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

Abstract

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

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 482,726, filed on February 1, 2023, and U.S. Provisional Application No. 63 / 351,132, filed on June 10, 2022, each of which is incorporated herein by reference in its entirety. Technical Field

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

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

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

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

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

[0007] U is a bond or NH;

[0008] Z is a bond, O, NR e or CR e R f , where R e and R f are independently hydrogen or C1-C3 alkyl;

[0009] R 1 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl;

[0010] R 2 and R 3 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 hydroxyl;

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

[0012] A is a four- to ten-membered nitrogen-containing monocyclic or bicyclic bridged, fused, or spirocyclic saturated, unsaturated, or partially unsaturated ring system optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring system is optionally substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halo, haloC1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo;

[0013] R' is halo;

[0014] R 4 is an aryl or heteroaryl ring; wherein the ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkoxyC1-C6 alkyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halo, haloC1-C3 alkoxy, haloC1-C3 alkyl, nitro, and oxo;

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

[0016] R 5 Selected from hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di (C1-C3 alkyl) amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR a R b C1-C6 alkyl, wherein aryl, the aryl portion of arylC1-C6 alkyl, C3-C6 cycloalkyl, the cycloalkyl portion of C3-C6 cycloalkylC1-C6 alkyl, heteroaryl, the heteroaryl portion of heteroarylC1-C6 alkyl, heterocyclyl, the heterocyclyl portion of heterocyclylC1-C6 alkyl are optionally substituted with one, two, three, or four groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)aminoC1-C3 alkyl, amino, aminoC1-C3 alkyl, azidoC1-C6 alkyl, carboxyl, cyano C1-C3 alkyl, halo, halo-substituted C1-C3 alkoxy, halo-substituted C1-C3 alkyl, heteroaryl C1-C3 alkyl, heterocyclyl, heterocyclyl C1-C3 alkyl, hydroxy, hydroxy C1-C3 alkyl, nitro and oxo; wherein the heteroaryl portion of heteroaryl C1-C3 alkyl, heterocyclyl and heterocyclyl C1-C3 alkyl are further optionally substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, halo, halo-substituted C1-C3 alkyl and (NR x R y ) C1-C3 alkyl; or

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

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

[0019] R x and R y One is hydrogen, and the other is selected from -C(O)C1-C6alkylheterocyclyl, wherein the heterocyclyl is optionally substituted with an oxo group.

[0020] In some aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0021] U is a bond or NH;

[0022] Z is a bond, O, NR e or CR e R f , where R e and R f are independently hydrogen or C1-C3 alkyl;

[0023] R 1 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl;

[0024] R 2 and R 3 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 hydroxyl;

[0025] Y is a bond, O, NR g (CR e R f ) m NR f, or CR e R f , wherein m is 1, 2, or 3, and wherein R e 、R f and R g are independently hydrogen or C1-C3 alkyl;

[0026] A is a four- to ten-membered nitrogen-containing monocyclic or bicyclic bridged, fused, or spirocyclic saturated, unsaturated, or partially unsaturated ring system optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring system is optionally substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halo, haloC1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo;

[0027] R' is halo;

[0028] R 4 is an aryl or heteroaryl ring; wherein the ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkoxyC1-C6 alkyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halo, haloC1-C3 alkoxy, haloC1-C3 alkyl, nitro, and oxo;

[0029] X is O or NR 16 , where R 16 is hydrogen or C1-C3 alkyl;

[0030] R 5 Selected from hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di (C1-C3 alkyl) amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR a R bC1-C6 alkyl, wherein aryl, the aryl portion of arylC1-C6 alkyl, C3-C6 cycloalkyl, the cycloalkyl portion of C3-C6 cycloalkylC1-C6 alkyl, heteroaryl, the heteroaryl portion of heteroarylC1-C6 alkyl, heterocyclyl, the heterocyclyl portion of heterocyclylC1-C6 alkyl are optionally substituted with one, two, three, or four groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)aminoC1-C3 alkyl, amino, aminoC1 -C3 alkyl, carboxyl, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoC1-C3 alkyl, halo, halo-C1-C3 alkoxy, halo-C1-C3 alkyl, heterocyclyl, heterocyclylC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, nitro and oxo; wherein the heterocyclyl and heterocyclyl portions of heterocyclylC1-C3 alkyl are further optionally substituted with one, two, or three groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo and halo-C1-C3 alkyl; or

[0031] R 5 and R 16 together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted with one, two, three, four, or five groups independently selected from: one, two, three, or four groups independently selected from: C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; and

[0032] R a and R b One of them is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, arylC1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkylC1-C6 alkyl.

[0033] In some aspects, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0034] U is a bond or NH;

[0035] Z is a bond, O, NR e or CR e R f , where R e and R f are independently hydrogen or C1-C3 alkyl;

[0036] R 1is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl;

[0037] R 2 and R 3 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 hydroxyl;

[0038] Y is a bond, O, NR g (CR e R f ) m NR f , or CR e R f , wherein m is 1, 2, or 3, and wherein R e 、R f and R g are independently hydrogen or C1-C3 alkyl;

[0039] A is a four- to ten-membered nitrogen-containing monocyclic or bicyclic bridged, fused, or spirocyclic saturated, unsaturated, or partially unsaturated ring system optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring system is optionally substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, cyano, halo, haloC1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo;

[0040] R' is halo;

[0041] R 4 is a five- or six-membered aromatic ring optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of C2-C4 alkenyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halo, haloC1-C3 alkoxy, haloC1-C3 alkyl, nitro, and oxo;

[0042] X is O or NR 16 , where R 16 is hydrogen or C1-C3 alkyl;

[0043] R 5Selected from hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di (C1-C3 alkyl) amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR a R b C1-C6 alkyl, wherein aryl, the aryl portion of arylC1-C6 alkyl, C3-C6 cycloalkyl, the cycloalkyl portion of C3-C6 cycloalkylC1-C6 alkyl, heteroaryl, the heteroaryl portion of heteroarylC1-C6 alkyl, heterocyclyl, the heterocyclyl portion of heterocyclylC1-C6 alkyl are optionally substituted with one, two, three, or four groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)aminoC1-C3 alkyl, amino, aminoC1 -C3 alkyl, carboxyl, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoC1-C3 alkyl, halo, halo-C1-C3 alkoxy, halo-C1-C3 alkyl, heterocyclyl, heterocyclylC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, nitro and oxo; wherein the heterocyclyl and heterocyclyl portions of heterocyclylC1-C3 alkyl are further optionally substituted with one, two, or three groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo and halo-C1-C3 alkyl; or

[0044] R 5 and R 16 together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted with one, two, three, four, or five groups independently selected from: one, two, three, or four groups independently selected from: C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; and

[0045] R a and R b One of them is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, arylC1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkylC1-C6 alkyl.

[0046] In some respects, R 4 is a five- or six-membered aromatic ring optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0047] In some aspects, Y is a bond.

[0048] In some aspects, Y is NR f In certain aspects, Y is NCH3.

[0049] In some aspects, A is a four- to nine-membered monocyclic or bicyclic bridged, spirocyclic, or fused saturated ring system optionally containing one or two nitrogen atoms.

[0050] In some respects, AU is in represents the point of attachment to the carbonyl group; and Indicates the point of attachment to Y.

[0051] In some respects, AU is in represents the point of attachment to the carbonyl group; and Indicates the point of attachment to Y.

[0052] In some respects, AU is in: represents the point of attachment to the carbonyl group; and Indicates the point of attachment to Y.

[0053] In some respects, R 2 is hydrogen or methoxy.

[0054] In some respects, R 3 It is halogenated.

[0055] In some respects, R 4 is selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl and triazolyl, wherein each ring is optionally substituted with one, two, or three groups independently selected from C2-C4 alkenyl, C1-C3 alkyl, halo, halo C1-C3 alkoxy, halo C1-C3 alkyl, nitro and oxo. In some aspects, R 4 is selected from imidazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, thiadiazolyl and thiazolyl, wherein each ring is optionally substituted with methyl or halo.

[0056] In some aspects, X is O.

[0057] In some respects, R 5 Selected from: wherein each ring is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo.

[0058] In some respects, R 5 is -(C1-C3 alkyl)-R 6 , where R 6 is a three- to five-membered monocyclic ring system, an eight- or nine-membered bicyclic fused saturated ring system, or a ten-membered tricyclic saturated ring system, wherein each ring system optionally contains one nitrogen atom, and wherein each ring system is optionally substituted with one or two groups independently selected from C1-C3 alkyl, halo, and (4- to 6-membered heterocyclyl)C1-C3 alkyl; wherein the heterocyclyl portion of the (4- to 6-membered heterocyclyl)C1-C3 alkyl is further optionally substituted with a halo group.

[0059] In some respects, R 5 yes

[0060] in Indicates the point of attachment to X.

[0061] In some respects, R 5 yes in: n is 0, 1, or 2; Each R 20 is halogenated; and Indicates the point of attachment to X.

[0062] In some aspects, Z is a bond.

[0063] In some respects, R 1 is a monocyclic heteroaryl ring containing one, two, or three nitrogen atoms, wherein the ring is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl.

[0064] In some respects, R 1 yes in Indicates the point of attachment to the parent molecule.

[0065] In some respects, R 1 is a bicyclic heteroaryl ring containing one, two, or three heteroatoms selected from nitrogen and sulfur, wherein the ring is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl.

[0066] In some respects, R 1 is a phenyl ring optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl.

[0067] In some respects, R 1 is a C6-C ... 10 Aryl: C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy and hydroxyC1-C3 alkyl. In some aspects, R 1 is naphthyl substituted with one, two, three, four, or five substituents independently selected from C1-C3 alkyl, C2-C4 alkynyl, halo, and hydroxy. 1 is naphthyl, wherein the naphthyl is substituted with one, two, or three groups independently selected from C2-C4 alkynyl, halo, and hydroxy.

[0068] In some respects, R 1 yes in Indicates the point of attachment to the parent molecule.

[0069] In some respects, R 1 yes in Indicates the point of attachment to the parent molecule.

[0070] In some aspects, R' is fluoro. In some aspects, R' is chloro.

[0071] In some aspects, the present disclosure provides a compound having formula (IC): or a pharmaceutically acceptable salt thereof, wherein: R' is chlorine or fluorine; AU is as well as R 4 is selected from imidazolyl, oxazolyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl; wherein each ring is optionally substituted with a halo or methyl group.

[0072] In some aspects, the present disclosure provides a compound selected from or a pharmaceutically acceptable salt thereof.

[0073] In some aspects, the present disclosure provides a compound selected from: (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]hept-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-chloronaphth-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-ethylnaphth-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-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-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)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-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)-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(2,5-difluorophenyl)-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-(2-(difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(2-(difluoromethyl)-5-fluorophenyl)-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)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)-4-(8-fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one; 8-(8-fluoro-4-(4-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthocarbonitrile; 8-(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)-1-naphthocarbonitrile; 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)-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-(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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-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-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one cis-isomer 1; (Z)-1-(3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one trans-isomer 1; (Z)-1-(3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((3R)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-diazepan-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(7-(2-cyclopropylphenyl)-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-((2S)-4-(7-(2-cyclobutylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(7-(2-cyclobutylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (Z)-1-((2S,5R)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-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-4-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-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]non-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]non-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]non-2-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-(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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthocarbonitrile; 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthocarbonitrile; (Z)-1-((R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; 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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-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-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(oxazol-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H-indole-4-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0074] In some aspects, the present disclosure provides atropisomers of the compounds of any of the aforementioned aspects. In certain aspects, the compound is a stable atropisomer as described herein.

[0075] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound according to any one of the preceding aspects or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0076] In some aspects, the present disclosure provides an oral dosage form comprising a compound according to any one of the preceding aspects, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0077] In some aspects, the disclosure provides a method of treating a cancer expressing KRAS G12C, G12D, and / or G12V mutations in a subject in need thereof, the method comprising administering to the subject a compound of any one of the preceding aspects, or a pharmaceutically acceptable salt thereof.

[0078] In some aspects, the present disclosure provides a method of treating a cancer expressing a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a compound of any one of the preceding aspects, or a pharmaceutically acceptable salt thereof.

[0079] In some aspects, the disclosure provides a method for treating a cancer sensitive to KRAS G12C inhibition in a subject in need thereof, the method comprising administering to the subject a compound of any one of the preceding aspects, or a pharmaceutically acceptable salt thereof.

[0080] In some aspects, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a compound of any one of the preceding aspects, or a pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, gastric cancer, or uterine cancer.

[0081] In some aspects, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of any one of the preceding aspects, or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer.

[0082] In some aspects of the method, the compound is an atropisomer of the compound of any of the preceding aspects. In certain aspects, the compound is a stable atropisomer as described herein.

[0083] In another aspect, the present disclosure provides a method for inhibiting KRAS G12C activity in a cell, comprising contacting the cell with a therapeutically effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one aspect, the contacting is in vitro. In one aspect, the contacting is in vivo.

[0084] In some aspects, the 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 thereof, or a pharmaceutical composition thereof.

[0085] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the inhibition of KRAS G12C.

[0086] In another aspect, the disclosure provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a disease or disorder associated with KRAS G12C.

[0087] 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 cancer. In some aspects, the cancer is lung cancer. In some aspects, the cancer is non-small cell lung cancer.

[0088] In another aspect, the disclosure provides the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the activity of KRAS G12C.

[0089] In another aspect, the disclosure provides the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder associated with KRAS G12C. DETAILED DESCRIPTION

[0090] Unless otherwise stated, any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0091] The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise.

[0092] As used herein, the term "or" is a logical disjunction (ie, and / or) and does not indicate a mutually exclusive disjunction unless expressly indicated by the terms "or," "unless," "alternatively," and words of similar effect.

[0093] As used herein, the phrase "or a pharmaceutically acceptable salt thereof" refers to at least one compound, or at least one salt of a compound, or a combination thereof. For example, "a compound of formula (I) or a pharmaceutically acceptable salt thereof" includes, but is not limited to, a compound of formula (I), two compounds of formula (I), a pharmaceutically acceptable salt of a compound of formula (I), a compound of formula (I) and one or more pharmaceutically acceptable salts of compounds of formula (I), and pharmaceutically acceptable salts of two or more compounds of formula (I).

[0094] As used herein, the term "C2-C4 alkenyl" refers to a group derived from a straight or branched chain hydrocarbon containing from two to four carbon atoms and one double bond.

[0095] The term "C1-C3 alkoxy," as used herein, refers to a C1-C3 alkyl group attached to the parent molecular moiety through an oxygen atom.

[0096] As used herein, the term "C1-C3 alkoxy C1-C6 alkyl," refers to a C1-C3 alkoxy group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0097] The term "C1-C3 alkoxycarbonyl," as used herein, refers to a C1-C3 alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0098] As used herein, the term "C1-C3 alkyl" refers to a group derived from a straight-chain or branched saturated hydrocarbon containing from one to three carbon atoms.

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

[0100] As used herein, the term "C2-C4 alkynyl" refers to a group derived from a straight or branched chain hydrocarbon containing from two to four carbon atoms and one triple bond.

[0101] As used herein, the term "amino" refers to -NH2.

[0102] The term "amino C1-C3 alkyl," as used herein, refers to an amino group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0103] As used herein, the term "aryl" refers to a phenyl group or a bicyclic fused ring system in which one or both rings are phenyl groups. The bicyclic fused ring system consists of a phenyl group fused to a four to six-membered aromatic or non-aromatic carbocyclic ring. The aryl group of the present disclosure can be attached to the parent molecular moiety through any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.

[0104] The term "aryl C1-C6 alkyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0105] As used herein, the term "azido" refers to -N3.

[0106] As used herein, the term "azido C1-C6 alkyl," refers to an azido group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0107] As used herein, the term "carboxyl" refers to -CO2H.

[0108] As used herein, the term "carboxy C1-C6 alkyl" refers to a C1-C6 alkyl group substituted with one, two, or three carboxyl groups.

[0109] As used herein, the term "C(O)-C1-C6 alkylheteroaryl" refers to a heteroaryl C1-C6 alkyl group attached to the parent molecular moiety through a carbonyl group.

[0110] As used herein, the term "cyano" refers to -CN.

[0111] As used herein, the term "C3-C4 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring system having three or four carbon atoms and zero heteroatoms.

[0112] As used herein, the term "C3-C6 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring system having three to six carbon atoms and zero heteroatoms.

[0113] As used herein, the term "C3-C6 cycloalkylC1-C6 alkyl," refers to a C3-C6 cycloalkyl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0114] As used herein, the term "di(C1-C6 alkyl)amino" refers to -NR z R z’ , where R z and R z’ are the same or different C1-C6 alkyl groups.

[0115] As used herein, the term "di(C1-C3 alkyl)amino C2-C6 alkyl" refers to -(C2-C6 alkyl)NR z R z’ , where R z and R z’ are the same or different C1-C6 alkyl groups.

[0116] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, or I.

[0117] As used herein, the term "halo C1-C3 alkoxy" refers to a C1-C3 alkoxy group substituted with one, two, or three halogen atoms.

[0118] As used herein, the term "haloC1-C3 alkyl" refers to a C1-C3 alkyl group substituted with one, two, or three halogen atoms.

[0119] As used herein, the term "halogenated C1-C6 alkyl" refers to a C1-C6 alkyl group substituted with one to six halogen atoms.

[0120] As used herein, the term "heteroaryl" refers to an aromatic five- or six-membered ring in which at least one atom is selected from N, O, and S, and the remaining atoms are carbon. The term "heteroaryl" also includes: bicyclic systems in which the heteroaryl ring is fused to a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S; and tricyclic systems in which the bicyclic system is fused to a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S. The heteroaryl group is attached to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. Representative examples of heteroaryl groups include, but are not limited to, alloxazine, benzo[1,2-d:4,5-d']bithiazole, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.

[0121] In those aspects where the term "heteroaryl" includes bicyclic ring systems, an aromatic five- or six-membered ring having at least one atom selected from N, O, and S is fused to a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S. In those aspects where the term "heteroaryl" includes tricyclic ring systems, a bicyclic ring system as defined in the preceding sentence is fused to a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S.

[0122] The term "heteroaryl C1-C3 alkyl," as used herein, refers to a heteroaryl group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0123] As used herein, the term "heteroaryl C1-C6 alkyl," refers to a heteroaryl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0124] As used herein, the term "heterocyclyl" refers to a five-, six-, seven-, eight-, nine-, ten-, eleven-, or twelve-membered saturated or partially unsaturated ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" also includes groups in which the heterocyclyl ring is fused to one, two, or three four- to six-membered aromatic or non-aromatic carbocyclic or monocyclic heterocyclyl groups. The term "heterocyclyl" also includes monocyclic or polycyclic heterocyclyl groups as described above, which are further substituted by one or more spirocyclic groups attached to the heterocyclyl group via a spiro carbon. Examples of heterocyclyl groups include, but are not limited to, dihydro-1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6',1"-cyclopropane], hexahydro-2H-1,4-dioxa-2a1-azacyclopenta[cd]pentalenyl, hexahydropyrrolizinyl, indolinyl, morpholinyl, octahydroindolizinyl, octahydroquinolizinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thiomorpholinyl.

[0125] The term "heterocyclyl C1-C6 alkyl," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0126] As used herein, the term "hydroxy" refers to -OH.

[0127] The term "hydroxy C1-C3 alkyl," as used herein, refers to a hydroxy group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0128] As used herein, the term "hydroxy C1-C6 alkyl," refers to a hydroxy group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0129] As used herein, the term "NR a R b -C(O)" refers to an NR attached to the parent molecular moiety through a carbonyl group a R b group.

[0130] As used herein, the term "NR a R b -C(O)-C1-C6 alkyl" refers to an NR group attached to the parent molecular moiety through a C1-C6 alkyl group a R b-C(O)- group.

[0131] As used herein, the term "NR a R b "C1-C6 alkyl" refers to an NR group attached to the parent molecular moiety through a C1-C6 alkyl group a R b group.

[0132] As used herein, the term "NR x R y "C1-C3 alkyl" refers to an NR group attached to the parent molecular moiety through a C1-C3 alkyl group x R y group.

[0133] As used herein, the term "nitro" refers to -NO2.

[0134] As used herein, the term "oxo" refers to =0.

[0135] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein using appropriate isotopically labeled reagents in place of unlabeled reagents that would otherwise be employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0136] Another aspect of the subject matter described herein is the use of the disclosed compounds as radiolabeled ligands for developing ligand binding assays or for monitoring in vivo adsorption, metabolism, distribution, receptor binding or occupancy, or compound disposition. For example, the compounds described herein can be prepared using radioisotopes, and the resulting radiolabeled compounds can be used to develop binding assays or for metabolic studies. Alternatively, and for the same purpose, the compounds described herein can be converted to a radiolabeled form by catalytic tritiation using methods known to those skilled in the art.

[0137] Certain compounds disclosed herein exist as stereoisomers. It should be understood that when stereochemistry is not specified, the present disclosure encompasses all stereochemically isomeric forms, or mixtures thereof, that have the ability to inhibit KRAS G12C. Individual stereoisomers of a compound can be prepared synthetically from commercially available starting materials containing a chiral center, or by preparing a mixture of enantiomeric products followed by separation, such as conversion into a mixture of diastereoisomers, followed by separation or recrystallization, chromatography techniques, or direct separation of enantiomers on a chiral chromatography column. Starting compounds of specific stereochemistry are commercially available or can be prepared and resolved by techniques known in the art.

