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

Abstract

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

Description

【Technical Field】 【0001】 Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 482,726, filed on February 1, 2023, and U.S. Provisional Patent Application No. 63 / 351,132, filed on June 10, 2022, and these provisional patent applications are hereby incorporated by reference in their entireties. 【0002】 The present disclosure provides a KRAS inhibitor. A method of treating cancer using this inhibitor is also provided. 【Background Art】 【0003】 The KRAS oncogene is a member of the RAS family of GTPases that are involved in many cell signaling processes. KRAS mutations are gain - of - function mutations present in up to 30% of all tumors, including about 90% of pancreatic cancers. KRAS functions as a molecular switch cycling between an inactive (GDP - bound) state and an active (GTP - bound) state, transducing upstream cell signals received from multiple tyrosine kinases to downstream effectors to regulate diverse processes including cell proliferation. A single nucleotide substitution resulting in missense mutations at codons 12 and 13 of the KRAS primary amino acid sequence accounts for about 40% of KRAS driver mutations in lung adenocarcinoma, and the G12C transversion is the most commonly observed activating mutation. The KRAS G12C mutation occurs in about 13% of lung adenocarcinomas and about 3% of colorectal adenocarcinomas, and is also present in breast cancer, bladder cancer, cervical cancer, ovarian cancer, pancreatic cancer, and uterine cancer. 【0004】 Despite several attempts to target KRAS having failed, compounds that inhibit KRAS activity, including those that disrupt effectors such as guanine nucleotide exchange factors and target KRAS G12C, are highly desirable. Clearly, the interest and attempts to develop inhibitors of KRAS, particularly inhibitors that activate KRAS mutants such as KRAS G12C, still continue. 【SUMMARY OF THE INVENTION】 【MEANS FOR SOLVING THE PROBLEM】 【0005】 The present disclosure is, in part, based on the discovery that, unlike other KRAS G12C inhibitors, the compounds of the present disclosure target the active KRAS G12C (ON) form of the KRAS G12C protein. By inhibiting G12C ON form of KRAS, the claimed compounds are expected to reduce cancer resistance to KRAS G12C inhibition and / or exhibit increased clinical efficacy. Without being bound by theory, inhibition of G12C ON form of KRAS G12C may be the result of the substituent at the 4-position of the pyridopyrimidine ring of formula (I). 【0006】 In a first aspect, the present disclosure provides a compound of formula (I): 【CHEMICAL】 (wherein, U is a bond or NH; Z is a bond, O, NR e or CR e R f and R e and R f are independently hydrogen or C1-C3 alkyl; R 1 is aryl or heteroaryl, and said aryl and said heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, halo C1-C3 alkyl, hydroxy and hydroxy C1-C3 alkyl; R 2 and R 3is independently selected from hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halo, halo C1-C3 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 and hydroxy; Y is a bond, O, NR g (CR e R f ) m 、NR f or CR e R f where m is 1, 2 or 3, and R e 、R f and R g are independently hydrogen or C1-C3 alkyl; A is a 4- to 10-membered nitrogen-containing monocyclic or bicyclic bridged, fused or spirocyclic saturated, unsaturated or partially unsaturated ring system optionally containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring system being optionally substituted with 1, 2 or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, cyano, cyano C1-C3 alkyl, halo, halo C1-C3 alkyl, amino, amino C1-C3 alkyl, hydroxy, hydroxy C1-C3 alkyl and oxo; R’ is halo; R 4 is an aryl or heteroaryl ring; the ring is optionally substituted with 1, 2 or 3 substituents independently selected from C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkoxy C1-C6 alkyl, C1-C3 alkyl, cyano, cyano C1-C3 alkyl, halo, halo C1-C3 alkoxy, halo C1-C3 alkyl, nitro and oxo; X is O or NR 16 where R 16 is hydrogen or C1-C3 alkyl; R 5is selected from hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di(C1-C3 alkyl)amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR a R b selected from C1-C6 alkyl, and the aryl moiety of aryl, aryl C1-C6 alkyl, C3-C6 cycloalkyl, the cycloalkyl moiety of C3-C6 cycloalkyl C1-C6 alkyl, heteroaryl, the heteroaryl moiety of heteroaryl C1-C6 alkyl, heterocyclyl, the heterocyclyl moiety of heterocyclyl C1-C6 alkyl is optionally substituted with 1, 2, 3 or 4 groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)amino C1-C3 alkyl, amino, amino C1-C3 alkyl, azido C1-C6 alkyl, carboxy, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino C1-C3 alkyl, halo, halo C1-C3 alkoxy, halo C1-C3 alkyl, heteroaryl C1-C3 alkyl, heterocyclyl, heterocyclyl C1-C3 alkyl, hydroxy, hydroxy C1-C3 alkyl, nitro and oxo; the heteroaryl moiety of heteroaryl C1-C3 alkyl, heterocyclyl and the heterocyclyl moiety of heterocyclyl C1-C3 alkyl are further optionally substituted with 1, 2 or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo, halo C1-C3 alkyl and (NR x R y )C1-C3 alkyl; or R 5 and R 16together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from 1, 2, 3 or 4 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, amino C1-C3 alkyl, hydroxy and hydroxy C1-C3 alkyl; R a and R b one of which is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, aryl C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkyl C1-C6 alkyl; and R x and R y one of which is hydrogen, and the other is selected from -C(O)C1-C6 alkylheterocyclyl, the heterocyclyl being optionally substituted with an oxo group) provides a compound of or a pharmaceutically acceptable salt thereof. 【0007】 In some embodiments, the disclosure provides a compound of formula (I) wherein U is a bond or NH; Z is a bond, O, NR e or CR e R f wherein R e and R f are independently hydrogen or C1-C3 alkyl; R 1 is aryl or heteroaryl, the aryl and heteroaryl being optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, halo C1-C3 alkyl, hydroxy and hydroxy C1-C3 alkyl; R 2 and R 3is independently selected from hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halo, halo C1-C3 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 and hydroxy; Y is a bond, O, NR g (CR e R f ) m 、NR f or CR e R f where m is 1, 2 or 3, and R e 、R f and R g are independently hydrogen or C1-C3 alkyl; A is a 4- to 10-membered nitrogen-containing monocyclic or bicyclic bridged, fused or spirocyclic saturated, unsaturated or partially unsaturated ring system optionally containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring system being optionally substituted with 1, 2 or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, cyano, cyano C1-C3 alkyl, halo, halo C1-C3 alkyl, amino, amino C1-C3 alkyl, hydroxy, hydroxy C1-C3 alkyl and oxo; R’ is halo; R 4 is an aryl or heteroaryl ring; the ring is optionally substituted with 1, 2 or 3 substituents independently selected from C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkoxy C1-C6 alkyl, C1-C3 alkyl, cyano, cyano C1-C3 alkyl, halo, halo C1-C3 alkoxy, halo C1-C3 alkyl, nitro and oxo; X is O or NR 16 where R 16 is hydrogen or C1-C3 alkyl; R 5is selected from hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di(C1-C3 alkyl)amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR a R b is selected from C1-C6 alkyl, and the aryl moiety of aryl, aryl C1-C6 alkyl, C3-C6 cycloalkyl, the cycloalkyl moiety of C3-C6 cycloalkyl C1-C6 alkyl, heteroaryl, the heteroaryl moiety of heteroaryl C1-C6 alkyl, heterocyclyl, the heterocyclyl moiety of heterocyclyl C1-C6 alkyl is optionally substituted with 1, 2, 3 or 4 groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)amino C1-C3 alkyl, amino, amino C1-C3 alkyl, carboxy, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino C1-C3 alkyl, halo, halo C1-C3 alkoxy, halo C1-C3 alkyl, heterocyclyl, heterocyclyl C1-C3 alkyl, hydroxy, hydroxy C1-C3 alkyl, nitro and oxo; and the heterocyclyl moiety of heterocyclyl and heterocyclyl C1-C3 alkyl is further optionally substituted with 1, 2 or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo and halo C1-C3 alkyl; or R 5 and R 16forms a heterocyclic group optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from 1, 2, 3 or 4 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, amino C1-C3 alkyl, hydroxy and hydroxy C1-C3 alkyl together with the nitrogen atom to which they are attached; and R a and R b one of which is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, aryl C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkyl C1-C6 alkyl) or a pharmaceutically acceptable salt thereof. 【0008】 In some embodiments, the disclosure provides a compound of formula (I) wherein U is a bond or NH; Z is a bond, O, NR e or CR e R f wherein R e and R f are independently hydrogen or C1-C3 alkyl; R 1 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, halo C1-C3 alkyl, hydroxy and hydroxy C1-C3 alkyl; R 2 and R 3 are independently selected from hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halo, halo C1-C3 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 and hydroxy; Y is a bond, O, NR g (CRe R f ) m 、 NR f or CR e R f wherein m is 1, 2 or 3, and R e 、 R f and R g are independently hydrogen or C1-C3 alkyl; A is a 4- to 10-membered nitrogen-containing monocyclic or bicyclic bridged, fused or spirocyclic saturated, unsaturated or partially unsaturated ring system optionally containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring system being optionally substituted with 1, 2 or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, cyano, halo, halo C1-C3 alkyl, amino, amino C1-C3 alkyl, hydroxy, hydroxy C1-C3 alkyl and oxo; R' is halo; R 4 is a 5- or 6-membered aromatic ring optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; said ring being optionally substituted with 1, 2 or 3 substituents independently selected from C2-C4 alkenyl, C1-C3 alkyl, cyano, cyano C1-C3 alkyl, halo, halo C1-C3 alkoxy, halo C1-C3 alkyl, nitro and oxo; X is O or NR 16 wherein R 16 is hydrogen or C1-C3 alkyl; R 5 is hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di(C1-C3 alkyl)amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR aR b Selected from C1-C6 alkyl, the aryl moiety of aryl C1-C6 alkyl, C3-C6 cycloalkyl, the cycloalkyl moiety of C3-C6 cycloalkyl C1-C6 alkyl, heteroaryl, the heteroaryl moiety of heteroaryl C1-C6 alkyl, heterocyclyl, the heterocyclyl moiety of heterocyclyl C1-C6 alkyl is optionally substituted with 1, 2, 3 or 4 groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)amino C1-C3 alkyl, amino, amino C1-C3 alkyl, carboxy, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino C1-C3 alkyl, halo, halo C1-C3 alkoxy, halo C1-C3 alkyl, heterocyclyl, heterocyclyl C1-C3 alkyl, hydroxy, hydroxy C1-C3 alkyl, nitro and oxo; the heterocyclyl moiety of heterocyclyl and heterocyclyl C1-C3 alkyl is further optionally substituted with 1, 2 or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo and halo C1-C3 alkyl; or R 5 and R 16 together with the nitrogen atom to which they are attached form a heterocyclic group optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from 1, 2, 3 or 4 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, amino C1-C3 alkyl, hydroxy and hydroxy C1-C3 alkyl; and R a and R b one of which is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, aryl C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkyl C1-C6 alkyl) To provide a compound or a pharmaceutically acceptable salt thereof. 【0009】 In some embodiments, R4 is a 5- or 6-membered aromatic ring optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 【0010】 In some embodiments, Y is a bond. 【0011】 In some embodiments, Y is NR f In certain embodiments, Y is NCH3. 【0012】 In some embodiments, A is a 4- to 9-membered monocyclic or bicyclic bridged, spirocyclic or fused saturated ring system optionally containing 1 or 2 nitrogen atoms. 【0013】 In some embodiments, A-U is 【Chemical formula】 【Chemical formula】 【Chemical formula】 wherein 【Chemical formula】 represents a point of attachment to a carbonyl group; and 【Chemical formula】 represents a point of attachment to Y. 【0014】 In some embodiments, A-U is 【Chemical formula】 wherein 【Chemical formula】 represents a point of attachment to a carbonyl group; and 【Chemical formula】 represents the attachment point to Y. 【0015】 In some embodiments, A-U is [Chemical formula] wherein [Chemical formula] represents the attachment point to the carbonyl group; and [Chemical formula] represents the attachment point to Y. 【0016】 In some embodiments, R 2 is hydrogen or methoxy. 【0017】 In some embodiments, R 3 is halo. 【0018】 In some embodiments, R 4 is selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl and triazolyl, and each ring is optionally substituted with one, two or three groups independently selected from C2-C4 alkenyl, C1-C3 alkyl, halo, halo C1-C3 alkoxy, halo C1-C3 alkyl, nitro and oxo. In some embodiments, R 4 is selected from imidazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, thiadiazolyl and thiazolyl, and each ring is optionally substituted with methyl or halo. 【0019】 In some embodiments, X is O. 【0020】 In some embodiments, R 5 is [Chemical formula] selected from, and each ring is optionally substituted with one, two or three groups independently selected from C1-C3 alkoxy, C1-C3 alkoxy C1-C3 alkyl, C1-C3 alkyl, benzyl, halo, halo C1-C3 alkyl, hydroxy, hydroxy C1-C3 alkyl and oxo. 【0021】 In some embodiments, R 5 is -(C1-C3 alkyl)-R 6 wherein R 6 is a 3- to 5-membered monocyclic ring system, an 8- or 9-membered bicyclic fused saturated ring system or a 10-membered tricyclic saturated ring system, each ring system optionally containing one nitrogen atom, and each ring system is optionally substituted with one or two groups independently selected from C1-C3 alkyl, halo and (4- to 6-membered heterocyclyl)C1-C3 alkyl; the heterocyclyl moiety of (4- to 6-membered heterocyclyl)C1-C3 alkyl is further optionally substituted with a halo group. 【0022】 In some embodiments, R 5 is 【Chemical formula】 wherein 【Chemical formula】 represents the point of attachment to X. 【0023】 In some embodiments, R 5 is 【Chemical formula】 wherein n is 0, 1 or 2; each R 20 is halo; and 【Chemical formula】 represents the point of attachment to X. 【0024】 In some embodiments, Z is a bond. 【0025】 In some embodiments, R 1 is a monocyclic heteroaryl ring containing 1, 2, or 3 nitrogen atoms, and the ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, halo C1-C3 alkyl, hydroxy, and hydroxy C1-C3 alkyl. 【0026】 In some embodiments, R 1 is 【Chemical formula】 wherein, 【Chemical formula】 represents a bonding point to the parent molecule moiety. 【0027】 In some embodiments, R 1 is a bicyclic heteroaryl ring containing 1, 2, or 3 heteroatoms selected from nitrogen and sulfur, and the ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, halo C1-C3 alkyl, hydroxy, and hydroxy C1-C3 alkyl. 【0028】 In some embodiments, R 1 is a phenyl ring optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, halo C1-C3 alkyl, hydroxy, and hydroxy C1-C3 alkyl. 【0029】 In some embodiments, R 1 is a C6-C aryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, halo C1-C3 alkyl, hydroxy and hydroxy C1-C3 alkyl. In some embodiments, R 10 is a C6-C aryl. In some embodiments, R 1 is a naphthyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from C1-C3 alkyl, C2-C4 alkynyl, halo and hydroxy. In some embodiments, R 1 is naphthyl, and the naphthyl is substituted with 1, 2 or 3 groups independently selected from C2-C4 alkynyl, halo and hydroxy. 【0030】 In some embodiments, R 1 is [Chemical formula] wherein [Chemical formula] represents a bonding point to the parent molecule moiety. 【0031】 In some embodiments, R 1 is [Chemical formula] wherein [Chemical formula] represents a bonding point to the parent molecule moiety. 【0032】 In some embodiments, R' is fluoro. In some embodiments, R' is chloro. 【0033】 In some embodiments, the present disclosure provides formula (IC): [Chemical formula] (IC) to provide a compound of or a pharmaceutically acceptable salt thereof, wherein R’ is chloro or fluoro; A-U is [Chemical formula] and R 4 is selected from imidazolyl, oxazolyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl; each ring is optionally substituted with a halo or methyl group. 【0034】 In some embodiments, the present disclosure [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] A compound selected from or a pharmaceutically acceptable salt thereof is provided. 【0035】 In some embodiments, the present disclosure (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(4-methylpyridin-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(oxazol-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(5-methylpyridin-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-chloro-3-(pyrimidin-yl)prop-2-en-1-one; (Z)-3-(5-Bromopyridin-2-yl)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoroprop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(6-methylpyridin-2-yl)prop-2-en-1-one; (Z)-3-(4-Bromothiazol-2-yl)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoroprop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one; (Z)-N-((1R,4R)-2-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-4-yl)-2-fluoro-3-(pyridin-2-yl)acrylamide; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(6-(methoxymethyl)pyridin-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyrazin-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(6-methoxypyridin-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyrimidin-4-yl)prop-2-en-1-one; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-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-(8-Fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)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-Chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyrimidin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(8-Fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (S,Z)-1-(4-(7-(8-Chloronaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; 2-((S)-1-((Z)-2-Fluoro-3-(thiazol-2-yl)acryloyl)-4-(8-fluoro-7-(2-fluoro-5-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(8-Ethylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (S,Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(6-methylpyrazin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-2-Fluoro-1-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-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)piperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(benzo[b]thiophen-3-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; 2-((S)-4-(7-(Benzo[b]thiophen-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)-4-(8-fluoro-7-(7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)-4-(8-fluoro-7-(7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; (Z)-2-fluoro-1-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-2-fluoro-1-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-3-(thiazol-2-yl)prop-2-en-1-one; 2-((S)-4-(7-(2,5-difluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-(2,5-Difluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(2-(Difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-(2-(Difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)-4-(8-fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)-4-(8-fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-1-((Z)-2-Fluoro-3-(thiazol-2-yl)acryloyl)-4-(8-fluoro-7-(5-chloro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one; 8-(8-Fluoro-4-(4-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; 8-(8-Fluoro-4-(4-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; 2-((S)-4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)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-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(oxazol-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyrazin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; 2-((S)-1-((Z)-2-Fluoro-3-(pyridin-2-yl)acryloyl)-4-(8-fluoro-7-(5-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-1-((Z)-2-Fluoro-3-(thiazol-2-yl)acryloyl)-4-(8-fluoro-7-(5-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; (Z)-1-((S)-4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((S)-4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((S)-4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((S)-4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-((S)-4-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(2-Amino-5,7-difluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(2-Amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((S)-4-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((S)-4-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; 2-((S)-1-((Z)-2-Fluoro-3-(thiazol-2-yl)acryloyl)-4-(8-fluoro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile; 2-((S)-4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxyphenyl)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (Z)-1-(3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one trans isomer 1; (Z)-1-(3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one trans isomer 2; (Z)-1-(3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one cis isomer; (Z)-1-(3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one cis isomer 2; (Z)-1-(3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one cis isomer 1; (Z)-1-(3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one cis isomer 2; (Z)-1-(3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one trans isomer 1; (Z)-1-(3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one trans isomer 2; (Z)-1-(3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((3R)-4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((3R)-4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-diazepan-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-diazepan-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; 2-((2S)-4-(7-(2-Cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-(2-Cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(7-(2-Cyclobutylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-(2-Cyclobutylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-((2S,5R)-4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((3R)-4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-((3aR,6aR)-1-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((3aR,6aR)-1-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynyl-4-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynyl-4-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-((S)-4-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-((S)-4-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-(2-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(2-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-(7-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; 2-((S)-4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-hydroxy-2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5-hydroxy-2-(trifluoromethyl)phenyl)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-Ethynyl-5-fluoronaphthalen-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-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynyl-5-fluoronaphthalen-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-2-yl)prop-2-en-1-one; (Z)-1-(4-(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)piperazin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-(4-(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)piperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((3aR,6aS)-5-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((3aR,6aS)-5-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-(6-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one, (Z)-1-(6-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-(6-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(6-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; 2-((S)-4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-6-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (S,Z)-1-(4-(2-((1-(3-azidopropyl)pyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; N-((1-(3-((S)-2-(((7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(4-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)propyl)-1H-1,2,3-triazol-4-yl)methyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide; 8-(8-Fluoro-4-(((R)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)pyrrolidin-3-yl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; 8-(8-Fluoro-4-(((R)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)pyrrolidin-3-yl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; (Z)-1-((R)-3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(thiazol-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-pyrrolidin-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-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((3R)-3-((7-(2-Amino-5,7-difluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolidin-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; tert-Butyl (5,7-difluoro-4-(8-fluoro-4-(((R)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)pyrrolidin-3-yl)(methyl)amino)-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate; 2-Amino-7-fluoro-4-(8-fluoro-4-(4-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-1-yl)-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophene-3-carbonitrile; 2-Amino-7-fluoro-4-(8-fluoro-4-(4-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-1-yl)-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophene-3-carbonitrile; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyrimidin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(oxazol-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(6-methylpyrazin-2-yl)prop-2-en-1-one; (Z)-2-Chloro-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridazin-3-yl)prop-2-en-1-one; (Z)-1-((3S,4R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-fluoropyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((3S,4R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-fluoropyrrolidin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; (Z)-1-((3S,4R)-3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-fluoropyrrolidin-1-yl)-2-fluoro-3-(pyrazin-2-yl)prop-2-en-1-one; (Z)-1-(4-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)piperidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)piperidin-1-yl)-2-fluoro-3-(thiazol-2-yl)prop-2-en-1-one; 3-(8-Fluoro-4-(4-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H-indole-4-carbonitrile; and 3-(8-Fluoro-4-(4-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H-indole-4-carbonitrile To provide a compound selected from or a pharmaceutically acceptable salt thereof. 【0036】 In some embodiments, the disclosure provides atropisomers of the compounds of any of the preceding embodiments. In certain embodiments, the compound is a stable atropisomer as described herein. 【0037】 In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 【0038】 In some embodiments, the disclosure provides an oral dosage form comprising a compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 【0039】 In some embodiments, the disclosure provides a method of treating cancer expressing a KRAS G12C, G12D, and / or G12V mutation in a subject in need thereof, the method comprising administering to the subject a compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof. 【0040】 In some embodiments, the disclosure provides a method of treating cancer expressing a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof. 【0041】 In some embodiments, the disclosure provides a method of treating cancer sensitive to KRAS G12C inhibition in a subject in need thereof, the method comprising administering to the subject a compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof. 【0042】 In some embodiments, the disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, gastric cancer, or uterine cancer. 【0043】 In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer. 【0044】 In some embodiments of the method, the compound is an atropisomer of a compound of any of the previous embodiments. In certain embodiments, the compound is a stable atropisomer as described herein. 【0045】 In another embodiment, the present disclosure provides a method of inhibiting KRAS G12C activity in a cell, comprising contacting the cell with a therapeutically effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. 【0046】 In some embodiments, the present disclosure provides a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting the cell with a therapeutically effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. 【0047】 In another embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in inhibiting KRAS G12C. 【0048】 In another embodiment, the present disclosure provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of a KRAS G12C-related disease or disorder. 【0049】 In another embodiment, the present disclosure provides the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer. 