KRAS inhibitors

Abstract

The present disclosure provides KRAS inhibitors. Methods of using the compounds to treat cancer are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application Nos. 63 / 498,576 (filed April 27, 2023), 63 / 493,037 (filed March 30, 2023), 63 / 482,229 (filed January 30, 2023), 63 / 476,436 (filed December 21, 2022), 63 / 384,884 (filed November 23, 2022), 63 / 378,352 (filed October 4, 2022), and 63 / 371,567 (filed August 16, 2022), all of which are incorporated herein by reference in their entireties.

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

[0003] The KRAS oncogene is a member of the RAS family of GTPases involved in many cell signaling processes. KRAS mutations are gain-of-function mutations present in up to 30% of all tumors, including approximately 90% of pancreatic cancers. Single nucleotide substitutions resulting in missense mutations at codons 12 and 13 of the KRAS primary amino acid sequence account for approximately 40% of KRAS driver mutations in lung adenocarcinomas, with the G12C transversion being the most common activating mutation. KRAS G12C mutations occur in approximately 13% of lung adenocarcinomas and approximately 3% of colorectal adenocarcinomas, and are also present in breast, bladder, cervical, ovarian, pancreatic, and uterine cancers. KRAS G12D mutations occur in 28% of all pancreatic ductal adenocarcinomas, 13% of all colorectal carcinomas, 4% of all non-small cell lung cancers, and 3% of all gastric cancers. See, for example, https: / / www.mycancergenome.org / content / alteration / kras-g12d / . Because of the clinical significance of this protein, many attempts have been made to develop RAS inhibitors, but these attempts have met with little success. Thus, there is a need for drugs that inhibit mutant KRAS. Summary of the Invention [Means for solving the problem]

[0004] In a first aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, Z is a bond, O, NR e or CR e R f and R e and R f are independently hydrogen or C1-C3 alkyl; R 1is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C-C alkenyl, C-C alkoxy, C-C alkyl, C-C alkynyl, C-C alkynyloxy, amino, aminoC-C alkyl, cyano, cyanoC-C alkoxy, C-C cycloalkyl (e.g., C-C cycloalkyl) optionally substituted with 1, 2, or 3 halo groups, halo, haloC-C alkyl, haloC-C alkoxy, hydroxy, hydroxyC-C alkyl, heteroaryl, heterocyclyl, and phenyl, wherein the heteroaryl, heterocyclyl, and phenyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C-C alkoxy, C-C alkyl, halo, and haloC-C alkyl; R 2 , R 3 and R 7 are independently selected from the group consisting of hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halo, haloC1-C3 alkyl, —C(O)NH2, —C(O)NH(C1-C3 alkyl), —C(O)N(C1-C3 alkyl)2, and hydroxy; R 4 -NHR 50 , or [ka] and R 50 is a 5-membered ring optionally containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen, and the ring is optionally substituted with 1 or 2 groups independently selected from C1-C3 alkyl and oxo; n' is 0, 1, 2 or 3; R 8 , R 8’ , R 9 , R 9’ , R 10 , R 10’ , R 13 and R 13’are each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, C1-C6 alkoxyC1-C6 alkyl, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; or R 8 and R 9 together form a C1-C3 alkylene; or R 8 and R 10 together form a C1-C3 alkylene; or R 8 and R 13 together form a C1-C3 alkylene; or R 9 and R 13 together form a C1-C3 alkylene; or R 10 and R 13 together form a C1-C3 alkylene; or R 8 and R 8’ together with the atoms to which they are attached form a 3-, 4- or 5-membered ring optionally containing an oxygen atom or an SO group, the ring being optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl and hydroxy; or R 9 and R 9’ together with the atoms to which they are attached form a 3-, 4-, or 5-membered ring optionally containing an oxygen atom or an SO group, the ring being optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy; or R 10 and R 10’ together with the atoms to which they are attached form a 3-, 4-, or 5-membered ring optionally containing an oxygen atom or an SO group, the ring being optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy; or R 13 and R13’ together with the atoms to which they are attached form a 3-, 4-, or 5-membered ring optionally containing an oxygen atom or an SO group, the ring being optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy; W 1 is CR 11 R 12 , N.R. 17 , N.R. 15’’ C(O), C(O)NR 15’’ , N(C(O)(CH2) n OR 15 ), O, CH2O, OCH2, SO2, SO2NR 15’ or P(O)CH3; n is 0 or 1; R 11 and R 12 are independently selected from the group consisting of hydrogen, C1-C3 alkoxy, C1-C6 alkoxyC1-C6 alkyl, C1-C3 alkyl, cyano, dimethylphosphino; dimethylsulfonamido, halo, hydroxy, and methylsulfonyl; or R 11 and R 12 together with the atoms to which they are attached form a 4-6 membered ring optionally containing an oxygen atom or an SO group, the ring being optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy; or R 11 and R 13 together with the atoms to which they are attached form a 3-, 4-, or 5-membered ring optionally containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, the ring optionally containing 1 or 2 double bonds, and the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy; or R 13 and R 15 come together to form CH2; R 15’ is C1-C3 alkyl or C1-C6 alkoxyC1-C6 alkyl; R 15’’ is hydrogen or C1-C3 alkyl; R 17 is selected from the group consisting of C1-C3 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, haloC1-C3 alkylcarbonyl, methylsulfonyl, and tetrahydropyranylcarbonyl, wherein the C3-C6 cycloalkyl and tetrahydropyranyl are optionally substituted with one or two substituents independently selected from the group consisting of cyano, halo, and hydroxy; X is O or NR 16 and R 16 is hydrogen or C1-C3 alkyl; R 5 is hydrogen, C1-C6 alkoxyC1-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, and the aryl, aryl portion of aryl C1-C6 alkyl, C3-C6 cycloalkyl, cycloalkyl portion of C3-C6 cycloalkyl C1-C6 alkyl, heteroaryl, heteroaryl portion of heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl portion of heterocyclyl C1-C6 alkyl are selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, deuterated C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)amino C1-C3 alkyl, amino, amino C1-C3 alkyl, carboxy, sialic acid, methyl ... optionally substituted with one, two, three, or four groups independently selected from nitro, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoC1-C3 alkyl, halo, haloC1-C3 alkoxy, haloC1-C3 alkyl, heterocyclyl, heterocyclylC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, nitro, and oxo; the heterocyclyl portion of the heterocyclyl and heterocyclylC1-C3 alkyl is further optionally substituted with one, two, or three groups independently selected from the group consisting of 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 with one, two, three, four, or five groups independently selected from the group consisting of one, two, three, or four groups selected from the group consisting of 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 which is selected from the group consisting of hydrogen and C1-C3 alkyl, and the other is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, arylC1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkylC1-C6 alkyl) or a pharmaceutically acceptable salt thereof.