[0138] Certain compounds of the present disclosure exist as atropisomers. The term "atropisomer" refers to a conformational stereoisomer that occurs when the rotation around a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule, and the substituents at both ends of the single bond are asymmetric (i.e., optical activity is produced without the need for an asymmetric carbon center or stereocenter). When the rotation barrier around a single bond is high enough and the interconversion between conformations is slow enough, separation and isolation of isomeric substances can be allowed. Atropisomers are enantiomers (or epimers) in the absence of a single asymmetric atom.

[0139] If the barrier to interconversion is high enough to allow little or no interconversion at room temperature for at least one week, the atropisomer can be considered stable. In some aspects, the atropisomer experiences little or no interconversion at room temperature for at least one year. In some aspects, when the atropisomer compound is in a substantially pure form (which is generally a solid state), the atropisomer compound of the present disclosure does not experience more than about 5% of the interconversion to its relative atropisomer during one week at room temperature. In some aspects, the atropisomer compound of the present disclosure does not experience more than about 5% of the interconversion to its relative atropisomer at room temperature (approximately 25 ° C) during one year. In some aspects, the atropisomer compound of the present disclosure is sufficiently stable to experience no more than about 5% of the interconversion in the aqueous pharmaceutical formulation at 0 ° C for at least one week. The chemical entity, pharmaceutical composition and method of the present invention are intended to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, single atropisomers and intermediate mixtures in optically pure forms.

[0140] The energy barrier to the thermal racemization of atropisomers can be determined by the steric hindrance to the free rotation of one or more bonds forming the chiral axis. Certain biaryl compounds exhibit atropisomerism, in which rotation around the inter-ring bond lacking C2 symmetry is restricted. The free energy barrier to isomerization (enantiomerization) is a measure of the stability of the inter-ring bond with respect to rotation. Optical and thermal excitations can promote the racemization of such isomers, depending on electronic and steric factors.

[0141] Ortho-substituted biaryl compounds can exhibit this type of conformational and rotational isomerism. Such biaryl compounds are enantiomeric and chiral atropisomers, where sp 2 -sp 2 The carbon-carbon, intercyclic bonds between the aryl rings have sufficiently high energy barriers to prevent free rotation, and wherein the substituent W 1 ≠W 2 and W 3 ≠W 4 Makes the molecule asymmetric.

[0142] W 1 :W 3 、W 1 :W 4 , and / or W 2 :W 4 、W 2 :W 3 The steric interactions between the two non-planar, axially chiral enantiomers are large enough to allow the planar conformation to be at an energy maximum. When the interconversion of two non-planar, axially chiral enantiomers is slow enough so that they can freely separate from each other, then they exist as atropisomers. The bold and dotted lines in the figures shown above indicate those parts, or parts of the molecule, that are spatially restricted due to the rotational energy barrier. The bold parts exist orthogonally above the plane of the page, and the dotted parts exist orthogonally below the plane of the page. The 'flat' part of the molecule (the left ring in each of the two depicted biaryls) is in the plane of the page.

[0143] The pharmaceutical composition of the present disclosure may include one or more pharmaceutically acceptable salts." pharmaceutically acceptable salts " refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesirable toxicological effects (see, for example, Berge, SM et al., J.Pharm.Sci. [Journal of Pharmaceutical Sciences], 66: 1-19 (1977)). These salts can be obtained during the final separation and purification of compounds as described herein, or by reacting the free base functional group of the compound with a suitable acid alone, or by reacting the acidic group of the compound with a suitable base. Acid addition salts include salts derived from nontoxic inorganic acids (such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, etc.) and salts derived from nontoxic organic acids (such as aliphatic monocarboxylic acids and aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.). Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, calcium, and the like, as well as from non-toxic organic amines such as N,N′-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like. Pharmaceutical composition

[0144] In another aspect, the present disclosure provides compositions, such as pharmaceutical compositions, containing one or a combination of compounds described herein formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present disclosure can also be administered in combination therapy, i.e., in combination with other agents as described herein.

[0145] As used herein, "pharmaceutically acceptable carriers" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In some aspects, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0146] The pharmaceutical composition of the present disclosure can be administered via one or more routes of administration using various methods known in the art. As will be appreciated by those skilled in the art, route of administration and / or pattern will vary depending on the desired result. In some aspects, the route of administration for the compound of the present disclosure includes intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal column or other parenteral routes of administration, such as by injection or infusion. As used herein, phrase "parenteral administration" means the mode of administration except enteral and topical administration, is usually administered by injection, and includes but is not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardial, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

[0147] Sterile injectable solutions can be prepared by optionally incorporating the active compound in the desired amount into a suitable solvent containing one or a combination of the above-listed ingredients, followed by sterilization microfiltration. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing an alkaline dispersion medium and the desired other ingredients from those described above. In the case of sterile powders for the preparation of sterile injectable solutions, some preparation methods are drying under reduced pressure and freeze drying (lyophilization), which produces a powder of the active ingredient plus any other desired ingredients from a previously sterile-filtered solution of the active ingredient plus any other desired ingredients.

[0148] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils, and injectable organic esters. Suitable fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin), by maintaining the desired particle size in the case of dispersions, and by the use of surfactants.

[0149] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents as pharmaceutically active substances is known in the art. Unless any conventional media or agents are incompatible with the active compound, the use of such media or agents in the pharmaceutical compositions of the present disclosure is contemplated. Supplementary active compounds may also be incorporated into the compositions.

[0150] Therapeutic compositions typically must be sterile and stable under manufacturing and storage conditions. Compositions can be formulated as solutions or liquids with an ordered structure suitable for high drug concentrations. Supporting agents can be solvents or dispersion media containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.) and suitable mixtures thereof. For example, suitable fluidity can be maintained by using a coating (such as lecithin), by maintaining the required particle size and by using a surfactant in the case of a dispersion. In many cases, it is desirable to include an isotonic agent, for example, sugar, polyols (such as mannitol, sorbitol) or sodium chloride in the composition. The extended absorption of injectable compositions can be achieved by including in the composition an agent (for example, monostearate and gelatin) that delays absorption.

[0151] Alternatively, the compounds of the disclosure may be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.

[0152] Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, for example, tablets, lozenges, dragees, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for making pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, the pharmaceutical composition according to this disclosure can contain at least one medicament selected from sweeteners, flavorings, coloring agents, demulcents, antioxidants, and preservatives.

[0153] Tablets can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient which is suitable for the manufacture of tablets.

[0154] Aqueous suspensions can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of aqueous suspensions, including, but not limited to, suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents such as, for example, naturally occurring phospholipids such as lecithin; condensation products of alkylene oxides with fatty acids such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long-chain aliphatic alcohols such as, for example, heptadecanethenyl-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as, for example, polyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, including, but not limited to, sucrose, saccharin, and aspartame.

[0155] Oily suspensions can for example be prepared by suspending at least one compound with formula (I) and / or at least one pharmaceutically acceptable salt thereof in a vegetable oil (such as peanut oil, sesame oil and coconut oil) or being suspended in a mineral oil (such as liquid paraffin). Oily suspensions can also contain at least one thickening agent, such as beeswax, hard paraffin and cetyl alcohol. In order to provide a delicious oily suspension, at least one sweetener and / or at least one flavoring agent already described above can be added to the oily suspension. Oily suspensions can further contain at least one preservative, including but not limited to for example antioxidants, such as butylated hydroxyanisole and alpha-tocopherol.

[0156] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersant and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersants, wetting agents, and suspending agents have been described above. Exemplary preservatives include, but are not limited to, antioxidants such as ascorbic acid. In addition, dispersible powders and granules may also contain at least one excipient, including, but not limited to, sweeteners, flavorings, and coloring agents.

[0157] The active compound can be prepared with a carrier that will prevent the rapid release of the compound, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods for preparing such formulations are patented or generally known to those skilled in the art. See, for example, Robinson, JR, ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0158] The therapeutic composition can be administered using medical devices known in the art. For example, in one aspect, the therapeutic composition of the present disclosure can be administered using a needle-free subcutaneous injection device, such as the devices disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556. Examples of well-known implants and modules that can be used in the present disclosure include: U.S. Patent No. 4,487,603, which discloses an implantable microinfusion pump for dispensing drugs at a controlled rate; U.S. Patent No. 4,486,194, which discloses a therapeutic device for administering drugs through the skin; U.S. Patent No. 4,447,233, which discloses a drug infusion pump for delivering drugs at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion device for continuous drug delivery; U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system with a multi-chamber compartment; and U.S. Patent No. 4,475,196, which discloses an osmotic drug delivery system. These patents are incorporated herein by reference. Many other such implants, delivery systems, and modules are known to those skilled in the art.

[0159] In certain aspects, the compounds of the disclosure can be administered parenterally, i.e., by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and / or infusion.

[0160] In some aspects, the compounds of the disclosure can be administered orally, ie, via gelatin capsules, tablets, hard or soft capsules, or liquid capsules. Uses / treatments of KRAS inhibitors

[0161] Administration of the therapeutic agents described herein may include administration of a therapeutically effective amount of the therapeutic agent. As used herein, the term "therapeutically effective amount" refers to, but is not limited to, an amount of a therapeutic agent to treat a condition treatable by administering a composition comprising a KRAS inhibitor as described herein. This amount is sufficient to exhibit a detectable therapeutic or ameliorative effect. The effect may include, for example, but is not limited to, the treatment of the conditions listed herein. The precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition being treated, the advice of the treating physician, and the therapy or combination of therapies selected for administration.

[0162] For administration of the compounds described herein, dosages range from about 0.0001 to 100 mg / kg host body weight and more typically 0.01 to 40 mg / kg host body weight. Exemplary treatment regimens entail administration once a day, twice a week, three times a week, weekly, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months, or once every three to six months.

[0163] The disclosed compounds strongly inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Therefore, in another aspect, the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising any compound disclosed herein and a pharmaceutically acceptable carrier.

[0164] Ras mutations, including but not limited to KRAS mutations, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, certain aspects relate to administering the disclosed compounds (e.g., in the form of pharmaceutical compositions) to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the compounds disclosed herein can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other aspects, these compounds can be used to treat lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0165] Determining whether a tumor or cancer contains a KRAS mutation can be performed by evaluating the nucleotide sequence encoding the KRAS protein, by evaluating the amino acid sequence of the KRAS protein, or by evaluating the characteristics of a putative KRAS mutant protein. The sequence of the wild-type human KRAS protein is known in the art.

[0166] Methods for detecting KRAS mutations are known to those skilled in the art. These methods include but are not limited to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting assay and microarray analysis. In some aspects, KRAS mutation evaluation is performed on the sample, including by real-time PCR. In real-time PCR, a fluorescent probe specific for KRAS mutations is used. When there is a mutation, the probe binds and detects fluorescence. In some aspects, a direct sequencing method of a specific region (e.g., exon 2 and / or exon 3) in the KRAS gene is used to identify KRAS mutations. This technology will identify all possible mutations in the region sequenced.

[0167] Methods for detecting mutations in KRAS proteins are known to those skilled in the art. These methods include, but are not limited to, detecting KRAS mutants using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0168] Methods for determining whether a tumor or cancer contains a KRAS mutation can use a variety of samples. In some aspects, the sample is taken from a subject with a tumor or cancer. In some aspects, the sample is taken from a subject with a cancer or tumor. In some aspects, the sample is a fresh tumor / cancer sample. In some aspects, the sample is a frozen tumor / cancer sample. In some aspects, the sample is a formalin-fixed paraffin-embedded sample. In some aspects, the sample is processed into a cell lysate. In some aspects, the sample is processed into DNA or RNA. The present disclosure also relates to a method for treating a hyperproliferative disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.In some aspects, the methods relate to the treatment of cancers such as acute myeloid leukemia, juvenile cancers, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphomas and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory glioma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic Neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oral In some aspects, the method is directed to treating a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

[0169] In certain aspects, the present disclosure relates to a method for treating lung cancer, comprising administering an effective amount of any of the above compounds (or a pharmaceutical composition comprising the same) to a subject in need thereof. In certain aspects, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In other aspects, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors, and undifferentiated carcinomas.Subjects that can be treated with the compounds of the present disclosure or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates or derivatives of the compounds according to the methods of the present disclosure include, for example, subjects who have been diagnosed with acute myeloid leukemia, acute myeloid leukemia, juvenile cancers, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchogenic carcinoma, Burkitt's lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germinal tumor, or the like. Cell tumors, primary lymphomas, cervical cancer, childhood cancers, chordomas, heart tumors, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory glioma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), SCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancers. In some aspects, subjects treated with the compounds of the disclosure include subjects who have been diagnosed with a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or the prostate (e.g., benign prostatic hypertrophy (BPH)).The present disclosure further provides a method for regulating the activity of mutant KRAS protein by contacting the protein with an effective amount of a compound of the present disclosure. Regulation can be to inhibit or activate protein activity. In some aspects, the present disclosure provides a method for inhibiting protein activity by contacting a mutant KRAS protein with an effective amount of a compound of the present disclosure in a solution. In some aspects, the present disclosure provides a method for inhibiting the activity of mutant KRAS protein by contacting cells, tissues, and organs expressing a protein of interest. In some aspects, the present disclosure provides a method for inhibiting protein activity in a subject (including but not limited to rodents and mammals (e.g., humans)) by administering an effective amount of a compound of the present disclosure to the subject. In some aspects, the regulation percentage exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the inhibition percentage exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the present disclosure provides methods for inhibiting KRAS activity in a cell by contacting the cell with a compound of the present disclosure in an amount sufficient to inhibit the activity of a KRAS mutant in the cell. In some aspects, the present disclosure provides methods for inhibiting mutant KRAS in a tissue by contacting the tissue with a compound of the present disclosure in an amount sufficient to inhibit the activity of mutant KRAS in the tissue. In some aspects, the present disclosure provides methods for inhibiting KRAS in an organism by contacting the organism with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the organism. In some aspects, the present disclosure provides methods for inhibiting KRAS activity in an animal by contacting the animal with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the animal. In some aspects, the present disclosure provides methods for inhibiting KRAS, including in a mammal, by contacting the mammal with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the mammal. In some aspects, the present disclosure provides methods for inhibiting KRAS activity in a human by contacting the human with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the human. The present disclosure provides methods for treating diseases mediated by KRAS activity in subjects in need of such treatment. The present disclosure also provides methods for combination therapy, wherein agents known to modulate other pathways, or other components of the same pathway, or even overlapping target enzyme groups are used in combination with the compounds of the present disclosure or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates or derivatives thereof. In one aspect, such therapy includes, but is not limited to, combinations of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies and radiation therapy.

[0170] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of the present disclosure. In some aspects, the chemotherapeutic agent is selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0171] The compounds described herein can be used in combination with the medicament disclosed herein or other suitable medicaments, depending on the condition being treated. Therefore, in some aspects, the one or more compounds of the present disclosure will be co-administered with other medicaments as described above. When used in combination therapy, the compound described herein and the second medicament are administered simultaneously or individually. The combined administration can include administering both medicaments simultaneously with the same dosage form, administering simultaneously with different dosage forms, and administering alone. That is, the compound described herein and any medicament described above can be formulated together with the same dosage form and administered simultaneously. Alternatively, the compound of the present disclosure and any medicament described above can be administered simultaneously, wherein the two medicaments are present in separate preparations. In another alternative, the compound of the present disclosure can be administered immediately after any of the medicaments described above, or vice versa. In some aspects of a separate administration scheme, the compound of the present disclosure and any medicament described above are administered at intervals of a few minutes, or at intervals of a few hours, or at intervals of a few days.

[0172] These compounds can be prepared by methods known in the art (including those methods described below and including variations within the art technology). Some reagents and intermediates are known in the art. Other reagents and intermediates can be prepared by methods known in the art using readily available materials. Any variable used to describe the synthesis of a compound (e.g., a numbered "R" substituent) is intended only to illustrate how to prepare the compound and should not be confused with the variables used in the claims or other parts of this specification. The following methods are for illustrative purposes and are not intended to limit the scope of this disclosure. synthesis

[0173] The aspects described herein are further defined in the following examples. It should be understood that these examples are provided by way of illustration only. From the above discussion and examples, those skilled in the art can determine the essential features of the aspects described herein, and, without departing from the spirit and scope thereof, various changes and modifications can be made to adapt them to various uses and conditions. Therefore, the aspects described herein are not limited by the illustrative examples set forth below herein, but are defined by the appended claims. abbreviation

[0174] The following abbreviations are used in the Examples section that follows and elsewhere herein: AA for ammonium acetate; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; Et for ethyl; EtOAc for ethyl acetate; h for hour; MeCN or CAN for acetonitrile; MeOH for methanol; TFA for trifluoroacetic acid; and THF for tetrahydrofuran. (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol)

[0175] This compound was prepared according to the synthetic procedure described in WO 2021 / 041671. 4-(4-((1R,4R)-4-amino-2-azabicyclo[2.2.1]hept-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0176] This compound was prepared by a procedure analogous to that described for Intermediate 1, substituting appropriate starting materials. Preparation of heteroaryl intermediates ;or (Z)-2-Fluoro-3-(thiazol-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate

[0177] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (1.1g, 4.5mmol) is dissolved in THF (25mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 0.18g, 4.5mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and thiazole-2-carboxaldehyde (0.51g, 4.5mmol) is added. The reaction mixture is allowed to warm to room temperature and stir for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (20mL). The solution is diluted with water (20mL) and EtOAc (150mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×50mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→60% acetone / hexanes) to afford ethyl (E)-2-fluoro-3-(thiazol-2-yl)acrylate (10:1 E / Z, as obtained by 1 1H NMR, 620 mg, 3.1 mmol, 68% yield). LC / MS (ESI) m / z: calculated for C8H9FNO2S [M+H] + 202.0; measured value 202.2; 1 H NMR (500MHz, CDCl3) δ7.94 (d, J = 3.2 Hz, 1H), 7.52 (d, J = 3.2 Hz, 1H), 7.34 (d, J = 22.2 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(thiazol-2-yl)acrylate

[0178] (E) -2- fluoro- 3- (thiazol-2-yl) ethyl acrylate (620 mg, 3.1 mmol) was dissolved in toluene (15 mL) and iodine (39 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 ° C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to provide (Z) -2- fluoro- 3- (thiazol-2-yl) ethyl acrylate (509 mg, 2.5 mmol, 82% yield). LC / MS (ESI) m / z: calculated for C8H9FNO2S [M + H] + 202.0; Measured value 202.0; 1 HNMR (500MHz, CDCl3) δ7.96 (dd, J=3.2, 2.6Hz, 1H), 7.57 (d, J=3.2Hz, 1H), 7.43 (dd, J=33.3, 0.8Hz, 1H), 4.38 (q, J=7.2Hz, 2H), 1.39 (t, J=7.1Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(thiazol-2-yl)acrylic acid

[0179] (Z) -2- fluoro -3- (thiazol-2-yl) ethyl acrylate (510mg, 2.5mmol) was dissolved in MeOH (15mL). The solution was cooled to 0°C and sodium hydroxide solution (1.0M, 2.5mL, 2.5mmol) was added. The reaction mixture was stirred for 5h. The solution was concentrated to remove methanol. Additional water (1.5mL) was added and the aqueous solution was cooled to 0°C. HCl solution (1.0M, 2.5mL, 2.5mmol) was added dropwise. After 10min, a white solid precipitated out. The solid was collected by filtration and washed with MeCN. The solid was dried under vacuum to provide (Z) -2- fluoro -3- (thiazol-2-yl) acrylic acid (337mg, 1.9mmol, 77% yield) as a white solid. LC / MS (ESI) m / z: calculated for C6H5FNO2S [M+H] + 174.0; measured value 173.8; 1 HNMR (500MHz, DMSO-d6) δ8.04 (s, 2H), 7.29 (d, J = 34.5Hz, 1H). (Z)-2-Fluoro-3-(pyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate

[0180] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (1.5g, 6.2mmol) is dissolved in THF (31mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 0.25g, 6.2mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and pyridine carboxaldehyde (0.66g, 6.2mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (15mL). The solution is diluted with water (20mL) and EtOAc (100mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×50mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to afford ethyl (E)-2-fluoro-3-(pyridin-2-yl)acrylate (3:1 E / Z mixture, as obtained by 1 1H NMR analysis: 910 mg, 4.6 mmol, 75% yield). LC / MS (ESI) m / z: for C 10 H 11Calculated value of FNO2 [M+H] + 196.1; Found 196.1; Reported E isomer: 1 H NMR (500MHz, CDCl3) δ8.59 (dd, J=4.9, 1.8Hz, 1H), 7.67 (ddd, J=7.9, 7.6, 1.8Hz, 1H), 7.56 (d, J=7.9Hz, 1H), 7.21 (dd, J=7.6, 4.9Hz, 1H), 6.90 (d, J=20.4Hz, 1H), 4.25 (q, J=7.2Hz, 2H), 1.23 (t, J=7.1Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyridin-2-yl)acrylate

