mL) was added 2 M aqueous solution of K3PO4 (0.527 mL, 1.054 mmol). The reaction mixture was purged under nitrogen for 3 min and added cataCXium A Pd G4(26.1 mg, 0.035 mmol). The resulting reaction mixture was stirred at 100 °C for 2h in a microwave reactor. After completion, the reaction mixture was quenched with cold water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (Biotage, Nuetra alumina, eluted with 35-50% ethyl acetate in petroleum ether) to provide the desiredproduct (220 mg, 0.258 mmol, 64 % yield) as off-white solid. MS (M+1) m / z: 842.4 [M+H] +. LC retention time 3.07 min [Method D].

[0293] Step 2: tert-butyl (R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidine-1-carboxylate: To a stirred solution of tert-butyl (R)-3-((8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-7- (8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidine-1-carboxylate (200 mg, 0.238 mmol) in tetrahydrofuran (5 mL) was added TBAF (0.713 mL, 0.713 mmol) dropwise at 0 °C. The reaction mixture was stirred at rt for 2h. After completion, the reaction mixture was^quenched with cold water (10 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, the filtrate was concentrated in vacuum to provide the desired product (130 mg, 0.183 mmol, 60 % yield) as a gummy solid. The crude product was used as such for the next step without further purification. MS (M+1) m / z: 685.3 [M+H]+. LC retention time 2.60 min [Method D].

[0294] Step 3: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-N-methyl-N-((R)- pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine: To a stirred solution of tert-butyl (R)-3- ((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine- 1-carboxylate (130 mg, 0.183 mmol) in acetonitrile (5 mL) was added 4N HCl in dioxane (0.292 mL, 1.168 mmol) dropwise at 0 °C. The resulting reaction mixture was stirred for 1h at this temperature. After completion, the reaction mixture was quenched with cold water (10 mL) and adjusted pH (~7) using triethyl amine and extracted with ethyl acetate (2 x 25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, the filtrate was concentrated in vacuum. The crude product was triturated with pentane (25 mL) and stirred for 10 min, the precipitate was filtered and dried under vacuum. The crude residue was purified under reverse phase Teledyne Isco-combi flash column chromatography [Redisep 80gm C18, 20-40 micron, THF:Water:ACN (50:20:30) as a diluent and 60% acetonitrile / 10mM ammonium bicarbonate as an eluent] to provide the desired product (44 mg, 0.075 mmol, 41% yield) as off-white solid. MS (M+1) m / z: 585.2 [M+H]+. LC retention time 1.61 min [Method C].1H NMR (400 MHz, DMSO-d6): δ 8.14 (t, J = 1.20 Hz, 2H), 7.75 (d,J = 7.20 Hz, 1H), 7.67-7.63 (m, 2H), 7.56 (t, J = 4.00 Hz, 1H), 5.28 (s, 1H), 4.95 (s, 1H), 4.12 (d, J = 7.20 Hz, 1H), 4.03 (d, J = 10.40 Hz, 1H), 3.80 (s, 3H), 3.79 (d, J = Hz, 1H), 3.08-3.00 (m, 8H), 2.84-2.83 (m, 2H), 2.14-2.05 (m, 4H), 2.00-1.77 (m, 3H), 1.72-1.65 (m, 1H), 1.33-1.31 (m, 1H), 0.94 (t, J = 7.60 Hz, 1H).19F NMR (400 MHz, DMSO-d6): δ - 172.11 (d, J = 23.20 Hz, 1F), -150.16 (d, J = 28.00 Hz, 1F).

[0295] The following intermediates (Intermediates 10-24) were prepared in a manner similar to the preparation of Intermediate 9.Table 2: Intermediate CharaterizationTable 3: Intermediate CharacterizationIntermediate 27:

[0296] Step 1. Preparation of 2-((S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile: To a stirred solution of benzyl (S)-4-(7-chloro-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1.0 g, 1.672 mmol) in ethanol (20 mL) and THF (5 mL) was added Pd / C (0.178 g, 0.167 mmol) and Pd(OH)2 on carbon (0.047 g, 0.334 mmol). The suspension was degassed under vacuum and purged with H2. The resulting mixture was stirred at rt for 8h under hydrogen bladder pressure. The mixture was filtered and washed with THF (100 mL) and the filtrate was concentrated to afford the desired 2- ((S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (500 mg, 64% yield) as a brown solid. MS (M+1) m / z: 464.0 [M+H]+. LC retention time 0.61 min [Method B].