【0050】 In another aspect, the present disclosure provides the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the activity of KRAS G12C. 【0051】 In another aspect, the present disclosure provides the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a KRAS G12C-related disease or disorder. 【DETAILED DESCRIPTION OF THE INVENTION】 【0052】 Unless otherwise indicated, any atom with an unsatisfied valence is assumed to have sufficient hydrogen atoms to satisfy its valence. 【0053】 The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. 【0054】 As used herein, the term "or" is inclusive (i.e., and / or) and does not denote exclusive disjunction unless explicitly indicated by terms such as "either", "otherwise", "instead" and words of similar effect. 【0055】 As used herein, the phrase "or a pharmaceutically acceptable salt thereof" refers to at least one compound or at least one salt of a compound or a combination thereof. For example, "a compound of formula (I) or a pharmaceutically acceptable salt thereof" includes a compound of formula (I), two compounds of formula (I), a pharmaceutically acceptable salt of a compound of formula (I), a compound of formula (I) and one or more pharmaceutically acceptable salts of a compound of formula (I), and two or more pharmaceutically acceptable salts of a compound of formula (I), but is not limited thereto. 【0056】 The term "C2-C4 alkenyl", as used herein, refers to a group derived from a straight-chain or branched-chain hydrocarbon containing 2 to 4 carbon atoms and one double bond. 【0057】 The term "C1-C3 alkoxy", as used herein, refers to a C1-C3 alkyl group bonded to the parent molecular moiety through an oxygen atom. 【0058】 The term "C1-C3 alkoxy C1-C6 alkyl", as used herein, refers to a C1-C3 alkoxy group bonded to the parent molecular moiety through a C1-C6 alkyl group. 【0059】 The term "C1-C3 alkoxycarbonyl", as used herein, refers to a C1-C3 alkoxy group bonded to the parent molecular moiety through a carbonyl group. 【0060】 The term "C1-C3 alkyl", as used herein, refers to a group derived from a straight-chain or branched-chain saturated hydrocarbon containing 1 to 3 carbon atoms. 【0061】 The term "C1-C3 alkylcarbonyl", as used herein, refers to a C1-C3 alkyl group bonded to the parent molecular moiety through a carbonyl group. 【0062】 The term "C2-C4 alkynyl", as used herein, refers to a group derived from a straight-chain or branched-chain hydrocarbon containing 2 to 4 carbon atoms and 1 triple bond. 【0063】 The term "amino", as used herein, refers to -NH2. 【0064】 The term "amino C1-C3 alkyl", as used herein, refers to an amino group bonded to the parent molecular moiety through a C1-C3 alkyl group. 【0065】 As used herein, the term "aryl" refers to a phenyl group or a bicyclic fused ring system in which one or both of the rings are phenyl groups. The bicyclic fused ring system consists of a phenyl group fused to a 4- to 6-membered aromatic or non-aromatic carbocyclic ring. The aryl groups of the present disclosure can be attached to the parent molecular moiety through any substitutable carbon atom of the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. 【0066】 As used herein, the term "aryl C1-C6 alkyl" refers to an aryl group attached to the parent molecular moiety through a C1-C6 alkyl group. 【0067】 As used herein, the term "azide" refers to -N3. 【0068】 As used herein, the term "azide C1-C6 alkyl" refers to an azide group attached to the parent molecular moiety through a C1-C6 alkyl group. 【0069】 As used herein, the term "carboxy" refers to -CO2H. 【0070】 As used herein, the term "carboxy C1-C6 alkyl" refers to a C1-C6 alkyl group substituted with one, two, or three carboxy groups. 【0071】 As used herein, the term "C(O)-C1-C6 alkyl heteroaryl" refers to a heteroaryl C1-C6 alkyl group attached to the parent molecular moiety through a carbonyl group. 【0072】 As used herein, the term "cyano" refers to -CN. 【0073】 As used herein, the term "C3-C4 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring system having 3 or 4 carbon atoms and 0 heteroatoms. 【0074】 The term "C3-C6 cycloalkyl" as used herein refers to a saturated monocyclic hydrocarbon ring system having 3 to 6 carbon atoms and 0 heteroatoms. 【0075】 The term "C3-C6 cycloalkyl C1-C6 alkyl" as used herein refers to C3-C6 cycloalkyl bonded to the parent molecular moiety via a C1-C6 alkyl group. 【0076】 The term "di(C1-C6 alkyl)amino" as used herein refers to -NR z R z’ (wherein R z and R z’ are the same or different C1-C6 alkyl groups). 【0077】 The term "di(C1-C3 alkyl)amino C2-C6 alkyl" as used herein refers to -(C2-C6 alkyl)NR z R z’ (wherein R z and R z’ are the same or different C1-C6 alkyl groups). 【0078】 The terms "halo" and "halogen" as used herein refer to F, Cl, Br or I. 【0079】 The term "halo C1-C3 alkoxy" as used herein refers to a C1-C3 alkoxy group substituted with 1, 2 or 3 halogen atoms. 【0080】 The term "halo C1-C3 alkyl" as used herein refers to a C1-C3 alkyl group substituted with 1, 2 or 3 halogen atoms. 【0081】 The term "halo C1-C6 alkyl" as used herein refers to a C1-C6 alkyl group substituted with 1 to 6 halogen atoms. 【0082】 As used herein, the term "heteroaryl" refers to an aromatic 5- or 6-membered ring in which at least one atom is selected from N, O, and S and the remaining atoms are carbon. The term "heteroaryl" includes bicyclic systems in which the heteroaryl ring is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S; and tricyclic systems in which the bicyclic system is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S. A heteroaryl group is attached to the parent molecular moiety via any replaceable carbon or nitrogen atom in the group. Representative examples of heteroaryl groups include, but are not limited to, alloxazine, benzo[1,2-d:4,5-d']bisthiazole, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl. 【0083】 In embodiments where the term "heteroaryl" includes a bicyclic system, the aromatic 5- or 6-membered ring having at least one atom selected from N, O, and S is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S. In embodiments where the term "heteroaryl" includes a tricyclic system, the bicyclic system defined in the previous sentence is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S. 【0084】 As used herein, the term "heteroaryl C1-C3 alkyl" refers to a heteroaryl group attached to the parent molecular moiety via a C1-C3 alkyl group. 【0085】 As used herein, the term "heteroaryl C1-C6 alkyl" refers to a heteroaryl group attached to the parent molecular moiety via a C1-C6 alkyl group. 【0086】 As used herein, the term "heterocyclyl" refers to a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered saturated or partially unsaturated ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The term "heterocyclyl" also includes groups in which the heterocyclyl ring is fused to one, two or three 4- to 6-membered aromatic or non-aromatic carbocyclic rings or monocyclic heterocyclyl groups. The term "heterocyclyl" also includes the above-mentioned monocyclic or polycyclic heterocyclyl groups further substituted with one or more spirocyclic groups attached to the heterocyclyl group via a spiro carbon. Examples of heterocyclyl groups include, but are not limited to, dihydro-1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolidine-6',1''-cyclopropane], hexahydro-2H-1,4-dioxa-2a1-azacyclopenta[cd]pentalenyl, hexahydropyrrolidinyl, indolinyl, morpholinyl, octahydroindolizinyl, octahydroquinolizinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl and thiomorpholinyl. 【0087】 As used herein, the term "heterocyclyl C1-C6 alkyl" refers to a heterocyclyl group attached to the parent molecular moiety via a C1-C6 alkyl group. 【0088】 As used herein, the term "hydroxy" refers to -OH. 【0089】 As used herein, the term "hydroxy C1-C3 alkyl" refers to a hydroxy group attached to the parent molecular moiety via a C1-C3 alkyl group. 【0090】 The term "hydroxy C1-C6 alkyl", as used herein, refers to a hydroxy group attached to the parent molecular moiety via a C1-C6 alkyl group. 【0091】 "NR a R b -C(O)", as used herein, refers to an NR a R b group attached to the parent molecular moiety via a carbonyl group. 【0092】 "NR a R b -C(O)-C1-C6 alkyl", as used herein, refers to an NR a R b -C(O)- group attached to the parent molecular moiety via a C1-C6 alkyl group. 【0093】 "NR a R b C1-C6 alkyl", as used herein, refers to an NR a R b group attached to the parent molecular moiety via a C1-C6 alkyl group. 【0094】 "NR x R y C1-C3 alkyl", as used herein, refers to an NR x R y group attached to the parent molecular moiety via a C1-C3 alkyl group. 【0095】 The term "nitro", as used herein, refers to -NO2. 【0096】 The term "oxo", as used herein, refers to =O. 【0097】 This disclosure contemplates the inclusion of all isotopes of atoms present in the compounds described herein. Isotopes include atoms having the same atomic number but different mass numbers. General examples include, without limitation, deuterium and tritium as isotopes of hydrogen. Isotopes of carbon include 13 C and 14 C. Compounds of the disclosure labeled with isotopes can generally be prepared by conventional techniques known to those skilled in the art using appropriately labeled reagents in place of the unlabeled reagents originally employed, or by processes similar to those described herein. Such compounds can have various potential uses, such as as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds can potentially advantageously alter biological, pharmacological, or pharmacokinetic properties. 【0098】 A further aspect of the subject matter described herein is the use of the disclosed compounds as radiolabeled ligands for the development of ligand binding assays or for monitoring in vivo adsorption, metabolism, distribution, receptor binding or occupancy, or compound disposition. For example, the compounds described herein can be prepared using radioactive isotopes, and the resulting radiolabeled compounds can be used to develop binding assays or for metabolic studies. Alternatively and for the same purpose, the compounds described herein can be converted to radiolabeled forms by catalytic tritiation using methods known to those skilled in the art. 【0099】 The specific compounds of the present disclosure exist as stereoisomers. When the stereochemistry is not specified, it should be understood that the present disclosure encompasses any stereochemical isomeric form or mixture thereof having the ability to inhibit KRAS G12C. The individual stereoisomers of the compound can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products followed by separation, for example, conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic methods or direct separation of enantiomers on a chiral chromatography column. Starting compounds of specific stereochemistry are commercially available or can be made and resolved by techniques known in the art. 【0100】 The specific compounds of the present disclosure exist as atropisomers. The term "atropisomer" refers to conformational stereoisomers that occur when rotation around a single bond in a molecule is prevented or significantly retarded as a result of steric interactions with other parts of the molecule, and the substituents at both ends of the single bond are asymmetric (i.e., optical activity occurs without the need for an asymmetric carbon center or stereocenter). When the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of the isomeric species may be possible. Atropisomers are enantiomers (or epimers) that do not have a single asymmetric atom. 【0101】 Atropisomers can be considered stable if the barrier to interconversion is high enough to allow the atropisomers to undergo little or no interconversion at room temperature for at least one week. In some embodiments, the atropisomers undergo little or no interconversion at room temperature for at least one year. In some embodiments, the atropisomeric compounds of the present disclosure, when the atropisomeric compound is in a substantially pure form and generally in the solid state, do not undergo more than about 5% interconversion to the opposite atropisomer at room temperature for one week. In some embodiments, the atropisomeric compounds of the present disclosure do not undergo more than about 5% interconversion to the opposite atropisomer at room temperature (about 25 °C) for one year. In some embodiments, the atropisomeric compounds of the present disclosure are sufficiently stable to undergo no more than about 5% interconversion in an aqueous pharmaceutical formulation held at 0 °C for at least one week. The present chemical substances, pharmaceutical compositions, and methods are intended to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of a single atropisomer, and intermediate mixtures. 【0102】 The energy barrier to thermal racemization of atropisomers can be determined by the steric hindrance to free rotation of one or more bonds forming the chiral axis. Certain biaryl compounds exhibit atropisomerism when rotation around the inter-ring bond lacking C2 symmetry is restricted. The free energy barrier to isomerization (enantiomerization) is a measure of the stability of the inter-ring bond to rotation. Optical and thermal excitation can promote racemization of such isomers depending on electronic and steric factors. 【0103】 Ortho-substituted biaryl compounds can exhibit rotational isomerism of this type of conformation. Such biaryls are chiral atropisomers of enantiomers, and the sp 2 -sp 2 carbon-carbon inter-ring bond has an energy barrier high enough to prevent free rotation, and substituents W 1 ≠W 2 and W 3 ≠W 4asymmetrically polarizes the molecule. [Chemical formula] 【0104】 W 1 :W 3 , W 1 :W 4 and / or W 2 :W 4 , W 2 :W 3 The steric interaction between them is large enough to make the planar conformation the most energetic. In this case, two non-planar axial chiral enantiomers, if their interconversion is slow enough so that they can be isolated without containing each other, exist as atropisomers. The thick and dashed lines in the figure shown above indicate parts or portions of the molecule that are sterically restricted due to the rotational energy barrier. The bold parts exist perpendicular to the plane of the paper, and the dashed parts exist perpendicular to the bottom of the paper. The "flat" part of the molecule (the ring on the left side of each of the two biaryls shown) is in the plane of the paper. 【0105】 The pharmaceutical compounds of the present disclosure may include one or more pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refer to salts that retain the desired biological activity of the parent compound and do not impart any undesirable toxicological effects (see, for example, Berge, S.M. et al., J. Pharm. Sci., 66:1-19 (1977)). The salts can be obtained during the final isolation and purification of the compounds described herein, or by separately reacting the free base functional groups of the compounds with appropriate acids or reacting the acidic groups of the compounds with appropriate bases. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous, and non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, calcium, and non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine. 【0106】 Pharmaceutical composition In another aspect, the present disclosure provides a composition, such as a pharmaceutical composition, containing one or a combination of the compounds described within the present disclosure, formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present disclosure can also be administered in combination therapies, i.e., in combination with other agents described herein. 【0107】 As used herein, "pharmaceutically acceptable carrier" includes any physiologically compatible solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. In some aspects, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound can be coated on a substance to protect the compound from the action of acids and other natural conditions that can inactivate the compound. 【0108】 The pharmaceutical compositions of the present disclosure can be administered via one or more routes of administration using one or more of the various methods known in the art. As will be understood by those skilled in the art, the route of administration and / or mode of administration will vary depending on the desired result. In some embodiments, the route of administration of the compounds of the present disclosure includes intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, such as by injection or infusion. The phrase "parenteral administration" as used herein means a mode of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intra-articular, intra-orbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intra-articular, sub-synovial, sub-arachnoid, intraspinal, epidural and intrasternal injections and infusions. 【0109】 Sterile injectable solutions can be prepared by incorporating the required amount of the active compound in an appropriate solvent, with one or a combination of the ingredients listed above as required, followed by sterile filtration. Generally, dispersions are prepared by incorporating the active compound in a sterile vehicle containing a basic dispersion medium and the necessary other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, some methods of preparation are vacuum drying and freeze-drying, whereby a powder of the active ingredient and any additional desired ingredients is obtained from its previously sterile-filtered solution. 【0110】 Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils and injectable organic esters. Suitable fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions and by the use of surfactants. 【0111】 Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. Such media and agents for pharmaceutically active substances are known in the art. Their use in the pharmaceutical compositions of the present disclosure is contemplated, except in cases where any conventional media or agent is incompatible with the active compound. Auxiliary active compounds can also be incorporated into the compositions. 【0112】 Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The compositions can be formulated as solutions or liquids having an ordered structure suitable for high drug concentrations. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.) and suitable mixtures thereof. Suitable fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions and by the use of surfactants. In many cases, it is desirable to include in the composition isotonic agents, such as sugars, polyhydric alcohols, such as mannitol, sorbitol or sodium chloride. Sustained absorption of injectable compositions can be brought about by including in the composition agents that delay absorption, such as monostearates and gelatin. 【0113】 Alternatively, the compounds of the present disclosure can be administered by parenteral routes, such as topical, epidermal or mucosal administration routes, such as intranasal, oral, intravaginal, rectal, sublingual or topical administration. 【0114】 Any pharmaceutical composition contemplated herein can be orally delivered, for example, via any acceptable and appropriate oral formulation. Exemplary oral formulations include, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups and elixirs, but are not limited thereto. A pharmaceutical composition intended for oral administration can be prepared according to any method known in the art for manufacturing a pharmaceutical composition intended for oral administration. To provide a pharmaceutically palatable formulation, the pharmaceutical composition according to the present disclosure can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, lubricants, antioxidants and preservatives. 【0115】 Tablets can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. 【0116】 An aqueous suspension can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension, including but not limited to suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, alginic acid, polyvinyl pyrrolidone, tragacanth gum, and gum arabic; dispersing agents or wetting agents such as naturally occurring phosphatides such as lecithin; condensation products of alkylene oxides and fatty acids such as polyoxyethylene stearate; condensation products of ethylene oxide and long-chain aliphatic alcohols such as heptadecylene-oxycetanol; condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. The aqueous suspension can also contain at least one preservative such as ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent including but not limited to sucrose, saccharin, and aspartame. 【0117】 An oily suspension can be prepared, for example, by suspending at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in any of vegetable oils such as peanut oil, sesame oil, and coconut oil; or mineral oils such as liquid paraffin. The oily suspension can also contain at least one thickening agent such as beeswax, hard paraffin, and cetyl alcohol. To provide a palatable oily suspension, at least one of the sweetening agents and / or at least one flavoring agent already described above in this specification can be added to the oily suspension. The oily suspension can further contain at least one preservative including but not limited to antioxidants such as butylated hydroxyanisole and alpha-tocopherol. 【0118】 Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersant and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersants, wetting agents and suspending agents have already been described above. Exemplary preservatives include, but are not limited to, antioxidants such as ascorbic acid. Furthermore, the dispersible powders and granules may contain at least one excipient including, but not limited to, sweeteners, flavoring agents and coloring agents. 【0119】 The active compounds can be prepared using controlled release formulations including carriers which protect the compounds from rapid release, such as implants, transdermal patches and microencapsulation delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Many methods for preparing such formulations are patented or generally known to those skilled in the art. See, for example, Robinson, J.R., ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978). 【0120】 The therapeutic composition can be administered using medical devices known in the art. For example, in one aspect, the therapeutic composition of the present disclosure can be administered using a needleless subcutaneous injection device such as the devices disclosed in U.S. Patent Nos. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556. Examples of well-known implants and modules useful in the present disclosure include the following: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing a drug at a controlled rate; U.S. Patent No. 4,486,194, which discloses a therapeutic device for administering a drug through the skin; U.S. Patent No. 4,447,233, which discloses a drug infusion pump for delivering a drug at an accurate infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow rate implantable infusion device for continuous drug delivery; U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system having a multi-chamber compartment; and U.S. Patent No. 4,475,196, which discloses an osmotic drug delivery system. These patents are hereby incorporated by reference into this specification. Many other such implants, delivery systems, and modules are known to those skilled in the art. 【0121】 In certain aspects, the compounds of the present disclosure can be administered parenterally, i.e., by injection and / or infusion including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subdural, intraspinal, epidural, and intrasternal. 【0122】 In some aspects, the compounds of the present disclosure can be administered orally, i.e., via gelatin capsules, tablets, hard or soft capsules, or liquid capsules. 【0123】 Use / Treatment Method of KRAS Inhibitor Administration of the therapeutic agents described herein may include administration of a therapeutically effective amount of a therapeutic agent. As used herein, the term "therapeutically effective amount" refers to, but is not limited to, the amount of a therapeutic agent for treating a condition treatable by administration of a composition comprising a KRAS inhibitor described herein. This amount is sufficient to exhibit an effect leading to a detectable therapeutic effect or improvement. Effects include, by way of example and without limitation, treatment of the conditions listed herein. The exact effective amount for a particular subject will depend upon the subject's body size and health, the nature and extent of the condition being treated, the advice of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration. 【0124】 For administration of the compounds described herein, the dosage ranges from about 0.0001 to 100 mg / kg of host body weight, more commonly from 0.01 to 40 mg / kg. Exemplary treatment regimens require administration once a day, twice a week, three times a week, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months, or once every three to six months. 【0125】 The disclosed compounds strongly inhibit anchorage-independent cell growth and thus have the potential to inhibit tumor metastasis. Thus, in another aspect, the present disclosure provides a method of inhibiting tumor metastasis, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of any of the compounds disclosed herein and a pharmaceutically acceptable carrier. 【0126】 Ras mutations, including but not limited to KRAS mutations, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain aspects relate to the administration of the disclosed compounds (e.g., in the form of a pharmaceutical composition) to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the compounds of the disclosure can be used in the treatment of diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other aspects, the compounds are useful in the treatment of lymphomas such as all subtypes of Hodgkin lymphoma or non-Hodgkin lymphoma. 【0127】 Determination of whether a tumor or cancer contains a KRAS mutation can be made by evaluating the nucleotide sequence encoding the KRAS protein, the amino acid sequence of the KRAS protein, or the properties of a putative KRAS mutant protein. The sequence of the wild-type human KRAS protein is known in the art. 【0128】 Methods for detecting KRAS mutations are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, a sample is evaluated for KRAS mutations, including those by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRAS mutation is used. If the mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRAS mutation is identified using, for example, a direct sequencing method of a specific region (e.g., exon 2 and / or exon 3) in the KRAS gene. This technique will identify all possible mutations in the sequenced region. 【0129】 Methods for detecting mutations in the KRAS protein are known to those skilled in the art. These methods include, but are not limited to, detection of KRAS mutants using a binding agent specific for the mutant protein (e.g., an antibody), protein electrophoresis and Western blotting, and direct sequencing of peptides. 【0130】 Methods for determining whether a tumor or cancer contains a KRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is taken from a subject having cancer or a tumor. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to become a cell lysate. In some embodiments, the sample is processed to DNA or RNA. The present disclosure also relates to a method for treating a mammalian hyperproliferative disorder, the method comprising administering to the mammal a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.In some embodiments, the method relates to the treatment of cancers such as acute myeloid leukemia, adolescent cancers, pediatric adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi sarcoma), anal cancer, appendiceal cancer, astrocytoma, anaplastic teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, osteosarcoma, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, anaplastic teratoma, germinoma, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), germinoma, CNS cancer, endometrial cancer, epithelioma, esophageal cancer, nasal neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary, midline duct carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, fungating polypoid tumor, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal and paranasal cavity cancer, oropharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, pediatric atypical cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer. In some embodiments, the method relates to the treatment of non-cancerous hyperproliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)). 