[0181] (E) -2- fluoro- 3- (pyridin-2-yl) ethyl acrylate (420 mg, 2.1 mmol) was dissolved in toluene (10 mL) and iodine (27 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 ° C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to provide (Z) -2- fluoro- 3- (pyridin-2-yl) ethyl acrylate (240 mg, 1.2 mmol, 58% yield). LC / MS (ESI) m / z: for C 10 H 11 Calculated value of FNO2 [M+H] + 196.1; measured value 196.1; 1 H NMR (500MHz, CDCl3) δ8.66(ddd,J=5.0,1.8,0.8Hz,1H),7.88(ddd,J=8.0,1.2,0.8Hz,1H),7.75(ddd,J=8.0,7.8,1 .8Hz, 1H), 7.25 (ddd, J=7.8, 5.0, 1.2Hz, 1H), 7.14 (d, J=34.9Hz, 1H), 4.36 (q, J=7.2Hz, 2H), 1.38 (t, J=7.2Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(pyridin-2-yl)acrylic acid

[0182] (Z) -2- fluoro -3- (pyridin-2-yl) ethyl acrylate (415 mg, 2.1 mmol) was dissolved in MeOH (15 mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0 M, 2.1 mL, 2.1 mmol) was added. The reaction mixture was stirred for 5 h. The solution was concentrated to remove methanol. Additional water (2.0 mL) was added and the aqueous solution was cooled to 0 ° C. HCl solution (1.0 M, 2.1 mL, 2.1 mmol) was added dropwise. After 10 min, a white solid precipitated out. The solid was collected by filtration and washed with Et2O. The solid was dried under vacuum to provide (Z) -2- fluoro -3- (pyridin-2-yl) acrylic acid (235 mg, 1.4 mmol, 66% yield) as a white solid. LC / MS (ESI) m / z: calculated for C8H7FNO2 [M+H] + 168.0; measured value 167.8. 1 HNMR(500MHz,DMSO-d6)δ8.66(ddd,J=4.8,1.8,0.8Hz,1H),7.89(ddd,J=8.0,7.5,1.8Hz,1H) ,7.81(ddd,J=8.0,1.1,0.8Hz,1H),7.40(dd,J=7.5,4.8,1.1Hz,1H),6.97(d,J=35.3Hz,1H). (Z)-2-Fluoro-3-(4-methylpyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylate

[0183] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and 2-formyl-4-methylpyridine (125mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by reverse phase HPLC (column: Xbridge C18, 30 mm x 100 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25° C.; gradient: 95:5 H 2 O:MeCN:0.05% TFA→5:95 H 2 O:MeCN:0.05% TFA; λ=220 nm) to afford (Z)-ethyl 2-fluoro-3-(4-methylpyridin-2-yl)acrylate (32 mg, 0.15 mmol, 15% yield). LC / MS (ESI) m / z: for C 11 H 13 Calculated value of FNO2 [M+H] + 210.2; measured value 209.8; 1 H NMR(500MHz, CDCl3)δ8.51(d,J=5.0Hz,1H),7.70(s,1H),7.11(d,J=35.0Hz,1H), 7.07 (d, J = 5.0 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(4-methylpyridin-2-yl)acrylic acid

[0184] (Z) -2- fluoro -3- (4- methylpyridin-2-yl) ethyl acrylate (32 mg, 0.15 mmol) was dissolved in MeOH (1.5 mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0 M, 0.15 mL, 0.15 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added and the aqueous solution was cooled to 0 ° C. HCl solution (1.0 M, 0.15 mL, 0.15 mmol) was added dropwise. The solution was frozen and directly lyophilized to provide (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: calculated for C9H8FNO2 [M + H] + 182.1; measured value 182.1. 1 H NMR (500MHz, DMSO-d6) δ 8.51 (d, J = 4.9 Hz, 1H), 7.65 (s, 1H), 7.24 (d, J = 4.9 Hz, 1H), 6.94 (d, J = 35.3 Hz, 1H), 2.36 (s, 3H). (Z)-2-Fluoro-3-(oxazol-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(oxazol-2-yl)acrylate

[0185] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and oxazole-2-carboxaldehyde (100mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). The layers are separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to provide (E)-ethyl 2-fluoro-3-(oxazol-2-yl)acrylate (6:1 E / Z, as judged by 1H NMR, 165 mg, 0.89 mmol, 86% yield). LC / MS (ESI) m / z: calculated for CHFNO [M+H] + 186.0; Found 186.0; Reported E isomer: 1H NMR (500MHz, CDCl3) δ7.69 (d, J = 0.7Hz, 1H), 7.25 (d, J = 0.7Hz, 1H), 6.62 (d, J = 17.6Hz, 1H), 4.35 (q, J = 7.2Hz, 2H), 1.32 (t, J = 7.2Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(oxazol-2-yl)acrylate

[0186] (E) -2- fluoro -3- (oxazole -2- bases) ethyl acrylate (165mg, 0.89mmol) is dissolved in toluene (2mL), and iodine (11mg, 0.045mmol) is added. The reaction mixture is heated at 100 ° C for 7 days. The solution is concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to provide (Z) -2- fluoro -3- (oxazole -2- bases) ethyl acrylate (22mg, 0.12mmol, 13% yield). LC / MS (ESI) m / z: for C8H9FNO3 calculated value [M+H] + 186.0; measured value 185.9 1 HNMR (500MHz, CDCl3) δ7.77 (s, 1H), 7.32 (s, 1H), 6.96 (d, J = 31.0Hz, 1H), 4.37 (q, J = 7.2Hz, 2H), 1.38 (t, J = 7.2Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(oxazol-2-yl)acrylic acid

[0187] (Z) -2- fluoro -3- (oxazole -2- bases) ethyl acrylate (22 mg, 0.12 mmol) was dissolved in MeOH (10 mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0 M, 0.12 mL, 0.12 mmol) was added. The reaction mixture was stirred for 4 h. The solution was concentrated to remove methanol. Additional water (0.3 mL) was added and the aqueous solution was cooled to 0 ° C. HCl solution (1.0 M, 0.12 mL, 0.12 mmol) was added dropwise. The solution was frozen and directly lyophilized to provide (Z) -2- fluoro -3- (oxazole -2- bases) acrylic acid (18 mg, 0.12 mmol, assuming quantitative yield; containing 1 equivalent of NaCl) as a white solid. LC / MS (ESI) m / z: calculated for CHFNO [M + H] + 158.0; measured value 157.8; 1 H NMR (600MHz, DMSO-d6) δ8.30 (s, 1H), 7.47 (s, 1H), 6.90 (d, J = 32.2Hz, 1H). (Z)-2-Fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylate

[0188] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and 1-methylimidazole-2-carboxaldehyde (114mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by reverse phase HPLC (column: Xbridge C18, 30 mm x 100 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25° C.; gradient: 95:5 H 2 O:MeCN:10 mM AA→100% 5:95 H 2 O:MeCN:10 nM AA; λ=220 nm) to afford (Z)-ethyl 2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylate (16 mg, 0.08 mmol, 8% yield). LC / MS (ESI) m / z: for C 9 H 12 Calculated value of FN2O2 [M+H] + 199.1; measured value 198.9; 1 H NMR (500MHz, CDCl3) δ7.22 (d, J = 0.7Hz, 1H), 6.94 (d, J = 0.7Hz, 1H), 6.84 (d, J = 30.5Hz, 1H), 4.33 (q, J = 7.1Hz, 2H), 3.71 (s, 3H), 1.35 (t, J = 7.1Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(1-methyl-1H-imidazol-2-yl)acrylic acid

[0189] (Z) -2- fluoro -3- (1- methyl -1H- imidazole -2- yl) ethyl acrylate (16 mg, 0.08 mmol) was dissolved in MeOH (10 mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0 M, 0.08 mL, 0.08 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (0.3 mL) was added and the aqueous solution was cooled to 0 ° C. HCl solution (1.0 M, 0.08 mL, 0.08 mmol) was added dropwise. The solution was frozen and directly lyophilized to provide (Z) -2- fluoro -3- (1- methyl -1H- imidazole -2- yl) acrylic acid (13 mg, 0.08 mmol, assuming quantitative yield; containing 1 equivalent of NaCl) as a white solid. LC / MS (ESI) m / z: calculated for C7H8FN2O2 [M + H] + 171.0; measured value 170.9; 1 H NMR (500MHz, DMSO-d6) δ7.31 (s, 1H), 7.11 (s, 1H), 6.87 (d, J = 31.6Hz, 1H), 3.72 (s, 3H). (Z)-2-Fluoro-3-(5-methylpyridin-2-yl)acrylic acid Step 1: Preparation of (Z)-ethyl 2-fluoro-3-(5-methylpyridin-2-yl)acrylate

[0190] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and 5-picoline carboxaldehyde (125mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (15mL). The solution is diluted with water (20mL) and EtOAc (100mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×50mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by reverse phase HPLC (column: Xbridge C18, 30 mm x 100 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25° C.; gradient: 95:5 H 2 O:MeCN:0.05% TFA→100% 5:95 H 2 O:MeCN:0.05% TFA; λ=220 nm) to afford (Z)-ethyl 2-fluoro-3-(4-methylpyridin-2-yl)acrylate (12 mg, 0.06 mmol, 6% yield). LC / MS (ESI) m / z: for C 11 H 13 Calculated value of FNO2 [M+H] + 210.2; measured value 210.1 1 H NMR (500MHz, CDCL3) δ8.49(d,J=1.8Hz,1H),7.79(d,J=8.2Hz,1H),7.55(dd,J=8.2,1.8H z, 1H), 7.12 (d, J = 35.3Hz, 1H), 4.35 (q, J = 7.2Hz, 2H), 2.37 (s, 3H), 1.37 (t, J = 7.2Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(5-methylpyridin-2-yl)acrylic acid

[0191] (Z) -2- fluoro -3- (5- methylpyridin-2-yl) ethyl acrylate (12 mg, 0.06 mmol) was dissolved in MeOH (0.5 mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0 M, 0.06 mL, 0.06 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added and the aqueous solution was cooled to 0 ° C. HCl solution (1.0 M, 0.06 mL, 0.06 mmol) was added dropwise. The solution was frozen and directly lyophilized to provide (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: calculated for C9H8FNO2 [M + H] + 182.1; measured value 181.6; 1 H NMR (500MHz, DMSO-d6) δ8.51 (s, 1H), 7.74-7.69 (m, 2H), 6.95 (d, J = 35.4Hz, 1H), 2.33 (s, 3H). (Z)-2-Fluoro-3-(pyrimidin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate

[0192] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (1.6g, 6.6mmol) is dissolved in THF (50mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 0.26g, 6.6mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and pyrimidine-2-carboxaldehyde (0.71g, 6.6mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (20mL). The solution is diluted with water (20mL) and EtOAc (150mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×50mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→90% EtOAc / hexanes) to provide ethyl (E)-2-fluoro-3-(pyrimidin-2-yl)acrylate (5:1 E / Z, as judged by 1H NMR, 592 mg, 3.0 mmol, 46% yield). LC / MS (ESI) m / z: for C9H 10 Calculated value of FN2O2 [M+H] + 197.2; measured value 197.1; 1H NMR (500MHz, CDCl3) δ 8.70 (d, J = 4.9 Hz, 2H), 7.18 (t, J = 4.9 Hz, 1H), 6.77 (d, J = 17.5 Hz, 1H), 4.28 (q, J = 7.2 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylate

[0193] (E) -2-fluoro-3- (pyrimidin-2-yl) ethyl acrylate (592 mg, 3.0 mmol) was dissolved in toluene (15 mL) and iodine (38 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 ° C for 7 days. The solution was concentrated and purified by column chromatography (0 → 100% EtOAc / hexane) to provide (Z) -2-fluoro-3- (pyrimidin-2-yl) ethyl acrylate (253 mg, 1.3 mmol, 43% yield). LC / MS (ESI) m / z: for C9H 10 Calculated value of FN2O2 [M+H] + 197.2; measured value 196.6; 1 H NMR (500MHz, CDCl3) δ 8.83 (d, J = 4.9 Hz, 2H), 7.21 (t, J = 4.9 Hz, 1H), 7.13 (d, J = 30.8 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(pyrimidin-2-yl)acrylic acid

[0194] (Z) -2- fluoro -3- (pyrimidin-2-yl) ethyl acrylate (253 mg, 1.3 mmol) was dissolved in MeOH (10 mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0 M, 1.3 mL, 1.3 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. Additional water (1.0 mL) was added and the aqueous solution was cooled to 0 ° C. HCl solution (1.0 M, 2.5 mL, 2.5 mmol) was added dropwise. After 10 min, a white solid precipitated. The solid was collected by filtration and dried under vacuum to provide (Z) -2- fluoro -3- (pyrimidin-2-yl) acrylic acid (190 mg, 1.1 mmol, 88% yield) as a white solid. LC / MS (ESI) m / z: calculated for C7H6FN2O2 [M + H] + 169.1; measured value 168.8; 1H NMR (500MHz, DMSO-d6) δ 8.90 (d, J = 4.9 Hz, 2H), 7.46 (t, J = 4.9 Hz, 1H), 6.94 (d, J = 31.5 Hz, 1H). (Z)-2-Chloro-3-(pyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-chloro-3-(pyridin-2-yl)acrylate

[0195] 2-chloro-2-(diethoxyphosphoryl)ethyl acetate (300mg, 1.2mmol) is dissolved in THF (5.8mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 46mg, 1.2mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and pyridine carboxaldehyde (124mg, 1.2mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (15mL). The solution is diluted with water (5mL) and EtOAc (50mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×50mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to provide (Z)-ethyl 2-chloro-3-(pyridin-2-yl)acrylate (79 mg, 0.37 mmol, 32% yield). LC / MS (ESI) m / z: for C 10 H 11 Calculated value of ClNO2 [M+H] + 212.0; measured value 211.6; 1 H NMR (500MHz, CDCl3) δ8.62(ddd,J=4.8,1.8,1.0Hz,1H),8.06(dt,J=8.0,1.0Hz,1H),7.97(s,1H),7.69(dd d, J=8.0, 7.6, 1.8Hz, 1H), 7.20 (ddd, J=7.6, 4.8, 1.0Hz, 1H), 4.28 (q, J=7.1Hz, 2H), 1.30 (t, J=7.2Hz, 3H). Step 2: Preparation of (Z)-2-chloro-3-(pyridin-2-yl)acrylic acid

[0196] (Z) -2- chloro -3- (pyridin-2-yl) ethyl acrylate (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 directly concentrated to provide (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: calculated for C8H7ClNO2 [M + H] + 184.0; measured value 183.8; 1 H NMR(500MHz,DMSO-d6)δ8.72(ddd,J=4.8,1.8,1.0Hz,1H),8.08(dt,J=8.0,1.0Hz,1H ), 7.96 (ddd, J=8.0, 7.6, 1.8Hz, 1H), 7.93 (s, 1H), 7.46 (ddd, J=7.6, 4.8, 1.0Hz, 1H). (Z)-3-(5-Bromopyridin-2-yl)-2-fluoroacrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(5-bromopyridin-2-yl)acrylate

[0197] At 0 DEG C, (2-ethoxy-1-fluoro-2-oxoethyl) triphenylphosphonium bromide (2.4g, 5.4mmol, prepared according to the synthetic procedure described in US9,345,791) is stirred in THF (30mL). nBuLi solution (1.6M in hexane, 3.4mL, 5.4mmol) is added dropwise into the mixture. The mixture is stirred for 10 minutes, and then 5-bromopicolinaldehyde (1.0g, 5.4mmol) is added as solid. The reaction mixture is allowed to warm to room temperature over two hours. The reaction mixture is concentrated, and the residue is directly purified by column chromatography (5→100% EtOAc / hexane) to provide the title product as a mixture of E / Z isomers. These isomers were then separated by HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 42.5 mL / min; column temperature: 25° C.; gradient: 5:95 MeCN: HO with 10 mM AA→95:5 MeCN: HO with 10 mM AA; λ=220 nm) to provide (Z)-ethyl 2-fluoro-3-(5-bromopyridin-2-yl)acrylate (550 mg, 2.0 mmol, 34%). LC / MS (ESI) m / z: for C 10 H 10 Calcd. value for BrFNO2 [M+H] + 274.0; Found 273.6; NMR: 1 H NMR (500MHz, CDCl3) δ8.73(d,J=2.3Hz,1H),7.91(dd,J=8.6,2.3Hz,1H),7.79(d,J =8.5Hz, 1H), 7.10 (d, J = 34.3Hz, 1H), 4.37 (q, J = 7.1Hz, 2H), 1.38 (t, J = 7.2Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(5-bromopyridin-3-yl)acrylic acid

[0198] (Z) -2- fluoro -3- (5- bromopyridin-3-yl) ethyl 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). After adding an aqueous solution of hydrochloric acid (1.0 M, 910 μL, 0.91 mmol), a precipitate was formed. The solid was collected by filtration and dried under vacuum to provide (Z) -2- fluoro -3- (5- bromopyridin-3-yl) acrylic acid (217 mg, 0.88 mmol, 97%). LC / MS (ESI) m / z: calculated for C8H6BrFNO2 [M + H]+ 246.0; Found 245.7; NMR: 1 H NMR (500MHz, 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). (Z)-2-Fluoro-3-(6-methylpyridin-2-yl)acrylic acid Step 1: Preparation of (Z)-ethyl 2-fluoro-3-(6-methylpyridin-2-yl)acrylate

[0199] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and 6-methylpyridine-2-carboxaldehyde (125mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). The layers are separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by HPLC (column: Xbridge C18, 5 μm particles; gradient: 5:95 MeCN:H 2 O with 0.05% TFA→95:5 MeCN:H 2 O with 0.05% TFA; λ=220 nm) to afford (Z)-ethyl 2-fluoro-3-(6-methylpyridin-2-yl)acrylate (31 mg, 0.15 mmol, 14% yield); LC / MS (ESI) m / z: for C 11 H 13 Calculated value of FNO2 [M+H] + 210.1; Found 209.7; NMR: 1 H NMR (500MHz, CDCl3) δ7.71(d,J=7.8Hz,1H),7.63(t,J=7.8Hz,1H),7.10(d,J=7.8Hz,1 H), 7.11 (d, J = 35.2Hz, 1H), 4.34 (q, J = 7.2Hz, 2H), 2.56 (s, 3H), 1.36 (t, J = 7.2Hz, 3H). Step 2: Preparation of (Z)-2-fluoro-3-(6-methylpyridin-2-yl)acrylic acid

[0200] (Z) -2-fluoro-3- (6-methylpyridin-4-yl) ethyl acrylate (31 mg, 0.15 mmol) was dissolved in MeOH (1.5 mL) and sodium hydroxide solution (1.0 M, 150 μL, 0.15 mmol) was added dropwise. The mixture was stirred for 2 h. The reaction mixture was concentrated, diluted with water (1 mL), and hydrochloric acid solution (1.0 M, 150 μL, 0.14 mmol) was added. The solution was lyophilized and the crude material was used without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: calculated for C9H9FNO2 [M+H] + 182.1; Found 182.1; NMR: 1 H NMR (500MHz, DMSO-d6) δ7.80 (t, J = 7.7Hz, 1H), 7.65 (d, J = 7.7Hz, 1H), 7.29 (d, J = 7.7Hz, 1H), 6.94 (d, J = 35.4Hz, 1H), 2.50 (s, 3H). (Z)-3-(4-Bromothiazol-2-yl)-2-fluoroacrylic acid Step 1: Preparation of ethyl (E)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate

[0201] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and 4-bromothiazole-2-carboxaldehyde (198mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to provide (E)-ethyl 3-(4-bromothiazol-2-yl)-2-fluoroacrylate (5:1 E / Z, as judged by 1H NMR, 168 mg, 0.60 mmol, 60% yield). LC / MS (ESI) m / z: Calcd. for C8H8BrFNO2S [M+H] + 279.9; measured value 279.9; 1H NMR (500MHz, CDCl3) δ7.41 (s, 1H), 7.28 (d, J = 21.7Hz, 2H), 4.43 (q, J = 7.2Hz, 2H), 1.41 (t, J = 7.2Hz, 3H). Step 2: Preparation of ethyl (Z)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate

[0202] (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 provide (Z) -3- (4- bromothiazol-2-yl) -2-fluoroacrylate (148 mg, 0.53 mmol, 88% yield). LC / MS (ESI) m / z: calculated for C8H8BrFNO2S [M + H] + 279.9; measured value 279.9; 1 H NMR (500MHz, CDCl3) δ7.44 (s, 1H), 7.38 (d, J = 33.0Hz, 1H), 4.38 (q, J = 7.1Hz, 2H), 1.38 (t, J = 7.1Hz, 3H). Step 3: Preparation of (Z)-3-(4-bromothiazol-2-yl)-2-fluoroacrylic acid

[0203] (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 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, 0.51 mL, 0.51 mmol) was added dropwise. The solution was frozen and directly lyophilized to provide (Z) -3- (4- bromothiazol-2-yl) -2- fluoroacrylate as a white solid (assuming quantitative yield). LC / MS (ESI) m / z: calculated for CHBrFNOS [M + H] + 251.9; measured value 251.7; 1 H NMR (500MHz, DMSO-d6) δ8.13 (s, 1H), 7.28 (d, J = 33.7Hz, 1H). (Z)-2-Fluoro-3-(pyridazin-3-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyridazin-3-yl)acrylate