[0297] Step 2: Preparation of 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile: To a stirred solution of 2-((S)- 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (500 mg, 1.078 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)silane (515 mg, 1.186 mmol) in 1,4-dioxane (8 mL) was added 2N aqueous solution of K3PO4(1.078 mL, 2.156 mmol) at room temperature and purged with nitrogen for 5 min then added CataCXium A Pd G3 (78 mg, 0.108 mmol) The resulting reaction mixture was stirred for 4 h at 110°C in microwave reactor. After completion, the reactionmixture was diluted with ice cold water (10 mL) and added extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The crude compound was purified by reverse phase column chromatography [Teledyne Isco-Combi flash; Redisep 80gm C18, 20-40 micron; Diluent : THF:Water:ACN(50:20:30); Compound elution (%) : 100% acetonitrile / 5mM ammonium formate in water] to afford desired 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (88 mg, 0.120 mmol, 9 % yield). MS (M+1) m / z: 736.2 [M+H]+. LC retention time 1.34 min [Method D].

[0298] Step 3: Preparation of 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)piperazin-2-yl)acetonitrile: To a stirred solution of 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile (90 mg, 0.120 mmol) in THF (5 mL) was added TBAF (0.272 mL, 0.272 mmol, 1M solution in THF) at 0 °C. The resulting reaction mixture was stirred for 2 h at 0 °C. After completion, the reaction mixture was diluted with ice cold water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain crude compound. The residue was purified by prep-HPLC [Diluent : WATER:THF:ACN (10:60:30),Column :X-Select C18 (150 x19)mm, 5 micron, Temperature: Ambient, Mobile phase A:10mM ABC in water, Mobile phase B: Acetonitrile, Flow :15mL / min] to afford 2-((S)-4-(7-(8- ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (6.5 mg, 0.011 mmol, 9 % yield) as off white solid. MS (M+1) m / z: 580.2 [M+H]+. LC retention time 1.35 min [Method C].1H-NMR (400 MHz, DMSO-d6): δ 9.06 (d, J = 8.00 Hz, 1H), 8.17-8.12 (m, 2H), 7.73-7.68 (m, 2H), 7.61-7.55 (m, 2H), 5.28 (d, J = 56.00 Hz, 1H), 4.50-4.12 (m, 4H), 3.70 (s, 1H), 3.51-3.31 (m, 1H), 3.14-3.02 (m, 6H), 2.67-2.51 (m, 4H), 1.77-1.24 (m, 7H).19F-NMR (400 MHz, DMSO-d6): δ 172.12 (s), 140.18 (d, J = 51.6 Hz).

[0299] Intermediate 28 was prepared in a similar way to Intermediate 27:2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile LC / MS (ESI) m / z: [M+H]+calc’d for C33H31F3N7O 598.3; found 598.3. Intermediate 297-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-N-methyl-N-(2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amineStep 1: Preparation of tert-butyl 2-methyl-3-(methylamino)pyrrolidine-1-carboxylate

[0300] Tert-butyl 2-methyl-3-oxopyrrolidine-1-carboxylate (1 g, 5.02 mmol) was dissolved in methylamine solution (33 wt% in EtOH, 19 ml, 151 mmol), and the reaction mixture was stirred at room temperature for 20 h. The soultion was concentrated, and the crude residue was resuspended in MeOH (50 mL). Palladium on carbon (10 wt. %, 0.5 g, 0.47 mmol) was added, and hydrogen gas (1 atm, balloon) was sparged through the solution for 5 min. The reaction mixture was stirred under an atmosphere of hydrogen for 20 h. The black suspension was filtered through a pad of CELITE, eluting with additional MeOH, and the filtrate was concentrate. The crude residue was used directly in the next step, without further purification (quantitative yield assumed).Step 2: Preparation of 2,7-dichloro-8-fluoro-N-methyl-N-(2-methylpyrrolidin-3- yl)pyrido[4,3-d]pyrimidin-4-amine

[0301] 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.2 g, 4.75 mmol) was suspended in DCM (24 mL) and the mixture was cooled to -5 °C (wet ice / acetone). DIPEA (0.83 mL, 4.75 mmol) was added followed by tert-butyl 2-methyl-3-(methylamino)pyrrolidine-1- carboxylate (1.0 g, 4.75 mmol). The reaction mixture was stirred for 5 min and was concentrated. The crude residue was used directly in the next step, without additional purification (quantitative yield assumed). LC / MS (ESI) m / z: [M+H]+calc’d for C18H23Cl2FN5O2430.1; found 430.1Step 3: Preparation of tert-butyl 3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2- methylpyrrolidine-1-carboxylate