【0131】 In certain aspects, the present disclosure relates to a method for treating lung cancer, the method comprising administering to a subject in need thereof an effective amount of any of the above compounds (or a pharmaceutical composition comprising the same). In certain aspects, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell carcinoma or large cell lung cancer. In other aspects, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, adenoid cystic tumors, carcinoid tumors and undifferentiated carcinomas.Subjects treatable with the compounds of the present disclosure or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates or derivatives of said compounds include, according to the methods of the present disclosure, for example, acute myeloid leukemia, acute myeloid leukemia, adolescent cancer, pediatric adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, osteosarcoma, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid rhabdoid tumor, germinoma, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T cell lymphoma, ductal carcinoma in situ (DCIS) of the breast, germinoma, CNS cancer, endometrial cancer, epithelioma, esophageal cancer, nasal neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary, midline ductal carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, fungating polyp, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal and paranasal cavity cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, pediatric dysplastic cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer.In some embodiments, subjects to be treated with the compounds of the present disclosure include subjects diagnosed with non-cancerous hyperproliferative diseases such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)). The present disclosure further provides a method of modulating the activity of a mutant KRAS protein by contacting the protein with an effective amount of a compound of the present disclosure. The modulation can be inhibiting or activating the protein activity. In some embodiments, the present disclosure provides a method of inhibiting the activity of a mutant KRAS protein by contacting the mutant KRAS protein with an effective amount of a compound of the present disclosure in solution. In some embodiments, the present disclosure provides a method of inhibiting the activity of a mutant KRAS protein by contacting a cell, tissue, or organ that expresses the protein of interest. In some embodiments, the present disclosure provides a method of inhibiting the activity of a protein in a subject by administering to the subject an effective amount of a compound of the present disclosure, including, but not limited to, rodents and mammals (e.g., humans). In some embodiments, the percentage of modulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibition exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the present disclosure provides a method of inhibiting the KRAS activity in a cell by contacting the cell with an amount of a compound of the present disclosure sufficient to inhibit the activity of an intracellular KRAS mutant. In some embodiments, the present disclosure provides a method of inhibiting mutant KRAS in a tissue by contacting the tissue with an amount of a compound of the present disclosure sufficient to inhibit the activity of the mutant KRAS in the tissue. In some embodiments, the present disclosure provides a method of inhibiting KRAS in an organism by contacting the organism with an amount of a compound of the present disclosure sufficient to inhibit the activity of KRAS in the organism. In some embodiments, the present disclosure provides a method of inhibiting the activity of KRAS in an animal by contacting the animal with an amount of a compound of the present disclosure sufficient to inhibit the activity of KRAS in the animal.In some embodiments, the present disclosure provides a method of inhibiting KRAS, including that in a mammal, by contacting the mammal with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the mammal. In some embodiments, the present disclosure provides a method of inhibiting the activity of KRAS in a human by contacting the human with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the human. The present disclosure provides a method of treating a disease mediated by KRAS activity in a subject in need of such treatment. The present disclosure also provides a method of combination therapy, in which an agent known to modulate other pathways or other components of the same pathway, or a target enzyme of an overlapping set, is used in combination with a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative thereof. In one embodiment, such therapies include, but are not limited to, combinations of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy. 【0132】 Currently, many chemotherapeutic agents are known in the art and can be used in combination with the compounds of the present disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormonal agents, angiogenesis inhibitors, and antiandrogens. 【0133】 The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition to be treated. Thus, in some embodiments, one or more compounds of the present disclosure will be co-administered with the other agents described above. When used in combination therapy, the compounds described herein are administered simultaneously with or separately from the second agent. This combined administration can include simultaneous administration of two agents in the same dosage form, simultaneous administration of separate dosage forms, and separate administrations. That is, the compounds described herein and any of the above agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure and any of the above agents can be administered simultaneously, and both agents are present in separate formulations. In another alternative, any of the above agents can be administered subsequent to the compounds of the present disclosure or vice versa. In some embodiments of separate administration protocols, the compounds of the present disclosure and any of the above agents are administered at intervals of minutes, or hours, or days. 【0134】 Compounds include those described below and can be made by methods known in the art, including modifications within the skill of the artisan. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. Any variable used to describe the synthesis of a compound (e.g., numbered "R" substituents) is intended only to illustrate the method of making the compound and should not be confused with variables used in the claims or other sections of this specification. The following methods are for illustrative purposes only and are not intended to limit the scope of the present disclosure. 【Examples】 【0135】 Synthesis The aspects described in this specification are further defined by the following examples. It should be understood that the examples are provided by way of illustration only. From the above description, consideration and examples, those skilled in the art will be able to identify the essential features of the aspects described in this specification and, without departing from the spirit and scope thereof, make various changes and modifications to adapt them to various uses and conditions. As a result, the aspects described in this specification are not limited by the exemplary embodiments described below in this specification, but rather are defined by the claims appended hereto. 【0136】 Abbreviations The following abbreviations are used in the following sections of the examples and elsewhere in this specification: AA is ammonium acetate; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; Et is ethyl; EtOAc is ethyl acetate; h is hour; MeCN or CAN is acetonitrile, MeOH is methanol; TFA is trifluoroacetic acid; and THF is tetrahydrofuran. 【0137】 【Chem.】 Intermediate 1 (4-(4-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol) This compound was prepared according to the synthetic procedure described in WO 2021 / 041671 pamphlet. 【0138】 【Chem.】 Intermediate 2 4-(4-((1R,4R)-4-Amino-2-azabicyclo[2.2.1]heptan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol This compound was prepared by replacing the appropriate starting materials and following a procedure similar to that described for Intermediate 1. 【0139】 Preparation of Heteroaryl Intermediates [Chemical Structure] Intermediate 3 (Z)-2-Fluoro-3-(thiazol-2-yl)acrylic Acid Step 1: Preparation of Ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1.1 g, 4.5 mmol) was dissolved in THF (25 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 0.18 g, 4.5 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and thiazole-2-carbaldehyde (0.51 g, 4.5 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). The solution was diluted with water (20 mL) and EtOAc (150 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0 → 60% acetone / hexane) to give ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate ( 1 determined by 1H NMR to be a 10:1 E / Z mixture, 620 mg, 3.1 mmol, 68% yield). LC / MS (ESI) m / z: [M+H] + Calculated for C8H9FNO2S 202.0; Found 202.2; 11H 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). 【0140】 Step 2: Preparation of ethyl (Z)-2-fluoro-3-(thiazol-2-yl)acrylate Ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate (620 mg, 3.1 mmol) was dissolved in toluene (15 mL), and iodine (39 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to give ethyl (Z)-2-fluoro-3-(thiazol-2-yl)acrylate (509 mg, 2.5 mmol, 82% yield). LC / MS (ESI) m / z: [M+H] + Calculated for C8H9FNO2S 202.0; found 202.0; 1 1H NMR (500 MHz, CDCl3) δ 7.96 (dd, J = 3.2, 2.6 Hz, 1H), 7.57 (d, J = 3.2 Hz, 1H), 7.43 (dd, J = 33.3, 0.8 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). 【0141】 Step 3: Preparation of (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (Z)-2-Fluoro-3-(thiazol-2-yl)acrylic acid ethyl ester (510 mg, 2.5 mmol) was dissolved in MeOH (15 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 2.5 mL, 2.5 mmol) was added. The reaction mixture was stirred for 5 h. The solution was concentrated to remove methanol. Additional water (1.5 mL) was added and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 2.5 mL, 2.5 mmol) was added dropwise. After 10 min, a white solid precipitated. The solid was collected by filtration and washed with MeCN. The solid was dried under reduced pressure to give (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (337 mg, 1.9 mmol, 77% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated for C6H5FNO2S 174.0; found 173.8; 1 H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 2H), 7.29 (d, J = 34.5 Hz, 1H). 【0142】 [Chemical formula] Intermediate 4 (Z)-2-Fluoro-3-(pyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1.5 g, 6.2 mmol) was dissolved in THF (31 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.2 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and picolinaldehyde (0.66 g, 6.2 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (15 mL). The solution was diluted with water (20 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0 → 100% EtOAc / hexane) to give ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate ( 1 determined by 1H NMR to be a 3:1 E / Z mixture, 910 mg, 4.6 mmol, 75% yield). LC / MS (ESI) m / z: [M+H] + C 10 H 11 calculated for C10H10FNO2 196.1; found 196.1; the E isomer is reported: 1 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). 【0143】 Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate Ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate (420 mg, 2.1 mmol) was dissolved in toluene (10 mL), and iodine (27 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0→100% EtOAc / hexane) to give ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate (240 mg, 1.2 mmol, 58% yield). LC / MS(ESI) m / z: LC / MS(ESI) m / z: [M+H] + C 10 H 11 Calculated for C8H7FNO2 196.1; found 196.1; 1 1H NMR (500 MHz, CDCl3) δ 8.66 (ddd, J = 5.0, 1.8, 0.8 Hz, 1H), 7.88 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H), 7.75 (ddd, J = 8.0, 7.8, 1.8 Hz, 1H), 7.25 (ddd, J = 7.8, 5.0, 1.2 Hz, 1H), 7.14 (d, J = 34.9 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H). 【0144】 Step 3: Preparation of (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate (415 mg, 2.1 mmol) was dissolved in MeOH (15 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 2.1 mL, 2.1 mmol) was added. The reaction mixture was stirred for 5 h. The solution was concentrated to remove methanol. Additional water (2.0 mL) was added, and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 2.1 mL, 2.1 mmol) was added dropwise. After 10 min, a white solid precipitated. The solid was collected by filtration and washed with Et2O. The solid was dried under reduced pressure to give (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid (235 mg, 1.4 mmol, 66% yield) as a white solid. LC / MS(ESI) m / z: [M+H] + Calculated for C8H7FNO2 168.0; found 167.8. 11H 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). 【0145】 [Chemical formula] Intermediate 5 (Z)-2-Fluoro-3-(4-methylpyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes, and 2-formyl-4-picoline (125 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by reverse-phase HPLC (column: Xbridge C18, 30 mm × 100 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25 °C; gradient: 95:5 H2O:MeCN:0.05% TFA → 5:95 H2O:MeCN:0.05% TFA; λ = 220 nm) to give ethyl (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylate (32 mg, 0.15 mmol, 15% yield). LC / MS (ESI) m / z: [M+H] + C 11 H 13 Calculated for C H FNO2 210.2; found 209.8; 11H NMR (500 MHz, CDCl3) δ 8.51 (d, J = 5.0 Hz, 1H), 7.70 (s, 1H), 7.11 (d, J = 35.0 Hz, 1H), 7.07 (d, J = 5.0 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). 【0146】 Step 2: Preparation of (Z)-2-Fluoro-3-(4-methylpyridin-2-yl)acrylic Acid Ethyl (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylate (32 mg, 0.15 mmol) was dissolved in MeOH (1.5 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 0.15 mL, 0.15 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added, and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.15 mL, 0.15 mmol) was added dropwise. The solution was frozen and freeze-dried directly to give (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylic acid (27 mg, 0.15 mmol, assuming quantitative yield; containing 1 equivalent of NaCl) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated for C9H8FNO2 182.1; found 182.1. 1 1H NMR (500 MHz, DMSO-d6) δ 8.51 (d, J = 4.9 Hz, 1H), 7.65 (s, 1H), 7.24 (d, J = 4.9 Hz, 1H), 6.94 (d, J = 35.3 Hz, 1H), 2.36 (s, 3H). 【0147】 [Chemical Structure] Intermediate 6 (Z)-2-Fluoro-3-(oxazol-2-yl)acrylic Acid Step 1: Preparation of Ethyl (E)-2-fluoro-3-(oxazol-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and then oxazole-2-carbaldehyde (100 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexane) to afford ethyl (E)-2-fluoro-3-(oxazol-2-yl)acrylate (a 6:1 E / Z ratio as determined by 1H NMR, 165 mg, 0.89 mmol, 86% yield). LC / MS (ESI) m / z: [M+H] + Calculated for C8H9FNO3 186.0; found 186.0; reported the E isomer: 1 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 0.7 Hz, 1H), 7.25 (d, J = 0.7 Hz, 1H), 6.62 (d, J = 17.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H). 【0148】 Step 2: Preparation of ethyl (Z)-2-fluoro-3-(oxazol-2-yl)acrylate Ethyl (E)-2-fluoro-3-(oxazol-2-yl)acrylate (165 mg, 0.89 mmol) was dissolved in toluene (2 mL) and iodine (11 mg, 0.045 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0→100% EtOAc / hexane) to afford ethyl (Z)-2-fluoro-3-(oxazol-2-yl)acrylate (22 mg, 0.12 mmol, 13% yield). LC / MS (ESI) m / z: [M+H] +Calculated value for C8H9FNO3: 186.0; Measured value: 185.9 1 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.32 (s, 1H), 6.96 (d, J = 31.0 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H). 【0149】 Step 3: Preparation of (Z)-2-Fluoro-3-(oxazol-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(oxazol-2-yl)acrylate (22 mg, 0.12 mmol) was dissolved in MeOH (1 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 0.12 mL, 0.12 mmol) was added. The reaction mixture was stirred for 4 h. The solution was concentrated to remove methanol. Additional water (0.3 mL) was added, and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.12 mL, 0.12 mmol) was added dropwise. The solution was frozen and directly freeze-dried to obtain (Z)-2-fluoro-3-(oxazol-2-yl)acrylic acid (18 mg, 0.12 mmol, assuming quantitative yield; containing 1 equivalent of NaCl) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated value for C6H5FNO3: 158.0; Measured value: 157.8; 1 1H NMR (600 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.47 (s, 1H), 6.90 (d, J = 32.2 Hz, 1H). 【0150】 【Chemical Structure】 Intermediate 7 (Z)-2-Fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylic acid Step 1: Preparation of Ethyl (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and 1-methylimidazole-2-carbaldehyde (114 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by reverse phase HPLC (column: Xbridge C18, 30 mm × 100 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25 °C; gradient: 95:5 H2O:MeCN:10 mM AA → 100% 5:95 H2O:MeCN:10 nM AA; λ = 220 nm) to give ethyl (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylate (16 mg, 0.08 mmol, 8% yield). LC / MS (ESI) m / z: [M+H] + C9H 12 Calculated for FN2O2 199.1; found 198.9; 1 H NMR (500 MHz, CDCl3) δ 7.22 (d, J = 0.7 Hz, 1H), 6.94 (d, J = 0.7 Hz, 1H), 6.84 (d, J = 30.5 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.71 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 【0151】 Step 2: Preparation of (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylate (16 mg, 0.08 mmol) was dissolved in MeOH (1 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 0.08 mL, 0.08 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (0.3 mL) was added and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.08 mL, 0.08 mmol) was added dropwise. The solution was frozen and freeze-dried directly to give (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylic acid (13 mg, 0.08 mmol, assuming quantitative yield; containing 1 equivalent of NaCl) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated for C7H8FN2O2 171.0; found 170.9; 1 H NMR (500 MHz, DMSO-d6) δ 7.31 (s, 1H), 7.11 (s, 1H), 6.87 (d, J = 31.6 Hz, 1H), 3.72 (s, 3H). 【0152】 【Chemical formula】 Intermediate 8 (Z)-2-Fluoro-3-(5-methylpyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(5-methylpyridin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes, and 5-methylpicolinaldehyde (125 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (15 mL). The solution was diluted with water (20 mL) and EtOAc (100 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by reverse-phase HPLC (column: Xbridge C18, 30 mm × 100 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25 °C; gradient: 95:5 H2O:MeCN:0.05% TFA → 100% 5:95 H2O:MeCN:0.05% TFA; λ = 220 nm) to give ethyl (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylate (12 mg, 0.06 mmol, 6% yield). LC / MS (ESI) m / z: LC / MS (ESI) m / z: [M+H] + C 11 H 13 Calculated for C10H10FNO2 210.2; found 210.1 1 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.55 (dd, J = 8.2, 1.8 Hz, 1H), 7.12 (d, J = 35.3 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). 【0153】 Step 2: Preparation of (Z)-2-fluoro-3-(5-methylpyridin-2-yl)acrylic acid (Z)-2-Fluoro-3-(5-methylpyridin-2-yl)acrylic acid ethyl ester (12 mg, 0.06 mmol) was dissolved in MeOH (0.5 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 0.06 mL, 0.06 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.06 mL, 0.06 mmol) was added dropwise. The solution was frozen and freeze-dried directly to give (Z)-2-fluoro-3-(5-methylpyridin-2-yl)acrylic acid (10 mg, 0.06 mmol, assuming quantitative yield; containing 1 equivalent of NaCl) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated for C9H8FNO2 182.1; found 181.6; 1 H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.74 - 7.69 (m, 2H), 6.95 (d, J = 35.4 Hz, 1H), 2.33 (s, 3H). 【0154】 [Chemical formula] Intermediate 9 (Z)-2-Fluoro-3-(pyrimidin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1.6 g, 6.6 mmol) was dissolved in THF (50 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 0.26 g, 6.6 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and pyrimidine-2-carbaldehyde (0.71 g, 6.6 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). The solution was diluted with water (20 mL) and EtOAc (150 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0 → 90% EtOAc / hexane) to give ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate (determined by 1H NMR as a 5:1 E / Z mixture, 592 mg, 3.0 mmol, 46% yield). LC / MS (ESI) m / z: LC / MS (ESI) m / z: [M+H] + C9H 10 Calculated for FN2O2 197.2; found 197.1; 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, 3H), 1.39 (t, J = 7.2 Hz, 3H). 【0155】 Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate Ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate (592 mg, 3.0 mmol) was dissolved in toluene (15 mL) and iodine (38 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to give ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate (253 mg, 1.3 mmol, 43% yield). LC / MS (ESI) m / z: [M+H] +C9H 10 Calculated value for FN2O2: 197.2; Measured value: 196.6; 1 1H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 4.9 Hz, 2H), 7.21 (t, J = 4.9 Hz, 1H), 7.13 (d, J = 30.8 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H). 【0156】 Step 3: Preparation of (Z)-2-Fluoro-3-(pyrimidin-2-yl)acrylic Acid Ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate (253 mg, 1.3 mmol) was dissolved in MeOH (10 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 1.3 mL, 1.3 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added, and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 2.5 mL, 2.5 mmol) was added dropwise. After 10 min, a white solid precipitated. The solid was collected by filtration and dried under reduced pressure to give (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylic acid (190 mg, 1.1 mmol, 88% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated value for C7H6FN2O2: 169.1; Measured value: 168.8; 1 1H NMR (500 MHz, DMSO-d6) δ 8.90 (d, J = 4.9 Hz, 2H), 7.46 (t, J = 4.9 Hz, 1H), 6.94 (d, J = 31.5 Hz, 1H). 【0157】 【Chemical Structure】 Intermediate 10 (Z)-2-Chloro-3-(pyridin-2-yl)acrylic Acid Step 1: Preparation of Ethyl (Z)-2-Chloro-3-(pyridin-2-yl)acrylate Ethyl 2-chloro-2-(diethoxyphosphoryl)acetate (300 mg, 1.2 mmol) was dissolved in THF (5.8 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 46 mg, 1.2 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and picolinaldehyde (124 mg, 1.2 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (15 mL). The solution was diluted with water (5 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0 → 100% EtOAc / hexane) to afford ethyl (Z)-2-chloro-3-(pyridin-2-yl)acrylate (79 mg, 0.37 mmol, 32% yield). LC / MS (ESI) m / z: [M+H] + C 10 H 11 Calculated for ClNO2 212.0; found 211.6; 1 H NMR (500 MHz, CDCl3) δ 8.62 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.06 (dt, J = 8.0, 1.0 Hz, 1H), 7.97 (s, 1H), 7.69 (ddd, J = 8.0, 7.6, 1.8 Hz, 1H), 7.20 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). 【0158】 Step 2: Preparation of (Z)-2-chloro-3-(pyridin-2-yl)acrylic acid (Z)-2-Chloro-3-(pyridin-2-yl)acrylic acid ethyl ester (79 mg, 0.37 mmol) was dissolved in MeOH (2 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 0.37 mL, 0.37 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added, and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.37 mL, 0.37 mmol) was added dropwise. After 10 min, the solution was concentrated directly to give (Z)-2-chloro-3-(pyridin-2-yl)acrylic acid (60 mg, 0.33 mmol, 88% yield) as a white solid. LC / MS (ESI) m / z: [M+H] + Calculated for C8H7ClNO2 184.0; found 183.8; 1 1H NMR (500 MHz, DMSO-d6) δ 8.72 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.08 (dt, J = 8.0, 1.0 Hz, 1H), 7.96 (ddd, J = 8.0, 7.6, 1.8 Hz, 1H), 7.93 (s, 1H), 7.46 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H). 【0159】 [Chemical formula] Intermediate 11 (Z)-3-(5-Bromopyridin-2-yl)-2-fluoroacrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(5-bromopyridin-2-yl)acrylate (2-Ethoxy-1-fluoro-2-oxoethyl)triphenylphosphonium bromide (2.4 g, 5.4 mmol, prepared according to the synthetic procedure described in U.S. Patent No. 9,345,791) was stirred in THF (30 mL) at 0 °C. To the mixture was added dropwise nBuLi solution (1.6 M in hexane, (3.4 mL, 5.4 mmol). The mixture was stirred for 10 minutes, and then 5-bromopicolinaldehyde (1.0 g, 5.4 mmol) was added as a solid. The reaction mixture was warmed to room temperature over 2 hours. The reaction mixture was concentrated, and the residue was purified directly by column chromatography (5→100% EtOAc / hexane) to give the title product as a mixture of E / Z isomers. Subsequently, these isomers were separated by HPLC (column: Xbridge C18, 19 mm×200 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25 °C; gradient: 5:95 MeCN:H2O (containing 10 mM AA) → 95:5 MeCN:H2O (containing 10 mM AA); λ = 220 nm) to give ethyl (Z)-2-fluoro-3-(5-bromopyridin-2-yl)acrylate (550 mg, 2.0 mmol, 34%). LC / MS (ESI) m / z: [M+H] + C 10 H 10 Calculated for BrFNO2 274.0; found 273.6; NMR: 1 H NMR (500 MHz, CDCl3) δ 8.73 (d, J = 2.3 Hz, 1H), 7.91 (dd, J = 8.6, 2.3 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 34.3 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H). 【0160】 Step 2: Preparation of (Z)-2-Fluoro-3-(5-bromopyridin-3-yl)acrylic acid (Z)-Ethyl 2-fluoro-3-(5-bromopyridin-3-yl)acrylate (250 mg, 0.91 mmol) was dissolved in MeOH (10 mL), and sodium hydroxide solution (1.0 M, 910 μL, 0.91 mmol) was added dropwise. The mixture was stirred for 2 h. The reaction mixture was concentrated and diluted with water (5 mL). Addition of aqueous hydrochloric acid (1.0 M, 910 μL, 0.91 mmol) formed a precipitate. The solid was collected by filtration and dried under reduced pressure to give (Z)-2-fluoro-3-(5-bromopyridin-3-yl)acrylic acid (217 mg, 0.88 mmol, 97%). LC / MS (ESI) m / z: [M+H] + Calculated for C8H6BrFNO2 246.0; found 245.7; NMR: 1 1H NMR (500 MHz, DMSO-d6) δ 8.79 (d, J = 2.5 Hz, 1H), 8.15 (dd, J = 8.4, 2.5 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 34.6 Hz, 1H). 【0161】 [Chemical formula] Intermediate 12 (Z)-2-Fluoro-3-(6-methylpyridin-2-yl)acrylic acid Step 1: Preparation of (Z)-ethyl 2-fluoro-3-(6-methylpyridin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and 6-methylpyridine-2-carbaldehyde (125 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by HPLC (column: Xbridge C18, 5 μm particles; gradient: 5:95 MeCN:H2O (containing 0.05% TFA) → 95:5 MeCN:H2O (containing 0.05% TFA); λ = 220 nm) to give ethyl (Z)-2-fluoro-3-(6-methylpyridin-2-yl)acrylate (31 mg, 0.15 mmol, 14% yield); LC / MS (ESI) m / z: [M+H] + C 11 H 13 Calculated for FNO2 210.1; found 209.7; NMR: 1 H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 35.2 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 2.56 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). 【0162】 Step 2: Preparation of (Z)-2-fluoro-3-(6-methylpyridin-2-yl)acrylic acid (Z)-2-Fluoro-3-(6-methylpyridin-4-yl)ethyl acrylate (31 mg, 0.15 mmol) was dissolved in MeOH (1.5 mL), and sodium hydroxide solution (1.0 M, 150 μL, 0.15 mmol) was added dropwise. The mixture was stirred for 2 h. The reaction mixture was concentrated, diluted with water (1 mL), and hydrochloric acid solution (1.0 M, 150 μL, 0.14 mmol) was added. This solution was lyophilized and used without further purification of the crude material (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + Calculated for C9H9FNO2 182.1; found 182.1; NMR: 1 H NMR (500 MHz, DMSO-d6) δ 7.80 (t, J = 7.7 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 35.4 Hz, 1H), 2.50 (s, 3H). 【0163】 [Chemical formula] Intermediate 13 (Z)-3-(4-Bromothiazol-2-yl)-2-fluoroacrylic acid Step 1: Preparation of ethyl (E)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and 4-bromothiazole-2-carbaldehyde (198 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexane) to give ethyl (E)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate (a 5:1 E / Z ratio as determined by 1H NMR, 168 mg, 0.60 mmol, 60% yield). LC / MS (ESI) m / z: [M+H] + Calculated for C8H8BrFNO2S 279.9; found 279.9; 1 1H NMR (500 MHz, CDCl3) δ 7.41 (s, 1H), 7.28 (d, J = 21.7 Hz, 2H), 4.43 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H). 【0164】 Step 2: Preparation of ethyl (Z)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate (E)-3-(4-Bromothiazol-2-yl)-2-fluoroacrylate (168 mg, 0.6 mmol) was dissolved in toluene (2 mL) and iodine (15 mg, 0.06 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0→100% EtOAc / hexane) to give ethyl (Z)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate (148 mg, 0.53 mmol, 88% yield). LC / MS (ESI) m / z: [M+H] +Calculated value for C8H8BrFNO2S: 279.9; Measured value: 279.9; 1 1H NMR (500 MHz, CDCl3) δ 7.44 (s, 1H), 7.38 (d, J = 33.0 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). 