[0204] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and pyridazine-3-carboxaldehyde (110mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to provide ethyl (E)-2-fluoro-3-(pyridazin-3-yl)acrylate (3:1 E / Z, as judged by 1H NMR, 168 mg, 0.60 mmol, 60% yield). LC / MS (ESI) m / z: for C9H 10 Calculated value of N2O2 [M+H] + 197.1; measured value 196.8; 1 H NMR (500MHz, CDCl3) δ9.11 (dd, J=5.0, 1.7Hz, 1H), 7.91 (dd, J=8.6, 1.7Hz, 1H), 7.47 (dd, J=8.6, 5.0Hz, 1H), 7.15 (d, J=19.9Hz, 1H), 4.27 (q, J=7.2Hz, 2H), 1.26 (t, J=7.2Hz, 3H). Step 2: Preparation of ethyl (Z)-3-(4-bromothiazol-2-yl)-2-fluoroacrylate

[0205] (E) -2- fluoro -3- (pyridazine -3- bases) ethyl 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 provide (Z) -3- (4- bromothiazol-2-yl) -2- fluoro ethyl acrylate (58 mg, 0.30 mmol, 59% yield). LC / MS (ESI) m / z: for C9H 10 Calculated value of N2O2 [M+H] + 197.1; measured value 196.8; 1HNMR (500MHz, CDCl3) δ9.12 (dd, J=4.9, 1.6Hz, 1H), 8.06 (dd, J=8.7, 1.6Hz, 1H), 7.54 (dd ,J=8.7,4.9Hz,1H),7.45(d,J=34.7Hz,1H),4.39(q,J=7.2Hz,2H),1.39(t,J=7.2Hz,3H). Step 3: Preparation of (Z)-2-fluoro-3-(pyridazin-3-yl)acrylic acid

[0206] (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 directly lyophilized to provide (Z) -2-fluoro-3- (pyridazine-3-yl) acrylic acid as a white solid (assuming quantitative yield). LC / MS (ESI) m / z: calculated for C7H6FN2O2 [M + H] + 169.0; measured value 168.8; 1 H NMR (500MHz, DMSO-d6) δ9.21 (dd, J = 4.9, 1.6 Hz, 1H), 8.06 (dd, J = 8.6, 1.6 Hz, 1H), 7.80 (dd, J = 8.6, 4.9 Hz, 1H), 7.22 (d, J = 34.7 Hz, 1H). (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

[0207] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) was dissolved in THF (5mL). The solution was cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) was added portionwise as a solid. The reaction mixture was stirred for 10min and 5-methyl-1,3,4-thiadiazole-2-carboxaldehyde (132mg, 1.0mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1h. The mixture was quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution was diluted with water (10mL) and EtOAc (50mL). The layers were separated, and the aqueous phase was further extracted with EtOAc (2×20mL). The combined organic layer was dried over magnesium sulfate, filtered and concentrated. The crude residue was not subjected to additional purification and was carried out to the next step (6:1E / Z, as described by 1 H, assuming quantitative yield). LC / MS (ESI) m / z: for C8H 10 Calculated value of FN2O2S [M+H] + 217.0; Found 216.8; Reported E isomer: 1 H NMR (500MHz, CDCL3) δ7.36 (d, J = 21.0Hz, 1H), 4.40 (t, J = 7.2Hz, 2H), 2.79 (s, 3H), 1.40 (t, J = 7.2Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)acrylate

[0208] (E) -2-fluoro-3- (5-methyl-1,3,4-thiadiazol-2-yl) ethyl acrylate (assumed 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 provide (Z) -2-fluoro-3- (5-methyl-1,3,4-thiadiazol-2-yl) ethyl acrylate (63 mg, 0.29 mmol, 29% yield over two steps). LC / MS (ESI) m / z: for CH 10 Calculated value of FN2O2S [M+H] + 217.0; measured value 216.8; 1 H NMR (500MHz, CDCl3) δ7.52 (d, J = 32.1Hz, 1H), 4.39 (q, J = 7.2Hz, 2H), 2.85 (s, 3H), 1.39 (t, J = 7.1Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)acrylic acid

[0209] (Z) -2-fluoro-3- (5-methyl -1,3,4- thiadiazol-2-yl) ethyl 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 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, 0.29 mL, 0.29 mmol) was added dropwise. A yellow precipitate was formed and collected by filtration. The solid was triturated with ether (2 × 2 mL) and dried under vacuum to provide (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: calculated for C6H6FN2O2S [M + H] + 189.0; measured value 188.8; 1 H NMR (500MHz, DMSO-d6) δ7.38 (d, J = 33.3Hz, 1H), 2.80 (s, 3H). (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

[0210] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and 6-(methoxymethyl)picolinaldehyde (156mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (10mL). The solution is diluted with water (10mL) and EtOAc (50mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×20mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to provide (E)-ethyl 2-fluoro-3-(6-(methoxymethyl)pyridin-2-yl)acrylate (3:1 E / Z, as judged by 1H NMR, 120 mg, 0.50 mmol, 49% yield). LC / MS (ESI) m / z: for C 12 H 15 Calculated value of FNO3 [M+H] + 240.1; Found 240.0; Reported E isomer: 1 H NMR (500MHz, CDCl3) δ7.68(t,J=7.8Hz,1H),7.45(d,J=7.8Hz,1H),7.35(d,J=7.8Hz,1H),6. 88(d,J=20.4Hz,1H),4.55(s,2H),4.24(q,J=7.2Hz,2H),3.47(s,3H),1.23(t,J=7.2Hz,3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(6-(methoxymethyl)pyridin-2-yl)acrylate

[0211] (E) -2-fluoro-3- (6- (methoxymethyl) pyridin-2-yl) ethyl 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 provide the desired product (59 mg, 0.25 mmol, 49% yield). LC / MS (ESI) m / z: for C 12 H 15 Calculated value of FNO3 [M+H] + 240.1; measured value 223.8; 1H NMR (500MHz, CDCl3) δ7.79(d,J=7.7Hz,1H),7.74(t,J=7.7Hz,1H),7.37(d,J=7.7Hz,1H),7. 12(d,J=35.0Hz,1H),4.56(s,2H),4.33(q,J=7.2Hz,2H),3.47(s,3H),1.35(t,J=7.2Hz,3H). Step 3: Preparation of (Z)-2-fluoro-3-(6-(methoxymethyl)pyridin-2-yl)acrylic acid

[0212] (Z) -2-fluoro-3- (6- (methoxymethyl) pyridin-2-yl) ethyl 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 directly lyophilized to provide the desired product, sodium chloride adduct (assuming quantitative yield) as a white solid. LC / MS (ESI) m / z: for C 10 H 11 Calculated value of FNO3 [M+H] + 212.1; measured value 211.8; 1 H NMR (500MHz, DMSO-d6) δ7.89(t,J=7.7Hz,1H),7.71(d,J=7.7Hz,1H),7.38(d,J=7.7Hz,1H),6.87(d,J=35.6Hz,1H),4.50(s,2H),3.37(s,3H). (Z)-2-Fluoro-3-(pyrazin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(pyrazin-2-yl)acrylate

[0213] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (1.7g, 7.0mmol) is dissolved in THF (35mL). The solution is cooled to 0 ° C. Sodium hydride (60% dispersion in mineral oil, 280mg, 7.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and pyrazine-2-carboxaldehyde (750mg, 7.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (50mL). The solution is diluted with water (50mL) and EtOAc (100mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×50mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to afford the desired product (6:1 E / Z, as judged by 1H NMR, 930 mg, 4.8 mmol, 68% yield). LC / MS (ESI) m / z: for C9H 10 Calculated value of FN2O2 [M+H] + 197.1; Found 197.0; Reported E isomer: 1 H NMR(500MHz, CDCl3) δ8.78(d,J=1.4Hz,1H),8.56(dd,J=2.5,1.4Hz,1H),8.49(d,J =2.5Hz, 1H), 6.86 (d, J = 19.1Hz, 1H), 4.27 (q, J = 7.2Hz, 2H), 1.24 (t, J = 7.2Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(pyrazin-2-yl)acrylate

[0214] (E) -2- fluoro- 3- (pyrazine -2- bases) ethyl acrylate (930mg, 4.8mmol) was dissolved in toluene (50mL) and iodine (240mg, 0.95mmol) 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 provide the desired product (710mg, 3.6mmol, 76% yield). LC / MS (ESI) m / z: for C9H 10 Calculated value of FN2O2 [M+H] + 197.1; measured value 197.0; 1H NMR(500MHz, CDCl3) δ9.10(d,J=1.5Hz,1H),8.63(dd,J=2.5,1.5Hz,1H),8.51(d,J =2.5Hz, 1H), 7.10 (d, J = 35.2Hz, 1H), 4.39 (q, J = 7.1Hz, 2H), 1.40 (t, J = 7.2Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(pyrazin-2-yl)acrylic acid

[0215] (Z) -2- fluoro- 3- (pyrazine -2- bases) ethyl acrylate (710mg, 3.6mmol) was dissolved in MeOH (25mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0M, 3.6mL, 3.6mmol) was added. The reaction mixture was stirred for 2h. The solution was concentrated to remove methanol. The resulting aqueous solution was cooled to 0 ° C. HCl solution (1.0M, 3.6mL, 3.6mmol) was added dropwise, and a precipitate was formed. After stirring for 10min, the precipitate was collected by filtration and dried under vacuum to provide the desired product (570mg, 3.4mmol, 94% yield). LC / MS (ESI) m / z: calculated value [M + H] for C7H6FN2O2 + 169.0; Measured value 169.0; 1 H NMR (500MHz, DMSO-d6) δ 8.98 (d, J = 1.1 Hz, 1H), 8.75 ( dd, J = 2.4, 1.1 Hz, 1H), 8.62 ( d, J = 2.4 Hz, 1H), 7.05 ( d, J = 34.9 Hz, 1H). (Z)-2-Fluoro-3-(6-methoxypyridin-2-yl)acrylic acid Step 1: Preparation of ethyl (E)-2-fluoro-3-(6-methoxypyridin-2-yl)acrylate

[0216] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and 6-methoxypyridinecarboxaldehyde (140mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (20mL). The solution is diluted with water (20mL) and EtOAc (10mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×5mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to afford the desired product (6:1 E / Z, as judged by 1H NMR, 170 mg, 0.75 mmol, 72% yield). LC / MS (ESI) m / z: for C 11 H 13 Calculated value of FNO3 [M+H] + 226.1; measured value 225.9. Step 2: Preparation of ethyl (Z)-2-fluoro-3-(6-methoxypyridin-2-yl)acrylate

[0217] (E) -2-fluoro-3- (6-methoxypyridin-2-yl) ethyl 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 provide the desired product (75 mg, 0.33 mmol, 45% yield); LC / MS (ESI) m / z: for C 11 H 13 Calculated value of FNO3 [M+H] + 226.1; measured value 226.1; 1 H NMR (500MHz, CDCL3) δ7.60(dd,J=8.2,7.4Hz,1H),7.41(d,J=7.4Hz,1H),6.98(d,J=34.7 Hz, 1H), 6.70 (d, J = 8.2Hz, 1H), 4.35 (q, J = 7.2Hz, 2H), 3.93 (s, 3H), 1.38 (t, J = 7.2Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(6-methoxypyridin-2-yl)acrylic acid

[0218] (Z) -2- fluoro -3- (6- methoxypyridin-2-yl) ethyl 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 h. 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 min, the precipitate was collected by filtration and dried under vacuum to provide the desired product (42 mg, 0.2 mmol, 67% yield). LC / MS (ESI) m / z: calculated for C9H9FNO3 [M + H] + 198.0; Measured value 198.0; 1 H NMR (500MHz, DMSO-d6) δ7.79 (dd, J=8.3, 7.0Hz, 1H), 7.41 (d, J=7.4Hz, 1H), 6.89 (d, J=34.5Hz, 1H), 6.84 (d, J=8.3Hz, 1H). (Z)-2-Fluoro-3-(pyrimidin-4-yl)acrylic acid Step 1: Preparation of ethyl (Z)-2-fluoro-3-(pyrimidin-4-yl)acrylate

[0219] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (1.1g, 4.6mmol) is dissolved in THF (11mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 185mg, 4.6mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and pyrimidine-4-carboxaldehyde (250mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (20mL). The solution is diluted with water (20mL) and EtOAc (10mL). The layers are separated, and the aqueous phase is further extracted with EtOAc (2×5mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated. The crude residue is purified by column chromatography (0→15% acetone / hexane) to provide the desired product (40mg, 0.2mmol, 9% yield). LC / MS (ESI) m / z: for C9H 10 Calculated value of FN2O2 [M+H] + 197.1; measured value 197.0; 1H NMR (500MHz, CDCl3) δ9.27(d,J=1.3Hz,1H),8.82(d,J=5.4Hz,1H),7.79(dd,J=5.3 ,1.5Hz,1H),7.03(d,J=33.9Hz,1H),4.39(q,J=7.2Hz,2H),1.40(t,J=7.2Hz,3H). Step 2: Preparation of (Z)-2-fluoro-3-(pyrimidin-4-yl)acrylic acid

[0220] (Z)-2-Fluoro-3-(pyrimidin-4-yl)ethyl acrylate (20 mg, 0.1 mmol) was dissolved in MeOH (1 mL). The solution was cooled to 0 ° C and sodium hydroxide solution (1.0 M, 0.1 mL, 0.1 mmol) was added. The reaction mixture was stirred for 2 h. The solution was concentrated to remove methanol. The resulting aqueous solution was cooled to 0 ° C. HCl solution (1.0 M, 0.1 mL, 0.1 mmol) was added dropwise. The solution was frozen and directly lyophilized to provide the desired product, sodium chloride adduct (assuming quantitative yield). LC / MS (ESI) m / z: calculated for C7H6FN2O2 [M+H] + 169.0; measured value 169.0. 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 Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0221] 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 dropwise addition of (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester (1.2 g, 4.75 mmol) as a solution in DCM (10 mL). The reaction mixture was stirred for 30 min, warmed to room temperature, and concentrated. The crude residue was directly purified by column chromatography (0 → 50% EtOAc / hexane) to provide the desired product (2.2 g, 4.64 mmol, 97%). LC / MS (ESI) m / z: for C 21 H 18 Calculated value of Cl2FN6O2 [M+H]+ 475.1; measured value 474.8; 1 H NMR(500MHz, CDCl3)δ8.93(s,1H),7.40-7.33(m,5H),5.20(d,J=12.3Hz,1H),5.17(d,J=12.3Hz,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=17.0,5.0Hz,1H). Step 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

[0222] (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. LiHMDS solution (1.0 M in THF, 0.88 mL, 0.88 mmol) was added dropwise and the resulting mixture was stirred for 10 min. (S)-2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (350 mg, 0.74 mmol) was dissolved in THF (2 mL) and added dropwise to the solution. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was partially concentrated and then directly purified by column chromatography (50→100% EtOAc w 5% Et3N / hexanes) to afford the desired product (350 mg, 0.63 mmol, 85% yield) as a white foam. LC / MS (ESI) m / z: for C 27 H 30 Calculated value of ClFN7O3 [M+H] + 554.2; measured value 554.1; 1H NMR(500MHz, CDCl3)δ8.79(s,1H),7.41-7.33(m,5H),5.22-5.16(m,2H),4.66(br s,1H),4.55(dd,J=10.9,4.8Hz,1H),4.38(dd,J=10.8,6.1Hz,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=7.5Hz,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). Step 3: Preparation of benzyl (S)-4-(7-(8-chloronaphth-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0223] (S)-benzyl 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 [cataCXiumRTM A PalladacycleGen.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 at 100 ° C in a microwave for 2 h. The reaction mixture was directly concentrated and the crude residue was purified by column chromatography (0→100% EtOAc w / 5% Et3N / hexane) to provide the desired product (80 mg, 0.12 mmol, 61% yield). LC / MS (ESI) m / z: for C 37 H 36 Calculated value of ClFN7O3 [M+H] + 680.3; measured value 680.4. 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

[0224] (S)-benzyl 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 (balloon) was bubbled through the reaction mixture for 5 min and the reaction mixture was kept under a hydrogen atmosphere. After 30 min, the reaction mixture was passed through celite. The crude residue containing an unquantified 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 additional purification. LC / MS (ESI) m / z: for C 28 H 31 Calcd. value of ClFN7O [M+H] + 546.2; measured value 546.1. (S)-7-(8-Chloronaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine Step 1: Preparation of tert-butyl 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0225] 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1g, 4.0mmol) was suspended in DCM (20mL) and the solution was cooled to -40 °C. DIPEA (1.0mL, 5.9mmol) was added, followed by tert-butyl piperazine-1-carboxylate (0.74g, 4.0mmol) as a solution in DCM (5mL). After 30min, the reaction mixture was warmed to room temperature and partially concentrated. The crude residue was purified by column chromatography (0 → 50% EtOAc / hexane) to provide the desired product (1.4g, 3.6mmol, 90% yield) as an off-white solid. LC / MS (ESI) m / z: for C 16 H 19 Calculated value of Cl2FN5O2 [M+H] + 402.1; measured value 401.9; 1 H NMR (500MHz, CDCl3) δ8.87 (s, 1H), 4.09-4.02 (m, 4H), 3.72-3.64 (m, 4H), 1.50 (s, 9H). Step 2: Preparation of (S)-tert-butyl 4-(7-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0226] (S)-(1-methylpyrrolidin-2-yl)methanol (0.6g, 5.2mmol) is dissolved in THF (17.4mL), and the solution is cooled to 0 DEG C.LiHMDS solution (1.0M in THF, 5.2mL, 5.2mmol) is added dropwise, and the resulting mixture is stirred for 10min.4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (1.4g, 3.5mmol) is suspended in THF (10mL) and added dropwise to the solution.The reaction mixture is allowed to warm to room temperature and stirred for 16h.The reaction mixture is partially concentrated, and the crude residue is passed through column chromatography (50→100% with 5% EtN EtOAc / hexane) purified to provide the desired product (1.5g, 3.1mmol, 90% yield). LC / MS (ESI) m / z: for C 22 H 31 Calculated value of ClFN6O3 [M+H] + 481.2; measured value 481.1; 1H NMR(500MHz, CDCl3)δ8.75(s,1H),4.53(dd,J=10.7,4.6Hz,1H),4.34(dd,J=10.7,6.7Hz,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=9.5,6.9Hz,1H),2.09-2.00(m,1H),1.89-1.73(m,3H),1.49(s,9H). Step 3: Preparation of (S)-tert-butyl 4-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0227] (S)-tert-Butyl 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 [cataCXiumRTM 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 performed 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 at 100 ° C in a microwave for 2 h. The reaction mixture was directly concentrated and the crude residue was purified by column chromatography (0→100% EtOAc w / 5% Et3N / hexane) to provide the desired product (84 mg, 0.14 mmol, 45% yield). LC / MS (ESI) m / z: for C 32 H 37 Calculated value of ClFN6O3 [M+H] + 607.3; measured value 607.2. Step 4: Preparation of (S)-7-(8-chloronaphth-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine

[0228] (S)-tert-Butyl 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 directly concentrated and the crude residue was used directly in the next step without additional purification. LC / MS (ESI) m / z: for C 27 H 29 Calcd. value of ClFN6O [M+H] + 507.2, measured value 507.1. 2-((S)-4-(8-fluoro-7-(2-fluoro-5-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methylpiperazin-2-yl)acetonitrile Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-7-(2-fluoro-5-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0229] (S)-4-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester (32 mg, 0.058 mmol) and methanesulfonato-(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct [cataCXiumRTM APalladacycle Gen.3] (4.2 mg, 5.8 μmol) are combined in a microwave vial as solids. The vial is sealed. The atmosphere is evacuated and replaced with nitrogen. This process is carried out three times. Degassed dioxane (0.9 mL) and potassium phosphate solution (2.0 M in water, 0.1 mL, 0.17 mmol) are added, and the reaction mixture is heated in a microwave at 100 ° C for 4 h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (80→100% EtOAc / hexanes with 5% Et3N→20% MeOH / EtOAc with 5% Et3N) to afford the desired product (30 mg, 0.048 mmol, 82% yield). LC / MS (ESI) m / z: for C 33 H34 Calculated value of F2N7O4 [M+H] + 630.3; measured value 630.2; 1 H NMR(500MHz,CDCL3)δ8.93(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). Step 2: Preparation of 2-((S)-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

[0230] (S)-benzyl 2-(cyanomethyl)-4-(8-fluoro-7-(2-fluoro-5-hydroxyphenyl)-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 was bubbled through the solution for 5 min and the reaction mixture was then kept under a hydrogen (balloon) atmosphere. After 30 min, the reaction mixture was passed through celite. Filtration on a pad of 4% HCl and direct concentration afforded the desired product (assuming quantitative yield). LC / MS (ESI) m / z: for C 25 H 28 Calculated for F2N7O2 [M+H] + 496.2; measured value 496.3. 2-((S)-4-(7-(8-ethylnaphth-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0231] (S)-benzyl 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 [ A Palladacycle Gen.3] (4.2 mg, 5.8 μmol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The 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 directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (35 mg, 0.04 mmol, 73% yield). LC / MS (ESI) m / z: for C 48 H 56 Calculated value of FN7O3Si [M+H] + 826.4; measured value 826.4; 1H NMR (500MHz, CDCl3) δ9.13-9.02(m,1H),7.99-7.90(m,2H),7.82(d,J=6.7Hz,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=7.7Hz,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). Step 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