[0302] Tert-butyl 3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)- 2-methylpyrrolidine-1-carboxylate (2 g, 4.65 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methanol (0.96 g, 6.04 mmol) were combined and dissolved in THF (23 mL). The souliton was cooled to 0 °C and LiHMDS solution (1.0 M in THF, 11.6 mL, 11.6 mmol) was added dropwise. The reaction mixture was allowed to warm to room tempreature and was stirred for 24 h. The solution was concentrated, and the crude residue was directly purified by column chromatography (0 → 100% EtOAc with 5% Et3N / hexanes) to provide the desired product (1.1 g, 2.0 mmol, 43 % yield) as a 6:6:1:1 cis:cis:trans:trans mixture of diastereomers. (Cis diastereomers reported). LC / MS (ESI)m / z: [M+H]+calc’d for C26H36ClF2N6O3553.2; found 553.4;1H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 5.26 (d, J=55.0 Hz, 1H), 5.00 - 4.91 (m, 1H), 4.59 - 4.46 (m, 1H), 4.36 - 4.13 (m, 2H), 3.70 - 3.57 (m, 1H), 3.50 (s, 3H), 3.45 - 3.32 (m, 2H), 3.27 - 3.11 (m, 3H), 3.02 - 2.92 (m, 1H), 2.51 - 2.26 (m, 1H), 2.27 - 2.06 (m, 3H), 1.97 - 1.79 (m, 3H), 1.49 - 1.47 (m, 9H), 1.03 (br d, J=6.4 Hz, 3H).Step 4: Preparation of tert-butyl 3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0303] Tert-butyl 3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1- carboxylate (250 mg, 0.45 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)naphthalen-1-yl)ethynyl)silane (295 mg, 0.45 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2- yl)palladium(II) dichloromethane adduct, [cataCXium A Palladacycle Gen.3] (3.3 mg, 4.5 µmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (2.2 mL) and potassium phosphate solution (2.0 M in water, 680 µL, 1.36 mmol) were added, and the reaction mixture was heated at 100 °C in the microwave for 1.5 h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (20 → 100% EtOAc with 5% Et3N / hexanes) to provide the desired product. LC / MS (ESI) m / z: [M+H]+calc’d for C47H63F2N6O3Si 825.5; found 825.4Step 5: Preparation of tert-butyl 3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0304] Tert-butyl 3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (370 mg, 0.448 mmol) was dissolved in THF (4.5 mL), and the solution was cooled to 0 °C. TBAF solution (1.0 M in THF, 540 µL, 0.540 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 min, the reaction mixture was concentrated, and the crude residue was purified by column chromatography (50 → 100% EtOAc with 5% Et3N / hexanes) to provide the desired product (270 mg, 0.404 mmol, 90 % yield over two steps) as a 6:6:1:1 cis:cis:trans:trans mixture of diastereomers (cis diastereomers reported).LC / MS (ESI) m / z: [M+H]+calc’d for C38H43F2N6O3 669.3; found 669.4;1H NMR (500 MHz, CDCl3) δ 9.19 - 9.15 (m, 1H), 8.01 - 7.94 (m, 2H), 7.75 (br d, J=6.9 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.46 (t, J=7.7 Hz, 1H), 0.00 (d, J=54.5 Hz, 1H), 5.10 - 4.89 (m, 1H), 4.66 - 4.52 (m, 1H), 4.38 - 4.15 (m, 2H), 3.66 - 3.60 (m, 1H), 3.59 - 3.54 (m, 3H), 3.43 - 3.38 (m, 1H), 3.29 - 3.20 (m, 2H), 3.18 - 3.15 (m, 1H), 3.00 - 2.94 (m, 1H), 2.57 - 2.53 (m, 1H), 2.43 - 2.33 (m, 1H), 2.29 - 2.09 (m, 4H), 1.98 - 1.85 (m, 3H), 1.50 - 1.48 (m, 9H), 1.10 - 1.05 (m, 3H).Step 6: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-(2-methylpyrrolidin-3- yl)pyrido[4,3-d]pyrimidin-4-amine

[0305] Tert-butyl 3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (270 mg, 0.404 mmol) was dissolved in MeCN (4.0 mL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 1.0 mL, 4.0 mmol) was added dropwise. After 2 h, 1-methylimidazole (500 μL) was added, and the reaction mixture was concentrated. The crude residue was used directly in the next step, without additional purification (quantitative yield assumed).LC / MS (ESI) m / z: [M+H]+calc’d for C33H35F2N6O 569.3; found 569.3