【0165】 Step 3: Preparation of (Z)-3-(4-bromothiazol-2-yl)-2-fluoroacrylic acid (Z)-3-(4-Bromothiazol-2-yl)-2-fluoroacrylate (142 mg, 0.51 mmol) was dissolved in MeOH (5 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 0.51 mL, 0.51 mmol) was added. The reaction mixture was stirred for 2 hours. The solution was concentrated to remove methanol. Additional water (1 mL) was added, and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.51 mL, 0.51 mmol) was added dropwise. The solution was frozen and freeze-dried directly to obtain (Z)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate as a white solid (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + Calculated value for C6H4BrFNO2S: 251.9; Measured value: 251.7; 1 1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.28 (d, J = 33.7 Hz, 1H). 【0166】 【Chemical Structure】 Intermediate 14 (Z)-2-Fluoro-3-(pyridazin-3-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyridazin-3-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes, and pyridazine-3-carbaldehyde (110 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0 → 100% EtOAc / hexane) to afford ethyl (E)-2-fluoro-3-(pyridazin-3-yl)acrylate (a 3:1 E / Z ratio as determined by 1H NMR, 168 mg, 0.60 mmol, 60% yield). LC / MS (ESI) m / z: [M+H] + C9H 10 Calculated for C9H8N2O2 197.1; found 196.8; 1 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). 【0167】 Step 2: Preparation of ethyl (Z)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate 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 / hexane) to give ethyl (Z)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate (58 mg, 0.30 mmol, 59% yield). LC / MS (ESI) m / z: [M+H] + C9H 10 Calculated for C9H5BrFN2O2 197.1; Found 196.8; 1 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). 【0168】 Step 3: Preparation of (Z)-2-fluoro-3-(pyridazin-3-yl)acrylic acid 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 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 freeze-dried directly to give (Z)-2-fluoro-3-(pyridazin-3-yl)acrylic acid as a white solid (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + Calculated for C7H6FN2O2 169.0; Found 168.8; 11H NMR (500 MHz, DMSO-d6) δ 9.21 (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). 【0169】 【Chem.】 Intermediate 15 (Z)-2-Fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and 5-methyl-1,3,4-thiadiazole-2-carbaldehyde (132 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was carried on to the next step without further purification ( 1 assuming a 6:1 E / Z ratio, quantitative yield as determined by 1H). LC / MS (ESI) m / z: [M+H] + C8H 10 Calculated for C8H9FN2O2S 217.0; found 216.8; reported E isomer: 1 1H NMR (500 MHz, CDCL3) δ 7.36 (d, J = 21.0 Hz, 1H), 4.40 (t, J = 7.2 Hz, 2H), 2.79 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H). 【0170】 Step 2: Preparation of Ethyl (Z)-2-Fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)acrylate Ethyl (E)-2-fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)acrylate (hypothetical 223 mg, 1.0 mmol) was dissolved in toluene (2 mL), and iodine (17 mg, 0.07 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0→100% EtOAc / hexane) to give ethyl (Z)-2-fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)acrylate (63 mg, 0.29 mmol, 29% yield over two steps). LC / MS (ESI) m / z: [M+H] + C8H 10 Calculated for C8H FN2O2S 217.0; found 216.8; 1 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 32.1 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 2.85 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 【0171】 Step 3: Preparation of (Z)-2-Fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)acrylic Acid Ethyl (Z)-2-fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)acrylate (63 mg, 0.29 mmol) was dissolved in MeOH (2 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 0.29 mL, 0.29 mmol) was added. The reaction mixture was stirred for 2 hours. The solution was concentrated to remove methanol. Additional water (1 mL) was added, and the aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.29 mL, 0.29 mmol) was added dropwise. A yellow precipitate was formed, which was collected by filtration. The solid was triturated with ether (2 × 2 mL) and dried under reduced pressure to give (Z)-2-fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)acrylic acid (35 mg, 0.18 mmol, 63% yield). LC / MS (ESI) m / z: [M+H] +Calculated value for C6H6FN2OS2: 189.0; Measured value: 188.8; 1 1H NMR (500 MHz, DMSO-d6) δ 7.38 (d, J = 33.3 Hz, 1H), 2.80 (s, 3H). 【0172】 【Chem.】 Intermediate 16 (Z)-2-Fluoro-3-(6-(methoxymethyl)pyridin-2-yl)acrylic acid Step 1: Preparation of Ethyl (E)-2-fluoro-3-(6-(methoxymethyl)pyridin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes, and 6-(methoxymethyl)picolinaldehyde (156 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The solution was diluted with water (10 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0 → 100% EtOAc / hexane) to give ethyl (E)-2-fluoro-3-(6-(methoxymethyl)pyridin-2-yl)acrylate (judged by 1H NMR to be a 3:1 E / Z mixture, 120 mg, 0.50 mmol, 49% yield). LC / MS (ESI) m / z: [M+H] + C 12 H 15 Calculated value for FNO3: 240.1; Measured value: 240.0; E isomer was reported: 11H NMR (500 MHz, CDCl3) δ 7.68 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 20.4 Hz, 1H), 4.55 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 3.47 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). 【0173】 Step 2: Preparation of ethyl (Z)-2-fluoro-3-(6-(methoxymethyl)pyridin-2-yl)acrylate Ethyl (E)-2-fluoro-3-(6-(methoxymethyl)pyridin-2-yl)acrylate (120 mg, 0.5 mmol) was dissolved in toluene (10 mL), and iodine (6 mg, 0.025 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 / hexane) to give the desired product (59 mg, 0.25 mmol, 49% yield). LC / MS (ESI) m / z: [M+H] + C 12 H 15 Calculated for C12H14FNO3 240.1; found 223.8; 1 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 35.0 Hz, 1H), 4.56 (s, 2H), 4.33 (q, J = 7.2 Hz, 2H), 3.47 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). 【0174】 Step 3: Preparation of (Z)-2-fluoro-3-(6-(methoxymethyl)pyridin-2-yl)acrylic acid (Z)-Ethyl 2-fluoro-3-(6-(methoxymethyl)pyridin-2-yl)acrylate (59 mg, 0.25 mmol) was dissolved in MeOH (3 mL). The solution was cooled to 0 °C and sodium hydroxide solution (1.0 M, 0.25 mL, 0.25 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove 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 freeze-dried directly to give the desired product, the sodium chloride adduct, as a white solid (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 10 H 11 Calculated for C9H8FNO3 212.1; found 211.8; 1 1H NMR (500 MHz, DMSO-d6) δ 7.89 (t, J = 7.7 Hz, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 35.6 Hz, 1H), 4.50 (s, 2H), 3.37 (s, 3H). 【0175】 【Chemical Structure】 Intermediate 17 (Z)-2-Fluoro-3-(pyrazin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyrazin-2-yl)acrylate 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 portionwise as a solid. The reaction mixture was stirred for 10 minutes and pyrazine-2-carbaldehyde (750 mg, 7.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (50 mL). The solution was diluted with water (50 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0 → 100% EtOAc / hexane) to afford the desired product (judged by 1H NMR as a 6:1 E / Z mixture, 930 mg, 4.8 mmol, 68% yield). LC / MS (ESI) m / z: [M+H] + C9H 10 Calculated for C9H FN2O2 197.1;; Found 197.0; Reported the E isomer: 1 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). 【0176】 Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyrazin-2-yl)acrylate 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 / hexane) to afford the desired product (710 mg, 3.6 mmol, 76% yield). LC / MS (ESI) m / z: [M+H] + C9H 10Calculated value for FN2O2: 197.1; Measured value: 197.0; 1 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). 【0177】 Step 3: Preparation of (Z)-2-Fluoro-3-(pyrazin-2-yl)acrylic Acid 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 hours. The solution was concentrated to remove 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 for 10 minutes, the precipitate was collected by filtration and dried under reduced pressure to obtain the desired product (570 mg, 3.4 mmol, 94% yield). LC / MS (ESI) m / z: [M+H] + Calculated value for C7H6FN2O2: 169.0; Measured value: 169.0; 1 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). 【0178】 【Chemical Structure】 Intermediate 18 (Z)-2-Fluoro-3-(6-methoxypyridin-2-yl)acrylic Acid Step 1: Preparation of Ethyl (E)-2-Fluoro-3-(6-methoxypyridin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and 6-methoxypicolinaldehyde (140 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The solution was diluted with water (20 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (0 → 100% EtOAc / hexane) to afford the desired product (6:1 E / Z as determined by 1H NMR, 170 mg, 0.75 mmol, 72% yield). LC / MS (ESI) m / z: [M+H] + C 11 H 13 Calculated for C10H10FNO3 226.1; found 225.9. 【0179】 Step 2: Preparation of ethyl (Z)-2-fluoro-3-(6-methoxypyridin-2-yl)acrylate Ethyl (E)-2-fluoro-3-(6-methoxypyridin-2-yl)acrylate (170 mg, 0.75 mmol) was dissolved in toluene (5 mL) and iodine (190 mg, 0.75 mmol) was added. The reaction mixture was heated at 100 °C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to afford the desired product (75 mg, 0.33 mmol, 45% yield).; LC / MS (ESI) m / z: [M+H] + C 11 H 13 Calculated for C10H10FNO3 226.1; found 226.1; 11H NMR (500 MHz, CDCl3) δ 7.60 (dd, J = 8.2, 7.4 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H), 6.98 (d, J = 34.7 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). 【0180】 Step 3: Preparation of (Z)-2-Fluoro-3-(6-methoxypyridin-2-yl)acrylic Acid Ethyl (Z)-2-fluoro-3-(6-methoxypyridin-2-yl)acrylate (71 mg, 0.32 mmol) was dissolved in MeOH (3 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 0.32 mL, 0.32 mmol) was added. The reaction mixture was stirred for 2 hours. The solution was concentrated to remove methanol. The resulting aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.32 mL, 0.32 mmol) was added dropwise, and a precipitate was formed. After stirring for 10 minutes, the precipitate was collected by filtration and dried under reduced pressure to obtain the desired product (42 mg, 0.2 mmol, 67% yield). LC / MS (ESI) m / z: [M+H] + Calculated for C9H9FNO3 198.0; Found 198.0; 1 1H NMR (500 MHz, DMSO-d6) δ 7.79 (dd, J = 8.3, 7.0 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H), 6.89 (d, J = 34.5 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H). 【0181】 [Chemical Structure Diagram] Intermediate 19 (Z)-2-Fluoro-3-(pyrimidin-4-yl)acrylic Acid Step 1: Preparation of Ethyl (Z)-2-Fluoro-3-(pyrimidin-4-yl)acrylate 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 portionwise as a solid. The reaction mixture was stirred for 10 minutes and pyrimidine-4-carbaldehyde (250 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). The solution was diluted with water (20 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 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 / hexane) to afford the desired product (40 mg, 0.2 mmol, 9% yield). LC / MS (ESI) m / z: [M+H] + C9H 10 Calculated for C9H FN2O2 197.1; found 197.0; 1 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). 【0182】 Step 2: Preparation of (Z)-2-fluoro-3-(pyrimidin-4-yl)acrylic acid 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 hours. The solution was concentrated to remove 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 lyophilized directly to afford the desired product, the sodium chloride adduct (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] +Calculated value for C7H6FN2O2: 169.0; Measured value: 169.0. 【0183】 【Chem.】 Intermediate 20 2 - ((S)-4-(7-(8-Chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 【Chem.】 Step 1: Preparation of Benzyl (S)-2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.2 g, 4.75 mmol) was suspended in DCM (24 mL), and the solution was cooled to -40 °C. DIPEA (1.2 mL, 7.1 mmol) was added dropwise, followed by a solution of Benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylate (1.2 g, 4.75 mmol) as a solution in DCM (10 mL). The reaction mixture was stirred for 30 minutes, warmed to room temperature, and concentrated. The crude residue was purified directly by column chromatography (0 → 50% EtOAc / hexane) to give the desired product (2.2 g, 4.64 mmol, 97%). LC / MS (ESI) m / z: [M+H] + C 21 H 18 Calculated value for Cl2FN6O2: 475.1; Measured value: 474.8; 11H NMR (500 MHz, CDCl3) δ 8.93 (s, 1H), 7.40 - 7.33 (m, 5H), 5.20 (d, J = 12.3 Hz, 1H), 5.17 (d, J = 12.3 Hz, 1H), 4.68 - 4.61 (m, 1H), 4.49 - 4.40 (m, 1H), 4.40 - 4.35 (m, 1H), 4.29 - 4.12 (m, 2H), 3.92 - 3.80 (m, 1H), 3.79 - 3.48 (m, 1H), 3.05 - 2.76 (m, 1H), 2.68 (dd, J = 17.0, 5.0 Hz, 1H). 【0184】 [Chemical formula] Process 2: Preparation of Benzyl (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (S)-(1-Methylpyrrolidin-2-yl)methanol (100 mg, 0.88 mmol) was dissolved in THF (7.4 mL), and the solution was cooled to 0 °C. A solution of LiHMDS (1.0 M in THF, 0.88 mL, 0.88 mmol) was added dropwise, and the resulting mixture was stirred for 10 minutes. Benzyl (S)-2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (350 mg, 0.74 mmol) was dissolved in THF (2 mL) and added dropwise to the solution. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was partially concentrated and then purified directly by column chromatography (50 → 100% EtOAc with 5% Et3N / hexane) to afford the desired product (350 mg, 0.63 mmol, 85% yield) as a white foam. LC / MS (ESI) m / z: [M + H] + C 27 H 30 Calculated for C25H26ClFN7O3 554.2; Found 554.1; 11H NMR (500 MHz, CDCl3) δ 8.79 (s, 1H), 7.41 - 7.33 (m, 5H), 5.22 - 5.16 (m, 2H), 4.66 (br s, 1H), 4.55 (dd, J = 10.9, 4.8 Hz, 1H), 4.38 (dd, J = 10.8, 6.1 Hz, 2H), 4.33 - 4.25 (m, 1H), 4.23 - 4.11 (m, 1H), 4.02 - 3.89 (m, 1H), 3.73 - 3.64 (m, 1H), 3.64 - 3.48 (m, 1H), 3.11 (br t, J = 7.5 Hz, 1H), 3.00 - 2.77 (m, 1H), 2.74 - 2.65 (m, 2H), 2.49 (s, 3H), 2.33 - 2.25 (m, 1H), 2.08 - 2.00 (m, 1H), 1.90 - 1.72 (m, 3H). 【0185】 [Chemical formula] Step 3: Preparation of Benzyl (S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate Benzyl (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.19 mmol), 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (84 mg, 0.29 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-1,1’-biphenyl-2-yl)palladium(II) dichloromethane adduct [cataCXium® A Palladacycle Gen.3] (7 mg, 9.6 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 (2.9 mL) and potassium phosphate solution (2.0 M in water, 0.3 mL, 0.58 mmol) were added, and the reaction mixture was heated in a microwave at 100 °C for 2 hours. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (0 → 100% EtOAc with 5% Et3N / hexane) to afford the desired product (80 mg, 0.12 mmol, 61% yield). LC / MS (ESI) m / z: [M+H] + C 37 H 36 Calculated for C37H40ClFN7O3 680.3; found 680.4. 【0186】 【Chem.】 Step 4: Preparation of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (80 mg, 0.12 mmol) was dissolved in MeOH (2.4 mL), and palladium on carbon (10 wt%, 63 mg, 0.06 mmol) was added. Hydrogen gas (balloon) was bubbled through the reaction mixture for 5 minutes, and the reaction mixture was maintained under a hydrogen atmosphere. After 30 minutes, the reaction mixture was filtered through a pad of Celite (registered trademark) and concentrated. The crude residue containing an undetermined amount of a mixture of the desired product and the dehalogenated product (2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile) was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 28 H 31 Calculated for ClFN7O 546.2; found 546.1. 【0187】 【Chem.】 Intermediate 21 (S)-7-(8-Chloronaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine 【Chem.】 Step 1: Preparation of tert-butyl 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (1 g, 4.0 mmol) was suspended in DCM (20 mL), and the solution was cooled to -40 °C. DIPEA (1.0 mL, 5.9 mmol) was added, followed by tert-butyl piperazine-1-carboxylate (0.74 g, 4.0 mmol) as a solution in DCM (5 mL). After 30 minutes, the reaction mixture was warmed to room temperature and partially concentrated. The crude residue was purified by column chromatography (0 → 50% EtOAc / hexane) to afford the desired product (1.4 g, 3.6 mmol, 90% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 16 H 19 Calculated for Cl2FN5O2 402.1; found 401.9; 1 H NMR (500 MHz, CDCl3) δ 8.87 (s, 1H), 4.09 - 4.02 (m, 4H), 3.72 - 3.64 (m, 4H), 1.50 (s, 9H). 【0188】 【Chemical Structure】 Step 2: Preparation of tert-butyl (S)-4-(7-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (S)-(1-Methylpyrrolidin-2-yl)methanol (0.6 g, 5.2 mmol) was dissolved in THF (17.4 mL), and the solution was cooled to 0 °C. A solution of LiHMDS (1.0 M in THF, 5.2 mL, 5.2 mmol) was added dropwise, and the resulting mixture was stirred for 10 minutes. tert-Butyl 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.4 g, 3.5 mmol) was suspended in THF (10 mL) and added dropwise to the solution. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was partially concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (1.5 g, 3.1 mmol, 90% yield). LC / MS (ESI) m / z: [M+H] + C 22 H 31 Calculated for ClFN6O3 481.2; found 481.1; 1 H NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 4.53 (dd, J = 10.7, 4.6 Hz, 1H), 4.34 (dd, J = 10.7, 6.7 Hz, 1H), 3.99 - 3.90 (m, 4H), 3.69 - 3.60 (m, 4H), 3.12 - 3.07 (m, 1H), 2.74 - 2.67 (m, 1H), 2.49 (s, 3H), 2.28 (td, J = 9.5, 6.9 Hz, 1H), 2.09 - 2.00 (m, 1H), 1.89 - 1.73 (m, 3H), 1.49 (s, 9H). 【0189】 【Chemical Structure】 Step 3: Preparation of tert-Butyl (S)-4-(7-(8-Chloronaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl (S)-4-(7-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (145 mg, 0.30 mmol), 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105 mg, 0.36 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct [cataCXium RTM A Palladacycle Gen.3] (22 mg, 0.03 mmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was carried out three times. Degassed dioxane (5 mL) and potassium phosphate solution (2.0 M in water, 0.45 mL, 0.90 mmol) were added, and the reaction mixture was heated in a microwave at 100 °C for 2 h. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (0 → 100% EtOAc with 5% Et3N / hexane) to give the desired product (84 mg, 0.14 mmol, 45% yield). LC / MS (ESI) m / z: [M+H] + C 32 H 37 Calculated for ClFN6O3 607.3; found 607.2. 【0190】 【Chem.】 Step 4: Preparation of (S)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine tert-Butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (15 mg, 0.025 mmol) was dissolved in DCM (1 mL), and TFA (0.25 mL, 3.2 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated directly, and the crude residue was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 27 H 29 Calculated for ClFN6O 507.2, found 507.1. 【0191】 【Chemical formula】 Intermediate 22 2-((S)-4-(8-Fluoro-7-(2-fluorophen-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methylpiperazin-2-yl)acetonitrile 【Chemical formula】 Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(2-fluorophen-5-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (32 mg, 0.058 mmol) and methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-1,1’-biphenyl-2-yl)palladium(II) dichloromethane adduct [cataCXiumRTM A Palladacycle Gen.3] (4.2 mg, 5.8 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (0.9 mL) and potassium phosphate solution (2.0 M in water, 0.1 mL, 0.17 mmol) were added and the reaction mixture was heated in the microwave at 100 °C for 4 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (80→100% EtOAc with 5% Et3N / hexane → 20% MeOH / EtOAc with 5% Et3N) to give the desired product (30 mg, 0.048 mmol, 82% yield). LC / MS (ESI) m / z: [M+H] + C 33 H 34 Calculated for F2N7O4 630.3; found 630.2; 1 H NMR (500 MHz, CDCL3) δ 8.93 (s, 1H), 7.43 - 7.30 (m, 6H), 7.05 - 6.86 (m, 3H), 5.19 (s, 2H), 4.71 - 4.56 (m, 2H), 4.52 - 4.44 (m, 1H), 4.40 - 4.32 (m, 1H), 4.28 - 4.18 (m, 1H), 4.15 - 3.96 (m, 1H), 3.70 - 3.54 (m, 2H), 3.50 - 3.39 (m, 1H), 3.36 - 3.23 (m, 1H), 3.04 - 2.93 (m, 1H), 2.87 - 2.72 (m, 1H), 2.70 - 2.61 (m, 4H), 2.54 - 2.44 (m, 1H), 2.15 - 2.08 (m, 1H), 2.05 - 1.83 (m, 3H). 【0192】 【Chemical Structure】 Step 2: Preparation of 2-((S)-4-(8-Fluoro-7-(2-fluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(2-fluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (30 mg, 0.048 mmol) was dissolved in MeOH (1.0 mL), and palladium on carbon (10 wt%, 25 mg, 0.024 mmol) was added. Hydrogen gas was bubbled through the solution for 5 minutes, and then the reaction mixture was kept under a hydrogen atmosphere (balloon). After 30 minutes, the reaction mixture was filtered through a pad of Celite® and concentrated directly to give the desired product (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 25 H 28 Calculated for C25H27F2N7O2: 496.2; found: 496.3. 【0193】 【Chemical Structure】 Intermediate 23 2-((S)-4-(7-(8-Ethylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 【Chemical Structure】 Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (32 mg, 0.058 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane ([This material was prepared according to the procedure detailed in WO 2022031678A1] 38 mg, 0.087 mmol) and methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-1,1’-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (4.2 mg, 5.8 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was carried out three times. Degassed dioxane (0.9 mL) and potassium phosphate solution (2.0 M in water, 90 μl, 0.17 mmol) were added and the reaction mixture was heated in a microwave at 100 °C for 4 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (35 mg, 0.04 mmol, 73% yield). LC / MS (ESI) m / z: [M+H]+ C 48 H 56 Calculated for FN7O3Si 826.4; found 826.4; 11H NMR (500 MHz, CDCl3) δ 9.13 - 9.02 (m, 1H), 7.99 - 7.90 (m, 2H), 7.82 (d, J = 6.7 Hz, 1H), 7.62 - 7.44 (m, 3H), 7.42 - 7.33 (m, 5H), 5.27 - 5.13 (m, 2H), 4.76 - 4.69 (m, 1H), 4.64 - 4.52 (m, 1H), 4.43 - 4.18 (m, 3H), 4.04 - 3.56 (m, 2H), 3.10 (br t, J = 7.7 Hz, 1H), 2.89 - 2.55 (m, 3H), 2.51 - 2.46 (m, 3H), 2.33 - 2.23 (m, 1H), 2.10 - 2.01 (m, 1H), 1.91 - 1.71 (m, 4H), 0.95 - 0.82 (m, 18H), 0.61 - 0.49 (m, 3H). 【0194】 【Chem.】 Process 2: Preparation of Benzyl (S)-2-(cyanomethyl)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (35 mg, 0.042 mmol) was dissolved in THF (0.8 mL), and tetra-n-butylammonium fluoride solution (1.0 M in THF, 40 μL, 0.04 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 10 minutes. The solution was concentrated directly, and the crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M + H] + C 39 H 37 Calculated for C43H52FN7O3 670.3; found 670.5. 【0195】 【Chem.】 Step 3: Preparation of 2-((S)-4-(7-(8-Ethylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-2-(cyanomethyl)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (assuming 28 mg, 0.042 mmol) was dissolved in MeOH (0.8 mL), and palladium on carbon (10 wt%, 22 mg, 0.021 mmol) was added. Hydrogen gas was bubbled through the solution for 5 minutes, and then the reaction mixture was maintained under a hydrogen atmosphere (balloon) for 1.5 hours. The reaction mixture was filtered through a plug of Celite (registered trademark), and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 31 H 35 Calculated for C H FN7O 540.3; found 540.4 【0196】 【Chemical Structure】 Intermediate 24 2-((S)-4-(7-(8-Ethylnaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 【Chemical Structure】 Step 1: Preparation of (S)-7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine (S)-tert-Butyl 4-(7-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (70 mg, 0.15 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (95 mg, 0.22 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (11 mg, 15 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 (1.5 mL) and potassium phosphate solution (2.0 M in water, 220 μl, 0.44 mmol) were added and the reaction mixture was heated in the microwave at 100 °C for 4 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (100 mg, 0.13 mmol, 91% yield). LC / MS (ESI) m / z: [M+H] + C 43 H 58 Calculated for C40H51FN6O3Si 753.4; found 753.4. 【0197】 [Chemical formula] Step 2: Preparation of (S)-tert-Butyl 4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (S)-tert-Butyl 4-(8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.133 mmol) was dissolved in THF (1.3 mL), and tetra-n-butylammonium fluoride solution (1.0 M in THF, 160 μL, 0.16 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 10 minutes. The solution was concentrated directly, and the crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 34 H 38 Calculated for C35H43FN6O3: 597.3; Found: 597.4. 【0198】 [Chemical formula] Step 3: Preparation of (S)-7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine (S)-tert-Butyl 4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (10 mg, 0.017 mmol) was dissolved in MeCN (300 μL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 42 μL, 0.168 mmol) was added dropwise, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with NaOH solution (1.0 M, 170 μL, 0.17 mmol), and the solution was concentrated. This material was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 29 H 30 Calculated for C28H31FN6O: 497.2; Found: 497.3. 【0199】 [Chemical formula] Intermediate 24A (Z)-2-Fluoro-3-(6-methylpyrazin-2-yl)acrylic acid Step 1: Preparation of Ethyl (E)-2-fluoro-3-(6-methylpyrazin-2-yl)acrylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (250 mg, 1.0 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes and 6-methylpyrazine-2-carbaldehyde (125 mg, 1.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (5 mL). The solution was diluted with water (5 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0 → 100% EtOAc / hexane) to give the desired product (>15:1 E / Z as determined by 1H NMR, 120 mg, 0.56 mmol, 55% yield). LC / MS (ESI) m / z: [M+H] + C 10 H 12 Calculated for C10H11FN2O2 211.1; found 210.9; 1 1H NMR (500 MHz, CDCl3) δ 8.56 (s, 1H), 8.36 (s, 1H), 6.81 (d, J = 19.1 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 2.55 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 【0200】 Step 2: Preparation of Ethyl (Z)-2-fluoro-3-(6-methylpyrazin-2-yl)acrylate Ethyl (E)-2-fluoro-3-(6-methylpyrazin-2-yl)acrylate (120 mg, 0.56 mmol) was dissolved in toluene (7 mL), and iodine (14 mg, 0.06 mmol) was added. The reaction mixture was heated at 100 °C for 5 days. The solution was concentrated and purified by column chromatography (5→100% EtOAc / hexane) to give the desired product (73 mg, 0.35 mmol, 62% yield). LC / MS (ESI) m / z: [M+H] + C 10 H 12 Calculated for C8H8FN2O2 211.1; found 210.9; 1 1H NMR (500 MHz, CDCl3) δ 8.92 (s, 1H), 8.39 (s, 1H), 7.07 (d, J = 35.6 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 2.58 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). 【0201】 Step 3: Preparation of (Z)-2-fluoro-3-(6-methylpyrazin-2-yl)acrylic acid Ethyl (Z)-2-fluoro-3-(6-methylpyrazin-2-yl)acrylate (73 mg, 0.35 mmol) was dissolved in MeOH (3 mL). The solution was cooled to 0 °C, and sodium hydroxide solution (1.0 M, 0.35 mL, 3.5 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. The resulting aqueous solution was cooled to 0 °C. HCl solution (1.0 M, 0.35 mL, 0.35 mmol) was added dropwise to form a precipitate. After stirring for 10 min, the precipitate was collected by filtration and dried under reduced pressure to give the desired product (34 mg, 0.19 mmol, 54% yield). LC / MS (ESI) m / z: [M+H] + Calculated for C8H8FN2O2 183.0; found 182.8; 1 1H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.52 (s, 1H), 6.98 (d, J = 35.0 Hz, 1H), 2.52 (s, 3H). 【0202】 【Chemical formula】 Intermediate 25 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 【Chemical formula】 Step 1: Preparation of tert-butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, HCl salt (1.9 g, 9.5 mmol) was suspended in THF (70 mL). The mixture was cooled to 0 °C and a solution of LiHMDS (1.0 M in THF, 22 mL, 22 mmol) was added dropwise. Once all the solids had dissolved (5 minutes), tert-butyl 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (3.5 g, 8.7 mmol) was added as a solution in THF (10 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was partially concentrated and the crude residue was purified by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (3.0 g, 5.7 mmol, 66% yield) as a white foam. LC / MS (ESI) m / z: [M+H] + C 24 H 32 Calculated for ClF2N6O3 525.2; found 525.5; 11H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 0.00 (d, J = 54.0 Hz, 1H), 4.26 (d, J = 10.5 Hz, 1H), 4.18 (d, J = 10.5 Hz, 1H), 3.99 - 3.89 (m, 4H), 3.69 - 3.59 (m, 4H), 3.31 - 3.12 (m, 3H), 3.01 - 2.93 (m, 1H), 2.25 - 2.18 (m, 1H), 2.14 (br dd, J = 14.7, 4.1 Hz, 1H), 1.99 - 1.80 (m, 4H), 1.49 (s, 9H). 【0203】 [Chemical formula] Step 2: Preparation of tert-butyl 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.57 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (440 mg, 0.86 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-1,1’-biphenyl-2-yl)palladium(II) dichloromethane adduct [CataCXiumRTM A Pd G3] (21 mg, 0.029 mmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen; this process was performed three times. Degassed dioxane (2.9 mL) and potassium phosphate solution (2.0 M in water, 860 μL, 1.7 mmol) were added, and the reaction mixture was heated at 100 °C for 1.5 h in a microwave. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (450 mg, 0.51 mmol, 90% yield). LC / MS (ESI) m / z: [M+H] + C 47 H 62 Calculated for F3N6O5Si 875.4; found 875.8. 【0204】 【Chem.】 Step 3: Preparation of tert-Butyl 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (500 mg, 0.57 mmol) was dissolved in THF (5.7 mL), and the solution was cooled to 0 °C. A solution of TBAF (1.0 M in THF, 0.7 mL, 0.7 mmol) was added dropwise, and the reaction mixture was stirred for 5 minutes. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (50 → 100% EtOAc with 5% Et3N / hexane) to give the desired product (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 38 H 41 Calculated for C37H43F3N6O5 719.3; found 719.6. 【0205】 【Chemical Structure】 Step 4: Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol tert-Butyl 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (410 mg, 0.57 mmol) was dissolved in MeCN (5.7 mL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 1.4 mL, 5.7 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 2 h, sodium hydroxide solution (1.0 M, 5.7 mL, 5.7 mmol) was added, and the solution was concentrated to remove volatile organics. The resulting aqueous solution was frozen and lyophilized directly to give the desired product together with sodium chloride. This material was of sufficient purity to be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 31 H 30 Calculated for C31H33F3N6O2 575.2; found 575.4. 【0206】 【Chemical Structure】 Intermediate 26 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine 【Chemical Structure】 Step 1: Preparation of tert-Butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (45 mg, 0.086 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (41 mg, 0.094 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-1,1’-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (3.1 mg, 4.3 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was carried out three times. Degassed dioxane (900 μL) and potassium phosphate solution (2.0 M in water, 130 μL, 0.26 mmol) were added and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexanes) to afford the desired product (57 mg, 0.072 mmol, 83% yield). LC / MS (ESI) m / z: [M+H] + C 45 H 59 Calculated for F2N6O3Si 797.4; found 797.6; 11H NMR (500 MHz, CDCl3) δ 9.05 (s, 1H), 7.96 (dd, J = 7.7, 1.5 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 6.9 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.46 (t, J = 7.7 Hz, 1H), 5.27 (d, J = 55.2 Hz, 1H), 4.33 - 4.22 (m, 1H), 4.20 - 4.10 (m, 1H), 3.92 (br d, J = 3.6 Hz, 4H), 3.76 - 3.58 (m, 4H), 3.28 - 3.14 (m, 2H), 2.97 (td, J = 9.1, 5.5 Hz, 1H), 2.34 - 2.21 (m, 2H), 2.20 - 2.09 (m, 2H), 2.01 - 1.82 (m, 3H), 1.24 (s, 9H), 0.87 (dd, J = 10.2, 7.5 Hz, 18H), 0.61 - 0.49 (m, 3H). 【0207】 【Chem.】 Process 2: Preparation of tert - butyl 4-(7-(8 - ethynylnaphthalen - 1 - yl)-8 - fluoro - 2 -(((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazine - 1 - carboxylate tert - butyl 4-(8 - fluoro - 2 -(((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)-7-(8 -((triisopropylsilyl)ethynyl)naphthalen - 1 - yl)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazine - 1 - carboxylate (55 mg, 0.069 mmol) and the solution were cooled to 0 °C. TBAF solution (1.0 M in THF, 90 μL, 0.09 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 minutes, the reaction mixture was concentrated, and the crude residue was purified by column chromatography (50 → 100% EtOAc with 5% Et3N / hexane) to give the desired product (42 mg, 0.066 mmol, 95% yield). LC / MS (ESI) m / z: [M + H] + C 36 H 39Calculated value for F2N6O3: 641.3; Measured value: 641.3. 【0208】 【Chem.】 Step 3: Preparation of 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine tert-Butyl 4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (40 mg, 0.062 mmol) was dissolved in MeCN (600 μL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 160 μl, 0.62 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 2 hours, the reaction mixture was quenched by the addition of NaOH solution (1.0 M, 0.62 mL, 0.62 mmol), and the reaction mixture was concentrated. The residue was azeotroped with toluene and used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 31 H 31 Calculated value for F2N6O: 541.2; Measured value: 541.3. 【0209】 【Chem.】 Intermediate 27 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine 【Chem.】 Step 1: Preparation of tert-butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 0.095 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (16.76 mg, 0.095 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-1,1’-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (6.9 mg, 9.5 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 (950 μL) and potassium phosphate solution (2.0 M in water, 190 μL, 0.26 mmol) were added and the reaction mixture was heated in the microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (9 mg, 0.014 mmol, 15% yield). LC / MS (ESI) m / z: [M+H] + C 32 H 39 Calculated for C31H35F2N8O3 621.3; found 621.3. 【0210】 【Chem.】 Step 2: Preparation of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine tert-Butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (9 mg, 0.014 mmol) was dissolved in MeCN (750 μL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 36 μl, 0.15 mmol) was added dropwise. After 2 h, the reaction mixture was concentrated and the crude material (as the HCl salt) was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 27 H 31 Calculated for C28H32F2N8O: 521.3; Found: 521.2. 【0211】 【Chemical Structure】 Intermediate 28 7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine 【Chemical Structure】 Step 1: Preparation of tert-Butyl 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (171 mg, 0.33 mmol), ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (98 mg, 0.22 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (15.8 mg, 22 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was carried out three times. Degassed dioxane (2.2 mL) and potassium phosphate solution (2.0 M in water, 430 μL, 0.65 mmol) were added, and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (43 mg, 0.053 mmol, 24% yield). LC / MS (ESI) m / z: [M+H] + C 45 H 58 Calculated for F3N6O3Si 815.4; found 815.9. 【0212】 【Chem.】 Step 2: Preparation of tert-Butyl 4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (39 mg, 0.048 mmol) was dissolved in THF (1.0 mL), and the solution was cooled to 0 °C. TBAF solution (1.0 M in THF, 57 μL, 0.057 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 minutes, the reaction mixture was concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (26 mg, 0.039 mmol, 82% yield). LC / MS (ESI) m / z: [M+H] + C 36 H 38 Calculated for C36H43F3N6O3 659.3; found 659.8. 【0213】 【Chemical formula】 Step 3: Preparation of 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine tert-Butyl 4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (27 mg, 0.04 mmol) was dissolved in MeCN (500 μL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 100 μl, 0.41 mmol) was added dropwise. After 2 hours, 1-methylimidazole (0.039 mL, 0.49 mmol) was added, and the solution was concentrated. The crude residue was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 31H 30 Calculated value for F3N6O: 559.2; Measured value: 559.4. 【0214】 【Chem.】 Intermediate 29 2 - ((S)-4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 【Chem.】 Step 1: Preparation of benzyl (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, HCl salt (680 mg, 3.5 mmol) was suspended in THF (16 mL). The mixture was cooled to 0 °C and a solution of LiHMDS (1.0 M in THF, 7.3 mL, 7.3 mmol) was added dropwise. After all the solids had dissolved (5 minutes), benzyl (S)-2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.5 g, 3.2 mmol) was added as a solution in THF (10 mL). The reaction mixture was warmed to room temperature and then gradually warmed to 35 °C over 4 hours. The reaction mixture was partially concentrated and the crude residue was purified by column chromatography (50 → 100% EtOAc with 5% Et3N / hexane) to give the desired product (1.6 g, 2.6 mmol, 83% yield) as a white foam. LC / MS (ESI) m / z: [M + H] + C 29 H 31 Calculated value for ClF2N7O3: 598.2; Measured value: 598.2;1 1H NMR (500 MHz, CDCl3) δ 8.78 (s, 1H), 7.37 (d, J = 1.4 Hz, 5H), 5.26 (d, J = 55.8 Hz, 1H), 5.20 - 5.17 (m, 2H), 4.69 - 4.61 (m, 1H), 4.47 - 4.38 (m, 1H), 4.32 - 4.24 (m, 2H), 4.22 - 4.13 (m, 2H), 3.97 - 3.82 (m, 1H), 3.74 - 3.63 (m, 1H), 3.61 - 3.44 (m, 1H), 3.30 - 3.20 (m, 2H), 3.17 - 3.13 (m, 1H), 3.01 - 2.93 (m, 1H), 2.91 - 2.77 (m, 1H), 2.72 - 2.64 (m, 1H), 2.29 - 2.06 (m, 3H), 1.98 - 1.80 (m, 3H). 【0215】 【Chem.】 Process 2: Preparation of Benzyl (S)-2-(Cyanomethyl)-4-(8-Fluoro-2-(((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(2-(Trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (50 mg, 0.084 mmol), 4,4,5,5-tetramethyl-2-(2-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (45.5 mg, 0.167 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (3.0 mg, 4 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was carried out three times. Degassed dioxane (0.8 mL) and potassium phosphate solution (2.0 M in water, 170 μL, 0.33 mmol) were added and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexanes) to afford the desired product (58 mg, 0.08 mmol, 98% yield). LC / MS (ESI) m / z: [M+H] + C 36 H 34 Calculated for C35H40F5N7O3 708.3; found 708.3; 11H NMR (500 MHz, CDCl3) δ 9.03 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.69 - 7.64 (m, 1H), 7.63 - 7.58 (m, 1H), 7.50 - 7.45 (m, 1H), 7.42 - 7.33 (m, 5H), 5.27 (d, J = 53.9 Hz, 1H), 5.21 (s, 2H), 4.74 - 4.66 (m, 1H), 4.53 - 4.43 (m, 1H), 4.41 - 4.34 (m, 1H), 4.30 (d, J = 10.4 Hz, 1H), 4.21 (d, J = 10.4 Hz, 1H), 4.25 - 4.16 (m, 1H), 3.94 - 3.79 (m, 1H), 3.75 - 3.65 (m, 1H), 3.63 - 3.46 (m, 1H), 3.28 - 3.18 (m, 2H), 3.01 - 2.93 (m, 1H), 2.93 - 2.79 (m, 1H), 2.78 - 2.69 (m, 1H), 2.31 - 2.09 (m, 3H), 2.00 - 1.81 (m, 3H). 【0216】 [Chemical formula] Step 3: Preparation of 2 - ((S) - 4 - (8 - fluoro - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy) - 7 - (2 - (trifluoromethyl)phenyl)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazin - 2 - yl)acetonitrile Benzyl (S) - 2 - (cyanomethyl) - 4 - (8 - fluoro - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy) - 7 - (2 - (trifluoromethyl)phenyl)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazine - 1 - carboxylate (58 mg, 0.08 mmol) was dissolved in MeOH (0.8 mL), and palladium on carbon (10 wt%, 18 mg, 0.017 mmol) was added. Hydrogen gas was bubbled through the solution for 5 minutes, and then the reaction mixture was maintained under a hydrogen atmosphere (balloon) for 1.5 hours. The reaction mixture was filtered through a plug of Celite (registered trademark) and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M + H]+ C 28 H 29 Calculated value for C5H5N7O: 574.3; measured value: 574.2. 【0217】 [Chemical formula] Intermediate 30 2 - ((S)-4-(7-(Benzo[b]thiophen-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [Chemical formula] Step 1: Preparation of benzyl (S)-4-(7-(benzo[b]thiophen-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate 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 (50 mg, 0.084 mmol), 2-(benzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (43.5 mg, 0.167 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (3.0 mg, 4 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was carried out three times. Degassed dioxane (0.8 mL) and potassium phosphate solution (2.0 M in water, 170 μL, 0.33 mmol) were added and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexanes) to afford the desired product (57 mg, 0.08 mmol, 98% yield). LC / MS (ESI) m / z: [M+H] + C 37 H 36 Calculated for F2N7O3S 696.2; found 696.2; 11H NMR (500 MHz, CDCl3) δ 9.13 (s, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 1.3 Hz, 1H), 7.95 - 7.92 (m, 1H), 7.47 - 7.35 (m, 7H), 5.28 (d, J = 53.6 Hz, 1H), 5.22 - 5.19 (m, 2H), 4.74 - 4.67 (m, 1H), 4.49 (br d, J = 12.6 Hz, 1H), 4.40 - 4.39 (m, 1H), 4.39 (br d, J = 11.9 Hz, 1H), 4.32 (d, J = 10.4 Hz, 1H), 4.27 - 4.18 (m, 1H), 4.23 (d, J = 10.4 Hz, 1H), 3.94 - 3.82 (m, 1H), 3.74 - 3.66 (m, 1H), 3.64 - 3.47 (m, 1H), 3.31 - 3.20 (m, 2H), 3.04 - 2.94 (m, 1H), 2.94 - 2.80 (m, 1H), 2.73 (dd, J = 16.7, 5.6 Hz, 1H), 2.29 - 2.11 (m, 2H), 2.01 - 1.83 (m, 3H). 【0218】 [Chemical formula] Process 2: Preparation of 2 - ((S) - 4 - (7 - (benzo[b]thiophen - 3 - yl) - 8 - fluoro - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazin - 2 - yl)acetonitrile Benzyl (S)-4-(7-(benzo[b]thiophen-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (57 mg, 0.082 mmol) was dissolved in MeOH (0.8 mL), and palladium carbon (10 wt%, 17 mg, 0.016 mmol) was added. Hydrogen gas was bubbled through the solution for 5 minutes, and then the reaction mixture was maintained under a hydrogen atmosphere (balloon) for 1.5 hours. The reaction mixture was filtered through a plug of Celite (registered trademark) and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 29 H 30 Calculated for F2N7OS 562.2; found 562.3. 【0219】 【Chem.】 Intermediate 31 2-((S)-4-(8-Fluoro-7-(7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 【Chem.】 Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (52 mg, 0.094 mmol), 2-(7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (33 mg, 0.12 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-1,1’-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (3.4 mg, 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 carried out three times. Degassed dioxane (0.9 mL) and potassium phosphate solution (2.0 M in water, 140 μL, 0.28 mmol) were added and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexanes) to afford the desired product (61 mg, 0.09 mmol, 98% yield). LC / MS (ESI) m / z: [M+H] + C 37 H 36 Calculated for C40H44F2N7O3 664.3; found 664.5; 11H NMR (500 MHz, CDCl3) δ 9.19 (s, 1H), 8.02 - 7.96 (m, 1H), 7.96 - 7.89 (m, 1H), 7.74 - 7.71 (m, 1H), 7.62 - 7.54 (m, 1H), 7.49 - 7.42 (m, 1H), 7.40 - 7.35 (m, 5H), 7.34 - 7.28 (m, 1H), 5.29 - 5.16 (m, 2H), 5.30 (d, J = 66.2 Hz, 2H), 4.86 - 4.59 (m, 3H), 4.49 - 4.43 (m, 1H), 4.33 - 4.16 (m, 1H), 4.11 - 4.01 (m, 1H), 3.99 - 3.91 (m, 1H), 3.89 - 3.82 (m, 1H), 3.74 - 3.50 (m, 2H), 3.13 - 3.04 (m, 3H), 3.00 - 2.83 (m, 2H), 2.45 - 2.33 (m, 2H), 2.28 - 2.17 (m, 1H), 2.13 - 2.09 (m, 1H). 【0220】 【Chem.】 Step 2: Preparation of 2 - ((S) - 4 - (8 - fluoro - 7 - (7 - fluoronaphthalen - 1 - yl) - 2 - (((S) - 1 - methylpyrrolidin - 2 - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazin - 2 - yl)acetonitrile Benzyl (S) - 2 - (cyanomethyl) - 4 - (8 - fluoro - 7 - (7 - fluoronaphthalen - 1 - yl) - 2 - (((S) - 1 - methylpyrrolidin - 2 - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazine - 1 - carboxylate (61 mg, 0.092 mmol) was dissolved in MeOH (2.0 mL), and palladium on carbon (10 wt%, 20 mg, 0.018 mmol) was added. Hydrogen gas was bubbled through the solution for 5 minutes, and then the reaction mixture was kept under a hydrogen atmosphere (balloon) for 1.5 hours. The reaction mixture was filtered through a plug of Celite® and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M + H] + C 29 H 30 Calculated for C28H26F2N7O 530.2; found 530.2. 【0221】 [Chem.] Intermediate 32 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine [Chem.] Step 1: Preparation of tert-butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (75 mg, 0.13 mmol), (1-methyl-1H-indazol-7-yl)boronic acid (38 mg, 0.21 mmol) and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (10.4 mg, 14 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was carried out 3 times. Degassed dioxane (1.4 mL) and potassium phosphate solution (2.0 M in water, 290 μL, 0.33 mmol) were added and the reaction mixture was heated in the microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (29 mg, 0.05 mmol, 33% yield). LC / MS (ESI) m / z: [M+H]+ C 32 H 39 Calculated value for F2N8O3: 621.3; Measured value: 621.4; 1 1H NMR (500 MHz, CDCl3) δ 9.10 (s, 1H), 8.07 (s, 1H), 7.85 (dd, J = 8.0, 1.0 Hz, 1H), 7.47 (d, J = 7.0 Hz, 1H), 7.25 (d, J = 1.2 Hz, 1H), 5.43 (d, J = 51.9 Hz, 1H), 4.04 (br s, 4H), 3.99 - 3.91 (m, 1H), 3.77 (s, 3H), 3.73 - 3.69 (m, 4H), 3.68 - 3.65 (m, 1H), 3.52 - 3.04 (m, 4H), 2.66 - 2.02 (m, 6H), 1.50 (s, 9H). 【0222】 【Chem.】 Step 2: Preparation of 8 - fluoro - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy) - 7 - (1 - methyl - 1H - indazol - 7 - yl) - 4 - (piperazin - 1 - yl)pyrido[4,3 - d]pyrimidine tert - Butyl 4 - (8 - fluoro - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy) - 7 - (1 - methyl - 1H - indazol - 7 - yl)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazine - 1 - carboxylate (29 mg, 0.047 mmol) was dissolved in MeCN (1.0 mL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 120 μl, 0.47 mmol) was added dropwise. After 2 hours, the solution was concentrated, and the crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M + H] + C 27 H 31 Calculated value for F2N8O: 521.3; Measured value: 521.3. 【0223】 【Chem.】 Intermediate 33 2-((S)-4-(7-(2,5-Difluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [Chemical Structure] Step 1: Benzyl (S)-2-(cyanomethyl)-4-(7-(2,5-difluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (40 mg, 0.067 mmol), (2,5-difluorophenyl)boronic acid (21 mg, 0.134 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (2.4 mg, 3 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was repeated three times. Degassed dioxane (0.7 mL) and potassium phosphate solution (2.0 M in water, 100 μL, 0.20 mmol) were added, and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (41 mg, 0.061 mmol, 91% yield). LC / MS (ESI) m / z: [M+H] + C 35 H 34 Calculated for C41H44F4N7O3 676.3; found 676.5;1 1H NMR (500 MHz, CDCl3) δ 9.06 (s, 1H), 7.38 (s, 6H), 7.20 - 7.13 (m, 2H), 5.27 (d, J = 53.8 Hz, 1H), 5.20 (s, 2H), 4.74 - 4.65 (m, 1H), 4.51 - 4.44 (m, 1H), 4.40 - 4.34 (m, 1H), 4.31 (d, J = 10.5 Hz, 1H), 4.22 (d, J = 10.5 Hz, 1H), 4.20 - 4.11 (m, 1H), 3.94 - 3.81 (m, 1H), 3.74 - 3.65 (m, 1H), 3.62 - 3.46 (m, 1H), 3.29 - 3.15 (m, 3H), 2.97 (td, J = 9.2, 5.8 Hz, 1H), 2.93 - 2.77 (m, 1H), 2.71 (dd, J = 16.7, 5.2 Hz, 1H), 2.27 - 2.08 (m, 3H), 2.00 - 1.82 (m, 3H). 【0224】 【Chem.】 Step 2: Preparation of 2 - ((S) - 4 - (7 - (2,5 - Difluorophenyl) - 8 - fluoro - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazin - 2 - yl)acetonitrile Benzyl (S) - 2 - (cyanomethyl) - 4 - (7 - (2,5 - difluorophenyl) - 8 - fluoro - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazine - 1 - carboxylate (40 mg, 0.059 mmol) was dissolved in MeOH (1.1 mL), and palladium on carbon (10 wt%, 13 mg, 0.012 mmol) was added. Hydrogen gas was bubbled through the solution for 5 minutes, and then the reaction mixture was maintained under a hydrogen atmosphere (balloon) for 1.5 hours. The reaction mixture was filtered through a plug of Celite® and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M + H] + C 27 H 28Calculated value for F4N7O: 542.2; Measured value: 542.3. 【0225】 [Chemical formula] Intermediate 34 2-((S)-4-(7-(2-(Difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile [Chemical formula] Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(7-(2-(difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (40 mg, 0.067 mmol), (2-(difluoromethyl)-5-fluorophenyl)boronic acid (25 mg, 0.13 mmol) and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (2.4 mg, 3 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was carried out three times. Degassed dioxane (0.7 mL) and potassium phosphate solution (2.0 M in water, 100 μL, 0.20 mmol) were added and the reaction mixture was heated in the microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexanes) to afford the desired product (45 mg, 0.064 mmol, 95% yield). LC / MS (ESI) m / z: [M+H] + C 36 H 35 Calculated for C41H45F5N7O3 708.3; found 708.6; 11H NMR (500 MHz, CDCl3) δ 9.05 (s, 1H), 7.84 (dd, J = 8.5, 5.3 Hz, 1H), 7.41 - 7.36 (m, 5H), 7.33 - 7.27 (m, 2H), 6.95 (t, J = 55.3 Hz, 1H), 5.27 (d, J = 54.6 Hz, 1H), 5.21 - 5.19 (m, 2H), 4.72 - 4.66 (m, 1H), 4.53 - 4.45 (m, 1H), 4.42 - 4.35 (m, 1H), 4.31 (d, J = 10.5 Hz, 1H), 4.22 (d, J = 10.5 Hz, 1H), 4.23 - 4.15 (m, 1H), 3.98 - 3.85 (m, 1H), 3.71 (td, J = 11.6, 3.9 Hz, 1H), 3.64 - 3.46 (m, 1H), 3.31 - 3.12 (m, 3H), 3.02 - 2.93 (m, 1H), 2.93 - 2.78 (m, 1H), 2.77 - 2.66 (m, 1H), 2.28 - 2.07 (m, 3H), 1.98 - 1.85 (m, 3H). 【0226】 【Chem.】 Process 2: Preparation of 2 - ((S) - 4 - (7 - (2 - (difluoromethyl) - 5 - fluorophenyl) - 8 - fluoro - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazin - 2 - yl)acetonitrile Benzyl (S)-2-(cyanomethyl)-4-(7-(2-(difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (40 mg, 0.057 mmol) was dissolved in MeOH (1.1 mL), and palladium on carbon (10 wt%, 12 mg, 0.011 mmol) was added. Hydrogen gas was bubbled through the solution for 5 minutes, and then the reaction mixture was maintained under a hydrogen atmosphere (balloon) for 1.5 hours. The reaction mixture was filtered through a plug of Celite (registered trademark) and concentrated. The crude residue was used directly in the next step without further purification (assuming a quantitative yield). LC / MS (ESI) m / z: [M+H] + C 28 H 29 Calculated for C32H35F5N7O 574.2; found 574.3. 【0227】 【Chemical formula】 Intermediate 35 2-((S)-4-(8-Fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 【Chemical formula】 Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate) Benzyl (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (40 mg, 0.067 mmol), (5-fluoro-2-(trifluoromethyl)phenyl)boronic acid (27.8 mg, 0.134 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-1,1’-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (2.4 mg, 3 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (0.7 mL) and potassium phosphate solution (2.0 M in water, 100 μL, 0.20 mmol) were added and the reaction mixture was heated in the microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexanes) to afford the desired product (45 mg, 0.062 mmol, 93% yield). LC / MS (ESI) m / z: [M+H] + C 36 H 34 Calculated for C36H35F6N7O3 726.3; found 726.6; 11H NMR (600 MHz, CDCl3) δ 9.02 (s, 1H), 7.83 (dd, J = 8.8, 5.2 Hz, 1H), 7.44 - 7.33 (m, 5H), 7.32 - 7.27 (m, 1H), 7.20 (dd, J = 8.5, 2.4 Hz, 1H), 5.27 (d, J = 54.3 Hz, 1H), 5.21 (s, 2H), 4.76 - 4.64 (m, 1H), 4.53 - 4.34 (m, 2H), 4.30 (d, J = 10.4 Hz, 1H), 4.21 (d, J = 10.4 Hz, 1H), 4.24 - 4.10 (m, 1H), 4.00 - 3.82 (m, 1H), 3.77 - 3.67 (m, 1H), 3.65 - 3.42 (m, 1H), 3.31 - 3.15 (m, 3H), 3.02 - 2.93 (m, 1H), 2.93 - 2.77 (m, 1H), 2.72 (br dd, J = 16.7, 5.3 Hz, 1H), 2.29 - 2.08 (m, 3H), 1.97 - 1.83 (m, 3H). 【0228】 【Chem.】 Process 2: Preparation of 2 - ((S) - 4 - (8 - fluoro - 7 - (5 - fluoro - 2 - (trifluoromethyl)phenyl) - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazin - 2 - yl)acetonitrile Benzyl (S) - 2 - (cyanomethyl) - 4 - (8 - fluoro - 7 - (5 - fluoro - 2 - (trifluoromethyl)phenyl) - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazine - 1 - carboxylate (40 mg, 0.055 mmol) was dissolved in MeOH (1.1 mL), and palladium carbon (10 wt%, 12 mg, 0.011 mmol) was added. Hydrogen gas was bubbled through the solution for 5 minutes, and then the reaction mixture was kept under a hydrogen atmosphere (balloon) for 1.5 hours. The reaction mixture was filtered through a plug of Celite (registered trademark) and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M + H]+ C 28 H 28 Calculated value for C6H6F7N2O is 592.2; measured value is 592.3. 【0229】 【Chem.】 Intermediate 36 2-((S)-4-(8-Fluoro-7-(5-chloro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 【Chem.】 Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(5-chloro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate) 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 (40 mg, 0.067 mmol), (5-chloro-2-(trifluoromethyl)phenyl)boronic acid (30 mg, 0.134 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-1,1’-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (2.4 mg, 3 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (0.7 mL) and potassium phosphate solution (2.0 M in water, 100 μL, 0.20 mmol) were added, and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (24 mg, 0.03 mmol, 48% yield). LC / MS (ESI) m / z: [M+H] + C 36 H 34 Calculated for ClF5N7O3 742.2; found 742.1; 1 H NMR (600 MHz, CDCl3) δ 9.02 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.49 - 7.47 (m, 1H), 7.42 - 7.34 (m, 5H), 5.27 (d, J = 54.0 Hz, 1H), 5.21 (s, 2H), 4.74 - 4.62 (m, 1H), 4.53 - 4.44 (m, 1H), 4.41 - 4.34 (m, 1H), 4.32 - 4.14 (m, 3H), 3.99 - 3.79 (m, 1H), 3.76 - 3.66 (m, 1H), 3.64 - 3.41 (m, 1H), 3.32 - 3.14 (m, 3H), 3.05 - 2.93 (m, 1H), 2.93 - 2.76 (m, 1H), 2.76 - 2.67 (m, 1H), 2.29 - 2.08 (m, 3H), 1.99 - 1.77 (m, 3H). 【0230】 【Chem.】 Process 2: Preparation of 2-((S)-4-(8-Fluoro-7-(5-chloro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(5-chloro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (20 mg, 0.027 mmol) was dissolved in MeOH (0.55 mL), and palladium on carbon (10 wt%, 6 mg, 0.027 mmol) was added. Hydrogen gas was bubbled through the solution for 5 minutes, and then the reaction mixture was maintained under a hydrogen atmosphere (balloon) for 1.5 hours. The reaction mixture was filtered through a plug of Celite (registered trademark) and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 28 H 28 Calculated for ClF5N7O 608.2; found 608.1. 【0231】 【Chem.】 Intermediate 37 8-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile 【Chem.】 Step 1: Preparation of tert-butyl 4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 0.095 mmol), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (35 mg, 0.125 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (6.9 mg, 9.5 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 THF (0.95 mL) and potassium phosphate solution (2.0 M in water, 190 μL, 0.29 mmol) were added and the reaction mixture was heated in a microwave at 65 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20 → 100% EtOAc with 5% Et3N / hexane) to afford the desired product (14 mg, 0.022 mmol, 23% yield). LC / MS (ESI) m / z: [M+H] + C 35 H 38 Calculated for C33H35F2N7O3 642.3; found 642.2. 【0232】 【Chem.】 Step 2: Preparation of 8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile tert-Butyl 4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (14.1 mg, 0.022 mmol) was dissolved in MeCN (1.0 mL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 55 μl, 0.22 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 2 hours, the solution was concentrated, and the crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 30 H 30 Calculated for C28H30F2N7O: 542.2; Found: 542.5. 【0233】 【Chemical Structure】 Intermediate 38 2-((S)-4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 【Chemical Structure】 Step 1: Preparation of Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate 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 (75 mg, 0.125 mmol), (1-methyl-1H-indazol-7-yl)boronic acid (33 mg, 0.19 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium® A Palladacycle Gen.3] (9.1 mg, 13 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was carried out three times. Degassed dioxane (1.3 mL) and potassium phosphate solution (2.0 M in water, 250 μL, 0.20 mmol) were added and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexanes) to afford the desired product (59 mg, 0.085 mmol, 68% yield). LC / MS (ESI) m / z: [M+H] + C 37 H 38 Calculated for C33H35F2N9O3 694.3; found 649.6. 【0234】 【Chem.】 Step 2: Preparation of 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (59 mg, 0.085 mmol) was dissolved in MeOH (3.0 mL), and palladium on carbon (10 wt%, 9 mg, 0.008 mmol) was added. Hydrogen gas was bubbled through the solution for 5 minutes, and then the reaction mixture was maintained under a hydrogen atmosphere (balloon) for 1.5 hours. The reaction mixture was filtered through a plug of Celite® and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 29 H 32 Calculated for C28H33F2N9O 560.3; found 560.6. 【0235】 【Chem.】 Intermediate 39 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 【Chem.】 Step 1: Preparation of tert-butyl 4-(7-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate ((4aS,7aR)-1-Methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (126 mg, 0.75 mmol, prepared according to the procedure described in WO 2022 / 192794) was dissolved in THF (2.5 mL), and the solution was cooled to 0 °C. A solution of LiHMDS (1.0 M in THF, 720 μL, 0.721 mmol) was added dropwise, and the reaction mixture was stirred for 10 minutes. tert-Butyl 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (200 mg, 0.5 mmol) was added as a solid. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was partially concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (240 mg, 0.45 mmol, 91% yield). LC / MS (ESI) m / z: [M+H] + C 26 H 37 Calculated for C22H32Cl2FN6O3 535.3; found 535.6; 1 1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 4.48 (d, J = 10.7 Hz, 1H), 4.28 (d, J = 10.6 Hz, 1H), 3.98 - 3.90 (m, 4H), 3.69 - 3.63 (m, 4H), 2.71 (t, J = 6.2 Hz, 1H), 2.58 (ddd, J = 11.2, 7.2, 4.2 Hz, 1H), 2.32 - 2.29 (m, 1H), 2.27 (s, 3H), 1.89 - 1.60 (m, 10H), 1.50 (s, 9H). 