[0005] In certain embodiments, R 7 is chloro.

[0006] In some embodiments, R 7 is hydrogen.

[0007] In certain aspects, the present disclosure provides a compound of formula (II): [ka] (In the formula, Z is a bond, O, or NR e or CR e R f and R e and R f are independently hydrogen or C1-C3 alkyl; R 1 is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C-C alkenyl, C-C alkoxy, C-C alkyl, C-C alkynyl, C-C alkynyloxy, amino, aminoC-C alkyl, cyano, cyanoC-C alkoxy, C-C cycloalkyl (e.g., C-C cycloalkyl) optionally substituted with 1, 2, or 3 halo groups, halo, haloC-C alkyl, haloC-C alkoxy, hydroxy, hydroxyC-C alkyl, heteroaryl, heterocyclyl, and phenyl, wherein the heteroaryl, heterocyclyl, and phenyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C-C alkoxy, C-C alkyl, halo, and haloC-C alkyl; R 2 and R 3 are independently selected from the group consisting of hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halo, haloC1-C3 alkyl, —C(O)NH2, —C(O)NH(C1-C3 alkyl), —C(O)N(C1-C3 alkyl)2, and hydroxy; R 4 -NHR 50, or [ka] and R 50 is a 5-membered ring optionally containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen, and the ring is optionally substituted with 1 or 2 groups independently selected from C1-C3 alkyl and oxo; n' is 0, 1, 2, 3; R 8 , R 8’ , R 9 , R 9’ , R 10 , R 10’ , R 13 and R 13’ are each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, C1-C6 alkoxyC1-C6 alkyl, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; or R 8 and R 9 together form a C1-C3 alkylene; or R 8 and R 10 together form a C1-C3 alkylene; or R 8 and R 13 together form a C1-C3 alkylene; or R 9 and R 13 together form a C1-C3 alkylene; or R 10 and R 13 together form a C1-C3 alkylene; or R 8 and R 8’ together with the atoms to which they are attached form a 3-, 4-, or 5-membered ring optionally containing an oxygen atom or an SO group, the ring being optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy; or R 9 and R 9’ together with the atoms to which they are attached form a 3-, 4-, or 5-membered ring optionally containing an oxygen atom or an SO group, the ring being optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy; or R 10 and R 10’ together with the atoms to which they are attached form a 3-, 4-, or 5-membered ring optionally containing an oxygen atom or an SO group, the ring being optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy; or R 13 and R 13’ together with the atoms to which they are attached form a 3-, 4-, or 5-membered ring optionally containing an oxygen atom or an SO group, the ring being optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy; W 1 is CR 11 R 12 , N.R. 17 , N.R. 15’’ C(O), C(O)NR 15’’ , N(C(O)(CH2) n OR 15 ), O, CH2O, OCH2, SO2, SO2NR 15’ or P(O)CH3; n is 0 or 1; R 11 and R 12 are independently selected from the group consisting of hydrogen, C1-C3 alkoxy, C1-C6 alkoxyC1-C6 alkyl, C1-C3 alkyl, cyano, dimethylphosphino; dimethylsulfonamido, halo, hydroxy, and methylsulfonyl; or R 11 and R 12together with the atoms to which they are attached form a 4- or 5-membered ring optionally containing an oxygen atom or an SO group, the ring being optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy; or R 11 and R 13 together with the atoms to which they are attached form a 3-, 4-, or 5-membered ring optionally containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, the ring optionally containing 1 or 2 double bonds, and the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy; or R 13 and R 15 come together to form CH2; R 15’ is C1-C3 alkyl or C1-C6 alkoxyC1-C6 alkyl; R 15’’ is hydrogen or C1-C3 alkyl; R 17 is selected from the group consisting of C1-C3 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, haloC1-C3 alkylcarbonyl, methylsulfonyl, and tetrahydropyranylcarbonyl, wherein the C3-C6 cycloalkyl and tetrahydropyranyl are optionally substituted with one or two substituents independently selected from the group consisting of cyano, halo, and hydroxy; X is O or NR 16 and R 16 is hydrogen or C1-C3 alkyl; R 5 is hydrogen, C1-C6 alkoxyC1-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, NRa R b -C(O)-C1-C6 alkyl), NR a R b C1-C6 alkyl, and the aryl, aryl moiety of aryl C1-C6 alkyl, C3-C6 cycloalkyl, cycloalkyl moiety of C3-C6 cycloalkyl C1-C6 alkyl, heteroaryl, heteroaryl moiety of heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl moiety of heterocyclyl C1-C6 alkyl are selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, deuterated C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)amino C1-C3 alkyl, amino, amino C1-C3 alkyl, carboxy, cyano, di optionally substituted with one, two, three, or four groups independently selected from the group consisting of (C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoC1-C3 alkyl, halo, haloC1-C3 alkoxy, haloC1-C3 alkyl, heterocyclyl, heterocyclylC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, nitro, and oxo; the heterocyclyl portion of the heterocyclyl and heterocyclylC1-C3 alkyl is further optionally substituted with one, two, or three groups independently selected from the group consisting of 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 with 1, 2, 3, 4, or 5 groups independently selected from the group consisting of 1, 2, 3, or 4 groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; and R a and R bone of which is selected from hydrogen and C1-C3 alkyl, and the other is selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, arylC1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkylC1-C6 alkyl) or a pharmaceutically acceptable salt thereof.

[0008] In some aspects, the present disclosure provides compounds of formula (II), wherein R 2 is methoxy.

[0009] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 4 -NHR 50 and R 50 is a 5-membered ring optionally containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen, and the ring is optionally substituted with 1 or 2 groups independently selected from C1-C3 alkyl and oxo.

[0010] In some aspects, the present disclosure provides a method for producing a medicament comprising: 1 But, CR 11 R 12 , N(C(O)(CH2) n OR 15 ), O, SO2, SO2NR 15’ or P(O)CH3, and R 11 , R 12 ,n,R 15 and R 15’ The present invention provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein:

[0011] In some aspects, the present disclosure provides a method for producing a medicament comprising: 1 is CR 11 R 12 or a pharmaceutically acceptable salt thereof.