[0232] (S)-benzyl 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 min. The solution was directly concentrated and the crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 39 H 37 Calculated value of FN7O3 [M+H] + 670.3; measured value 670.5. Step 3: Preparation of 2-((S)-4-(7-(8-ethylnaphth-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0233] (S)-benzyl 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 (assumed 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 was bubbled through the solution for 5 min and then the reaction mixture was kept under a hydrogen (balloon) atmosphere for 1.5 h. The reaction mixture was passed through celite. The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 31 H 35 Calculated value of FN7O [M+H] + 540.3; measured value 540.4. 2-((S)-4-(7-(8-ethylnaphth-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile 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

[0234] (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 [ A Palladacycle Gen.3] (11 mg, 15 μmol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out 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 a microwave at 100 ° C for 4 h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (100 mg, 0.13 mmol, 91% yield). LC / MS (ESI) m / z: for C 43 H 58 Calculated value of FN6O3Si [M+H] + 753.4; measured value 753.4. 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

[0235] (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 min. The solution was directly concentrated and the crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 34 H 38 Calculated value of FN6O3 [M+H] + 597.3; measured value 597.4. 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

[0236] (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 h. The reaction mixture was quenched with NaOH solution (1.0 M, 170 μL, 0.17 mmol) and the solution was concentrated. The material was used directly in the next step without additional purification. LC / MS (ESI) m / z: for C 29 H 30 Calculated value of FN6O [M+H] + 497.2; measured value 497.3. (Z)-2-Fluoro-3-(6-methylpyrazin-2-yl)acrylic acid Step 1: Preparation of (E)-ethyl 2-fluoro-3-(6-methylpyrazin-2-yl)acrylate

[0237] 2-(diethoxyphosphoryl)-2-fluoroacetic acid ethyl ester (250mg, 1.0mmol) is dissolved in THF (5mL). The solution is cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 41mg, 1.0mmol) is added portionwise as a solid. The reaction mixture is stirred for 10min and 6-methylpyrazine-2-carboxaldehyde (125mg, 1.0mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 1h. The mixture is quenched by adding saturated aqueous ammonium chloride solution (5mL). The solution is diluted with water (5mL) and EtOAc (10mL). Each layer is separated, and the aqueous phase is further extracted with EtOAc (2×5mL). The combined organic layer is dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (0→100% EtOAc / hexanes) to afford the desired product (>15:1 E / Z, as judged by 1H NMR, 120 mg, 0.56 mmol, 55% yield). LC / MS (ESI) m / z: for C 10 H 12 Calculated value of FN2O2 [M+H] + 211.1; measured value 210.9; 1H NMR (500MHz, CDCl3) δ8.56 (s, 1H), 8.36 (s, 1H), 6.81 (d, J = 19.1Hz, 1H), 4.26 (q, J = 7.2Hz, 2H), 2.55 (s, 3H), 1.24 (t, J = 7.1Hz, 3H). Step 2: Preparation of ethyl (Z)-2-fluoro-3-(6-methylpyrazin-2-yl)acrylate

[0238] (E) -2-fluoro-3- (6-methylpyrazine-2-yl) ethyl 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 provide the desired product (73 mg, 0.35 mmol, 62% yield). LC / MS (ESI) m / z: for C 10 H 12 Calculated value of FN2O2 [M+H] + 211.1; measured value 210.9; 1 H NMR (500MHz, CDCl3) δ8.92 (s, 1H), 8.39 (s, 1H), 7.07 (d, J = 35.6Hz, 1H), 4.37 (q, J = 7.2Hz, 2H), 2.58 (s, 3H), 1.38 (t, J = 7.2Hz, 3H). Step 3: Preparation of (Z)-2-fluoro-3-(6-methylpyrazin-2-yl)acrylic acid

[0239] (Z) -2- fluoro -3- (6- methylpyrazine -2- bases) ethyl 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 vacuum to provide the desired product (34 mg, 0.19 mmol, 54% yield). LC / MS (ESI) m / z: calculated for C8H8FN2O2 [M + H] + 183.0; measured value 182.8; 1 H NMR (500MHz, DMSO-d6) δ8.79 (s, 1H), 8.52 (s, 1H), 6.98 (d, J = 35.0Hz, 1H), 2.52 (s, 3H). 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol Step 1: Preparation of 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

[0240] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizine-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 LiHMDS solution (1.0 M in THF, 22 mL, 22 mmol) was added dropwise. Once all the solids had gone into solution (5 min), 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 allowed to warm to room temperature and stirred for 16 h. The reaction mixture was partially concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (3.0 g, 5.7 mmol, 66% yield) as a white foam. LC / MS (ESI) m / z: for C 24 H 32 Calculated value of ClF2N6O3 [M+H] + 525.2; measured value 525.5; 1 H NMR (500MHz, CDCl3) δ8.74(s,1H),0.00(d,J=54.0Hz,1H),4.26(d,J=10.5Hz,1H),4.18(d,J=10.5Hz,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=14.7,4.1Hz,1H),1.99-1.80(m,4H),1.49(s,9H). 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0241]

[0266] 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 (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 bottle was sealed. The atmosphere was evacuated and replaced with nitrogen; This process was carried out 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 in a microwave at 100 ° C for 1.5 h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (450 mg, 0.51 mmol, 90% yield). LC / MS (ESI) m / z: for C 47 H 62 Calculated value of F3N6O5Si [M+H] + 875.4; measured value 875.8. 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0242] tert-Butyl 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-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. TBAF solution (1.0 M in THF, 0.7 mL, 0.7 mmol) was added dropwise and the reaction mixture was stirred for 5 min. The reaction mixture was directly concentrated and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to provide the desired product (assuming quantitative yield). LC / MS (ESI) m / z: for C 38 H 41 Calculated value of F3N6O5 [M+H] + 719.3; measured value 719.6. Step 4: Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0243] Tert-butyl 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)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 allowed to warm 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 directly lyophilized to afford the desired product as well as sodium chloride. The material was of sufficient purity to be used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 31 H 30 Calculated value of F3N6O2 [M+H] + 575.2; measured value 575.4. 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine Step 1: Preparation of tert-butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0244] 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 [ A Palladacycle Gen.3] (3.1 mg, 4.3 μmol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out three times. Degassed dioxane (900 μL) and potassium phosphate solution (2.0M 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 directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (57 mg, 0.072 mmol, 83% yield). LC / MS (ESI) m / z: for C 45 H 59 Calculated value of F2N6O3Si [M+H] + 797.4; measured value 797.6; 1H NMR(500MHz, CDCl3)δ9.05(s,1H),7.96(dd,J=7.7,1.5Hz,1H),7.92(d,J=7.9Hz,1H),7.81(d,J=6.9Hz,1H),7 .60-7.52(m,2H),7.46(t,J=7.7Hz,1H),5.27(d,J=55.2Hz,1H),4.33-4.22(m,1H),4.20-4.10(m,1H),3.92(br d,J=3.6Hz,4H),3.76-3.58(m,4H),3.28-3.14(m,2H),2.97(td,J=9.1,5.5Hz,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=10.2,7.5Hz,18H),0.61-0.49(m,3H). Step 2: Preparation of tert-butyl 4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0245] tert-Butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-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 min, the reaction mixture was concentrated and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (42 mg, 0.066 mmol, 95% yield). LC / MS (ESI) m / z: for C 36 H 39 Calculated value of F2N6O3 [M+H] + 641.3; measured value 641.3. Step 3: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine

[0246] Tert-butyl 4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-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. After 2 h, 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 from toluene and used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 31 H 31 Calculated for F2N6O [M+H] + 541.2; measured value 541.3. 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine Step 1: Preparation of tert-butyl 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)piperazine-1-carboxylate

[0247] 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 (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 [ A Palladacycle Gen.3] (6.9 mg, 9.5 μmol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out 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 a microwave at 100 ° C for 1.5 h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (9 mg, 0.014 mmol, 15% yield). LC / MS (ESI) m / z: for C 32 H 39 Calculated value of F2N8O3 [M+H] + 621.3; measured value 621.3. Step 2: Preparation of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine

[0248] Tert-butyl 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)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 additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 27 H 31 Calculated for F2N8O [M+H] + 521.3; measured value 521.2. 7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine Step 1: Preparation of tert-butyl 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0249] 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 (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 [ A Palladacycle Gen.3] (15.8 mg, 22 μmol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The 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 directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (43 mg, 0.053 mmol, 24% yield). LC / MS (ESI) m / z: for C 45 H 58 Calculated value of F3N6O3Si [M+H] + 815.4; measured value 815.9. Step 2: Preparation of tert-butyl 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)piperazine-1-carboxylate

[0250] tert-Butyl 4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-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 min, the reaction mixture was concentrated and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (26 mg, 0.039 mmol, 82% yield). LC / MS (ESI) m / z: for C 36 H 38 Calculated value of F3N6O3 [M+H] + 659.3; measured value 659.8. Step 3: Preparation of 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine

[0251] Tert-butyl 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)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 h, 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 additional purification. LC / MS (ESI) m / z: for C 31 H 30 Calculated for F3N6O [M+H] + 559.2; measured value 559.4. 2-((S)-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy 2-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Step 1: Preparation of (S)-benzyl 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

[0252] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizine-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. Once all the solids had entered the solution (5 min), (S)-2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (1.5 g, 3.2 mmol) was added as a solution in THF (10 mL). The reaction mixture was allowed to warm to room temperature and then slowly warmed to 35 ° C. for 4 h. The reaction mixture was partially concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (1.6 g, 2.6 mmol, 83% yield) as a white foam. LC / MS (ESI) m / z: for C 29 H 31 Calculated value of ClF2N7O3 [M+H] + 598.2; measured value 598.2; 1 H NMR (500MHz, CDCl3) δ8.78 (s, 1H), 7.37 (d, J = 1.4Hz, 5H), 5.26 (d, J = 55.8Hz, 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),3.0 1-2.93(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). Step 2: Preparation of benzyl (S)-2-(cyanomethyl)-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)piperazine-1-carboxylate

[0253] (S)-benzyl 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), 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 [ A Palladacycle Gen.3] (3.0 mg, 4 μmol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The 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 directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (58 mg, 0.08 mmol, 98% yield). LC / MS (ESI) m / z: for C 36 H 34 Calculated value of F5N7O3 [M+H] + 708.3; measured value 708.3; 1H NMR (500MHz, CDCl3) δ9.03 (s, 1H), 7.83 (d, J = 7.6Hz, 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=53.9Hz,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=10.4Hz,1H),4.21(d,J=10.4Hz,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). Step 3: Preparation of 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)piperazin-2-yl)acetonitrile

[0254] (S)-benzyl 2-(cyanomethyl)-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)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 was bubbled through the solution for 5 min and then the reaction mixture was kept under a hydrogen (balloon) atmosphere for 1.5 h. The reaction mixture was passed through celite The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 28 H 29 Calculated for F5N7O [M+H] + 574.3; measured value 574.2. 2-((S)-4-(7-(Benzo[b]thiophen-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine -7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Step 1: Preparation of (S)-benzyl 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)-2-(cyanomethyl)piperazine-1-carboxylate

[0255] (S)-benzyl 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 [ A Palladacycle Gen.3] (3.0 mg, 4 μmol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The 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 directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (57 mg, 0.08 mmol, 98% yield). LC / MS (ESI) m / z: for C 37 H 36 Calcd. for F2N7O3S [M+H] + 696.2; measured value 696.2; 1H NMR(500MHz, CDCl3)δ9.13(s,1H),8.48(d,J=7.6Hz,1H),8.12(d,J=1.3Hz,1H),7.95-7.92(m, 1H),7.47-7.35(m,7H),5.28(d,J=53.6Hz,1H),5.22-5.19(m,2H),4.74-4.67(m,1H),4.49(br d,J=12.6Hz,1H),4.40-4.39(m,1H),4.39(br d,J=11.9Hz,1H),4.32(d,J=10.4Hz,1H),4.27-4.18(m,1H),4.23(d,J=10.4Hz,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=16.7,5.6Hz,1H),2.29-2.11(m,2H),2.01-1.83(m,3H). Step 2: Preparation of 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)piperazin-2-yl)acetonitrile

[0256] (S)-benzyl 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)-2-(cyanomethyl)piperazine-1-carboxylate (57 mg, 0.082 mmol) was dissolved in MeOH (0.8 mL) and palladium on carbon (10 wt.%, 17 mg, 0.016 mmol) was added. Hydrogen was bubbled through the solution for 5 min and then the reaction mixture was kept under a hydrogen (balloon) atmosphere for 1.5 h. The reaction mixture was passed through celite The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 29 H 30 Calculated value of F2N7OS [M+H] + 562.2; measured value 562.3. 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 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

[0257] (S)-benzyl 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, [ A Palladacycle Gen.3] (3.4 mg, 5 μ mol) was merged into a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out three times. Degassed dioxane (0.9 mL) and potassium phosphate solution (2.0 M in water, 140 μ L, 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 directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (61 mg, 0.09 mmol, 98% yield). LC / MS (ESI) m / z: for C 37 H 36 Calculated for F2N7O3 [M+H] + 664.3; measured value 664.5; 1H NMR(500MHz, CDCl3)δ9.19(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=66.2Hz,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),3.7 4-3.50(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). 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

[0258] (S)-benzyl 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 was bubbled through the solution for 5 min and then the reaction mixture was kept under a hydrogen (balloon) atmosphere for 1.5 h. The reaction mixture was passed through celite. The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 29 H 30 Calculated for F2N7O [M+H] + 530.2; measured value 530.2. 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine Step 1: Preparation of tert-butyl 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)piperazine-1-carboxylate

[0259] 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 (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 [ A Palladacycle Gen.3] (10.4 mg, 14 μmol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out three 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 a microwave at 100 ° C for 1.5 h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (29 mg, 0.05 mmol, 33% yield). LC / MS (ESI) m / z: for C 32 H 39 Calculated value of F2N8O3 [M+H] + 621.3; measured value 621.4; 1 H NMR (500MHz, CDCl3) δ9.10(s,1H),8.07(s,1H),7.85(dd,J=8.0,1.0Hz,1H),7.47(d,J=7.0Hz,1H),7.25(d,J=1.2Hz,1H),5.43(d,J=51.9Hz,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). Step 2: Preparation of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(1-methyl-1H-indazol-7-yl)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine

[0260] Tert-butyl 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)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 h, the solution was concentrated and the crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 27 H 31 Calculated for F2N8O [M+H] + 521.3; measured value 521.3. 2-((S)-4-(7-(2,5-difluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Step 1: (S)-benzyl 2-(cyanomethyl)-4-(7-(2,5-difluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0261] (S)-benzyl 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), (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 [ A Palladacycle Gen.3] (2.4 mg, 3 μ mol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out three times. Degassed dioxane (0.7 mL) and potassium phosphate solution (2.0 M in water, 100 μ L, 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 directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (41 mg, 0.061 mmol, 91% yield). LC / MS (ESI) m / z: for C 35 H 34 Calculated value of F4N7O3 [M+H] + 676.3; measured value 676.5; 1 H NMR (500MHz, CDCl3) δ9.06 (s, 1H), 7.38 (s, 6H), 7.20-7.13 (m, 2H), 5.27 (d, J = 53.8Hz, 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=10.5Hz,1H),4.22(d,J=10.5Hz,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 =9.2,5.8Hz,1H),2.93-2.77(m,1H),2.71(dd,J=16.7,5.2Hz,1H),2.27-2.08(m,3H),2.00-1.82(m,3H). Step 2: Preparation of 2-((S)-4-(7-(2,5-difluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0262] (S)-benzyl 2-(cyanomethyl)-4-(7-(2,5-difluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 was bubbled through the solution for 5 min and then the reaction mixture was kept under a hydrogen (balloon) atmosphere for 1.5 h. The reaction mixture was passed through celite The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 27 H 28 Calculated for F4N7O [M+H] + 542.2; measured value 542.3. 2-((S)-4-(7-(2-(difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine -7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Step 1: Preparation of benzyl (S)-2-(cyanomethyl)-4-(7-(2-(difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0263] (S)-benzyl 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), (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 [ A Palladacycle Gen.3] (2.4 mg, 3 μ mol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out three times. Degassed dioxane (0.7 mL) and potassium phosphate solution (2.0 M in water, 100 μ L, 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 directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (45 mg, 0.064 mmol, 95% yield). LC / MS (ESI) m / z: for C 36 H 35 Calculated value of F5N7O3 [M+H] + 708.3; measured value 708.6; 1 H NMR(500MHz, CDCl3)δ9.05(s,1H),7.84(dd,J=8.5,5.3Hz,1H),7.41-7.36(m,5H),7.33-7.27(m,2H),6.95(t,J=55.3H z,1H),5.27(d,J=54.6Hz,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=1 0.5Hz,1H),4.22(d,J=10.5Hz,1H),4.23-4.15(m,1H),3.98-3.85(m,1H),3.71(td,J=11.6,3.9Hz,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). Step 2: Preparation of 2-((S)-4-(7-(2-(difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0264] (S)-benzyl 2-(cyanomethyl)-4-(7-(2-(difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 was bubbled through the solution for 5 min and then the reaction mixture was kept under a hydrogen (balloon) atmosphere for 1.5 h. The reaction mixture was passed through celite The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 28 H 29 Calculated for F5N7O [M+H] + 574.2; measured value 574.3. 2-((S)-4-(8-fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine -7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Step 1: Preparation of (S)-benzyl 2-(cyanomethyl)-4-(8-fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0265] (S)-benzyl 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-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 [ A Palladacycle Gen.3] (2.4 mg, 3 μ mol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out three times. Degassed dioxane (0.7 mL) and potassium phosphate solution (2.0 M in water, 100 μ L, 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 directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (45 mg, 0.062 mmol, 93% yield). LC / MS (ESI) m / z: for C 36 H 34 Calculated value of F6N7O3 [M+H] + 726.3; measured value 726.6; 1 H NMR (600MHz, CDCl3) δ9.02 (s, 1H), 7.83 (dd, J = 8.8, 5.2Hz, 1H), 7.44-7.33 (m, 5H), 7.32-7.27 (m, 1 H),7.20(dd,J=8.5,2.4Hz,1H),5.27(d,J=54.3Hz,1H),5.21(s,2H),4.76-4.64(m,1H),4.53-4.34 (m,2H),4.30(d,J=10.4Hz,1H),4.21(d,J=10.4Hz,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=16.7,5.3Hz,1H),2.29-2.08(m,3H),1.97-1.83(m,3H). Step 2: Preparation of 2-((S)-4-(8-fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0266] (S)-benzyl 2-(cyanomethyl)-4-(8-fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 on carbon (10 wt.%, 12 mg, 0.011 mmol) was added. Hydrogen was bubbled through the solution for 5 min and then the reaction mixture was kept under a hydrogen (balloon) atmosphere for 1.5 h. The reaction mixture was passed through celite The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 28 H 28 Calculated for F6N7O [M+H] + 592.2; measured value 592.3. 2-((S)-4-(8-fluoro-7-(5-chloro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine -7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile Step 1: Preparation of (S)-benzyl 2-(cyanomethyl)-4-(8-fluoro-7-(5-chloro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0267] (S)-benzyl 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 [ A Palladacycle Gen.3] (2.4 mg, 3 μ mol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out three times. Degassed dioxane (0.7 mL) and potassium phosphate solution (2.0 M in water, 100 μ L, 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 directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (24 mg, 0.03 mmol, 48% yield). LC / MS (ESI) m / z: for C 36 H 34 Calculated value of ClF5N7O3 [M+H] + 742.2; measured value 742.1; 1 H NMR(600MHz, CDCl3)δ9.02(s,1H),7.76(d,J=8.5Hz,1H),7.58(d,J=8.4Hz,1H),7.49-7.47(m,1H),7 .42-7.34(m,5H),5.27(d,J=54.0Hz,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). Step 2: Preparation of 2-((S)-4-(8-fluoro-7-(5-chloro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0268] (S)-benzyl 2-(cyanomethyl)-4-(8-fluoro-7-(5-chloro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 was bubbled through the solution for 5 min and then the reaction mixture was kept under a hydrogen (balloon) atmosphere for 1.5 h. The reaction mixture was passed through celite The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 28 H 28 Calcd. value of ClF5N7O [M+H] + 608.2; measured value 608.1. 8-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile Step 1: Preparation of tert-butyl 4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0269] 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 (50 mg, 0.095 mmol), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthocarbonitrile (35 mg, 0.125 mmol) and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct [ A pAlladacycle Gen.3] (6.9 mg, 9.5 μmol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out 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 directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (14 mg, 0.022 mmol, 23% yield). LC / MS (ESI) m / z: for C 35 H 38 Calculated for F2N7O3 [M+H] + 642.3; measured value 642.2. Step 2: Preparation of 8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthocarbonitrile

[0270] Tert-butyl 4-(7-(8-cyanonaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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. After 2 h, the solution was concentrated and the crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 30 H 30 Calculated for F2N7O [M+H] + 542.2; measured value 542.5. 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 Step 1: Preparation of (S)-benzyl 2-(cyanomethyl)-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)piperazine-1-carboxylate