【0236】 【Chemical Structure】 Step 2: Preparation of tert-Butyl 4-(8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (240 mg, 0.449 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (440 mg, 0.86 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct [cataCXium® A Pd G3] (16 mg, 0.022 mmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen; this process was performed 3 times. Degassed dioxane (2.2 mL) and potassium phosphate solution (2.0 M in water, 670 μL, 1.3 mmol) were added, and the reaction mixture was heated at 100 °C for 1.5 h in the microwave. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 49 H 67 Calculated for F2N6O5Si 885.5; found 885.9; 11H NMR (500 MHz, CDCl3) δ 9.04 (d, J = 1.0 Hz, 1H), 7.78 (dd, J = 9.1, 5.6 Hz, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.29 (t, J = 8.8 Hz, 1H), 5.31 (d, J = 7.0 Hz, 1H), 5.28 (d, J = 7.0 Hz, 1H), 4.50 (d, J = 10.6 Hz, 1H), 4.43 (d, J = 10.8 Hz, 1H), 4.31 (d, J = 10.8 Hz, 1H), 4.23 (d, J = 10.6 Hz, 1H), 4.03 - 3.96 (m, 2H), 3.94 - 3.87 (m, 2H), 3.78 - 3.70 (m, 2H), 3.69 - 3.61 (m, 2H), 3.51 (s, 3H), 2.66 (t, J = 5.5 Hz, 1H), 2.64 - 2.57 (m, 1H), 2.30 - 2.23 (m, 4H), 1.91 - 1.60 (m, 8H), 1.51 (s, 9H), 0.89 - 0.85 (m, 18H), 0.60 - 0.51 (m, 3H). 【0237】 【Chem.】 Step 3: Preparation of tert-butyl 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (360 mg, 0.407 mmol) was dissolved in THF (4.1 mL), and the solution was cooled to 0 °C. A solution of TBAF (1.0 M in THF, 0.6 mL, 0.6 mmol) was added dropwise, and the reaction mixture was stirred for 5 minutes. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (250 mg, 0.34 mmol, 84% yield over two steps). LC / MS (ESI) m / z: [M+H] + C 40 H 47 Calculated for C40H52F2N6O5 729.4; found 729.7; 1 H NMR (600 MHz, CDCl3) δ 8.99 (s, 1H), 7.83 (dd, J = 9.1, 5.6 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.37 (t, J = 2.2 Hz, 1H), 7.29 (t, J = 8.7 Hz, 1H), 5.32 (d, J = 6.9 Hz, 1H), 5.30 (d, J = 6.9 Hz, 1H), 4.49 (dd, J = 10.7, 6.7 Hz, 1H), 4.30 (dd, J = 10.7, 2.5 Hz, 1H), 4.01 - 3.96 (m, 4H), 3.70 (br d, J = 4.5 Hz, 4H), 3.52 (s, 3H), 2.81 (d, J = 6.5 Hz, 1H), 2.70 (t, J = 6.0 Hz, 1H), 2.31 - 2.28 (m, 1H), 2.27 (s, 3H), 1.90 - 1.64 (m, 11H), 1.51 (s, 9H). 【0238】 【Chemical Structure】 Preparation of 4:5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol tert-Butyl 4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.137 mmol) was dissolved in MeCN (1.4 mL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 0.34 mL, 1.37 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 2 hours, sodium hydroxide solution (1.0 M, 1.37 mL, 1.37 mmol) was added, and the solution was concentrated to remove volatile organics. The resulting aqueous solution was frozen and lyophilized directly to give the desired product together with sodium chloride. This material was of sufficient purity to be used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 33 H 35 Calculated for C F2N6O2 585.3; found 585.5. 【0239】 【Chemical Structure】 Intermediate 40 2-((S)-4-(8-Fluoro-7-(5-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 【Chemical Structure】 Process 1: Preparation of Benzyl (S)-2-(Cyanomethyl)-4-(8-Fluoro-7-(5-Fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate Benzyl (S)-4-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (50 mg, 0.084 mmol), 5-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (26 mg, 0.17 mmol), cesium carbonate (82 mg, 0.25 mmol), BINAP (10.4 mg, 0.017 mmol), and palladium(II) acetate (1.9 mg, 8 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (2.0 mL) was added and the reaction mixture was heated in the microwave at 100 °C for 16 hours. The reaction mixture was filtered through a pad of Celite® and concentrated. The crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (15.8 mg, 0.022 mmol, 26% yield). LC / MS (ESI) m / z: [M+H] + C 37 H 38 Calculated for C34H35F3N8O4 715.3; found 715.2. 【0240】 【Chemical Structure】 Step 2: Preparation of 2-((S)-4-(8-Fluoro-7-(5-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(5-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (16 mg, 0.022 mmol) was dissolved in MeOH (2.0 mL), and palladium on carbon (10 wt%, 2 mg, 0.002 mmol) was added. Hydrogen gas was bubbled through the solution for 5 minutes, and then the reaction mixture was maintained under a hydrogen atmosphere (balloon) for 1.5 hours. The reaction mixture was filtered through a plug of Celite (registered trademark) and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 29 H 32 Calculated for C28H33F3N8O2 581.3; found 581.5. 【0241】 【Chemical Structure】 Intermediate 41 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidine 【Chemical Structure】 Step 1: Preparation of tert-Butyl (S)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.5 g, 9.9 mmol) was dissolved in DCM (100 mL), and the solution was cooled to -40 °C. DIPEA (2.6 mL, 15 mmol) was then added dropwise, followed by tert-butyl (S)-3-methylpiperazine-1-carboxylate (2.0 g, 9.9 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. The solution was concentrated, and the crude residue was purified by column chromatography (0 → 60% EtOAc / hexane) to afford the desired product (3.7 g, 8.8 mmol, 89% yield). LC / MS (ESI) m / z: [M+H] + C 17 H 21 Calculated for C14H18Cl2FN5O2 416.1; found 416.0; 1 H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 4.94 - 4.86 (m, 1H), 4.52 - 4.42 (m, 1H), 4.31 - 4.09 (m, 1H), 4.07 - 3.95 (m, 1H), 3.78 - 3.66 (m, 1H), 3.31 - 3.07 (m, 2H), 1.54 (d, J = 6.8 Hz, 3H), 1.52 (s, 9H). 【0242】 【Chem.】 Step 2: Preparation of tert-butyl (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (1.61 g, 10.1 mmol) was dissolved in THF (45 mL), and the solution was cooled to 0 °C. A solution of LiHMDS (1.0 M in THF, 10.6 mL, 10.6 mmol) was added dropwise, and the resulting mixture was stirred for 10 minutes. tert-Butyl (S)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (3.7 g, 8.8 mmol) as a solution in THF (50 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 hours. The solution was partially concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (4.55 g, 8.4 mmol, 96% yield) as a yellow foam. LC / MS (ESI) m / z: [M+H] + C 25 H 34 Calculated for C25H35ClF2N6O3 539.2; found 539.5; 1 1H NMR (600 MHz, CDCl3) δ 8.70 (s, 1H), 0.00 (d, J = 52.7 Hz, 1H), 4.78 (br s, 1H), 4.33 (br d, J = 13.1 Hz, 1H), 4.25 (d, J = 10.4 Hz, 1H), 4.15 (d, J = 10.4 Hz, 1H), 4.26 - 3.82 (m, 2H), 3.67 - 3.56 (m, 1H), 3.28 - 2.94 (m, 6H), 2.29 - 2.09 (m, 3H), 1.99 - 1.82 (m, 3H), 1.49 (s, 9H), 1.46 (d, J = 6.7 Hz, 3H). 【0243】 【Chemical Structure】 Step 3: Preparation of tert-Butyl (S)-4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-Butyl (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (45 mg, 0.083 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (54 mg, 0.13 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium A Palladacycle Gen.3] (3.0 mg, 4.2 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was carried out three times. Degassed dioxane (400 μL) and potassium phosphate solution (2.0 M in water, 125 μL, 0.25 mmol) were added and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (66 mg, 0.081 mmol, 97% yield). LC / MS (ESI) m / z: [M+H] + C 46 H 61 Calculated for F2N6O3Si 811.4; found 811.4; 1 H NMR (600 MHz, CDCl3) δ 9.07 - 8.96 (m, 1H), 7.99 - 7.89 (m, 2H), 7.84 - 7.77 (m, 1H), 7.60 - 7.51 (m, 2H), 7.48 - 7.43 (m, 1H), 5.35 - 5.20 (m, 1H), 5.05 - 4.67 (m, 1H), 4.55 - 3.70 (m, 6H), 3.58 - 2.95 (m, 6H), 2.34 - 2.09 (m, 3H), 1.97 - 1.84 (m, 3H), 1.55 - 1.49 (m, 12H), 0.91 - 0.83 (m, 18H), 0.60 - 0.48 (m, 3H). 【0244】 【Chem.】 Step 4: Preparation of tert-butyl (S)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-Butyl (S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (66 mg, 0.081 mmol) was dissolved in THF (800 μL), and the solution was cooled to 0 °C. A solution of TBAF (1.0 M in THF, 120 μL, 0.12 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 minutes, the reaction mixture was concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (53 mg, 0.08 mmol, 99% yield). LC / MS (ESI) m / z: [M+H] + C 37 H 41 Calculated for C40H50F2N6O3 655.3; found 655.4; 1 1H NMR (600 MHz, CDCl3) δ 9.01 - 8.93 (m, 1H), 8.01 - 7.93 (m, 2H), 7.77 - 7.73 (m, 1H), 7.63 - 7.55 (m, 2H), 7.49 - 7.43 (m, 1H), 5.28 (d, J = 53.6 Hz, 1H), 4.93 - 4.78 (m, 1H), 4.49 - 4.36 (m, 1H), 4.31 - 4.25 (m, 1H), 4.21 - 4.16 (m, 1H), 4.30 - 3.87 (m, 2H), 3.70 - 3.59 (m, 1H), 3.35 - 2.94 (m, 6H), 2.30 - 2.13 (m, 3H), 1.97 - 1.87 (m, 4H), 1.51 - 1.46 (m, 12H). 【0245】 【Chemical Structure】 Step 5: Preparation of 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidine tert-Butyl (S)-4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (59 mg, 0.090 mmol) was dissolved in MeCN (900 μL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 230 μL, 0.90 mmol) was added dropwise. After 2 hours, 1-methylimidazole (100 μL) was added, and the reaction mixture was concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 32 H 33 Calculated for C29H33F2N6O: 555.3; Found: 555.2 【0246】 【Chemical Structure】 Intermediate 42 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 【Chemical Structure】 Process 1: Preparation of tert-butyl (S)-4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-Butyl (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.19 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (140 mg, 0.28 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium A Palladacycle Gen.3] (6.8 mg, 9.3 μmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (900 μL) and potassium phosphate solution (2.0 M in water, 270 μL, 0.54 mmol) were added, and the reaction mixture was heated in the microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (160 mg, 0.18 mmol, 97% yield). LCMS (ESI) m / z: [M+H] + C 48 H 64 Calculated for C45H61F3N6O5Si 889.5; found 889.5. 【0247】 【Chemical Structure】 Step 2: Preparation of tert-butyl (S)-4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-Butyl (S)-4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (160 mg, 0.180 mmol) was dissolved in THF (1.8 mL), and the solution was cooled to 0 °C. A solution of TBAF (1.0 M in THF, 180 μL, 0.18 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 minutes, the reaction mixture was concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (128 mg, 0.175 mmol, 97% yield). LCMS (ESI) m / z: [M+H] + C 39 H 44 Calculated for C37H43F3N6O5 733.3; found 733.3; 1 1H NMR (500 MHz, CDCl3) δ 8.99 - 8.91 (m, 1H), 7.86 - 7.80 (m, 1H), 7.55 - 7.52 (m, 1H), 7.39 - 7.35 (m, 1H), 7.31 - 7.26 (m, 1H), 5.32 (d, J = 6.8 Hz, 1H), 5.29 (d, J = 6.8 Hz, 1H), 5.28 (d, J = 54.6 Hz, 1H), 4.93 - 4.80 (m, 1H), 4.45 - 4.35 (m, 1H), 4.32 - 4.23 (m, 1H), 4.21 - 4.15 (m, 1H), 4.00 - 3.89 (m, 1H), 3.71 - 3.58 (m, 1H), 3.52 (s, 3H), 3.34 - 3.04 (m, 5H), 3.02 - 2.93 (m, 1H), 2.31 - 2.11 (m, 3H), 1.99 - 1.84 (m, 5H), 1.52 - 1.45 (m, 12H). 【0248】 【Chem.】 Process 3: Preparation of 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol tert-Butyl (S)-4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (120 mg, 0.164 mmol) was dissolved in MeCN (1.6 mL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 410 μL, 1.6 mmol) was added dropwise. After 2 h, 1-methylimidazole (200 μL) was added, and the reaction mixture was concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LCMS (ESI) m / z: [M+H] + C 32 H 32 Calculated for C33H36F3N6O2 589.2; found 589.2. 【0249】 【Chem.】 Intermediate 43 tert-Butyl (5,7-difluoro-4-(8-fluoro-4-(4-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate 【Chem.】 Process 1: Preparation of tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (20 mg, 0.038 mmol), (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)boronic acid (19 mg, 0.057 mmol) [commercially available], and [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate methanesulfonate [BrettPhos Pd G3] (3.5 mg, 0.0038 mmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was performed three times. Degassed dioxane (400 μL) and potassium phosphate solution (2.0 M in water, 60 μL, 0.11 mmol) were added, and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to give the desired product (16 mg, 0.020 mmol, 54% yield). LCMS (ESI) m / z: [M+H] + C 36 H 43 Calculated for C41H47F4N8O5S 775.3; found 775.3; 11H NMR (600 MHz, CDCl3) δ 9.08 (s, 1H), 8.17 (br s, 1H), 6.95 (t, J = 9.4 Hz, 1H), 5.27 (d, J = 54.3 Hz, 1H), 4.29 (br d, J = 10.5 Hz, 1H), 4.19 (d, J = 10.4 Hz, 1H), 4.00 - 3.93 (m, 4H), 3.69 - 3.63 (m, 4H), 3.28 - 3.24 (m, 1H), 3.23 - 3.19 (m, 1H), 3.17 (s, 1H), 3.03 - 2.92 (m, 1H), 2.30 - 2.11 (m, 3H), 1.99 - 1.85 (m, 3H), 1.54 (s, 9H), 1.50 (s, 9H). 【0250】 【Chem.】 Step 2: Preparation of tert - butyl (5,7 - difluoro - 4-(8 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)-4-(piperazin - 1 - yl)pyrido[4,3 - d]pyrimidin - 7 - yl)benzo[d]thiazol - 2 - yl)carbamate tert - butyl 4-(7-(2 - ((tert - butoxycarbonyl)amino)-5,7 - difluorobenzo[d]thiazol - 4 - yl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)piperazine - 1 - carboxylate (16 mg, 0.021 mmol) was dissolved in MeCN (1.0 mL), and HCl solution (4.0 M in dioxane, 50 μL, 0.2 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 20 h. 1 - Methylimidazole (50 μL) was added and the solution was concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LCMS (ESI) m / z: [M + H] + C 31 H 35 Calculated for C29H35F4N8O3S 675.2; found 675.2. 【0251】 【Chem.】 Step 3: Preparation of tert-butyl (5,7-difluoro-4-(8-fluoro-4-(4-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate tert-Butyl (5,7-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate (13 mg, 0.019 mmol) and (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (10 mg, 0.06 mmol) were combined as solids and dissolved in MeCN (400 μL). After adding 1-methylimidazole (9 μL, 0.19 mmol), chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (36 mg, 0.127 mmol) was added. The reaction mixture was stirred for 5 minutes and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LCMS (ESI) m / z: [M+H] + C 37 H 37 Calculated for C41H50F5N9O4S2: 830.2; found: 830.3. 【0252】 【Chemical Structure】 Intermediate 44 tert-Butyl (5,7-difluoro-4-(8-fluoro-4-(4-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate 【Chem.】 Step 1: Preparation of tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (30 mg, 0.057 mmol), (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (27 mg, 0.086 mmol) [commercially available], and [(2-dicyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate methanesulfonate [BrettPhos Pd G3] (5.2 mg, 0.0057 mmol) were combined as solids in a microwave vial. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. This process was carried out three times. Degassed dioxane (600 μL) and potassium phosphate solution (2.0 M in water, 86 μL, 0.17 mmol) were added, and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to give the desired product (25 mg, 0.033 mmol, 58% yield). LCMS (ESI) m / z: [M+H] + C 36 H 44 Calculated for C37H43F3N8O5S 757.3; found 757.6; 11H NMR (600 MHz, CDCl3) δ 9.08 (s, 1H), 8.17 (br s, 1H), 6.95 (t, J = 9.4 Hz, 1H), 5.27 (d, J = 54.3 Hz, 1H), 4.29 (br d, J = 10.5 Hz, 1H), 4.19 (d, J = 10.4 Hz, 1H), 4.00 - 3.93 (m, 4H), 3.69 - 3.63 (m, 4H), 3.28 - 3.24 (m, 1H), 3.23 - 3.19 (m, 1H), 3.17 (s, 1H), 3.03 - 2.92 (m, 1H), 2.30 - 2.11 (m, 3H), 1.99 - 1.85 (m, 3H), 1.54 (s, 9H), 1.50 (s, 9H). 【0253】 【Chem.】 Step 2: Preparation of tert-butyl (7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (25 mg, 0.033 mmol) was dissolved in MeCN (1.6 mL), and HCl solution (4.0 M in dioxane, 83 μL, 0.33 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. 1-Methylimidazole (50 μL) was added and the solution was concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LCMS (ESI) m / z: [M + H] + C 31 H 36 Calculated for C33H38F3N8O3S 657.3; found 657.2. 【0254】 【Chem.】 Step 3: Preparation of tert-butyl (7-fluoro-4-(8-fluoro-4-(4-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate tert-Butyl (7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate (21 mg, 0.032 mmol) and (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid (17 mg, 0.096 mmol) were combined as solids and dissolved in MeCN (650 μL). After adding 1-methylimidazole (15 μL, 0.32 mmol), chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (27 mg, 0.096 mmol) was added. The reaction mixture was stirred for 5 minutes and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LCMS (ESI) m / z: [M+H] + C 37 H 38 Calculated for C41H49F4N9O4S2 812.2; found 812.2. 【0255】 【Chemical Structure】 Intermediate 45 7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidine 【Chemical Structure】 Process 1: Preparation of tert-butyl (S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-Butyl (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (25 mg, 0.046 mmol), ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (31.5 mg, 0.070 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium A Palladacycle Gen.3] (1.7 mg, 2.1 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 (400 μL) and potassium phosphate solution (2.0 M in water, 70 μL, 0.14 mmol) were added, and the reaction mixture was heated in a microwave at 100 °C for 1.5 hours. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to give the desired product (30 mg, 0.036 mmol, 78% yield). LCMS (ESI) m / z: [M+H] + C 46 H 60 Calculated for C52H66F3N6O3Si 829.4; found 829.5; 11H NMR (600 MHz, CDCl3) δ 9.05 - 8.97 (m, 1H), 7.96 - 7.93 (m, 1H), 7.92 - 7.88 (m, 1H), 7.59 - 7.51 (m, 2H), 7.36 - 7.31 (m, 1H), 5.39 - 5.19 (m, 1H), 5.06 - 4.65 (m, 1H), 4.43 (s, 1H), 4.32 - 3.69 (m, 4H), 3.65 - 3.48 (m, 1H), 3.44 - 2.91 (m, 6H), 2.34 - 2.10 (m, 3H), 1.97 - 1.85 (m, 3H), 1.52 - 1.49 (m, 12H), 0.89 - 0.85 (m, 18H), 0.61 - 0.50 (m, 3H). 【0256】 [Chemical formula] Step 2: Preparation of tert-Butyl (S)-4-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-Butyl (S)-4-(8-Fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (30 mg, 0.036 mmol) was dissolved in THF (400 μL), and the solution was cooled to 0 °C. A solution of TBAF (1.0 M in THF, 54 μL, 0.54 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 minutes, the reaction mixture was concentrated, and the crude residue was purified by column chromatography (50 → 100% EtOAc with 5% Et3N / hexane) to afford the desired product (24 mg, 0.0 mmol, 99% yield). LCMS (ESI) m / z: [M + H] + C 37 H 40 Calculated for C29H35F3N6O3 673.3; found 673.6; 11H NMR (600 MHz, CDCl3) δ 9.00 - 8.94 (m, 1H), 7.99 - 7.92 (m, 2H), 7.66 - 7.55 (m, 2H), 7.37 - 7.30 (m, 1H), 5.28 (d, J = 53.6 Hz, 1H), 4.93 - 4.76 (m, 1H), 4.52 - 3.86 (m, 5H), 3.73 - 3.55 (m, 1H), 3.34 - 2.83 (m, 7H), 2.35 - 2.10 (m, 3H), 2.00 - 1.81 (m, 3H), 1.52 - 1.49 (m, 12H). 【0257】 [Chemical formula] Process 3: Preparation of 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidine tert-Butyl (S)-4-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (24 mg, 0.036 mmol) was dissolved in MeCN (350 μL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 89 μL, 0.36 mmol) was added dropwise. After 2 hours, 1-methylimidazole (50 μL) was added, and the reaction mixture was concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LCMS (ESI) m / z: [M + H] + C 32 H 32 Calculated for C29H33F3N6O 573.3; Found 573.2. 【0258】 [Chemical formula] Intermediate 46 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-methyl-N-(2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine 【Chem.】 Step 1: Preparation of tert-butyl 2-methyl-3-(methylamino)pyrrolidine-1-carboxylate 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 solution 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 a hydrogen atmosphere for 20 h. The black suspension was filtered through a pad of Celite® with elution with additional MeOH, and the filtrate was concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). 【0259】 【Chem.】 Step 2: Preparation of 2,7-dichloro-8-fluoro-N-methyl-N-(2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine 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). After addition of DIPEA (0.83 mL, 4.75 mmol), tert-butyl 2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (1.0 g, 4.75 mmol) was added. The reaction mixture was stirred for 5 min and concentrated. The crude residue was used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 18 H 23 Calculated for Cl2FN5O2 430.1; Found 430.1. 【0260】 【Chemical Structure】 Step 3: Preparation of tert-butyl 3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate 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-pyrrolidin-7a(5H)-yl)methanol (0.96 g, 6.04 mmol) were combined and dissolved in THF (23 mL). The solution was cooled to 0 °C and a solution of LiHMDS (1.0 M in THF, 11.6 mL, 11.6 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 24 h. The solution was concentrated and the crude residue was purified directly by column chromatography (0→100% EtOAc with 5% Et3N / hexane) to give 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 were reported). LC / MS (ESI) m / z: [M+H] + C 26 H 36 Calculated for ClF2N6O3 553.2; Found 553.4; 11H 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). 【0261】 [Chemical formula] Step 4: Preparation of tert-butyl 3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate tert-Butyl 3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexanes) to afford the desired product. LCMS (ESI) m / z: [M+H] + C 47 H 63 Calculated for C43H53F2N6O3Si 825.5; found 825.4. 【0262】 【Chem.】 Step 5: Preparation of tert-Butyl 3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate tert-Butyl 3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (370 mg, 0.448 mmol) was dissolved in THF (4.5 mL), and the solution was cooled to 0 °C. A solution of TBAF (1.0 M in THF, 540 μL, 0.540 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 minutes, the reaction mixture was concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (270 mg, 0.404 mmol, 90% yield over 2 steps) as a 6:6:1:1 cis:cis:trans:trans mixture of diastereomers (the cis diastereomer was reported). LCMS (ESI) m / z: [M+H] + C 38 H 43 Calculated for C40H52F2N6O3 669.3; found 669.4; 1 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). 【0263】 【Chemical Structure】 Step 5: Preparation of 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-methyl-N-(2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine tert-Butyl 3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-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 further purification (assuming quantitative yield). LCMS (ESI) m / z: [M+H] + C 33 H 35 Calculated for C29H32F2N6O: 569.3; Found: 569.3 【0264】 【Chemical Structure】 Intermediate 47 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine 【Chemical Structure】 Step 1: Preparation of tert-Butyl 4-(2,7-dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate 2,4,7-Trichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine (500 mg, 1.770 mmol) [see CN115304623 specification] was dissolved in DCM (9.0 mL), and the solution was cooled to -10 °C (wet ice / acetone). DIPEA (0.46 mL, 2.7 mmol) was added dropwise as a solid, followed by tert-butyl piperazine-1-carboxylate (330 mg, 1.77 mmol). The reaction mixture was warmed to room temperature and stirred for 5 minutes. The reaction mixture was concentrated, and the crude residue was used directly in the next step without further purification (assuming quantitative yield). LCMS (ESI) m / z: [M+H] + C 17 H 21 Calculated for Cl2FN5O3 432.1; found 432.1; 1 H NMR (500 MHz, CDCl3) δ 4.09 (s, 3H), 3.75 - 3.66 (m, 4H), 3.61 - 3.56 (m, 4H), 1.48 (s, 9H). 【0265】 【Chemical formula】 Step 2: Preparation of tert-butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(2,7-dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (735 mg, 1.70 mmol) was suspended in THF (8.5 mL), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (406 mg, 2.55 mmol) was added. The mixture was cooled to 0 °C, and a solution of LiHMDS (1.0 M in THF, 3.7 mL, 3.7 mmol) was added dropwise. After the addition, the reaction mixture was warmed to room temperature and stirred for 24 h. The solution was concentrated, and the crude residue was purified by column chromatography (0→100% EtOAc with 5% Et3N / hexane) to afford the desired product (850 mg, 1.53 mmol, 90% yield) as a pale yellow solid. LC / MS (ESI) m / z: [M+H] + C 25 H 34 Calculated for ClF2N6O3 555.2; found 555.1; 1 H NMR (500 MHz, CDCl3) δ 5.23 (d, J = 53.0 Hz, 1H), 4.20 (d, J = 10.4 Hz, 1H), 4.08 (d, J = 10.4 Hz, 1H), 4.04 (s, 3H), 3.63 - 3.58 (m, 4H), 3.57 - 3.52 (m, 4H), 3.25 - 3.07 (m, 3H), 2.94 (s, 1H), 2.27 - 2.07 (m, 3H), 1.97 - 1.80 (m, 3H), 1.47 (s, 9H). 【0266】 【Chemical Structure】 Step 3: Preparation of tert-Butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 0.090 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (39 mg, 0.09 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 (0.45 mL) and potassium phosphate solution (2.0 M in water, 130 μL, 0.27 mmol) were added and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product (74 mg, 0.089 mmol, 99% yield). LC / MS (ESI) m / z: [M+H] + C 46 H 61 Calculated for F2N6O4Si 827.4; found 827.9; 1 H NMR (500 MHz, CDCl3) δ 7.95 - 7.89 (m, 2H), 7.80 (d, J = 7.2 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.47 - 7.43 (m, 1H), 5.24 (d, J = 54.1 Hz, 1H), 4.24 (dd, J = 10.5, 0.8 Hz, 1H), 4.10 (t, J = 9.8 Hz, 1H), 4.00 (s, 3H), 3.73 - 3.62 (m, 4H), 3.62 - 3.51 (m, 4H), 3.21 (s, 3H), 3.00 - 2.92 (m, 1H), 2.33 - 2.10 (m, 3H), 1.98 - 1.81 (m, 3H), 1.50 (s, 9H), 0.88 - 0.85 (m, 18H), 0.58 (spt, J = 7.4 Hz, 3H). 【0267】 【Chem.】 Process 4: Preparation of tert-butyl 4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (74 mg, 0.089 mmol) was dissolved in THF (0.9 mL), and the solution was cooled to 0 °C. A solution of TBAF (1.0 M in THF, 89 μL, 0.089 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 minutes, the reaction mixture was concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to afford the desired product (54 mg, 0.081 mmol, 90% yield). LC / MS (ESI) m / z: [M+H] + C 37 H 41 Calculated for C40H48F2N6O4 671.3; found 671.6; 1 1H NMR (500 MHz, CDCl3) δ 7.99 - 7.92 (m, 2H), 7.75 (dd, J = 7.2, 1.3 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.45 (dd, J = 8.1, 7.3 Hz, 1H), 5.25 (d, J = 54.0 Hz, 1H), 4.28 - 4.23 (m, 1H), 4.16 - 4.11 (m, 1H), 3.99 (s, 3H), 3.70 - 3.64 (m, 4H), 3.64 - 3.59 (m, 4H), 3.28 - 3.12 (m, 3H), 3.00 - 2.92 (m, 1H), 2.61 - 2.58 (m, 1H), 2.30 - 2.11 (m, 3H), 1.90 (s, 3H), 1.50 (s, 9H). 【0268】 [Chemical] Step 5: Preparation of 5:7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxy-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine tert-Butyl 4-(7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (54 mg, 0.081 mmol) was dissolved in MeCN (0.8 mL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 200 μL, 0.8 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 1.5 h, 1-Methylimidazole (100 μL) was added, and the solution was concentrated. The crude residue was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 32 H 33 Calculated for F2N6O2 571.3; found 571.4. 【0269】 [Chemical] Intermediate 48 (S)-4-(2-((1-(3-Azidopropyl)pyrrolidin-2-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [Chemical] Step 1: Preparation of (S)-(1-(3-Azidopropyl)pyrrolidin-2-yl)methanol (S)-Pyrrolidin-2-ylmethanol (350 mg, 3.46 mmol) was dissolved in MeCN (3.5 mL), potassium carbonate (1.4 g, 10.4 mmol) was added, and then 3-azidopropyl 4-methylbenzenesulfonate (972 mg, 3.81 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered through a pad of Celite (registered trademark) and concentrated. The crude residue was shaken in EtOAc (100 mL) and extracted with HCl (3 × 50 mL). The combined aqueous layers were neutralized with NaOH solution (3 M, 50 mL), and the solution was lyophilized. EtOAc (50 mL) was added to the crude residue, the solution was filtered, and concentrated to give the desired product (450 mg, 2.4 mmol, 71% yield). 1 H NMR (600 MHz, CDCl3) δ 3.65 - 3.57 (m, 1H), 3.41 - 3.30 (m, 3H), 3.20 - 3.11 (m, 1H), 2.87 - 2.77 (m, 1H), 2.61 - 2.54 (m, 1H), 2.58 (br s, 1H), 2.39 - 2.29 (m, 1H), 2.27 - 2.18 (m, 1H), 1.92 - 1.82 (m, 1H), 1.81 - 1.68 (m, 5H). 【0270】 【Chemical Structure】 Step 2: Preparation of tert-butyl (S)-4-(2-((1-(3-azidopropyl)pyrrolidin-2-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (400 mg, 0.994 mmol) was suspended in THF (5.0 mL), and (S)-(1-(3-azidopropyl)pyrrolidin-2-yl)methanol (183 mg, 0.994 mmol) was added. The mixture was cooled to 0 °C, and a solution of LiHMDS (1.0 M in THF, 2.2 mL, 2.2 mmol) was added dropwise. After the addition, the reaction mixture was warmed to room temperature and stirred for 24 h. The solution was concentrated, and the crude residue was purified by column chromatography (0→100% EtOAc with 5% Et3N / hexane) to afford the desired product (340 mg, 0.62 mmol, 62% yield). LC / MS (ESI) m / z: [M+H] + C 24 H 34 Calculated for C27H34Cl2FN9O3 550.2; found 550.3. 【0271】 【Chem.】 