[0012] In some aspects, the present disclosure provides a method for producing a medicament comprising:1 NR 17 or a pharmaceutically acceptable salt thereof.

[0013] In some aspects, the present disclosure provides a method for producing a medicament comprising: 1 NR 15’’ C(O), or a pharmaceutically acceptable salt thereof.

[0014] In some aspects, the present disclosure provides a method for producing a medicament comprising: 1 is C(O)NR 15’’ or a pharmaceutically acceptable salt thereof.

[0015] In some aspects, the present disclosure provides a method for producing a medicament comprising: 1 N(C(O)(CH2) n OR 15 or a pharmaceutically acceptable salt thereof.

[0016] In some aspects, the present disclosure provides a method for producing a medicament comprising: 1 is O, or a pharmaceutically acceptable salt thereof.

[0017] In some aspects, the present disclosure provides a method for producing a medicament comprising: 1 is CHO, or a pharmaceutically acceptable salt thereof.

[0018] In some aspects, the present disclosure provides a method for producing a medicament comprising: 1 is OCH2, or a pharmaceutically acceptable salt thereof.

[0019] In some aspects, the present disclosure provides a method for producing a medicament comprising: 1 is SO2, or a pharmaceutically acceptable salt thereof.

[0020] In some aspects, the present disclosure provides a method for producing a medicament comprising: 1 SO2NR15’ or a pharmaceutically acceptable salt thereof.

[0021] In some aspects, the present disclosure provides a method for producing a medicament comprising: 1 is P(O)CH3, or a pharmaceutically acceptable salt thereof.

[0022] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 4 teeth, [ka] [ka] [ka] and [ka] represents the point of attachment to the core of formula (I) or (II).

[0023] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 4 teeth, [ka] and [ka] represents the point of attachment to the core of formula (II).

[0024] In some aspects, the present disclosure provides 2 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0025] In some aspects, the present disclosure provides 3is halo, or a pharmaceutically acceptable salt thereof.

[0026] In some aspects, the disclosure provides compounds of formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X is O.

[0027] In some aspects, the present disclosure provides 5 but, [ka] wherein each ring is optionally substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, deuterated C1-C3 alkyl, C3-C6 cycloalkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo; R c and R d together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, the ring being optionally substituted with one, two or three groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl and oxo; or R c and R d one of which is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, and C1-C3 alkylcarbonyl) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0028] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 is -(C1-C3 alkyl)-R6 and R 6 is a 3-6 membered monocyclic ring system, an 8- or 9-membered bicyclic fused saturated ring system, a 10-membered tricyclic saturated ring system, or a 12-membered tetracyclic saturated ring system, each ring system optionally containing one or more nitrogen, oxygen, and / or sulfur atoms, and each ring system is optionally substituted with one to four groups independently selected from the group consisting of C1-C3 alkyl, halo, oxo, and (4-6 membered heterocyclyl)C1-C3 alkyl, wherein the heterocyclyl portion of the (4-6 membered heterocyclyl)C1-C3 alkyl is further optionally substituted with a halo group.

[0029] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 teeth, [ka] and [ka] represents the point of attachment to X.

[0030] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 teeth, [ka] and; [ka] represents the point of attachment to X.

[0031] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 teeth, [ka] (In the formula, n is 0, 1 or 2; Each R20 is a halo; and [ka] represents the connection point to X) is.

[0032] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 teeth, [ka] (wherein r is 1 or 2; q is 0, 1 or 2; R x is 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; and [ka] represents the connection point to X) is.

[0033] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 teeth, [ka] (In the formula, R 21 is selected from the group consisting of C1-C3 alkyl, deuterated C1-C3 alkyl, and C3-C6 cycloalkyl; R 22 is halo; p is 0 or 1; and [ka] represents the connection point to X) is.

[0034] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 teeth, [ka] (In the formula, [ka] represents the connection point to X; p is 0 or 1; R 21 is selected from the group consisting of C1-C3 alkyl, deuterated C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 is halo; p is 0 or 1; and [ka] indicates the connection point to X) is.

[0035] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 teeth, [ka] and [ka] represents the point of attachment to X.

[0036] In some aspects, the disclosure provides compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

[0037] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1is a monocyclic heteroaryl ring containing 1, 2, or 3 nitrogen atoms, and the ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 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, haloC1-C3 alkoxy, hydroxy, and hydroxyC1-C3 alkyl.