[0271] (S)-benzyl 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 [ A Palladacycle Gen.3] (9.1mg, 13μmol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out three times. Degassed dioxane (1.3mL) and potassium phosphate solution (2.0M in water, 250μL, 0.20mmol) were added, and the reaction mixture was heated in a microwave at 100°C for 1.5h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (20→100% with 5% Et3N EtOAc / hexane) to provide the desired product (59mg, 0.085mmol, 68% yield). LC / MS (ESI) m / z: for C 37 H 38 Calculated for F2N9O3 [M+H] + 694.3; measured value 649.6. 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

[0272] (S)-benzyl 2-(cyanomethyl)-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)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 was bubbled through the solution for 5 min and then the reaction mixture was kept under a hydrogen (balloon) atmosphere for 1.5 h. The reaction mixture was passed through celite The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 29 H 32 Calculated for F2N9O [M+H] + 560.3; measured value 560.6. 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 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

[0273] By ((4aS, 7aR) -1- methyloctahydro -4aH- cyclopenta [b] pyridin-4a-yl) methanol (according to the procedure described in WO 2022 / 192794, 126 mg, 0.75 mmol) dissolved in THF (2.5 mL), and the solution was cooled to 0 ° C. LiHMDS solution (1.0 M in THF, 720 μL, 0.721 mmol) was added dropwise, and the reaction mixture was stirred for 10 min. 4- (2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin-4-yl) piperazine -1- carboxylic acid tert-butyl ester (200 mg, 0.5 mmol) was added as a solid. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was partially concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (240 mg, 0.45 mmol, 91% yield). LC / MS (ESI) m / z: for C26 H 37 Calculated value of ClFN6O3 [M+H] + 535.3; measured value 535.6; 1 H NMR (500MHz, CDCl3) δ8.74(s,1H),4.48(d,J=10.7Hz,1H),4.28(d,J=10.6Hz,1H),3.98-3.90(m,4H),3.69-3.63(m,4H),2 .71(t,J=6.2Hz,1H),2.58(ddd,J=11.2,7.2,4.2Hz,1H),2.32-2.29(m,1H),2.27(s,3H),1.89-1.60(m,10H),1.50(s,9H). 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

[0274] 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 [ A Pd G3] (16 mg, 0.022 mmol) was combined in a microwave vial as a solid. 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, 670 μL, 1.3 mmol) were added, and the reaction mixture was heated in a microwave at 100 ° C for 1.5 h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (20 → 100% EtOAc / hexane with 5% Et3N) to provide the desired product (assuming quantitative yield). LC / MS (ESI) m / z: for C 49 H 67 Calculated value of F2N6O5Si [M+H]+ 885.5; measured value 885.9; 1 H NMR (500MHz, CDCl3) δ9.04(d,J=1.0Hz,1H),7.78(dd,J=9.1,5.6Hz,1H),7.51(d,J=2.6Hz,1H),7.33(d,J=2.5Hz,1H),7.29(t ,J=8.8Hz,1H),5.31(d,J=7.0Hz,1H),5.28(d,J=7.0Hz,1H),4.50(d,J=10.6Hz,1H),4.43(d,J=10.8Hz,1H),4.31(d,J=10.8Hz ,1H),4.23(d,J=10.6Hz,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=5.5Hz,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). 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

[0275] 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. TBAF solution (1.0 M in THF, 0.6 mL, 0.6 mmol) was added dropwise, and the reaction mixture was stirred for 5 min. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (250 mg, 0.34 mmol, 84% yield over two steps). LC / MS (ESI) m / z: for C 40 H 47Calculated value of F2N6O5 [M+H] + 729.4; measured value 729.7; 1 H NMR (600MHz, CDCl3) δ8.99(s,1H),7.83(dd,J=9.1,5.6Hz,1H),7.54(d,J=2.5Hz,1H),7.37(t,J=2.2Hz,1H),7.29(t,J=8.7Hz,1H), 5.32(d,J=6.9Hz,1H),5.30(d,J=6.9Hz,1H),4.49(dd,J=10.7,6.7Hz,1H),4.30(dd,J=10.7,2.5Hz,1H),4.01-3.96(m,4H),3.70(br d,J=4.5Hz,4H),3.52(s,3H),2.81(d,J=6.5Hz,1H),2.70(t,J=6.0Hz,1H),2.31-2.28(m,1H),2.27(s,3H),1.90-1.64(m,11H),1.51(s,9H). Step 4: Preparation of 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)naphthol

[0276] 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 allowed to warm to room temperature. After 2 h, 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 directly lyophilized to provide the desired product as well as sodium chloride. The material was of sufficient purity to be used in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 33 H 35 Calculated value of F2N6O2 [M+H] + 585.3; measured value 585.5. 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)ethyl Step 1: Preparation of (S)-benzyl 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0277] (S)-benzyl 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), 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 a microwave at 100 ° C for 16 h. The reaction mixture was passed through celite The crude residue was purified by column chromatography (20→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (15.8 mg, 0.022 mmol, 26% yield). LC / MS (ESI) m / z: for C 37 H 38 Calculated value of F3N8O4 [M+H] + 715.3; measured value 715.2. 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

[0278] (S)-benzyl 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-pyrrolizin-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 was bubbled through the solution for 5 min and then the reaction mixture was kept under a hydrogen (balloon) atmosphere for 1.5 h. The reaction mixture was passed through celite The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 29 H 32 Calculated value of F3N8O2 [M+H] + 581.3; measured value 581.5. 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidine Step 1: Preparation of tert-butyl (S)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

[0279] 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 added dropwise, followed by dropwise addition of (S)-3-methylpiperazine-1-tert-butyl carboxylate (2.0 g, 9.9 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The solution was concentrated, and the crude residue was purified by column chromatography (0 → 60% EtOAc / hexane) to provide the desired product (3.7 g, 8.8 mmol, 89% yield). LC / MS (ESI) m / z: for C 17 H 21 Calculated value of Cl2FN5O2 [M+H] + 416.1; measured value 416.0; 1H NMR(500MHz, CDCl3)δ8.85(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=6.8Hz,3H),1.52(s,9H). Step 2: Preparation of (S)-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)-3-methylpiperazine-1-carboxylate

[0280] ((2R, 7aS) -2-fluorotetrahydro -1H- pyrrolizine -7a (5H) -yl) methanol (1.61 g, 10.1 mmol) was dissolved in THF (45 mL) and the solution was cooled to 0 ° C. LiHMDS solution (1.0 M in THF, 10.6 mL, 10.6 mmol) was added dropwise and the resulting mixture was stirred for 10 min. (S) -4- (2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin-4-yl) -3-methylpiperazine -1- carboxylic acid tert-butyl ester (3.7 g, 8.8 mmol) was added dropwise as a solution in THF (50 mL). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The solution was partially concentrated, and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (4.55 g, 8.4 mmol, 96% yield) as a yellow foam. LC / MS (ESI) m / z: for C 25 H 34 Calculated value of ClF2N6O3 [M+H] + 539.2; measured value 539.5; 1 H NMR (600MHz, CDCl3) δ8.70 (s, 1H), 0.00 (d, J = 52.7Hz, 1H), 4.78 (br s, 1H), 4.33 (br d,J=13.1Hz,1H),4.25(d,J=10.4Hz,1H),4.15(d,J=10.4Hz,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=6.7Hz,3H).

[0281] Step 3: Preparation of (S)-tert-butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. Tert-butyl pizo[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 performed 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 at 100° C. in a microwave for 1.5 h. The reaction mixture was directly concentrated and the crude residue was purified by column chromatography (20→100% EtOAc / hexanes with 5% Et3N) to provide the desired product (66 mg, 0.081 mmol, 97% yield). LC / MS (ESI) m / z: for C 46 H 61 Calculated value of F2N6O3Si [M+H] + 811.4; measured value 811.4; 1 H NMR (600MHz, CDCl3) δ9.07-8.96(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),5.05-4.6 7(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). Step 4: Preparation of (S)-tert-butyl 4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

[0282] (S)-tert-Butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (66 mg, 0.081 mmol) was dissolved in THF (800 μL), and the solution was cooled to 0° C. TBAF solution (1.0 M in THF, 120 μL, 0.12 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 min, the reaction mixture was concentrated and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (53 mg, 0.08 mmol, 99% yield). LC / MS (ESI) m / z: for C 37 H 41 Calculated value of F2N6O3 [M+H] + 655.3; measured value 655.4; 1 H NMR (600MHz, CDCl3) δ9.01-8.93(m,1H),8.01-7.93(m,2H),7.77-7.73(m,1H),7.6 3-7.55(m,2H),7.49-7.43(m,1H),5.28(d,J=53.6Hz,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). Step 5: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidine

[0283] (S)-tert-Butyl 4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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 h, 1-methylimidazole (100 μL) was added and the reaction mixture was concentrated. The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 32 H 33 Calculated for F2N6O [M+H] + 555.3; measured value 555.2. 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 Step 1: Preparation of (S)-tert-butyl 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

[0284] (S)-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)-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 were added. Gen.3] (6.8 mg, 9.3 μmol) was combined in a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out 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 a microwave at 100 ° C for 1.5 h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product (160 mg, 0.18 mmol, 97% yield). LCMS (ESI) m / z: for C 48 H 64 Calculated value of F3N6O5Si [M+H] + 889.5; measured value 889.5. Step 2: Preparation of (S)-tert-butyl 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

[0285] (S)-tert-Butyl 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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. TBAF solution (1.0 M in THF, 180 μL, 0.18 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 min, the reaction mixture was concentrated and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (128 mg, 0.175 mmol, 97% yield). LCMS (ESI) m / z: for C 39 H 44 Calculated value of F3N6O5 [M+H] + 733.3; measured value 733.3; 1 H NMR (500MHz, CDCl3) δ8.99-8.91(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=6.8Hz,1H),5.29(d,J=6.8Hz,1H),5.28(d,J=54.6Hz,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). Step 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

[0286] (S)-tert-Butyl 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 additional purification (assuming quantitative yield). LCMS (ESI) m / z: for C 32 H 32 Calculated value of F3N6O2 [M+H] + 589.2; measured value 589.2. 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 Step 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0287] 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 (20 mg, 0.038 mmol), (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)boronic acid (19 mg, 0.057 mmol) [commercial] and [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II) methanesulfonate [BrettPhos Pd G3] (3.5mg, 0.0038mmol) was merged into a microwave vial as a solid. The vial was sealed. The atmosphere was evacuated and replaced with nitrogen. The process was carried out three times. Degassed dioxane (400 μL) and potassium phosphate solution (2.0M in water, 60 μL, 0.11mmol) were added, and the reaction mixture was heated in a microwave at 100 ° C for 1.5h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (20→100% with 5% Et3N EtOAc / hexane) to provide the desired product (16mg, 0.020mmol, 54% yield). LCMS (ESI) m / z: for C 36 H 43 Calcd. for F4N8O5S [M+H] + 775.3; measured value 775.3; 1 H NMR (600MHz, CDCl3) δ9.08 (s, 1H), 8.17 (br s, 1H), 6.95 (t, J = 9.4Hz, 1H), 5.27 (d, J = 54.3Hz, 1H), 4.29 (br d,J=10.5Hz,1H),4.19(d,J=10.4Hz,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). Step 2: Preparation of tert-butyl (5,7-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate

[0288] tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 additional purification (assuming quantitative yield). LCMS (ESI) m / z: for C 31 H 35 Calcd. for F4N8O3S [M+H] + 675.2; measured value 675.2. 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate

[0289] Tert-butyl (5,7-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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). 1-Methylimidazole (9 μL, 0.19 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (36 mg, 0.127 mmol). The reaction mixture was stirred for 5 min and concentrated. The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LCMS (ESI) m / z: for C 37 H 37 Calculated for F5N9O4S2 [M+H] + 830.2; measured value 830.3. 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 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0290] 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 (30 mg, 0.057 mmol), (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (27 mg, 0.086 mmol) [commercial], and [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II) methanesulfonate [BrettPhos Pd G3] (5.2 mg, 0.0057 mmol) were combined as solids in a microwave vial. To the 4-nitro-2-oxo-1-yl pyridine-2-yl pyridine-3 ... 36 H 44 Calculated for F3N8O5S [M+H] + 757.3; measured value 757.6; 1H NMR (600MHz, CDCl3) δ9.08 (s, 1H), 8.17 (br s, 1H), 6.95 (t, J = 9.4Hz, 1H), 5.27 (d, J = 54.3Hz, 1H), 4.29 (br d,J=10.5Hz,1H),4.19(d,J=10.4Hz,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). Step 2: Preparation of tert-butyl (7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate

[0291] tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 additional purification (assuming quantitative yield). LCMS (ESI) m / z: for C 31 H 36 Calcd. for F3N8O3S [M+H] + 657.3; measured value 657.2. 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate

[0292] Tert-butyl (7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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). 1-Methylimidazole (15 μL, 0.32 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (27 mg, 0.096 mmol). The reaction mixture was stirred for 5 min and concentrated. The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LCMS (ESI) m / z: for C 37 H 38 Calculated for F4N9O4S2 [M+H] + 812.2; measured value 812.2. 7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidine Step 1: Preparation of (S)-tert-butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

[0293] (S)-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)-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. To the 4-nitro-2-oxo-1-oxo-2-oxo-4-oxo-1-oxo-4-oxo-2 ... 46 H 60 Calculated value of F3N6O3Si [M+H] + 829.4; measured value 829.5; 1 H NMR (600MHz, CDCl3) δ9.05-8.97(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). Step 2: Preparation of (S)-tert-butyl 4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

[0294] (S)-tert-Butyl 4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-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. TBAF solution (1.0 M in THF, 54 μL, 0.54 mmol) was added dropwise and the reaction mixture was warmed to room temperature. After 5 min, the reaction mixture was concentrated and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% EtN) to afford the desired product (24 mg, 0.0 mmol, 99% yield). LCMS (ESI) m / z: for C 37 H 40 Calculated value of F3N6O3 [M+H] + 673.3; measured value 673.6; 1 H NMR (600MHz, CDCl3) δ9.00-8.94(m,1H),7.99-7.92(m,2H),7.66-7.55(m,2H),7.37-7.30(m,1H),5.28(d,J=53.6Hz,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). Step 3: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidine

[0295] (S)-tert-Butyl 4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-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 h, 1-methylimidazole (50 μL) was added and the reaction mixture was concentrated. The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LCMS (ESI) m / z: for C 32 H 32 Calculated for F3N6O [M+H] + 573.3; measured value 573.2. 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-(2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine Step 1: Preparation of tert-butyl 2-methyl-3-(methylamino)pyrrolidine-1-carboxylate

[0296] 2-methyl-3-oxopyrrolidine-1-tert-butyl formate (1g, 5.02mmol) is dissolved in methylamine solution (33wt% in EtOH, 19ml, 151mmol), and the reaction mixture is stirred at room temperature for 20h. The solution is concentrated, and the thick residue is resuspended in MeOH (50mL). Palladium / carbon (10wt.%, 0.5g, 0.47mmol) is added, and hydrogen (1atm, balloon) is bubbled through the solution for 5min. The reaction mixture is stirred for 20h under a hydrogen atmosphere. The black suspension is passed through diatomaceous earth. The crude residue was used directly in the next step without further purification (assuming quantitative yield). Step 2: Preparation of 2,7-dichloro-8-fluoro-N-methyl-N-(2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0297] 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.2 g, 4.75 mmol) was suspended in DCM (24 mL) and the mixture was cooled to -5 °C (wet ice / acetone). DIPEA (0.83 mL, 4.75 mmol) was added followed by tert-butyl 2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (1.0 g, 4.75 mmol). The reaction mixture was stirred for 5 min and concentrated. The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 18 H 23 Calculated value of Cl2FN5O2 [M+H] + 430.1; measured value 430.1. Step 3: Preparation of tert-butyl 3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0298] Tert-butyl 3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (2 g, 4.65 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.96 g, 6.04 mmol) were combined and dissolved in THF (23 mL). The solution was cooled to 0 °C and LiHMDS solution (1.0 M in THF, 11.6 mL, 11.6 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 24 h. The solution was concentrated, and the crude residue was directly purified by column chromatography (0→100% EtOAc / hexanes with 5% Et3N) to provide the desired product (1.1 g, 2.0 mmol, 43% yield) as a 6:6:1:1 cis:cis:trans:trans mixture of diastereomers. (reported cis diastereomer). LC / MS (ESI) m / z: for C 26 H 36 Calculated value of ClF2N6O3 [M+H] + 553.2; measured value 553.4; 1H NMR (500MHz, CDCl3) δ8.91 (s, 1H), 5.26 (d, J = 55.0Hz, 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, 3 H),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=6.4Hz,3H). Step 4: Preparation of tert-butyl 3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0299]

[0266] Tert-butyl 3-((7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (250 mg, 0.45 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (295 mg, 0.45 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct [cataCXium APalladacycle 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. The process was carried out three times. Degassed dioxane (2.2mL) and potassium phosphate solution (2.0M in water, 680 μL, 1.36mmol) were added, and the reaction mixture was heated in a microwave at 100°C for 1.5h. The reaction mixture was directly concentrated, and the crude residue was purified by column chromatography (20→100% with 5% Et3N EtOAc / hexane) to provide the desired product. LCMS (ESI) m / z: for C 47 H 63 Calculated value of F2N6O3Si [M+H] + 825.5; measured value 825.4. Step 5: Preparation of tert-butyl 3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate

[0300] Tert-butyl 3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (370 mg, 0.448 mmol) was dissolved in THF (4.5 mL), and the solution was cooled to 0° C. TBAF solution (1.0 M in THF, 540 μL, 0.540 mmol) was added dropwise, and the reaction mixture was warmed to room temperature. After 5 min, the reaction mixture was concentrated and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (270 mg, 0.404 mmol, 90% yield over two steps) as a 6:6:1:1 cis:cis:trans:trans mixture of diastereomers (reported cis diastereomer). LCMS (ESI) m / z: for C 38 H 43 Calculated value of F2N6O3 [M+H] + 669.3; measured value 669.4; 1 H NMR (500MHz, CDCl3) δ9.19-9.15(m,1H),8.01-7.94(m,2H),7.75(br d,J=6.9Hz,1H),7.65-7.56(m,2H),7.46(t,J=7.7Hz,1H),0.00(d,J=54.5Hz,1H),5.10-4.8 9(m,1H),4.66-4.52(m,1H),4.38-4.15(m,2H),3.66-3.60(m,1H),3.59-3.54(m,3H),3.43- 3.38(m,1H),3.29-3.20(m,2H),3.18-3.15(m,1H),3.00-2.94(m,1H),2.57-2.53(m,1H),2. 43-2.33(m,1H),2.29-2.09(m,4H),1.98-1.85(m,3H),1.50-1.48(m,9H),1.10-1.05(m,3H). Step 5: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-(2-methylpyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0301] Tert-butyl 3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (270 mg, 0.404 mmol) was dissolved in MeCN (4.0 mL) and the solution was cooled to 0 °C. HCl solution (4.0 M in dioxane, 1.0 mL, 4.0 mmol) was added dropwise. After 2 h, 1-methylimidazole (500 μL) was added and the reaction mixture was concentrated. The crude residue was used directly in the next step without additional purification (assuming quantitative yield). LCMS (ESI) m / z: for C 33 H 35 Calculated for F2N6O [M+H] + 569.3; measured value 569.3. 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine Step 1: Preparation of tert-butyl 4-(2,7-dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0302] 2,4,7-trichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine (500 mg, 1.770 mmol) [see CN115304623] 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, followed by dropwise addition of tert-butyl piperazine-1-carboxylate (330 mg, 1.77 mmol) as a solid. The reaction mixture was allowed to warm to room temperature and stirred for 5 min. The reaction mixture was concentrated, and the crude residue was used directly in the next step without additional purification (assuming quantitative yield). LCMS (ESI) m / z: for C 17 H 21Calculated value of Cl2FN5O3 [M+H] + 432.1; measured value 432.1; 1 H NMR (500MHz, CDCl3) δ4.09 (s, 3H), 3.75-3.66 (m, 4H), 3.61-3.56 (m, 4H), 1.48 (s, 9H). Step 2: Preparation of tert-butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0303] 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-pyrrolizine-7a(5H)-yl)methanol (406 mg, 2.55 mmol) was added. The mixture was cooled to 0 ° C. and a LiHMDS solution (1.0 M in THF, 3.7 mL, 3.7 mmol) was added dropwise. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 24 h. The solution was concentrated, and the crude residue was purified by column chromatography (0 → 100% EtOAc / hexane with 5% EtN) to provide the desired product (850 mg, 1.53 mmol, 90% yield) as a pale yellow solid. LC / MS (ESI) m / z: for C 25 H 34 Calculated value of ClF2N6O3 [M+H] + 555.2; measured value 555.1; 1 H NMR (500MHz, CDCl3) δ5.23(d,J=53.0Hz,1H),4.20(d,J=10.4Hz,1H),4.08(d,J=10.4Hz,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). Step 3: Preparation of tert-butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0304]