Step 3: Preparation of tert-Butyl (S)-4-(2-((1-(3-azidopropyl)pyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl (S)-4-(2-((1-(3-azidopropyl)pyrrolidin-2-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (340 mg, 0.618 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (475 mg, 0.927 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, [cataCXium A Palladacycle Gen.3] (4.5 mg, 6.2 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 (3.1 mL) and potassium phosphate solution (2.0 M in water, 930 μL, 1.85 mmol) were added, and the reaction mixture was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was concentrated directly, and the crude residue was purified by column chromatography (20→100% EtOAc with 5% Et3N / hexane) to afford the desired product. LCMS (ESI) m / z: [M+H] + C 47 H 64 Calculated for C44H61F2N9O5Si 900.5; found 900.5. 【0272】 【Chem.】 Step 4: Preparation of tert-Butyl (S)-4-(2-((1-(3-azidopropyl)pyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (S)-4-(2-((1-(3-azidopropyl)pyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (550 mg, 0.61 mmol) was dissolved in THF (6.1 mL), and the solution was cooled to 0 °C. TBAF solution (1.0 M in THF, 610 μL, 0.61 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 minutes, the reaction mixture was concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (400 mg, 0.54 mmol, 88% yield). LC / MS (ESI) m / z: [M+H] + C 38 H 44 Calculated for C37H43F2N9O5 744.3; found 744.3. 【0273】 【Chemical formula】 Step 5: Preparation of (S)-4-(2-((1-(3-azidopropyl)pyrrolidin-2-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (S)-4-(2-((1-(3-azidopropyl)pyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (400 mg, 0.538 mmol) was dissolved in MeCN (5.4 mL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 1.3 mL, 5.4 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 1 hour, 1-methylimidazole (1 mL) was added, and the solution was concentrated. The crude residue was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + C 31 H32 Calculated value for F2N9O2: 600.3; measured value: 600.2. 【0274】 【Chem.】 Intermediate 49 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol 【Chem.】 Step 1: Preparation of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-ol tert-Butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.2 g, 1.505 mmol) was dissolved in ethanol (10 mL), and the solution was cooled to 0 °C. After adding an aqueous sodium hydroxide solution (1.0 M, 4.5 mL, 4.5 mmol), MeOH (1 drop, about 20 μL) was added. The resulting reaction mixture was heated at 70 °C for 3 hours. The reaction mixture was quenched with ice-cold water (20 mL), and ethyl acetate (50 mL) was added. The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue (900 mg) was used directly in the next step without further purification. LC / MS (ESI) m / z: [M+H] + C 36 H 43 Calculated value for F2N4O2Si: 629.3; measured value: 629.0. 【0275】 【Chem.】 Step 2: Preparation of 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-ol (900 mg, 1.43 mmol) was dissolved in THF (20 mL), and the solution was cooled to 0 °C. A solution of TBAF (1.0 M in THF, 2.9 mL, 2.9 mmol) was added dropwise, and the resulting reaction mixture was stirred at 0 °C for 2 hours. After completion, the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography to give the desired product (400 mg, 0.84 mmol, 56% yield over 2 steps). LC / MS (ESI) m / z: [M+H] + C 27 H 23 Calculated for C F2N4O2 473.2; found 473.0. 【0276】 General scheme for the preparation of the following two intermediates: 【Chemical Structure】 Intermediate 50 4-(1,4-Diazepan-1-yl)-7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (100 mg, 0.212 mmol) was dissolved in MeCN (5 mL), 1,4-diazepane (21 mg, 0.21 mmol) was added, followed by DIPEA (0.11 mL, 0.64 mmol) and PyBOP (220 mg, 0.42 mmol). The resulting reaction mixture was heated at 60 °C for 1 h. The solution was concentrated and the crude residue was purified directly by reverse phase column chromatography [Redisep 40 gm C18, 20 - 40 micron, THF:water:ACN (50:20:30) as diluent and 72% methanol in 10 mM ammonium bicarbonate as eluent] to afford the desired product (14 mg, 12% yield) as an off-white solid. LC / MS (ESI) m / z: [M+H] + C 32 H 33 Calculated for C28H28F2N6O 555.3; found 555.2; 1 1H NMR (400 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.17 - 8.12 (m, 2H), 7.74 - 7.68 (m, 2H), 7.60 - 7.55 (m, 2H), 5.28 (d, J = 53.60 Hz, 1H), 4.07 - 4.02 (m, 6H), 3.71 (d, J = 1.20 Hz, 1H), 3.35 - 3.02 (m, 6H), 2.87 - 2.83 (m, 3H), 2.05 - 1.77 (m, 8H). 【0277】 【Chemical Structure】 Intermediate 51 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[4,3-d]pyrimidine This intermediate was prepared according to the above general procedure using (3as,6as)-octahydropyrrolo[3,4-c]pyrrole instead of 1,4-diazepane. LCMS(ESI) m / z: [M+H] + C 33 H 33 Calculated for F2N6O 567.3; found 567.2; 1 H NMR(400MHz, DMSO-d6): 1H-NMR(400MHz, DMSO-d6): δ 9.22(s, 1H), 8.15(t, J = 8.00Hz, 2H), 7.75 - 7.69(m, 2H), 7.61 - 7.57(m, 2H), 5.29(d, J = 53.60Hz, 1H), 4.15 - 3.78(m, 4H), 3.61(s, 1H), 3.11 - 3.02(m, 5H), 2.71 - 2.70(m, 3H), 2.14 - 2.06(m, 3H), 1.78 - 1.76(m, 3H), 1.35 - 1.31(m, 3H), 0.93 - 0.88(m, 2H). 【0278】 General scheme for the preparation of the following intermediates: 【Chemical formula】 Intermediate 52 4-((2R,5S)-2,5-Dimethylpiperazin-1-yl)-7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine Step 1: Preparation of tert-butyl (2S,5R)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (160 mg, 0.34 mmol) was dissolved in MeCN (8 mL), and DIPEA (0.18 mL, 1.02 mmol) and tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate (72 mg, 0.34 mmol) were added. Then PyBOP (350 mg, 0.68 mmol) was added. The reaction mixture was heated at 60 °C for 1 h. The solution was concentrated, and the crude residue was triturated with n-pentane (2 × 20 mL) and dried to give the desired product (200 mg) as a brown solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + C 38 H 43 Calculated for C + H 38 F2N6O3 669.3; found 669.2. 【0279】 Step 2: Preparation of 4-((2R,5S)-2,5-dimethylpiperazin-1-yl)-7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine tert-Butyl (2S,5R)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (200 mg, 0.299 mmol) was dissolved in MeCN (4 mL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 0.75 mL, 3.0 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 2 hours, the reaction mixture was concentrated, and the crude residue was purified by reverse-phase column chromatography [Redisep 50 gm C18, 20 - 40 micron, THF:water:ACN (50:20:30) as diluent and 20% ACN in 5 mM ammonium formate as eluent] to give the desired product as its formate salt. The material was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (10 mL). The layers were separated, the organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was lyophilized to give the desired product (18 mg, 0.032 mmol, 9% yield over 2 steps) as a brown solid. LC / MS (ESI) m / z: [M+H] + C 33 H 35 Calculated for C29H32F2N6O 569.3; found 569.3; 1 1H-NMR (400 MHz, DMSO-d6): δ 9.04 - 8.98 (m, 1H), 8.20 - 8.16 (m, 2H), 7.86 - 7.70 (m, 2H), 7.64 - 7.56 (m, 2H), 5.28 (d, J = 56.00 Hz, 1H), 4.12 - 3.59 (m, 4H), 3.10 - 3.01 (m, 4H), 2.35 - 1.72 (m, 9H), 1.44 - 0.88 (m, 9H). 【0280】 【Chemical Structure】 Intermediate 53 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidine This intermediate was prepared according to the above general procedure using tert-butyl (R)-3-methylpiperazine-1-carboxylate instead of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate. LCMS (ESI) m / z: [M+H] + C 32 H 33 Calculated for C29H32F2N6O 555.3; found 555.2; 1 1H NMR (400 MHz, DMSO-d6): δ 9.04 - 8.97 (m, 1H), 8.15 (t, J = 8.40 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.62 - 7.58 (m, 1H), 5.28 (d, J = 56.00 Hz, 1H), 4.11 - 3.87 (m, 1H), 3.71 - 3.69 (m, 1H), 3.49 - 3.42 (m, 1H), 3.31 - 3.00 (m, 7H), 2.99 - 2.84 (m, 2H), 2.13 - 1.77 (m, 2H), 1.60 - 1.47 (m, 3H), 1.35 - 1.29 (m, 4H), 0.96 - 0.92 (m, 6H). 【0281】 【Chemical Structure】 Intermediate 54 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrido[4,3-d]pyrimidine This intermediate was prepared according to the above general procedure using tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate instead of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate. LCMS (ESI) m / z: [M+H] + C 34 H35 Calculated value for F2N6O: 581.3; Measured value: 581.2; 1 H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H), 8.14 (dt, J = 0.80, 11.07 Hz, 1H), 7.72 - 7.67 (m, 1H), 7.56 (dd, J = 7.60 Hz, 1H), 5.27 (d, J = 54.40 Hz, 1H), 4.50 (s, 2H), 4.11 - 3.98 (m, 5H), 3.71 (s, 1H), 3.31 - 3.01 (m, 3H), 2.83 - 2.82 (m, 1H), 2.69 - 2.55 (m, 5H), 2.12 - 2.11 (m, 1H), 2.04 - 2.03 (m, 1H), 1.85 - 1.73 (m, 10H). 【0282】 【Chem.】 Intermediate 55 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrido[4,3-d]pyrimidine This intermediate was prepared according to the above general procedure using tert-butyl (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate instead of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate. LCMS (ESI) m / z: [M + H] + C 33 H 33 Calculated value for F2N6O: 567.3; Measured value: 567.2; 11H NMR (400 MHz, DMSO-d6): δ 9.21 - 9.18 (m, 1H), 8.15 (t, J = 8.00 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.62 - 7.58 (m, 2H), 5.28 (d, J = 56.00 Hz, 1H), 4.9 - 5.0 (m, 1H), 4.17 - 4.04 (m, 4H), 3.75 - 3.66 (m, 1H), 3.13 - 2.83 (m, 8H), 2.07 - 1.78 (m, 8H), 1.35 - 1.24 (m, 2H). 【0283】 [Chemical] Intermediate 56 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)pyrido[4,3-d]pyrimidine This intermediate was prepared according to the above general procedure using tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate instead of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate. LCMS (ESI) m / z: [M+H] + C 34 H 35 Calculated for C30H33F2N6O 581.3; Found 581.2; 1 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.17 - 8.13 (m, 2H), 7.73 - 7.67 (m, 2H), 7.62 - 7.55 (m, 2H), 5.28 (d, J = 56.00 Hz, 1H), 4.05 - 4.03 (m, 1H), 3.84 (s, 2H), 3.70 (s, 1H), 3.36 - 3.33 (m, 2H), 3.08 - 3.00 (m, 4H), 2.13 - 1.94 (m, 10H), 1.34 - 1.24 (m, 3H), 0.88 - 0.87 (m, 3H). 【0284】 [Chemical] Intermediate 57 4-((2S,5R)-2,5-Dimethylpiperazin-1-yl)-7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine This intermediate was prepared according to the above general procedure using tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate instead of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate and BOP instead of PyBOP. LCMS(ESI) m / z: [M+H] + C 33 H 35 Calculated for C28H30F2N6O 569.3; Found 569.3; 1 1H NMR (400 MHz, DMSO-d6): δ 9.08 (d, J = 21.20 Hz, 1H), 8.16 (t, J = 8.40 Hz, 2H), 7.71 - 7.74 (m, 2H), 7.56 - 7.62 (m, 2H), 5.30 (d, J = 52.00 Hz, 1H), 4.63 (m, 1H), 4.07 - 4.18 (m, 3H), 3.73 - 3.78 (m, 1H), 3.43 - 3.58 (m, 3H), 2.52 - 3.05 (m, 5H), 1.80 - 2.15 (m, 7H), 1.50 (dd, J = 6.80, 25.20 Hz, 3H), 1.26 (dd, J = 6.80, 25.60 Hz, 3H). 【0285】 【Chemical Structure】 Intermediate 58 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,6-diazaspiro[3.4]octan-6-yl)pyrido[4,3-d]pyrimidine Isomer 1 and Isomer 2 These intermediates were prepared according to the above general procedure using tert-butyl 1,6-diazaspiro[3.4]octane-1-carboxylate instead of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate. Further, the starting materials provided by these steps were further purified by preparative SFC (column: Chiralcel AD-H, 4.6 mm × 250 mm, 5 μm particles; flow rate: 100 mL / min; column temperature: 40 °C; isocratic: 55% CO2:45% 1:1 MeCN / MeOH (containing 0.2% ammonia)). 【0286】 Isomer 1: LC / MS (ESI) m / z: [M+H] + C 33 H 33 Calculated for C H F2N6O 567.3; found 567.0; 1 1H NMR (400 MHz, DMSO-d6): δ 9.25 - 9.20 (m, 1H), 8.16 - 8.12 (m, 2H), 7.73 - 7.68 (m, 2H), 7.60 - 7.54 (m, 2H), 5.28 (d, J = 52.40 Hz, 1H), 4.93 (s, 1H), 4.14 - 4.01 (m, 4H), 3.88 - 3.76 (m, 1H), 3.02 - 2.80 (m, 5H), 2.25 - 2.01 (m, 13H). 【0287】 Isomer 2: LC / MS (ESI) m / z: [M+H] + C 33 H 33 Calculated for C H F2N6O 567.3; found 567.2; 1 1H NMR (400 MHz, DMSO-d6): δ 9.25 - 9.20 (m, 1H), 8.14 (t, J = 8.00 Hz, 2H), 7.71 - 7.67 (m, 2H), 7.60 - 7.56 (m, 2H), 5.28 (d, J = 53.60 Hz, 1H), 4.80 (s, 1H), 4.13 - 4.01 (m, 4H), 3.81 - 3.64 (m, 1H), 3.11 - 2.80 (m, 5H), 2.05 - 1.77 (m, 13H). 【0288】 【Chemical Structure】 Intermediate 59 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)pyrido[4,3-d]pyrimidine Isomer 1 and Isomer 2 These intermediates were prepared according to the above general procedure using tert-butyl hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate instead of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate. Further, the starting materials provided by these steps were purified by preparative SFC (column: Chiralcel AD-H, 4.6 mm × 250 mm, 5 μm particles; flow rate: 100 mL / min; column temperature: 40 °C; isocratic: 55% CO2: 45% 1:1 MeCN / MeOH (containing 0.2% ammonia)) to obtain two isomers. 【0289】 Isomer 1: LC / MS (ESI) m / z: [M+H] + C 33 H 33 Calculated value for C25H25F2N6O 567.3; measured value 567.0. 【0290】 Isomer 2: LC / MS (ESI) m / z: [M+H] + C 33 H 33 Calculated value for C25H25F2N6O 567.3; measured value 567.2. 【0291】 General scheme for the preparation of the following intermediates: 【Chemical formula】 Intermediate 60 7-(8-Ethynyl-4-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine Step 1: Preparation of 4-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol 4-Fluoronaphthalen-1-ol (1 g, 6.17 mmol) and (bromomethyl)triisopropylsilane (1.93 g, 7.40 mmol) were dissolved in DCE (15 mL). Potassium carbonate (0.85 g, 6.17 mmol), sodium acetate (0.10 g, 1.23 mmol) and dichloro(p-cymene)ruthenium(II) dimer (0.94 g, 1.542 mmol) were added and the reaction mixture was heated at 40 °C for 16 h. The reaction mixture was filtered through a pad of Celite® while eluting with additional DCM (2 × 50 mL). The combined filtrates were concentrated under reduced pressure. The crude residue was purified by column chromatography (0 → 10% EtOAc / hexane) to afford the desired product (1.5 g, 4.38 mmol, 71% yield).; 1 H NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 7.96 (t, J = 7.60 Hz, 1H), 7.69 (dd, J = 1.20, 7.20 Hz, 1H), 7.52 (dd, J = 7.20, 8.40 Hz, 1H), 7.18 (dd, J = 8.40, 10.40 Hz, 1H), 6.83 (dd, J = 4.80, 8.40 Hz, 1H), 1.14 (s, 21H). 【0292】 Step 2: Preparation of 4-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate 4-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (500 mg, 1.460 mmol) was dissolved in DCM (10 mL), and DIPEA (0.765 mL, 4.38 mmol) was added. The solution was cooled to -40 °C, and trifluoromethanesulfonic anhydride (0.370 mL, 2.190 mmol) was added dropwise at this temperature. The reaction mixture was warmed to -20 °C and stirred for 1 hour. The reaction mixture was quenched with cold water (20 mL), and DCM (30 mL) was added. The layers were separated, and the aqueous layer was further extracted with DCM (2 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (5% EtOAc / hexane) to afford the desired product (500 mg, 1.01 mmol, 69% yield) as a colorless gel; 1 H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J = 8.80 Hz, 1H), 8.02 (dd, J = 1.20, 7.40 Hz, 1H), 7.78 - 7.74 (m, 2H), 7.58 (t, J = 8.80 Hz, 1H), 1.20 - 1.12 (m, 21H). 【0293】 Step 3: Preparation of ((5-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane 4-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (500 mg, 1.054 mmol) was dissolved in dioxane (10 mL), and B2pin2 (400 mg, 1.56 mmol) and potassium acetate (310 mg, 3.16 mmol) were added. The solution was sparged with nitrogen for 5 minutes, and Pd(dppf)Cl2 (77 mg, 0.10 mmol) was added. The reaction mixture was heated at 100 °C for 24 hours. Cold water (50 mL) and EtOAc (50 mL) were added, and the layers were separated. The aqueous phase was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (extracted with ethyl acetate (3 × 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude residue was purified by column chromatography (5→10% EtOAc / hexane) to give the desired product (400 mg, 0.813 mmol, 77% yield). 【0294】 Step 4: Preparation of tert-butyl 4-(8-fluoro-7-(4-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate: tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (250 mg, 0.476 mmol) and ((5-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (539 mg, 0.714 mmol) were combined and dissolved in dioxane (5 mL). Aqueous potassium phosphate solution (2.0 M, 0.95 mL, 1.905 mmol) was added and the solution was sparged with nitrogen for 5 minutes. CataCXium A Pd G3 (35 mg, 0.048 mmol) was added and the reaction mixture was heated at 100 °C for 1 hour. Cold water (10 mL) and EtOAc (25 mL) were added and the layers were separated. The aqueous phase was further extracted with EtOAc (25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography to afford the desired product (400 mg, 0.314 mmol, 66% yield) as an off-white solid. LCMS (ESI) m / z: [M+H] + C 45 H 58 Calculated for C43H53F3N6O3Si 815.4; found 815.2. 【0295】 Step 5: Preparation of tert-Butyl 4-(7-(8-ethynyl-4-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(8-fluoro-7-(4-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (350 mg, 0.275 mmol) was dissolved in THF (10 mL), and the solution was cooled to 0 °C. TBAF solution (1.0 M in THF, 0.28 mL, 0.28 mmol) was added, and the reaction mixture was stirred for 1 h. Cold water (20 mL) and EtOAc (50 mL) were added, and the layers were separated. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography on neutral alumina (35% EtOAc / hexane) to afford the desired product (200 mg, 0.18 mmol, 66% yield) as an off-white solid. LCMS (ESI) m / z: [M+H] + C 36 H 38 Calculated for C37H45F3N6O3 659.3; found 659.2. 【0296】 Step 6: Preparation of 7-(8-ethynyl-4-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine tert-Butyl 4-(7-(8-ethynyl-4-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (200 mg, 0.304 mmol) was dissolved in MeCN (5 mL), and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 0.076 mL, 0.30 mmol) was added dropwise, and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated, and the crude residue was purified by preparative HPLC. 4N HCl in 1,4-dioxane (0.076 mL, 0.304 mmol) was added at 0 °C. The reaction mixture was stirred at this temperature for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC [eluent: THF: ACN: water (10:60:30); column: X-Select C18 (150×19) mm, 5 micron; temperature: ambient; mobile phase A: 5 mM ammonium formate; mobile phase B: acetonitrile; flow rate: 15 mL / min] to obtain the desired product as its formate salt. This material was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (10 mL). The layers were separated, the organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was lyophilized to obtain the desired product (30 mg, 0.054 mmol, 16% yield) as an off-white solid. LCMS (ESI) m / z: [M+H] + C 31 H 30 Calculated for C31H32F3N6O 559.2; found 559.1; 1 1H NMR (400 MHz, DMSO-d6): δ 9.04 (s, 1H), 8.26 (d, J = 8.40 Hz, 1H), 7.83 (s, 1H), 7.69 (t, J = 7.60 Hz, 1H), 7.63 (t, J = 6.00 Hz, 1H), 7.57 (t, J = 8.00 Hz, 1H), 5.28 (d, J = 54.40 Hz, 1H), 4.01 - 4.15 (m, 2H), 3.88 - 3.93 (m, 4H), 3.82 (s, 1H), 2.84 - 3.08 (m, 9H), 2.01 - 2.14 (m, 3H), 1.77 - 1.83 (m, 3H). 【0297】 [Chemistry] Intermediate 61 7-(8-Ethynyl-6,7-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine This intermediate was prepared according to the above general procedure using 6,7-difluoronaphthalen-1-ol instead of 4-fluoronaphthalen-1-ol. LCMS(ESI) m / z: [M+H] + C 31 H 29 Calculated value for C 1 H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.28 - 8.16 (m, 4H), 7.75 (t, J = 8.00 Hz, 1H), 7.66 (d, J = 7.20 Hz, 1H), 5.28 (d, J = 54.00 Hz, 1H), 4.27 (s, 1H), 4.16 - 4.04 (m, 2H), 3.93 - 3.88 (m, 4H), 3.10 - 2.84 (m, 8H), 2.15 - 1.78 (m, 5H). 【0298】 [Chemistry] Intermediate 62 7-(8-Ethynyl-5-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine This intermediate was prepared according to the above general procedure using 5-fluoronaphthalen-1-ol instead of 4-fluoronaphthalen-1-ol. LCMS(ESI) m / z: [M+H] + C 31 H 30 Calculated value for C 11H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.30 (d, J = 8.40 Hz, 1H), 8.17 (d, J = 6.80 Hz, 1H), 7.84 (t, J = 0.80 Hz, 1H), 7.74 - 7.72 (m, 2H), 7.45 (q, J = 8.00 Hz, 1H), 5.22 (d, J = 52 Hz, 1H), 4.15 - 4.06 (m, 2H), 3.93 - 3.88 (m, 5H), 3.11 - 2.99 (m, 8H), 2.84 (d, J = 6.40 Hz, 1H), 2.14 - 2.01 (m, 2H), 1.83 - 0.78 (m, 3H). 【0299】 [Chemical formula] Intermediate 63 8-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methyl((R)-pyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile [Chemical formula] Step 1: Preparation of tert-butyl (R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate A stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (320 mg, 1.268 mmol) in DCM (10 mL) was cooled to 0 °C, and DIPEA (0.487 mL, 2.79 mmol) was added thereto, followed by a solution of tert-butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate (254 mg, 1.268 mmol) in DCM (2 mL). Stirring was continued at 0 °C for 1 hour. The mixture was warmed to room temperature and concentrated. The resulting residue was purified by flash column chromatography (gradient of 5 → 100% EtOAc / hexane) to give the desired product (453 mg, 1.088 mmol, 86% yield). LC / MS (ESI) m / z: [M + H] + C 17 H 20Calculated value for Cl2FN5O2: 416.1; Measured value: 416.1; 1 1H NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 5.45 (br t, J = 7.8 Hz, 1H), 3.86 (br t, J = 9.6 Hz, 1H), 3.76 - 3.64 (m, 1H), 3.48 - 3.40 (m, 2H), 3.46 (s, 3H), 2.42 - 2.32 (m, 1H), 2.24 - 2.15 (m, 1H), 1.51 (s, 9H). 【0300】 [Chemical formula] Step 2: tert-Butyl (R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate To a stirred solution of tert-butyl (R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (300 mg, 0.72 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, HCl (155 mg, 0.79 mmol) in anhydrous THF (5 mL) was added dropwise via syringe a solution of LiHMDS (1.0 M in THF, 1.80 mL, 1.80 mmol). The mixture was stirred for 18 h, concentrated in part, and purified by flash column chromatography (gradient of 50 → 100% EtOAc with 5% Et3N / hexane) to afford the desired product (256 mg, 0.475 mmol, 66% yield). LC / MS (ESI) m / z: [M + H] + C 25 H 33 Calculated value for ClF2N6O3: 539.2; Measured value: 539.3; 11H NMR (500 MHz, CDCl3) δ 8.88 (s, 1H), 5.41 - 5.20 (m, 2H), 4.35 - 4.27 (m, 1H), 4.25 (s, 1H), 3.84 (dd, J = 11.5, 8.1 Hz, 1H), 3.74 - 3.56 (m, 1H), 3.51 - 3.40 (m, 2H), 3.38 (s, 3H), 3.34 - 3.16 (m, 3H), 3.00 (br d, J = 9.2 Hz, 1H), 2.38 - 2.08 (m, 5H), 2.02 - 1.84 (m, 3H), 1.51 (s, 9H). 【0301】 [Chemical formula] Step 3: Preparation of tert-butyl (R)-3-((7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (R)-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)pyrrolidine-1-carboxylate (30 mg, 0.056 mmol), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (23.30 mg, 0.083 mmol), and a solution of tripotassium phosphate (1.5 M in water, 0.11 mL, 0.167 mmol) were stirred in degassed dioxane (1.5 mL) in a pressure vial. Methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (cataCXium A Palladacycle Gen3) (4.05 mg, 5.57 μmol) was added and the vial was sealed. The atmosphere was evacuated and replaced with nitrogen (3 times). The mixture was heated at 80 °C for 3 h, concentrated, and purified directly by flash column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (21 mg, 0.032 mmol, 58% yield). LC / MS (ESI) m / z: [M+H] + C 36 H 39 Calculated for C33H39F2N7O3 656.3; found 656.3. 【0302】 【Chemical Structure】 Step 4: Preparation of 8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(methyl((R)-pyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile A solution of tert-butyl (R)-3-((7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (21 mg, 0.032 mmol) in acetonitrile (1 mL) was treated with a solution of HCl (4 M in dioxane, 0.080 mL, 0.320 mmol). The mixture was stirred for 1 h and then basified by the addition of 1-methylimidazole (0.038 mL, 0.480 mmol). The solution was concentrated and used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 31 H 31 Calculated for C27H32F2N7O: 556.2; Found: 556.2. 【0303】 【Chemical Structure】 Intermediate 64 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine 【Chemical Structure】 Step 1: Preparation of tert-butyl (R)-3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate tert-Butyl (R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (50 mg, 0.093 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (60.5 mg, 0.139 mmol), and a solution of tripotassium phosphate (1.5 M in water, 0.19 mL, 0.278 mmol) were stirred in degassed dioxane (1.5 mL) in a pressure vial. Methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-1,1’-biphenyl-2-yl)palladium(II) dichloromethane adduct (cataCXium A Palladacycle Gen3) (4.8 mg, 9.28 μmol) was added and the vial was sealed. The atmosphere was evacuated and replaced with nitrogen (3 times). The mixture was heated at 80 °C for 3 h, concentrated, and purified directly by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (62 mg, 0.076 mmol, 82.0% yield). LC / MS (ESI) m / z: [M+H] + C 46 H 60 Calculated for C40H62F2N6O3Si 811.4; found 811.4; 1 H NMR (500 MHz, CDCl3) δ 9.22 (s, 1H), 8.01 - 7.97 (m, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.61 - 7.57 (m, 2H), 7.48 (t, J = 7.7 Hz, 1H), 5.32 (s, 3H), 4.65 - 4.40 (m, 1H), 3.97 - 3.86 (m, 1H), 3.84 - 3.51 (m, 3H), 3.38 - 3.02 (m, 2H), 2.69 - 2.36 (m, 3H), 2.30 - 2.05 (m, 3H), 1.80 - 1.55 (m, 5H), 1.51 (s, 9H), 1.19 - 1.11 (m, 2H), 0.93 - 0.83 (m, 18H), 0.58 (quin, J = 7.4 Hz, 3H). 【0304】 【Chem.】 Engineering 2: Preparation of tert-Butyl (R)-3-((7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate To a stirred solution of tert-Butyl (R)-3-((8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (285 mg, 0.351 mmol) in THF (3 mL) was added TBAF (1 M in THF, 0.422 mL, 0.422 mmol). The mixture was stirred for 30 minutes. The mixture was concentrated and purified directly by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to afford the desired product (199 mg, 0.304 mmol, 86% yield). LC / MS (ESI) m / z: [M+H] + C 37 H 40 Calculated for C40H44F2N6O3 655.3; Found 655.4; 1 H NMR (500 MHz, CDCl3) δ 9.14 (s, 1H), 8.05 - 7.92 (m, 2H), 7.77 (d, J = 7.1 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.47 (t, J = 7.7 Hz, 1H), 5.44 - 5.15 (m, 2H), 4.45 - 4.23 (m, 2H), 3.93 - 3.83 (m, 1H), 3.76 - 3.53 (m, 1H), 3.43 (d, J = 3.7 Hz, 4H), 3.36 - 3.15 (m, 3H), 3.07 - 2.93 (m, 1H), 2.60 (br d, J = 7.7 Hz, 1H), 2.42 - 2.10 (m, 6H), 2.02 - 1.88 (m, 3H), 1.51 (s, 9H). 【0305】 [Chemistry] Process 3: Preparation of 3:7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine To a solution of tert-butyl (R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (140 mg, 0.214 mmol) in acetonitrile (2 mL) was added a solution of HCl (4 M in dioxane 0.54 mL, 2.140 mmol). The mixture was stirred for 1 hour and then basified by the addition of 1-methylimidazole (0.26 mL, 3.210 mmol). The solution was concentrated and used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: [M+H] + C 32 H 32 Calculated for F2N6O 555.3; found 555.4. 【0306】 [Chemistry] Intermediate 65 7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine [Chemistry] Process 1: Preparation of tert-butyl (R)-3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate A mixture of tert-butyl (R)-3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (31.8 mg, 0.059 mmol), ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (40 mg, 0.088 mmol), and a solution of tripotassium phosphate (1.5 M in water, 0.12 mL, 0.177 mmol) was stirred in degassed dioxane (1.5 mL) in a pressure vial. Methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (cataCXium A Palladacycle Gen3) (4.3 mg, 5.89 μmol) was added and the vial was sealed. The atmosphere was evacuated and replaced with nitrogen (3 times). The mixture was heated at 80 °C for 3 hours, concentrated, and purified directly by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to give the desired product (62 mg, 0.076 mmol, 82.0% yield). LC / MS (ESI) m / z: [M+H] + C 46 H 59 Calculated for F3N6O3Si 829.7; found 829.4; 11H NMR (500 MHz, CDCl3) δ 9.30 - 9.15 (m, 1H), 7.97 (br d, J = 8.0 Hz, 2H), 7.66 - 7.51 (m, 2H), 7.36 (s, 1H), 5.63 - 5.36 (m, 3H), 3.95 - 3.66 (m, 3H), 3.60 - 3.46 (m, 2H), 3.45 (s, 3H), 3.44 - 3.04 (m, 4H), 2.72 - 2.23 (m, 8H), 1.51 (s, 9H), 0.99 - 0.83 (m, 18H), 0.65 - 0.49 (m, 3H). 【0307】 【Chem.】 Step 2: Preparation of tert - butyl (R)-3 - ((7-(8 - ethynyl - 7 - fluoronaphthalen - 1 - yl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)(methyl)amino)pyrrolidine - 1 - carboxylate To a stirred solution of tert - butyl (R)-3 - ((8 - fluoro - 7-(7 - fluoro - 8 - ((triisopropylsilyl)ethynyl)naphthalen - 1 - yl)-2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)(methyl)amino)pyrrolidine - 1 - carboxylate (50 mg, 0.060 mmol) in THF (1 mL) was added TBAF (1 M in THF, 0.072 mL, 0.072 mmol). The mixture was stirred for 30 minutes. The mixture was concentrated and purified directly by column chromatography (50→100% EtOAc with 5% Et3N / hexane) to afford the desired product (22 mg, 0.033 mmol, 54% yield). LC / MS (ESI) m / z: [M + H] + C 37 H 39 Calculated for C35H43F3N6O3 673.3; found 673.3. 【0308】 【Chem.】 Step 3: Preparation of 7-(8-Ethynyl-7-fluoro-1-naphthalenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine A solution of tert-butyl (R)-3-((7-(8-ethy...