[0038] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] and; [ka] indicates the point of attachment to the core of formula (I) or (II).

[0039] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 is a C6-C alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, cyano, C3-C5 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentanyl), halo, halo C1-C3 alkyl, hydroxy, and hydroxy C1-C3 alkyl. 10 It is aryl.

[0040] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkynyl, C2-C4 alkynyloxy, amino, cyano, cyanoC1-C3 alkoxy, C3-C4 cycloalkyl optionally substituted with 1 or 2 halo groups, halo, haloC1-C3 alkoxy, 4- to 6-membered heterocyclyl, and hydroxy.

[0041] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 is naphthyl, wherein the naphthyl is substituted with 1, 2, or 3 groups independently selected from the group consisting of C2-C4 alkynyl, halo, and hydroxy.

[0042] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] (In the formula, R 53 is C1-C3 alkyl, halo, haloC1-C3 alkyl, haloC1-C3 alkoxy, 4- to 6-membered heterocyclyl, or hydroxy; q is an integer from 0 to 4; [ka] indicates the point of attachment to the core of formula (I) or (II) is.

[0043] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, wherein the phenyl is substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkyl, C3-C5 cycloalkyl, heterocyclyl, and hydroxy.

[0044] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 is isoquinolinyl, which is substituted with one, two, or three groups independently selected from the group consisting of halo C1-C3 alkyl and halo C1-C3 alkoxy. 1 teeth, [ka] (In the formula, R 51 is haloC1-C3 alkyl; R 52 is hydrogen or haloC1-C3 alkyl; and [ka] indicates the point of attachment to the core of formula (I) or (II) is.

[0045] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 is indolyl substituted with haloC1-C3 alkyl. In some of these embodiments, R 1 teeth, [ka] and [ka] indicates the point of attachment to the core of formula (I) or (II).

[0046] In some aspects, the disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 is indazolyl substituted with 1, 2, or 3 substituents selected from C1-C3 alkyl and halo. In some of these embodiments, R 1 teeth, [ka] is.

[0047] In some aspects, the disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth, [ka] (In the formula, R 53 is C1-C3 alkyl, halo, haloC1-C3 alkyl, haloC1-C3 alkoxy, 4- to 6-membered heterocyclyl, or hydroxy; and q is an integer from 0 to 4. and; R 4 teeth, [ka] and R 5 teeth, [ka] and [ka] represents the connection point to X; p is 0 or 1; R 21 is selected from the group consisting of C1-C3 alkyl, deuterated C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 is halo; p is 0 or 1; [ka] indicates the point of attachment to the parent molecular moiety.

[0048] In some aspects, the disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth, [ka] (In the formula, R 53 is C1-C3 alkyl, halo, haloC1-C3 alkyl, haloC1-C3 alkoxy, 4- to 6-membered heterocyclyl, or hydroxy; and q is an integer of 0 to 4. and; R 4 teeth, [ka] and R 5 teeth, [ka] and [ka] represents the connection point to X; p is 0 or 1; R 21 is selected from the group consisting of C1-C3 alkyl, deuterated C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 is halo; p is 0 or 1; [ka] indicates the point of attachment to the parent molecular moiety.

[0049] In some aspects, the disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth, [ka] (In the formula, R 53 is C1-C3 alkyl, halo, haloC1-C3 alkyl, haloC1-C3 alkoxy, 4- to 6-membered heterocyclyl, or hydroxyl; and q is an integer from 0 to 4. and; R 4 teeth, [ka] and R 5 teeth, [ka] and [ka] represents the connection point to X; p is 0 or 1; R 21 is selected from the group consisting of C1-C3 alkyl, deuterated C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 is halo; p is 0 or 1; [ka] indicates the point of attachment to the parent molecular moiety.

[0050] In some aspects, the disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth, [ka] (In the formula, R 53 is C1-C3 alkyl, halo, haloC1-C3 alkyl, haloC1-C3 alkoxy, 4- to 6-membered heterocyclyl, or hydroxy; and q is an integer from 0 to 4. and; R 4 teeth, [ka] and R 5 teeth, [ka] and [ka] represents the connection point to X; p is 0 or 1; R 21 is selected from the group consisting of C1-C3 alkyl, deuterated C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 is halo; p is 0 or 1; [ka] indicates the point of attachment to the parent molecular moiety.