[0266] Tert-butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 a solid in a microwave vial. The vial was sealed. Atmosphere is evacuated and replaced with nitrogen.This process is carried out three times.Add degassed dioxane (0.45mL) and potassium phosphate solution (2.0M in water, 130 μ L, 0.27mmol), and reactant mixture is heated in microwave at 100 DEG C for 1.5h.Reactant mixture is directly concentrated, and crude residue is passed through into column chromatography (20→100% with 5% Et3N EtOAc / hexane) purifying to provide desired product (74mg, 0.089mmol, 99% yield).LC / MS(ESI)m / z:For C 46 H 61 Calculated value of F2N6O4Si [M+H] + 827.4; measured value 827.9; 1H NMR (500MHz, CDCl3) δ7.95-7.89(m,2H),7.80(d,J=7.2Hz,1H),7.61-7.54(m,2H),7.47-7 .43(m,1H),5.24(d,J=54.1Hz,1H),4.24(dd,J=10.5,0.8Hz,1H),4.10(t,J=9.8Hz,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=7.4Hz,3H). Step 4: Preparation of tert-butyl 4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0305] tert-Butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-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. TBAF solution (1.0 M in THF, 89 μL, 0.089 mmol) was added dropwise and the reaction mixture was warmed to room temperature. After 5 min, the reaction mixture was concentrated and the crude residue was purified by column chromatography (50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (54 mg, 0.081 mmol, 90% yield). LC / MS (ESI) m / z: for C 37 H 41 Calculated value of F2N6O4 [M+H] + 671.3; measured value 671.6; 1H NMR (500MHz, CDCl3) δ7.99-7.92(m,2H),7.75(dd,J=7.2,1.3Hz,1H),7.63-7.58(m ,2H),7.45(dd,J=8.1,7.3Hz,1H),5.25(d,J=54.0Hz,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). Step 5: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine

[0306] Tert-butyl 4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-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 allowed to warm 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 additional purification. LC / MS (ESI) m / z: for C 32 H 33 Calculated value of F2N6O2 [M+H] + 571.3; measured value 571.4. (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-fluoronaphthalene-2-ol Step 1: Preparation of (S)-(1-(3-azidopropyl)pyrrolidin-2-yl)methanol

[0307] (S)-pyrrolidin-2-ylmethanol (350 mg, 3.46 mmol) was dissolved in MeCN (3.5 ml_) and potassium carbonate (1.4 g, 10.4 mmol) was added followed by 3-azidopropyl-4-methylbenzenesulfonate (972 mg, 3.81 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered through celite. The product was stirred for 2 hours at 4 ℃ for 10 minutes.Then, 4 hours was stirred for 2 hours.Then, 4 hours was stirred for 3 hours.Then, 4 hours was stirred for 1 hour.Then, 4 hours was stirred for 3 hours.Then, 4 hours was stirred for 1 hour.Then, 4 hours was stirred for 2 hours.Then, 4 hours was stirred for 3 hours.Then, 4 hours was stirred for 3 hours.Then, 4 hours was stirred for 3 hours.Then, 4 hours was stirred for 1 hour.Then, 4 hours was stirred for 3 hours.Then, 4 hours was stirred for 1 hour.Then, 4 hours was stirred for 2 hours.Then, 4 hours was stirred for 3 hours. 1 H NMR (600MHz, CDCl3) δ3.65-3.57(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). Step 2: Preparation of (S)-tert-butyl 4-(2-((1-(3-azidopropyl)pyrrolidin-2-yl)methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0308] 4- (2,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin-4-yl) piperazine -1- carboxylic acid tert-butyl ester (400mg, 0.994mmol) was suspended in THF (5.0mL) and (S) - (1- (3- azidopropyl) pyrrolidin-2-yl) methanol (183mg, 0.994mmol) was added. The mixture was cooled to 0 ° C and a LiHMDS solution (1.0M in THF, 2.2mL, 2.2mmol) was added dropwise. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 24h. The solution was concentrated and the crude residue was purified by column chromatography (0 → 100% with 5% EtN EtOAc / hexane) to provide the desired product (340mg, 0.62mmol, 62% yield). LC / MS (ESI) m / z: for C 24 H 34 Calculated value of ClFN9O3 [M+H] + 550.2; measured value 550.3. Step 3: Preparation of (S)-tert-butyl 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

[0309] (S)-tert-Butyl 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 APalladacycle 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. The process was carried out three times. Degassed dioxane (3.1mL) and potassium phosphate solution (2.0M in water, 930 μL, 1.85mmol) were added, and the reaction mixture was heated in a microwave at 100 ° C for 1.5h. The reaction mixture was directly concentrated, and the crude residue was passed through column chromatography (20 → 100% with 5% Et3N EtOAc / hexane) to provide the desired product. LCMS (ESI) m / z: for C 47 H 64 Calculated value of F2N9O5Si [M+H] + 900.5; measured value 900.5. Step 4: Preparation of (S)-tert-butyl 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

[0310] (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- carboxylic acid tert-butyl ester (550mg, 0.61mmol) was dissolved in THF (6.1mL) and the solution was cooled to 0 ° C. TBAF solution (1.0M in THF, 610 μL, 0.61mmol) was added dropwise and the reaction mixture was warmed to room temperature. After 5min, the reaction mixture was concentrated and the crude residue was purified by column chromatography (50→100% with 5% EtN in EtOAc / hexanes) to provide the desired product (400mg, 0.54mmol, 88% yield). LC / MS (ESI) m / z: for C 38 H 44 Calculated value of F2N9O5 [M+H] + 744.3; measured value 744.3. 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

[0311] (S)-tert-Butyl 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 allowed to warm to room temperature. After 1 h, 1-methylimidazole (1 mL) was added and the solution was concentrated. The crude residue was used directly in the next step without additional purification. LCMS (ESI) m / z: for C 31 H 32 Calculated for F2N9O2 [M+H] + 600.3; measured value 600.2. 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol Step 1: Preparation of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-ol

[0312] Tert-butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-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. Aqueous sodium hydroxide solution (1.0 M, 4.5 mL, 4.5 mmol) was added, followed by MeOH (one drop, approximately 20 μL). The resulting reaction mixture was heated at 70 ° C for 3 h. 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 phase 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 additional purification. LC / MS (ESI) m / z: for C 36 H 43 Calculated value of F2N4O2Si[M+H] + 629.3; measured value 629.0. Step 2: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol

[0313] 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-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. TBAF solution (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 h. After completion, the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous phase 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 afford the desired product (400 mg, 0.84 mmol, 56% yield over two steps). LC / MS (ESI) m / z: for C 27 H 23 Calculated value of F2N4O2 [M+H] + 473.2; measured value 473.0.

[0314] General scheme for the preparation of the following two intermediates: 4-(1,4-diazepan-1-yl)-7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0315] 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (100 mg, 0.212 mmol) was dissolved in MeCN (5 mL) and 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 directly purified 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: for C 32 H 33Calculated for F2N6O [M+H] + 555.3; measured value 555.2; 1 H NMR (400MHz, DMSO-d6): δ9.10 (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. 60Hz, 1H), 4.07-4.02 (m, 6H), 3.71 (d, J = 1.20Hz, 1H), 3.35-3.02 (m, 6H), 2.87-2.83 (m, 3H), 2.05-1.77 (m, 8H). 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[4,3-d]pyrimidine

[0316] This intermediate was prepared according to the general procedure above using (3as,6as)-octahydropyrrolo[3,4-c]pyrrole instead of 1,4-diazepane. LCMS (ESI) m / z: for C 33 H 33 Calculated for F2N6O [M+H] + 567.3; measured value 567.2; 1 HNMR (400MHz, DMSO-d6): 1H-NMR (400MHz, DMSO-d6): δ9.22 (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, 1 H),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).

[0317] General scheme for the preparation of the following intermediates: 4-((2R,5S)-2,5-dimethylpiperazin-1-yl)-7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate

[0318] 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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, followed by PyBOP (350 mg, 0.68 mmol). 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 afford the desired product (200 mg) as a brown solid, which was used directly in the next step without additional purification. LCMS (ESI) m / z: for C 38 H 43 Calculated value of F2N6O3 [M+H] + 669.3; measured value 669.2. 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0319] Tert-butyl (2S,5R)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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 allowed to warm to room temperature. After 2 h, the reaction mixture was concentrated and the crude residue was purified by reverse phase column chromatography [Redisep 50 gm C18, 20-40 microns, THF: water: ACN (50: 20: 30) as diluent and 20% ACN in 5 mM ammonium formate as eluent] to provide the desired product as its formate salt. The material was partitioned between EtOAc (20 mL) and a saturated aqueous solution of NaHCO 3 (10 mL). The layers were separated and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was lyophilized to provide the desired product (18 mg, 0.032 mmol, 9% yield over two steps) as a brown solid. LC / MS (ESI) m / z: for C 33 H 35 Calculated for F2N6O [M+H] + 569.3; measured value 569.3; 1 H-NMR (400MHz, DMSO-d6): δ9.04-8.98(m,1H),8.20-8.16(m,2H),7.86-7.70(m,2H),7.64-7.56(m,2H) ,5.28(d,J=56.00Hz,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). 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidine

[0320] This intermediate was prepared according to the general procedure above using (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester instead of (2S,5R)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester. LCMS (ESI) m / z: for C 32 H 33 Calculated for F2N6O [M+H] +555.3; measured value 555.2; 1 H NMR (400MHz, DMSO-d6): δ9.04-8.97 (m, 1H), 8.15 (t, J = 8.40Hz, 1H), 7.74-7 .68(m,1H),7.62-7.58(m,1H),5.28(d,J=56.00Hz,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). 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrido[4,3-d]pyrimidine

[0321] This intermediate was prepared according to the general procedure above 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: for C 34 H 35 Calculated for F2N6O [M+H] + 581.3; measured value 581.2; 1 H NMR (400MHz, DMSO-d6): δ8.95 (s, 1H), 8.14 (dt, J = 0.80, 11.07Hz, 1H), 7.72 -7.67(m,1H),7.56(dd,J=7.60,Hz,1H),5.27(d,J=54.40Hz,1H),4.50(s,2 H),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). 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrido[4,3-d]pyrimidine

[0322] This intermediate was prepared according to the general procedure above using (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester instead of (2S,5R)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester. LCMS (ESI) m / z: for C 33 H 33 Calculated for F2N6O [M+H] + 567.3; measured value 567.2; 1 H NMR (400MHz, DMSO-d6): δ9.21-9.18(m,1H),8.15(t,J=8.00Hz,1H),7.75-7.68(m,2H),7.62-7.58(m,2H),5.28(d,J=56.0 0Hz,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). 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)pyrido[4,3-d]pyrimidine

[0323] This intermediate was prepared according to the general procedure above 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: for C 34 H 35 Calculated for F2N6O [M+H] + 581.3; measured value 581.2; 1H NMR (400MHz, DMSO-d6): δ9.00(s,1H),8.17-8.13(m,2H),7.73-7.67(m,2H),7.62-7.55(m,2H),5.28(d,J=56.00Hz,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). 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0324] This intermediate was prepared according to the general procedure above, using (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester instead of (2S,5R)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester and using BOP instead of PyBOP. LCMS (ESI) m / z: for C 33 H 35 Calculated for F2N6O [M+H] + 569.3; measured value 569.3; 1 H NMR (400MHz, DMSO-d6): δ9.08 (d, J=21.20Hz, 1H), 8.16 (t, J=8.40Hz, 2H), 7.7 1-7.74(m,2H),7.56-7.62(m,2H),5.30(d,J=52.00Hz,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=6.80,25.20Hz,3H),1.26(dd,J=6.80,25.60Hz,3H). 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,6-diazaspiro[3.4]octan-6-yl)pyrido[4,3-d]pyrimidine Isomer 1 and Isomer 2

[0325] These intermediates were prepared according to the general procedure above using tert-butyl 1,6-diazaspiro[3.4]octane-1-carboxylate instead of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate. In addition, the starting materials provided by these steps were further purified by preparative SFC (column: Chiralcel AD-H, 4.6 mm x 250 mm, 5 μm particles; flow rate: 100 mL / min; column temperature: 40°C; isocratic: 55% CO2:45% 1:1 MeCN / MeOH with 0.2% ammonia).

[0326] Isomer 1: LC / MS (ESI) m / z: for C 33 H 33 Calculated for F2N6O [M+H] + 567.3; measured value 567.0; 1 HNMR (400MHz, DMSO-d6): δ9.25-9.20(m,1H),8.16-8.12(m,2H),7.73-7.68(m,2H),7.60-7.54(m,2H),5.28( d,J=52.40Hz,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).

[0327] Isomer 2: LC / MS (ESI) m / z: for C 33 H 33 Calculated for F2N6O [M+H] + 567.3; measured value 567.2; 1 HNMR (400MHz, DMSO-d6): δ9.25-9.20(m,1H),8.14(t,J=8.00Hz,2H),7.71-7.67(m,2H),7.60-7.56(m,2H),5.2 8(d,J=53.60Hz,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). 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)pyrido[4,3-d]pyrimidine Isomer 1 and Isomer 2

[0328] These intermediates were prepared according to the general procedure above using tert-butyl hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate instead of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate. In addition, the starting material provided by these steps was further purified by preparative SFC (column: Chiralcel AD-H, 4.6 mm x 250 mm, 5 μm particles; flow rate: 100 mL / min; column temperature: 40° C.; isocratic: 55% CO 2 :45% 1:1 MeCN / MeOH with 0.2% ammonia) to provide two isomers.

[0329] Isomer 1: LC / MS (ESI) m / z: for C 33 H 33 Calculated for F2N6O [M+H] + 567.3; measured value 567.0.

[0330] Isomer 2: LC / MS (ESI) m / z: for C 33 H 33 Calculated for F2N6O [M+H] + 567.3; measured value 567.2.

[0331] General scheme for the preparation of the following intermediates: 7-(8-Ethynyl-4-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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

[0332] 4-Fluoronaphthalene-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 passed through celite. The product was filtered through a pad of Celite® (eluted 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 / hexanes) to afford the desired product (1.5 g, 4.38 mmol, 71% yield);1 H NMR (400MHz, DMSO-d6): δ10.03(s,1H),7.96(t,J=7.60Hz,1H),7.69(dd,J=1.20,7.20Hz,1H),7.52(d d, J=7.20, 8.40Hz, 1H), 7.18 (dd, J=8.40, 10.40Hz, 1H), 6.83 (dd, J=4.80, 8.40Hz, 1H), 1.14 (s, 21H). Step 2: Preparation of 4-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate

[0333] 4-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (500mg, 1.460mmol) was dissolved in DCM (10mL) and DIPEA (0.765mL, 4.38mmol) was added. The solution was cooled to -40°C and trifluoromethanesulfonic anhydride (0.370mL, 2.190mmol) was added dropwise at this temperature. The reaction mixture was allowed to warm to -20°C and stirred for 1h. The reaction mixture was quenched with cold water (20mL) and DCM (30mL) was added. The layers were separated and the aqueous phase was further extracted with DCM (2×30mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (5% EtOAc / hexane) to provide the desired product (500mg, 1.01mmol, 69% yield) as a colorless gel; 1 H NMR (400MHz, DMSO-d6): δ8.22 (d, J = 8.80Hz, 1H), 8.02 (dd, J = 1.20, 7.40Hz, 1H), 7.78-7.74 (m, 2H), 7.58 (t, J = 8.80Hz, 1H), 1.20-1.12 (m, 21H). Step 3: Preparation of ((5-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0334] 4-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl trifluoromethanesulfonate (500mg, 1.054mmol) is dissolved in dioxane (10mL), and B2pin2 (400mg, 1.56mmol) and potassium acetate (310mg, 3.16mmol) are added. Nitrogen is bubbled through the solution for 5min, and Pd(dppf)Cl2 (77mg, 0.10mmol) is added. The reaction mixture is heated at 100°C for 24h. Cold water (50mL) and EtOAc (50mL) are added, and the layers are separated. The aqueous phase is further extracted with EtOAc (2×50mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated. The crude residue is purified by column chromatography (extracted with ethyl acetate (3×50mL)). The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude residue was purified by column chromatography (5→10% EtOAc / hexanes) to afford the desired product (400 mg, 0.813 mmol, 77% yield). Step 4: Preparation of tert-butyl 4-(8-fluoro-7-(4-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0335]

[0266] 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 (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 (2.0 M, 0.95 mL, 1.905 mmol) was added and nitrogen was bubbled through the solution for 5 min. CataCXium A Pd G3 (35 mg, 0.048 mmol) was added, and the reaction mixture was heated at 100 ° C for 1 h. 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 layer was dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography to provide the desired product (400 mg, 0.314 mmol, 66% yield) as a pale white solid. LCMS (ESI) m / z: for C 45 H 58Calculated value of F3N6O3Si [M+H] + 815.4; measured value 815.2. Step 5: Preparation of tert-butyl 4-(7-(8-ethynyl-4-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0336] tert-Butyl 4-(8-fluoro-7-(4-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 / hexanes) to afford the desired product (200 mg, 0.18 mmol, 66% yield) as an off-white solid. LCMS (ESI) m / z: for C 36 H 38 Calculated value of F3N6O3 [M+H] + 659.3; measured value 659.2. Step 6: Preparation of 7-(8-ethynyl-4-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine

[0337] Tert-butyl 4-(7-(8-ethynyl-4-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 and added to 4N HCl (0.076 mL, 0.304 mmol) in 1,4-dioxane at 0 ° C. The reaction mixture was stirred for 2 h at this temperature. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC [diluent: THF:ACN:water (10:60:30); column: X-Select C18 (150 x 19) mm, 5 microns; temperature: ambient; mobile phase A: 5MM ammonium formate; mobile phase B: acetonitrile; flow rate: 15 mL / min] to provide the desired product as its formate salt. The material was partitioned between EtOAc (20 mL) and saturated NaHCO3 aqueous solution (10 mL). The layers were separated and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was lyophilized to provide the desired product (30 mg, 0.054 mmol, 16% yield) as an off-white solid. LCMS (ESI) m / z: for C 31 H 30 Calculated for F3N6O [M+H] + 559.2; measured value 559.1; 1 H NMR (400MHz, DMSO-d6): 1H-NMR (400MHz, DMSO-d6): δ9.04 (s, 1H), 8.26 (d, J = 8.40Hz, 1H), 7.83 (s, 1H), 7.69 (t, J = 7.60Hz, 1H), 7.63 (t, J = 6.00Hz, 1H), 7.5 7(t,J=8.00Hz,1H),5.28(d,J=54.40Hz,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). 7-(8-Ethynyl-6,7-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine

[0338] This intermediate was prepared according to the general procedure above using 6,7-difluoronaphthalene-1-ol instead of 4-fluoronaphthalene-1-ol. LCMS (ESI) m / z: for C 31 H 29 Calculated for F4N6O [M+H] + 577.2; measured value 577.2; 1 H NMR (400MHz, DMSO-d6): δ9.05 (s, 1H), 8.28-8.16 (m, 4H), 7.75 (t, J = 8.00Hz, 1H), 7.66 (d, J = 7.20Hz, 1H), 5.28 (d,J=54.00Hz,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). 7-(8-Ethynyl-5-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine

[0339] This intermediate was prepared according to the general procedure above using 5-fluoronaphthalene-1-ol instead of 4-fluoronaphthalene-1-ol. LCMS (ESI) m / z: for C 31 H 30 Calculated for F3N6O [M+H] + 559.2; measured value 559.2; 1 H NMR (400MHz, DMSO-d6): δ9.05(s,1H),8.30(d,J=8.40Hz,1H),8.17(d,J=6.80Hz,1H),7.84(t,J=0.80Hz,1H),7.74-7.72(m,2H),7.45(q,J=8.00Hz ,1H),5.22(d,J=52Hz,1H),4.15-4.06(m,2H),3.93-3.88(m,5H),3.11-2 .99(m,8H),2.84(d,J=6.40Hz,1H),2.14-2.01(m,2H),1.83-0.78(m,3H). 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 Step 1: Preparation of tert-butyl (R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0340] 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 at 0 ° C., and DIPEA (0.487 mL, 2.79 mmol) was added thereto, followed by a solution of (R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (254 mg, 1.268 mmol) in DCM (2 mL). Stirring was continued at 0 ° C. for 1 h. The mixture was warmed to room temperature and concentrated. The resulting residue was purified by flash column chromatography (gradient 5 → 100% EtOAc / hexane) to provide the desired product (453 mg, 1.088 mmol, 86% yield). LC / MS (ESI) m / z: for C 17 H 20 Calculated value of Cl2FN5O2 [M+H] + 416.1; measured value 416.1; 1 HNMR (500MHz, CDCl3) δ9.02 (s, 1H), 5.45 (br t, J = 7.8Hz, 1H), 3.86 (br t,J=9.6Hz,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). Step 2: (R)-tert-Butyl 3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0341] To a stirred solution of (R)-tert-butyl 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-pyrrolizin-7a(5H)-yl)methanol, HCl (155 mg, 0.79 mmol) in anhydrous THF (5 mL) was added a solution of LiHMDS (1.0 M in THF, 1.80 mL, 1.80 mmol) dropwise via syringe. The mixture was stirred for 18 h, partially concentrated and purified by flash column chromatography (gradient 50→100% EtOAc / hexanes with 5% Et3N) to afford the desired product (256 mg, 0.475 mmol, 66% yield). LC / MS (ESI) m / z: for C 25 H 33 Calculated value of ClF2N6O3 [M+H] + 539.2; measured value 539.3; 1 H NMR(500MHz, CDCl3)δ8.88(s,1H),5.41-5.20(m,2H),4.35-4.27(m,1H),4.25(s,1H),3.84(dd,J =11.5,8.1Hz,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=9.2Hz,1H),2.38-2.08(m,5H),2.02-1.84(m,3H),1.51(s,9H). Step 3: Preparation of (R)-tert-butyl 3-((7-(8-cyanonaphthalen-1-yl)-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