[0306] Intermediate 30 was prepared in a similar way to Intermediate 29:7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-N-methyl-N-(2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine LC / MS (ESI) m / z: [M+H]+calc’d for C33H34F3N6O 587.3; found 587.3 General Scheme for the preparation of the intermediates 31-33.Intermediate 31:(S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-amine Step 1: Preparation of tert-butyl ((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)carbamate

[0307] A solution of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4- ol, TFA (35 mg, 0.047 mmol), DIPEA (57.6 µl, 0.330 mmol), and HATU (90 mg, 0.236 mmol) was stirred at rt for 1 h. Tert-butyl (S)-(1,4-oxazepan-6-yl)carbamate (10.19 mg, 0.047 mmol) was added and stirring was continued for 18 h at 60 °C. The mixture was diluted with acetonitrile and was purified by reverse phase HPLC (column: Xbridge C18, 30 mm x 100 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25 °C; gradient: 100% 95:5 H2O / MeCN with 0.05%TFA / 0% 5:95 H2O / MeCN with 0.05%TFA → 0% 95:5 H2O / MeCN with 0.05%TFA / 100% 5:95 H2O / MeCN with 0.05%TFA; λ = 220 nm). The fractions were neutralized by passing through a SPE carbonate cartridge (Agilent Technologies PL-HCO3 MP SPE) to provide the desired product (9.8 mg, 0.012 mmol, 25.% yield). LC / MS (ESI) m / z: [M+H]+calc’d for C46H60F2N6O4Si 827.4; found 827.3.

[0308] 1HNMR (400 MHz, CDCl3) δ 9.26 - 9.07 (m, 1H), 8.02 - 7.90 (m, 2H), 7.83 (br d, J=7.3 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.48 (t, J=7.7 Hz, 1H), 5.78 - 5.14 (m, 2H), 4.51 - 3.67 (m, 10H), 3.43 - 3.16 (m, 3H), 3.08 - 2.96 (m, 1H), 2.38 - 1.90 (m, 6H), 1.52 - 1.39 (m, 9H), 1.01 - 0.96 (m, 3H), 0.92 - 0.85 (m, 18H). Step 2: Preparation of tert-butyl ((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-1,4-oxazepan-6-yl)carbamate

[0309] To a stirred solution of tert-butyl ((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)carbamate (19 mg, 0.023 mmol) in THF (1 mL) was added TBAF (1M in THF, 0.028 mL, 0.028 mmol). The mixture was stirred for 30 min. The mixture was concentrated and was directly purified by column chromatography (50→ 100% EtOAc w / 5% Et3N / hexanes) to provide the desired product (7.2 mg, 0.011 mmol, 47 % yield). LC / MS (ESI) m / z: [M+H]+calc’d for C37H40F2N6O4 671.3; found 671.5 Step 3: Preparation of (S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepan-6-amine

[0310] To a solution of tert-butyl ((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-1,4-oxazepan-6-yl)carbamate (7 mg, 10.4 mmol) in acetonitrile (0.3 mL) was added a solution of HCl (4M in dioxane (0.026 mL, 0.104 mmol). The mixture was stirred for 1 h and then made basic by addition of 1-methylimidazole (0.012 mL, 0.157 mmol). The solution was concentrated and used directly in the next step, without further purification (quantitative yield assumed). LC / MS (ESI) m / z: [M+H]+calc’d for C32H32F2N6O2571.3; found 571.2.

[0311] Intermediates 32 and 33 were prepared in a similar way to Intermediate 31: Intermediate 32(R)-1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-amine LC / MS (ESI) m / z: [M+H]+calc’d for C33H35F2N6O 569.3; found 569.2.Intermediate 337-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(octahydro-4H-pyrrolo[3,2-b]pyridin-4-yl)pyrido[4,3-d]pyrimidine LC / MS (ESI) m / z: [M+H]+calc’d for C34H35F2N6O 581.3; found 581.1. BIOLOGICAL ACTIVITY KRASG12CRAF Disruption Assay

[0312] This is a functional assay that measures activity of compounds against KRAS- G12C(ON), i.e., the active form of KRAS G12C. Recombinant guanosine 5′-[β,γ- imido]triphosphate-loaded KRAS G12C (5 nM) was treated with compound at room temperature for 20 minutes in assay buffer (50 mM Tris pH 7.5, 100 mM NaCl, 1 mM MgCl2, 1 mM DTT, 100 ug / ml BSA). Recombinant glutathione S-transferase-Raf1 Ras binding domain fusion protein (9 nM) was added, and the reaction mixture was incubated for 20 minutes. SA-Tb (0.25 nM) was added, and the reaction mixture was incubated for 3 hours. Homogeneous time resolved fluorescence signal was measured (PerkinElmer Envision), the signal ratio (λem 520 / λem 495) was calculated, and IC50 values were calculated from the dose-response curve.