Claims

[Claim 1] Equation (I): 【Chemistry 1】 (In the formula, U is a combination or NH; Z is bond, O, NR ｅ or CR ｅ R ｆ And R ｅ and R ｆ These are, independently, hydrogen or C １ ~C ３ It is alkyl; R １ is aryl or heteroaryl, and the aryl and heteroaryl are C １ -C ３ alkoxy, C １ -C ３ alkyl, C ２ -C ４ alkenyl, C ２ -C ４ alkynyl, amino, amino C １ -C ３ alkyl, cyano, C ３ -C ４ cycloalkyl, halo, halo C １ -C ３ alkyl, hydroxy and hydroxy C １ -C ３ optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from; R ２ and R ３ These are, independently, hydrogen and C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, cyano, halo, halo C １ ~C ３ Alkyl, -C(O)NH ２ , -C(O)NH(C １ ~C ３ Alkyl), -C(O)N(C １ ~C ３ Alkyl) ２ Selected from hydroxyl; Y is bond, O, NR ｇ (CR ｅ R ｆ ) ｍ , NR ｆ or CR ｅ R ｆ And m is 1, 2 or 3, R ｅ , R ｆ and R ｇ These are, independently, hydrogen or C １ ~C ３ It is alkyl; A is a 4- to 10-membered nitrogen-containing monocyclic or bicyclic bridged, condensed, or spirocyclic saturated, unsaturated, or partially unsaturated ring system that optionally contains one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring system is C １ ~C ３ Alkoxy, C １ ~C ３ Alkoxyalkyl, C １ ~C ３ Alkyl, cyano, cyano C １ ~C ３ alkyl, halo, halo C １ ~C ３ Alkyl, amino, amino C １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ Optionally substituted with one, two, or three groups independently selected from alkyl and oxo groups; R' is a halo; R ４ is an aryl or heteroaryl ring; the ring is C ２ ~C ４ Alkenil, C １ ~C ３ Alkoxy, C １ ~C ３ Alkoxy C １ ~C ６ Alkyl, C １ ~C ３ Alkyl, cyano, cyano C １ ~C ３ alkyl, halo, halo C １ ~C ３ Alkoxy, Halo C １ ~C ３ Optionally substituted with one, two, or three substituents independently selected from alkyl, nitro, and oxo; X is O or NR １６ And R １６ is hydrogen or C １ ~C ３ It is alkyl; R ５ is hydrogen, C １ ~C ６ alkoxy C １ ~C ６ alkyl, C １ ~C ６ alkyl, aryl, aryl C １ ~C ６ alkyl, carboxy C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, C ３ ~C ６ cycloalkyl C １ ~C ６ alkyl, di(C １ ~C ３ alkyl)amino C ２ ~C ６ alkyl, halo C １ ~C ６ alkyl, heteroaryl, heteroaryl C １ ~C ６ alkyl, heterocyclyl, heterocyclyl C １ ~C ６ alkyl, hydroxy C １ ~C ６ alkyl, NR ａ R ｂ -C(O)-C １ ~C ６ alkyl), NR ａ R ｂ C １ ~C ６ is selected from alkyl, and the aryl, the aryl C １ ~C ６ alkyl aryl moiety, the C ３ ~C ６ cycloalkyl, the C ３ ~C ６ cycloalkyl C １ ~C ６ alkyl cycloalkyl moiety, the heteroaryl, the heteroaryl C １ ~C ６ alkyl heteroaryl moiety, the heterocyclyl, the heterocyclyl C １ ~C ６ alkyl heterocyclyl moiety is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, (C １ ~C ６ Alkyl)amino, (C １ ~C ６ Alkyl) Amino C １ ~C ３ Alkyl, amino, amino C １ ~C ３ Alkyl, Azide C １ ~C ６ Alkyl, carboxy, cyano, di(C) １ ~C ６ Alkyl)amino, di(C) １ ~C ６ Alkyl) Amino C １ ~C ３ alkyl, halo, halo C １ ~C ３ Alkoxy, Halo C １ ~C ３ Alkyl, heteroaryl C １ ~C ３ Alkyl, heterocyclyl, heterocyclyl C １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ The heteroaryl C is optionally substituted with one, two, three, or four groups independently selected from alkyl, nitro, and oxo; １ ~C ３ The heteroaryl portion of the alkyl group, the heterocyclyl, and the heterocyclyl C １ ~C ３ The heterocyclyl portion of the alkyl group is C １ ~C ３ Alkoxy, C １ ~C ３ alkyl, halo, halo C １ ~C ３ Alkyl and (NR ｘ R ｙ ) C １ ~C ３ It may be further optionally substituted with one, two, or three groups independently selected from the alkyl group; or R ５ and R １６ Along with the nitrogen atom to which they are bonded, C １ ~C ３ Alkoxy, C １ ~C ３ Alkoxyalkyl, C １ ~C ３ Alkyl, amino, amino C １ ~C ３ Alkyl, hydroxy, and hydroxy C １ ~C ３ A heterocyclic group is formed which is optionally substituted with one, two, three, or four groups independently selected from the alkyl group; R ａ and R ｂ One of them is hydrogen and C １ ~C ３ Selected from alkyl, and the other is hydrogen, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxycarbonyl, C １ ~C ３ Alkylcarbonyl, aryl C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and C ３ ~C ６ Cycloalkyl C １ ~C ６ Selected from alkyl; and R ｘ and R ｙ One is hydrogen, and the other is -C(O)C １ ~C ６ (Selected from alkyl heterocyclyls, the heterocyclyl is optionally substituted with an oxo group.) A compound of or a pharmaceutically acceptable salt thereof. [Claim 2] U is a combination or NH; Z is bond, O, NR ｅ or CR ｅ R ｆ And R ｅ and R ｆ These are, independently, hydrogen or C １ ~C ３ It is alkyl; R １ is an aryl or heteroaryl, and the aryl and the heteroaryl are C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, Amino, Amino C １ ~C ３ Alkyl, cyano, C ３ ~C ４ Cycloalkyl, Halo, Halo C １ ~C ３ Alkyl, hydroxy, and hydroxy C １ ~C ３ Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the alkyl group; R ２ and R ３ These are, independently, hydrogen and C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, cyano, halo, halo C １ ~C ３ Alkyl, -C(O)NH ２ , -C(O)NH(C １ ~C ３ Alkyl), -C(O)N(C １ ~C ３ Alkyl) ２ Selected from hydroxyl; Y is bond, O, NR ｇ (CR ｅ R ｆ ) ｍ , NR ｆ or CR ｅ R ｆ And m is 1, 2 or 3, R ｅ , R ｆ and R ｇ These are, independently, hydrogen or C １ ~C ３ It is alkyl; A is a 4- to 10-membered nitrogen-containing monocyclic or bicyclic bridged, condensed, or spirocyclic saturated, unsaturated, or partially unsaturated ring system that optionally contains one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring system is C １ ~C ３ Alkoxy, C １ ~C ３ Alkoxyalkyl, C １ ~C ３ Alkyl, cyano, cyano C １ ~C ３ alkyl, halo, halo C １ ~C ３ Alkyl, amino, amino C １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ Optionally substituted with one, two, or three groups independently selected from alkyl and oxo groups; R' is a halo; R ４ is an aryl or heteroaryl ring; the ring is C ２ ~C ４ Alkenil, C １ ~C ３ Alkoxy, C １ ~C ３ Alkoxy C １ ~C ６ Alkyl, C １ ~C ３ Alkyl, cyano, cyano C １ ~C ３ alkyl, halo, halo C １ ~C ３ Alkoxy, Halo C １ ~C ３ Optionally substituted with one, two, or three substituents independently selected from alkyl, nitro, and oxo; X is O or NR １６ And R １６ is hydrogen or C １ ~C ３ It is alkyl; R ５ is hydrogen, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, aryl, aryl C １ ~C ６ Alkyl, CarboxyC １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkyl C １ ~C ６ Alkyl, di(C) １ ~C ３ Alkyl) Amino C ２ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, heteroaryl, heteroaryl C １ ~C ６ Alkyl, heterocyclyl, heterocyclyl C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, NR ａ R ｂ -C(O)-C １ ~C ６ Alkyl), NR ａ R ｂ C １ ~C ６ Selected from alkyl, the aryl, the aryl C １ ~C ６ The aryl portion of the alkyl group, the C ３ ~C ６ Cycloalkyl, the C ３ ~C ６ Cycloalkyl C １ ~C ６ The cycloalkyl portion of the alkyl group, the heteroaryl group, and the heteroaryl group C １ ~C ６ The heteroaryl portion of the alkyl group, the heterocyclyl, and the heterocyclyl C １ ~C ６ The heterocyclyl portion of the alkyl group is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, (C １ ~C ６ Alkyl)amino, (C １ ~C ６ Alkyl) Amino C １ ~C ３ Alkyl, amino, amino C １ ~C ３ Alkyl, carboxy, cyano, di(C) １ ~C ６ Alkyl)amino, di(C) １ ~C ６ Alkyl) Amino C １ ~C ３ alkyl, halo, halo C １ ~C ３ Alkoxy, Halo C １ ~C ３ Alkyl, heterocyclyl, heterocyclyl C １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ Optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl, nitro, and oxo; the heterocyclyl and the heterocyclyl C １ ~C ３ The heterocyclyl portion of the alkyl group is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, Halo, and Halo C １ ~C ３ It may be further optionally substituted with one, two, or three groups independently selected from the alkyl group; or R ５ and R １６ Along with the nitrogen atom to which they are bonded, C １ ~C ３ Alkoxy, C １ ~C ３ Alkoxyalkyl, C １ ~C ３ Alkyl, amino, amino C １ ~C ３ Alkyl, hydroxy, and hydroxy C １ ~C ３ Forming heterocyclic groups which are optionally substituted with 1, 2, 3, 4, or 5 groups which are optionally substituted with 1, 2, 3, or 4 groups which are optionally substituted with alkyl R ａ and R ｂ One of them is hydrogen and C １ ~C ３ Selected from alkyl, and the other is hydrogen, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxycarbonyl, C １ ~C ３ Alkylcarbonyl, aryl C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and C ３ ~C ６ Cycloalkyl C １ ~C ６ A compound according to claim 1, selected from alkyl groups, or a pharmaceutically acceptable salt thereof. [Claim 3] U is a combination or NH; Z is bond, O, NR ｅ or CR ｅ R ｆ And R ｅ and R ｆ These are, independently, hydrogen or C １ ~C ３ It is alkyl; R １ is an aryl or heteroaryl, and the aryl and the heteroaryl are C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, Amino, Amino C １ ~C ３ Alkyl, cyano, C ３ ~C ４ Cycloalkyl, Halo, Halo C １ ~C ３ Alkyl, hydroxy, and hydroxy C １ ~C ３ Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the alkyl group; R ２ and R ３ These are, independently, hydrogen and C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, cyano, halo, halo C １ ~C ３ Alkyl, -C(O)NH ２ , -C(O)NH(C １ ~C ３ Alkyl), -C(O)N(C １ ~C ３ Alkyl) ２ Selected from hydroxyl; Y is bond, O, NR ｇ (CR ｅ R ｆ ) ｍ , NR ｆ or CR ｅ R ｆ And m is 1, 2 or 3, R ｅ , R ｆ and R ｇ These are, independently, hydrogen or C １ ~C ３ It is alkyl; A is a 4- to 10-membered nitrogen-containing monocyclic or bicyclic bridged, condensed, or spirocyclic saturated, unsaturated, or partially unsaturated ring system that optionally contains one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring system is C １ ~C ３ Alkoxy, C １ ~C ３ Alkoxyalkyl, C １ ~C ３ Alkyl, cyano, halo, halo C １ ~C ３ Alkyl, amino, amino C １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ Optionally substituted with one, two, or three groups independently selected from alkyl and oxo groups; R' is a halo; R ４ is a five-membered or six-membered aromatic ring optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur; the ring is C ２ ~C ４ Alkenil, C １ ~C ３ Alkyl, cyano, cyano C １ ~C ３ alkyl, halo, halo C １ ~C ３ Alkoxy, Halo C １ ~C ３ Optionally substituted with one, two, or three substituents independently selected from alkyl, nitro, and oxo; X is O or NR １６ And R １６ is hydrogen or C １ ~C ３ It is alkyl; R ５ is hydrogen, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, aryl, aryl C １ ~C ６ Alkyl, CarboxyC １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkyl C １ ~C ６ Alkyl, di(C) １ ~C ３ Alkyl) Amino C ２ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, heteroaryl, heteroaryl C １ ~C ６ Alkyl, heterocyclyl, heterocyclyl C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, NR ａ R ｂ -C(O)-C １ ~C ６ Alkyl), NR ａ R ｂ C １ ~C ６ Selected from alkyl, the aryl, the aryl C １ ~C ６ The aryl portion of the alkyl group, the C ３ ~C ６ Cycloalkyl, the C ３ ~C ６ Cycloalkyl C １ ~C ６ The cycloalkyl portion of the alkyl group, the heteroaryl group, and the heteroaryl group C １ ~C ６ The heteroaryl portion of the alkyl group, the heterocyclyl, and the heterocyclyl C １ ~C ６ The heterocyclyl portion of the alkyl group is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, (C １ ~C ６ Alkyl)amino, (C １ ~C ６ Alkyl) Amino C １ ~C ３ Alkyl, amino, amino C １ ~C ３ Alkyl, carboxy, cyano, di(C) １ ~C ６ Alkyl)amino, di(C) １ ~C ６ Alkyl) Amino C １ ~C ３ alkyl, halo, halo C １ ~C ３ Alkoxy, Halo C １ ~C ３ Alkyl, heterocyclyl, heterocyclyl C １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ Optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl, nitro, and oxo; the heterocyclyl and the heterocyclyl C １ ~C ３ The heterocyclyl portion of the alkyl group is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, Halo, and Halo C １ ~C ３ It may be further optionally substituted with one, two, or three groups independently selected from the alkyl group; or R ５ and R １６ Along with the nitrogen atom to which they are bonded, C １ ~C ３ Alkoxy, C １ ~C ３ Alkoxyalkyl, C １ ~C ３ Alkyl, amino, amino C １ ~C ３ Alkyl, hydroxy, and hydroxy C １ ~C ３ Forming heterocyclic groups which are optionally substituted with 1, 2, 3, 4, or 5 groups which are optionally substituted with 1, 2, 3, or 4 groups which are optionally substituted with alkyl R ａ and R ｂ One of them is hydrogen and C １ ~C ３ Selected from alkyl, and the other is hydrogen, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxycarbonyl, C １ ~C ３ Alkylcarbonyl, aryl C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and C ３ ~C ６ Cycloalkyl C １ ~C ６ A compound according to claim 1, selected from alkyl groups, or a pharmaceutically acceptable salt thereof. [Claim 4] R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a five-membered or six-membered aromatic ring optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. [Claim 5] Y is a bond, the compound according to claim 1 or a pharmaceutically acceptable salt thereof. [Claim 6] Y is NR ｆ The compound according to claim 1 or a pharmaceutically acceptable salt thereof. [Claim 7] Y is NCH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof. [Claim 8] A is a 4- to 9-membered monocyclic or bicyclic bridge, spirocyclic or condensed saturated ring system optionally containing one or two nitrogen atoms, according to claim 1, or a pharmaceutically acceptable salt thereof. [Claim 9] A-U is 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 And in the formula, 【Transformation 5】 represents the bond point to the carbonyl group; and 【Transformation 6】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a bond site to Y. [Claim 10] A-U is 【Transformation 7】 And in the formula, 【Transformation 8】 represents the bond point to the carbonyl group; and 【Chemistry 9】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a bond site to Y. [Claim 11] A-U is 【Chemistry 10】 And in the formula, 【Chemistry 11】 represents the bond point to the carbonyl group; and 【Chemistry 12】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a bond site to Y. [Claim 12] R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is hydrogen or methoxy. [Claim 13] R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a halo. [Claim 14] R ４ The compounds are selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyrazinyl, pyridadinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, thiadiazolyl and triazolyl, and each ring is C ２ ~C ４ Alkenil, C １ ~C ３ alkyl, halo, halo C １ ~C ３ Alkoxy, Halo C １ ~C ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, or three groups independently selected from alkyl, nitro, and oxo. [Claim 15] R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is selected from imidazolyl, oxazolyl, pyridadinyl, pyridinyl, pyrimidinyl, and thiazolyl, and each ring is optionally substituted with methyl or halo. [Claim 16] The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O. [Claim 17] R ５ teeth, 【Chemistry 13】 Selected from, each ring is C １ ~C ３ Alkoxy, C １ ~C ３ Alkoxy C １ ~C ３ Alkyl, C １ ~C ３ alkyl, benzyl, halo, halo C １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, or three groups independently selected from alkyl and oxo groups. [Claim 18] R ５ is, -(C １ ~C ３ Alkyl)-R ６ And R ６ These are monocyclic ring systems with 3 to 5 members, bicyclic condensed saturated ring systems with 8 or 9 members, or tricyclic saturated ring systems with 10 members, and each ring system optionally contains one nitrogen atom, and each ring system is C １ ~C ３ Alkyl, halo, and (4- to 6-membered heterocyclyl) C １ ~C ３ Optionally substituted with one or two groups independently selected from alkyl groups; the (4-membered to 6-membered heterocyclyl) C １ ~C ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the alkyl heterocyclyl portion is further optionally substituted with a halo group. [Claim 19] R ５ teeth, 【Chemistry 14】 and 【Chemistry 15】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a bond site to X. [Claim 20] R ５ teeth, 【Chemistry 16】 And in the formula, n is 0, 1, or 2; Each R ２０ is a halo; and 【Chemistry 17】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a bond site to X. [Claim 21] Z is a bond, the compound according to claim 1 or a pharmaceutically acceptable salt thereof. [Claim 22] R １ This is a monocyclic heteroaryl ring containing one, two, or three nitrogen atoms, wherein the ring is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, Amino, Amino C １ ~C ３ Alkyl, cyano, C ３ ~C ４ Cycloalkyl, Halo, Halo C １ ~C ３ Alkyl, hydroxy, and hydroxy C １ ~C ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, three, four, or five substituents independently selected from the alkyl group. [Claim 23] R １ This is a bicyclic heteroaryl ring containing one, two, or three heteroatoms selected from nitrogen and sulfur, wherein the ring is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, Amino, Amino C １ ~C ３ Alkyl, cyano, C ３ ~C ４ Cycloalkyl, Halo, Halo C １ ~C ３ Alkyl, hydroxy, and hydroxy C １ ~C ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, three, four, or five substituents independently selected from the alkyl group. [Claim 24] R １ C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, Amino, Amino C １ ~C ３ Alkyl, cyano, C ３ ~C ４ Cycloalkyl, Halo, Halo C １ ~C ３ Alkyl, hydroxy, and hydroxy C １ ~C ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the phenyl ring is optionally substituted with one, two, three, four, or five substituents independently selected from the alkyl group. [Claim 25] R １ C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, Amino, Amino C １ ~C ３ Alkyl, cyano, C ３ ~C ４ Cycloalkyl, Halo, Halo C １ ~C ３ Alkyl, hydroxy, and hydroxy C １ ~C ３ C is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the alkyl group. ６ ~C １０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an aryl compound. [Claim 26] R １ C １ ~C ３ Alkyl, C ２ ~C ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is naphthyl substituted with one, two, three, four, or five substituents independently selected from alkynyl, halo, and hydroxyl. [Claim 27] R １ is naphthyl, and the naphthyl is C ２ ~C ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one, two, or three groups independently selected from alkynyl, halo, and hydroxyl. [Claim 28] R １ teeth, [Chemistry 18] And in the formula, 【Chemistry 19】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a bonding site to the parent molecule. [Claim 29] R １ teeth, 【Chemistry 20】 And in the formula, 【Chemistry 21】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a bonding site to the parent molecule. [Claim 30] The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R' is fluoro. [Claim 31] The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R' is chloro. [Claim 32] The following: 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof. [Claim 33] (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(4-methylpyridine-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(oxazole-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(1-methyl-1H-imidazole-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(5-methylpyridine-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-chloro-3-(pyrimidine-yl)propa-2-en-1-one; (Z)-3-(5-bromopyridine-2-yl)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoropropa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(6-methylpyridine-2-yl)propa-2-en-1-one; (Z)-3-(4-bromothiazole-2-yl)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoropropa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyridazine-3-yl)propa-2-en-1-one; (Z)-N-((1R,4R)-2-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-azabicyclo[2.2.1]heptan-4-yl)-2-fluoro-3-(pyridine-2-yl)acrylamide; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(5-methyl-1,3,4-thiadiazole-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(6-(methoxymethyl)pyridine-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyrazine-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(6-methoxypyridine-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(pyrimidine-4-yl)propa-2-en-1-one; 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(naphthalene-1-yl)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyrimidine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(naphthalene-1-yl)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; (S,Z)-1-(4-(7-(8-chloronaphthalene-1-yl)-8-fluoro-2-((1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; 2-((S)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)-4-(8-fluoro-7-(2-fluoro-5-hydroxyphenyl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(8-ethylnaphthalene-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; (S,Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-((1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluoro-3-(6-methylpyrazine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-2-fluoro-1-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazole-4-yl)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(benzo[b]thiophen-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(benzo[b]thiophen-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)-4-(8-fluoro-7-(7-fluoronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)-4-(8-fluoro-7-(7-fluoronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile; (Z)-2-fluoro-1-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazole-7-yl)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-2-fluoro-1-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazole-7-yl)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-3-(thiazole-2-yl)propa-2-en-1-one; 2-((S)-4-(7-(2,5-difluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(2,5-difluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(2-(difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(7-(2-(difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)-4-(8-fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)-4-(8-fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)-4-(8-fluoro-7-(5-chloro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile; (Z)-1-(4-(7-(8-ethinylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridazin-2-yl)propa-2-en-1-one; 8-(8-fluoro-4-(4-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-1-naphthonitrile; 8-(8-fluoro-4-(4-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-1-naphthonitrile; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazole-7-yl)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazole-7-yl)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; (Z)-1-(4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(oxazole-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridazin-3-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyrazine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; 2-((S)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)-4-(8-fluoro-7-(5-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)-4-(8-fluoro-7-(5-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile; (Z)-1-((S)-4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(2-amino-5,7-difluorobenzo[d]thiazole-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(2-amino-7-fluorobenzo[d]thiazole-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; 2-((S)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)-4-(8-fluoro-7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-2-yl)acetonitrile; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-hydroxyphenyl)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; (Z)-1-(3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-on trans isomer 1; (Z)-1-(3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)-2-fluoro-3-(thiazole-2-yl)prop-2-en-1-on trans isomer 2; (Z)-1-(3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-oncis isomer; (Z)-1-(3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-oncis isomer 2; (Z)-1-(3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)-2-fluoro-3-(pyridine-2-yl)prop-2-en-1-oncis isomer 1; (Z)-1-(3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)-2-fluoro-3-(pyridine-2-yl)propane-2-en-1-oncis isomer 2; (Z)-1-(3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)-2-fluoro-3-(pyridine-2-yl)prop-2-en-1-on trans isomer 1; (Z)-1-(3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)-2-fluoro-3-(pyridine-2-yl)prop-2-en-1-on trans isomer 2; (Z)-1-(3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-2-methylpyrrolidine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((3R)-4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((3R)-4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-diazepan-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethinylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-diazepan-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; 2-((2S)-4-(7-(2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((2S)-4-(7-(2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((2S)-4-(7-(2-cyclobutylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((2S)-4-(7-(2-cyclobutylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; (Z)-1-((2S,5R)-4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2,5-dimethylpiperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((3R)-4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-((3aR,6aR)-1-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((3aR,6aR)-1-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-4-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-4-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-(2-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(2-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-(7-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(5-hydroxy-2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(5-hydroxy-2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-2-yl)acetonitrile; (Z)-1-(4-(7-(8-ethynyl-5-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-5-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-6,7-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynyl-6,7-difluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((3aR,6aS)-5-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((3aR,6aS)-5-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-(6-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(6-(7-(8-ethinylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-(6-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(6-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazole-6-yl)pyrido[4,3-d]pyrimidine-4-yl)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-2-yl)acetonitrile; (Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (S,Z)-1-(4-(2-((1-(3-azidopropyl)pyrrolidine-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; N-((1-(3-((S)-2-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(4-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-1-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)pyrrolidine-1-yl)propyl)-1H-1,2,3-triazole-4-yl)methyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazole-4-yl)pentanamide; 8-(8-fluoro-4-(((R)-1-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)pyrrolidine-3-yl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-1-naphthonitrile; 8-(8-fluoro-4-(((R)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)pyrrolidine-3-yl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-1-naphthonitrile; (Z)-1-((R)-3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((3R)-3-((7-(2-amino-5,7-difluorobenzo[d]thiazole-4-yl)-8-fluoro-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)pyrrolidine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; tert-butyl(5,7-difluoro-4-(8-fluoro-4-(((R)-1-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)pyrrolidine-3-yl)(methyl)amino)-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)benzo[d]thiazole-2-yl)carbamate; 2-amino-7-fluoro-4-(8-fluoro-4-(4-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-1-yl)-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)benzo[b]thiophene-3-carbonitriel; 2-amino-7-fluoro-4-(8-fluoro-4-(4-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-1-yl)-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)benzo[b]thiophene-3-carbonitriel; (Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyrimidine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(oxazole-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(6-methylpyrazine-2-yl)propa-2-en-1-one; (Z)-2-chloro-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)-2-fluoro-3-(pyridazin-3-yl)propa-2-en-1-one; (Z)-1-((3S,4R)-3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-fluoropyrrolidine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-((3S,4R)-3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-fluoropyrrolidine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; (Z)-1-((3S,4R)-3-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)-4-fluoropyrrolidine-1-yl)-2-fluoro-3-(pyrazine-2-yl)propa-2-en-1-one; (Z)-1-(4-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)piperidine-1-yl)-2-fluoro-3-(pyridine-2-yl)propa-2-en-1-one; (Z)-1-(4-((7-(8-ethynylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)(methyl)amino)piperidine-1-yl)-2-fluoro-3-(thiazole-2-yl)propa-2-en-1-one; 3-(8-fluoro-4-(4-((Z)-2-fluoro-3-(pyridine-2-yl)acryloyl)piperazine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-1H-indole-4-carbonitrile; and 3-(8-fluoro-4-(4-((Z)-2-fluoro-3-(thiazole-2-yl)acryloyl)piperazine-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-1H-indole-4-carbonitrile A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof. [Claim 34] A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [Claim 35] An oral preparation comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [Claim 36] A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, for treating cancer expressing KRAS G12C, G12D, and / or G12V mutations. [Claim 37] A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, for treating cancer expressing the KRAS G12C mutation. [Claim 38] A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, for treating cancers sensitive to KRAS G12C inhibition. [Claim 39] A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, for the treatment of lung cancer, colorectal cancer, pancreatic cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, gastric cancer, or uterine cancer. [Claim 40] A pharmaceutical composition for treating non-small cell lung cancer, comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof.

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