[0342] A mixture of (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-naphthalene (23.30 mg, 0.083 mmol) and a solution of tripotassium phosphate (1.5 M in water, 0.11 mL, 0.167 mmol) was stirred in degassed dioxane (1.5 mL) in a pressure vial. Methanesulfonate (diadamantyl-n-butylphosphino) -2 '-amino -1,1 '-biphenyl -2- base) palladium (II) dichloromethane adduct (cataCXium A Palladacycle Gen3) (4.05 mg, 5.57 μ mol) 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 directly purified by flash column chromatography (50 → 100% EtOAc w / 5% Et3N / hexane) to provide the desired product (21 mg, 0.032 mmol, 58% yield). LC / MS (ESI) m / z: for C 36 H 39 Calculated for F2N7O3 [M+H] + 656.3; measured value 656.3. 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-naphthocarbonitrile

[0343] To a solution of (R)-tert-butyl 3-((7-(8-cyanonaphthalen-1-yl)-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 (21 mg, 0.032 mmol) in acetonitrile (1 mL) was added a solution of HCl (4 M in dioxane, 0.080 mL, 0.320 mmol). The mixture was stirred for 1 h and then made basic 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: for C 31 H 31 Calculated for F2N7O [M+H]+ 556.2; measured value 556.2. 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine Step 1: Preparation of (R)-tert-butyl 3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0344] A mixture of (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 (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) was stirred in degassed dioxane (1.5 mL) in a pressure vial. Methanesulfonate (diadamantyl-n-butylphosphino) -2 '-amino -1,1 '-biphenyl -2- base) palladium (II) dichloromethane adduct (cataCXium A Palladacycle Gen3) (4.8 mg, 9.28 μ mol) 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 directly purified by column chromatography (50 → 100% EtOAc w / 5% Et3N / hexane) to provide the desired product (62 mg, 0.076 mmol, 82.0% yield). LC / MS (ESI) m / z: for C 46 H 60 Calculated value of F2N6O3Si [M+H] + 811.4; measured value 811.4; 1H NMR (500MHz, CDCl3) δ9.22 (s, 1H), 8.01-7.97 (m, 1H), 7.95 (d, J = 8.2Hz, 1H), 7.83 (d, J = 7.3 Hz,1H),7.61-7.57(m,2H),7.48(t,J=7.7Hz,1H),5.32(s,3H),4.65-4.40(m,1H),3.97-3.8 6(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=7.4Hz,3H). Step 2: Preparation of tert-butyl (R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0345] To a stirred solution of (R)-tert-butyl 3-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)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 min. The mixture was concentrated and directly purified by column chromatography (50→100% EtOAc w / 5% Et3N / hexanes) to afford the desired product (199 mg, 0.304 mmol, 86% yield). LC / MS (ESI) m / z: for C 37 H 40 Calculated value of F2N6O3 [M+H] + 655.3; measured value 655.4; 1H NMR (500MHz, CDCl3) δ9.14(s,1H),8.05-7.92(m,2H),7.77(d,J=7.1Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.7Hz,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=3.7Hz,4H),3.36-3.15(m,3H),3.07-2.93(m,1H),2.60(br d,J=7.7Hz,1H),2.42-2.10(m,6H),2.02-1.88(m,3H),1.51(s,9H). Step 3: Preparation of 7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0346] To a solution of (R)-tert-butyl 3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)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 h and then made basic 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: for C 32 H 32 Calculated for F2N6O [M+H] + 555.3; measured value 555.4. 7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine Step 1: Preparation of (R)-tert-butyl 3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0347] A mixture of (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 (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. Methanesulfonate (diadamantyl-n-butylphosphino) -2 '-amino -1,1 '-biphenyl -2- base) palladium (II) dichloromethane adduct (cataCXium A Palladacycle Gen3) (4.3 mg, 5.89 μ mol) 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 directly purified by column chromatography (50 → 100% EtOAc w / 5% Et3N / hexane) to provide the desired product (62 mg, 0.076 mmol, 82.0% yield). LC / MS (ESI) m / z: for C 46 H 59 Calculated value of F3N6O3Si [M+H] + 829.7; measured value 829.4; 1 H NMR(500MHz, CDCl3)δ9.30-9.15(m,1H),7.97(br d,J=8.0Hz,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). Step 2: Preparation of (R)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0348] To a stirred solution of (R)-tert-butyl 3-((8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 min. The mixture was concentrated and directly purified by column chromatography (50→100% EtOAc w / 5% Et3N / hexanes) to afford the desired product (22 mg, 0.033 mmol, 54% yield). LC / MS (ESI) m / z: for C 37 H 39 Calculated value of F3N6O3 [M+H] + 673.3; measured value 673.3 Step 3: Preparation of 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methyl-N-((R)-pyrrolidin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0349] To a solution of (R)-tert-butyl 3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (22 mg, 0.033 mmol) in acetonitrile (1 mL) was added a solution of HCl (4 M in dioxane, 0.082 mL, 0.327 mmol). The mixture was stirred for 1 h and then made basic by the addition of 1-methylimidazole (0.039 mL, 0.491 mmol). The solution was concentrated and used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 32 H 31 Calculated for F3N6O [M+H] +573.3; measured value 573.4. tert-Butyl (5,7-difluoro-4-(8-fluoro-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(methyl((R)-pyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate Step 1: Preparation of tert-butyl (3R)-3-((7-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0350] A mixture of (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 (33 mg, 0.061 mmol), (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)boronic acid (20 mg, 0.061 mmol) and a solution of tripotassium phosphate (1.5 M in water, 0.12 mL, 0.182 mmol) was stirred in degassed dioxane (1.0 mL) in a pressure vial. [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonic acid palladium(II) methanesulfonate (BRETTPHOS PD G3) (5.5 mg, 6.06 μmol) was added and the vial was sealed. The atmosphere was evacuated and replaced with nitrogen (3 times). The mixture was heated at 85° C. for 3 hours, concentrated and directly purified by column chromatography (50→100% EtOAc w / 5% Et3N / hexane) to provide the desired product (34 mg, 0.043 mmol, 71% yield). LC / MS (ESI) m / z: for C 37 H 44 Calcd. for F4N8O5S [M+H] + 789.3; measured value 789.6. Step 2: tert-Butyl (5,7-difluoro-4-(8-fluoro-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(methyl((R)-pyrrolidin-3-yl)amino)pyrido[4,3-d]pyrimidin-7-yl)benzo[d]thiazol-2-yl)carbamate

[0351] To a solution of tert-butyl (3R)-3-((7-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (34 mg, 0.043 mmol) in acetonitrile (1 mL) was added a solution of HCl (4 M in dioxane, 0.108 mL, 0.431 mmol). The mixture was stirred for 1 h and made basic by the addition of 1-methylimidazole (0.052 mL, 0.646 mmol). The solution was concentrated and used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 37 H 44 Calcd. for F4N8O5S [M+H] + 689.3; measured value 689.4. 2-Amino-7-fluoro-4-(8-fluoro-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy 4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophene-3-carbonitrile Step 1: Preparation of tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0352] A mixture of (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 (50 mg, 0.095 mmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (67 mg, 0.162 mmol) and a solution of potassium phosphate tripotassium phosphate (1.5 M in water, 0.19 mL, 0.286 mmol) was stirred in degassed dioxane (2 mL) in a pressure vial. Methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (cataCXium A Palladacycle Gen3) (6.9 mg, 9.52 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 2 h, concentrated and purified by reverse phase HPLC (column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25° C.; gradient: 95% 5:95 MeCN: HO with 10 mM AA / 5% 95:5 MeCN: HO with 10 mM AA → 100% 95:5 MeCN: HO with 10 mM AA; λ = 220 nm) to afford the desired product (36.8 mg, 0.470 mmol, 49.5% yield) as a yellow solid. LC / MS (ESI) m / z: for C 38 H 43 Calculated for F3N8O5S [M+H] + 781.3; measured value 781.6; 1 H NMR (500MHz, CDCl3) δ9.12(m,1H),7.85-7.57(m,1H),7.42(t,J=8.3Hz,0.5H),7.19(t,J=8.6Hz,0.5H),5.68-5.3 9(m,1H),5.12-4.60(m,2H),4.28-3.44(m,11H),3.35-3.10(m,1H),2.93-2.21(m,7H),1.58(s,9H),1.53(s,9H). Step 2: Preparation of 2-amino-7-fluoro-4-(8-fluoro-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophene-3-carbonitrile

[0353] To a solution of tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(((7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (13 mg, 0.017 mmol) in acetonitrile (1 mL) was added a solution of HCl (4 M in dioxane, 0.042 mL, 0.166 mmol). The mixture was stirred for 1 h and then made basic by the addition of 1-methylimidazole (0.020 mL, 0.250 mmol). The solution was concentrated and used directly in the next step without further purification (assuming quantitative yield). LC / MS (ESI) m / z: for C 28 Calculated value of H27F3N8OS [M+H] + 581.2; measured value 581.3. 7-(8-Ethynylnaphthalen-1-yl)-8-fluoro-N-((3S,4R)-4-fluoropyrrolidin-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine Step 1: Preparation of tert-butyl (3S,4R)-3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-fluoropyrrolidine-1-carboxylate

[0354] A solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (375 mg, 1.484 mmol) in DCM (15 mL) was cooled to 0 ° C. To this solution was added DIPEA (0.570 mL, 3.27 mmol), followed by the addition of (3R, 4S)-3-fluoro-4-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in WO 2022 / 173722, 324 mg, 1.484 mmol) in 2 mL of CH2Cl2. The reaction mixture was stirred at 0 ° C for 1 h. The mixture was warmed to room temperature, concentrated, and directly purified by column chromatography (5 → 100% EtOAc / hexane) to provide the desired product (415 mg, 0.956 mmol, 64% yield). LC / MS (ESI) m / z: for C 17 H 19 Calculated value of Cl2F2N5O2 [M+H] + 434.1, measured value 434.1; 1 H NMR (500MHz, CDCl3) δ9.12(s,1H),5.71-5.41(m,1H),5.40-5.15(m,1H),4.01-3.69(m,4H),3.67(s,3H),1.53(s,9H). Step 2: Preparation of tert-butyl (3S,4R)-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)-4-fluoropyrrolidine-1-carboxylate

[0355] To a stirred solution of (3S,4R)-tert-butyl 3-((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-4-fluoropyrrolidine-1-carboxylate (415 mg, 0.956 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, HCl (206 mg, 1.051 mmol) in anhydrous THF (15 mL) was added LiHMDS (1 M in THF, 2.389 mL, 2.389 mmol) dropwise via syringe at room temperature. The mixture was stirred for 18 h, concentrated and directly purified by column chromatography (gradient 50→100% EtOAc / hexanes with 5% EtN) to afford the desired product (271 mg, 0.487 mmol, 51% yield). LC / MS (ESI) m / z: for C 25 H 32 Calculated value of ClF3N6O3 [M+H]+ 557.2, measured value 557.4; 1 H NMR (500MHz, CDCl3) δ9.00 (s, 1H), 5.70-5.03 (m, 3H), 4.58-4.30 (m, 1H), 4.14 (q, J = 7.1Hz, 1H), 3.9 8-3.69(m,4H),3.61(s,3H),3.55-2.83(m,4H),2.56-2.17(m,3H),2.11-1.87(m,3H),1.52(s,9H). Step 3: Preparation of tert-butyl (3R,4S)-3-fluoro-4-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate

[0356] A mixture of tert-butyl (3S,4R)-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)-4-fluoropyrrolidine-1-carboxylate (120 mg, 0.215 mmol), triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (140 mg, 0.323 mmol) and a solution of tripotassium phosphate (1.5 M in water, 0.43 mL, 0.646 mmol) was stirred in degassed dioxane (5 mL) in a pressure vial. Methanesulfonate (diadamantyl-n-butylphosphino) -2 '-amino -1,1 '-biphenyl -2- base) palladium (II) dichloromethane adduct (cataCXium A Palladacycle Gen3) (15.7 mg, 0.022 mmol) 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 directly purified by column chromatography (50 → 100% EtOAc w / 5% Et3N / hexane) to provide the desired product (149 mg, 0.180 mmol, 83% yield). LCMS (ESI) m / z: for C 46 H 59 Calculated value of F3N6O3Si [M+H] + 829.4, measured value 829.7; 1H NMR (500MHz, CDCl3) δ9.42-9.22(m,1H),8.04-7.90(m,2H),7.88-7.78(m,1H),7.66-7.57(m,2H),7.48(br d,J=3.2Hz,1H),5.85-5.12(m,4H),4.60-4.35(m,1H),4.05-3.75(m,4H),3.67(br d,J=6.1Hz,3H),3.55-2.96(m,4H),2.15-2.00(m,3H),1.92-1.63(s,3H),1.54(s,9H),0.96-0.81(m,18H),0.70-0.54(m,3H). Step 4: Preparation of tert-butyl (3S,4R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydr...

Claims

1. A compound having formula (I): or a pharmaceutically acceptable salt thereof, wherein: U is a bond or NH; Z is a bond, O, NR e or CR e R f , where R e and R f are independently hydrogen or C1-C3 alkyl; R 1 is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; R 2 and R 3 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 hydroxyl; Y is a bond, O, NR g (CR e R f ) m NR f , or CR e R f , wherein m is 1, 2, or 3, and wherein R e , R f and R g are independently hydrogen or C1-C3 alkyl; A is a four- to ten-membered nitrogen-containing monocyclic or bicyclic bridged, fused, or spirocyclic saturated, unsaturated, or partially unsaturated ring system optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring system is optionally substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halo, haloC1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo; R' is halo; R 4 is an aryl or heteroaryl ring; wherein the ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkoxyC1-C6 alkyl, C1-C3 alkyl, cyano, cyanoC1-C3 alkyl, halo, haloC1-C3 alkoxy, haloC1-C3 alkyl, nitro, and oxo; X is O or NR 16 , where R 16 is hydrogen or C1-C3 alkyl; R 5 is selected from hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di(C1-C3 alkyl)amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-C1-C6 alkyl), NR a R b C1-C6 alkyl, wherein the aryl, the aryl portion of the arylC1-C6 alkyl, the C3-C6 cycloalkyl, the cycloalkyl portion of the C3-C6 cycloalkylC1-C6 alkyl, the heteroaryl, the heteroaryl portion of the heteroarylC1-C6 alkyl, the heterocyclyl, the heterocyclyl portion of the heterocyclylC1-C6 alkyl is optionally substituted by one, two, three, or four groups independently selected from the following: C1-C3 alkoxy, C1-C3 alkyl, (C1-C6 alkyl) amino, (C1-C6 alkyl) aminoC1-C3 alkyl, amino, aminoC1-C3 alkyl, azidoC1-C6 alkyl, carboxyl The invention also includes but is not limited to: alkyl, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoC1-C3 alkyl, halo, halo-substituted C1-C3 alkoxy, halo-substituted C1-C3 alkyl, heteroarylC1-C3 alkyl, heterocyclyl, heterocyclylC1-C3 alkyl, hydroxyl, hydroxyC1-C3 alkyl, nitro and oxo; wherein the heteroaryl portion of the heteroarylC1-C3 alkyl, the heterocyclyl and the heterocyclyl portion of the heterocyclylC1-C3 alkyl are further optionally substituted by one, two, or three groups independently selected from the following: C1-C3 alkoxy, C1-C3 alkyl, halo, halo-substituted C1-C3 alkyl and (NR x R y ) C1-C3 alkyl; or R 5 and R 16 together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted by one, two, three, four, or five groups independently selected from: one, two, three, or four groups independently selected from: C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy and hydroxyC1-C3 alkyl; R a and R b one is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, arylC1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkylC1-C6 alkyl; and R x and R y One is hydrogen and the other is selected from -C(O)C1-C6alkylheterocyclyl, wherein the heterocyclyl is optionally substituted with an oxo group.

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

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

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: R 4 is a five- or six-membered aromatic ring optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen and sulfur.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: Y is a bond.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: Y is NR f .

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein: Y is NCH3.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein A is a four- to nine-membered monocyclic or bicyclic bridged, spirocyclic, or fused saturated ring system optionally containing one or two nitrogen atoms.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein: AU is in represents the point of attachment to the carbonyl group; and Indicates the point of attachment to Y.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein: AU is in represents the point of attachment to the carbonyl group; and Indicates the point of attachment to Y.

11. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein: AU is in represents the point of attachment to the carbonyl group; and Indicates the point of attachment to Y.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein: R 2 is hydrogen or methoxy.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein: R 3 It is halogenated.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein: R 4 Selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, thiadiazolyl and triazolyl, wherein each ring is optionally substituted with one, two, or three groups independently selected from the following: C2-C4 alkenyl, C1-C3 alkyl, halo, halo C1-C3 alkoxy, halo C1-C3 alkyl, nitro and oxo.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein: R 4 is selected from imidazolyl, oxazolyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl, wherein each ring is optionally substituted with methyl or halo.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein: X is O.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein: R 5 Selected from: Wherein each ring is optionally substituted by 1, 2, or 3 groups independently selected from the following: C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl and oxo.

18. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein: R 5 is -(C1-C3 alkyl)-R 6 , where R 6 is a three- to five-membered monocyclic ring system, an eight- or nine-membered bicyclic fused saturated ring system, or a ten-membered tricyclic saturated ring system, wherein each ring system optionally contains one nitrogen atom, and wherein each ring system is optionally substituted with one or two groups independently selected from C1-C3 alkyl, halo and (4- to 6-membered heterocyclyl)C1-C3 alkyl; wherein the heterocyclyl portion of the (4- to 6-membered heterocyclyl)C1-C3 alkyl is further optionally substituted with a halo group.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein: R 5 yes and Indicates the point of attachment to X.

20. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein: R 5 yes Where n is 0, 1, or 2; Each R 20 is halogenated; and Indicates the point of attachment to X.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein: Z is the key.

22. The compound according to any one of claims 1 to 21, wherein R 1 is a monocyclic heteroaryl ring containing one, two, or three nitrogen atoms, wherein the ring is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl.

23. A compound according to any one of claims 1 to 21, wherein R 1 is a bicyclic heteroaryl ring containing one, two, or three heteroatoms selected from nitrogen and sulfur, wherein the ring is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl.

24. A compound according to any one of claims 1 to 21, wherein R 1 is a phenyl ring optionally substituted by one, two, three, four, or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl.

25. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a C6-C 10 Aryl: C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy and hydroxyC1-C3 alkyl.

26. The compound according to any one of claims 1 to 21 and 25, or a pharmaceutically acceptable salt thereof, wherein R 1 is naphthyl substituted with one, two, three, four, or five substituents independently selected from C1-C3 alkyl, C2-C4 alkynyl, halo and hydroxy.

27. The compound according to any one of claims 1 to 21, 25 and 26, or a pharmaceutically acceptable salt thereof, wherein: R 1 is naphthyl, wherein the naphthyl is substituted with one, two, or three groups independently selected from C2-C4 alkynyl, halo and hydroxy.

28. A compound as described in any one of claims 1 to 21 and 25 to 27, or a pharmaceutically acceptable salt thereof, wherein: R 1 yes in Indicates the point of attachment to the parent molecule.

29. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein: R 1 yes in Indicates the point of attachment to the parent molecule.

30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein: R' is fluorine.

31. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein: R' is chlorine.

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

33. A compound selected from the group consisting of: (Z)-1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]hept-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-ethylnaphth-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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-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-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)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-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)-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(2,5-difluorophenyl)-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-(2-(difluoromethyl)-5-fluorophenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((S)-4-(7-(2-(difluoromethyl)-5-fluorophenyl)-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)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)-4-(8-fluoro-7-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(pyridazin-2-yl)prop-2-en-1-one; 8-(8-Fluoro-4-(4-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthocarbonitrile; 8-(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)-1-naphthocarbonitrile; 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)-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-(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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-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-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one cis-isomer 1; (Z)-1-(3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one trans-isomer 1; (Z)-1-(3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((3R)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-diazepan-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(7-(2-cyclopropylphenyl)-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-((2S)-4-(7-(2-cyclobutylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(pyridin-2-yl)acryloyl)piperazin-2-yl)acetonitrile; 2-((2S)-4-(7-(2-cyclobutylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-((Z)-2-fluoro-3-(thiazol-2-yl)acryloyl)piperazin-2-yl)acetonitrile; (Z)-1-((2S,5R)-4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-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-4-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-((S)-4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]non-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]non-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]non-2-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-(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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthocarbonitrile; 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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthocarbonitrile; (Z)-1-((R)-3-((7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; (Z)-1-((R)-3-((7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-2-fluoro-3-(pyridin-2-yl)prop-2-en-1-one; 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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-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-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(oxazol-2-yl)prop-2-en-1-one; (Z)-1-(4-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoro-3-(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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H-indole-4-carbonitrile; or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

35. An oral dosage form comprising a compound as claimed in any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

36. A method of treating a cancer expressing a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

37. A method of treating a cancer expressing a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

38. A method of treating a cancer sensitive to KRAS G12C inhibition in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

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

40. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound as described in any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, wherein, The cancer is non-small cell lung cancer.

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