[0313] The IC50values for compounds described herein are shown in Table 4. Table 4

[0314] It is to be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections can set forth one or more but not all exemplary aspects of the present disclosure as contemplated by the inventor(s), and thus, are not intended to limit the present disclosure and the appended claims in any way.

[0315] The present disclosure has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.

[0316] All of the references cited herein are incorporated herein by reference in their entireties.

[0317] The foregoing description of the specific aspects will so fully reveal the general nature of the disclosure that others can, by applying knowledge within the skill of the art, readily modify and / or adapt for various applications such specific aspects, without undue experimentation, without departing from the general concept of the present disclosure. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed aspects, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purposeof description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

[0318] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, whereinR1is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, or three substituents independently selected from the group consisting of cyclopropyl, ethynyl, halo, hydroxy, methyl, and trifluoromethyl; R2is heteroaryl; R3is hydrogen or methoxy; R4is methyl or ethyl; R5is hydrogen or cyanomethyl; and X is O or CH2.

2. A compound of formula (IA):or a pharmaceutically acceptable salt thereof, wherein: R1is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, or three substituents independently selected from the group consisting of cyclopropyl, ethynyl, halo, hydroxy, methyl, and trifluoromethyl; R2is heteroaryl; R4is methyl or ethyl; and R5is hydrogen or methoxy.

3. A compound of formula (IB):(IB); or a pharmaceutically acceptable salt thereof, wherein: R1is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of ethynyl and halo; R2is heteroaryl; and X is O or CH2.

4. A compound of formula (IC):or a pharmaceutically acceptable salt thereof, wherein: R1is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, or three substituents independently selected from the group consisting of ethynyl, halo, and methyl; R2is heteroaryl; and R3is hydrogen or cyanomethyl.

5. A compound of any one of claim 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl optionally substituted with one, two, or three substituents independently selected from the group consisting of cyclopropyl, halo, and trifluoromethyl.

6. A compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1is naphthyl optionally substituted with one, two, or three substituents independently selected from the group consisting of ethynyl, halo, and hydroxy.

7. A compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1is indazolyl optionally substituted with one, two, or three halo groups.

8. A compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R2is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and thazolyl.

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

10. A compound selected from the group consisting of: (Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one; 2-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3- (pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (Z)-1-(3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyrazin-2-yl)prop-2-en-1-one;(Z)-1-((R)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- diazepan-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- diazepan-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynyl-6,7-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynyl-6,7-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-((2S,3S)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-3-yl)prop-2-en-1-one; (Z)-1-((2R,3R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-3-yl)prop-2-en-1-one; (Z)-1-((2S,3S)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1- one; (Z)-1-((2R,3R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1- one; (Z)-1-(3-(ethyl(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;(Z)-1-(3-(ethyl(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one; (Z)-2-fluoro-1-((R)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxy-7-(2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one; (Z)-2-fluoro-1-((R)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(3-methyl-2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((2S,3S)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one; (Z)-1-((2R,3R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one; (Z)-1-((2S,3S)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one; (Z)-1-((2R,3R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one; (Z)-1-((2R,3R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyrazin-2-yl)prop-2-en-1-one;(Z)-1-((2S,3S)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((2R,3R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(2-cyclopropyl-3-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(2-cyclopropyl-3-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one; (Z)-2-fluoro-1-((R)-3-((8-fluoro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-2-fluoro-1-((R)-3-((8-fluoro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(pyridazin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;(Z)-1-((R)-3-((7-(3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one; 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(pyridazin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(pyrazin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (Z)-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro- 3-(pyrimidin-4-yl)prop-2-en-1-one; (Z)-N-((S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepan-6-yl)-2-fluoro-3-(pyridin-2-yl)acrylamide; (Z)-N-((R)-1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan- 3-yl)-2-fluoro-3-(pyridin-2-yl)acrylamide; (Z)-N-((R)-1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan- 3-yl)-2-fluoro-3-(pyridazin-2-yl)acrylamide; (Z)-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one;2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; and 2-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)- 2-fluoro-3-(pyridazin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

12. An oral dosage form comprising a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

13. A method of treating cancer expressing 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 10, or a pharmaceutically acceptable salt thereof.

14. A method of treating cancer expressing 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 10, or a pharmaceutically acceptable salt thereof.

15. A method for treating a cancer susceptible 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 10, or a pharmaceutically acceptable salt thereof.

16. A method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1 to 10, 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 cancer of the uterus.

17. A method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer.

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