[0051] In some aspects, the disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth, [ka] (In the formula, R 53 is C1-C3 alkyl, halo, haloC1-C3 alkyl, haloC1-C3 alkoxy, 4- to 6-membered heterocyclyl, or hydroxy; and q is an integer from 0 to 4. and; R 4 teeth, [ka] and R 5 teeth, [ka] and; [ka] represents the connection point to X; p is 0 or 1; R 21 is selected from the group consisting of C1-C3 alkyl, deuterated C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 is halo; p is 0 or 1; [ka] indicates the point of attachment to the parent molecular moiety.

[0052] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0053] In some aspects, the present disclosure provides oral dosage forms comprising a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0054] In some embodiments of the method, the compound is an atropisomer of the compound of any of the previous embodiments. In certain embodiments, the compound is a stable atropisomer as described herein.

[0055] In another aspect, the disclosure provides a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0056] In another aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to a subject in need of cancer treatment a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure or a pharmaceutically acceptable salt thereof.

[0057] In another aspect, the present disclosure provides a method of treating a KRAS G12D-associated disease or a disorder associated with KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0058] In another aspect, the disclosure provides a method of treating a cancer amenable to KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H inhibition in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0059] In another aspect, the disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer, colorectal cancer, lung cancer, gastric cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, uterine cancer, or a combination thereof.

[0060] In another aspect, the disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in inhibiting KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H.

[0061] In another aspect, the disclosure provides a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of a disease or disorder associated with KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H.

[0062] In another aspect, the disclosure provides the use of a compound of Formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0063] In another aspect, the disclosure provides the use of a compound of Formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the activity of inhibiting KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H.

[0064] In another aspect, the disclosure provides the use of a compound of Formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H.

[0065] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0066] In some aspects, the present disclosure provides: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0067] In some aspects, the present disclosure provides: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0068] In some aspects, the present disclosure provides: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0069] In some aspects, the present disclosure provides: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(1-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}cyclopropyl)methoxy]-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; 4-[2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-[8-fluoro-4-(morpholin-4-yl)-2-({1-[(piperidin-1-yl)methyl]cyclopropyl}methoxy)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 6-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2λ 6 -Thia-6-azaspiro[3.3]heptane-2,2-dione; 4-[2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (8aR)-7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethylpiperidine-4-sulfonamide; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(4-methanesulfonylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[2-(hydroxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile isomer 1; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile isomer 2; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-[8-fluoro-2-({1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl}methoxy)-4-[(3R)-3-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(3R)-3-ethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]heptan-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol; 5-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-methyl-1λ 6 ,2,5-thiadiazepane-1,1-dione; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{9-oxa-2-azaspiro[5.5]undecan-2-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol isomer 1; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol isomer 2; 1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl}methoxy)pyrido[4,3-d]pyrimidin-4-yl]piperidine-3-carbonitrile isomer 1; 1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl}methoxy)pyrido[4,3-d]pyrimidin-4-yl]piperidine-3-carbonitrile isomer 2; 7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-7-azaspiro[3.5]nonan-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{hexahydro-1H-furo[3,4-c]pyrrol-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{8-azabicyclo[3.2.1]octan-8-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{2-azabicyclo[2.2.1]heptan-2-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(4-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[3-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-methyl-3-azabicyclo[3.2.1]octan-8-ol; (3aR,5R,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5-(difluoromethyl)-octahydrocyclopenta[c]pyrrol-5-ol; (1R,5S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.1]heptan-6-ol; 2-[1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl]acetonitrile; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.3.1]nonan-9-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-hydroxypiperidine-3-carbonitrile isomer 1; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-hydroxypiperidine-3-carbonitrile isomer 2; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[3-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[3-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 2; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(methoxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-(methoxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[4-(dimethylphosphoryl)piperidin-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3aR,5S,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5-methyl-octahydrocyclopenta[c]pyrrol-5-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[4-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3-carbonitrile isomer 1; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3-carbonitrile isomer 2; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[3-(dimethylphosphoryl)piperidin-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[3-(dimethylphosphoryl)piperidin-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 2; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 2; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]heptan-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(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)-4-methyl-1,4-azaphosphinane 4-oxide; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[6-(hydroxymethyl)-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[6-(hydroxymethyl)-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[2-(hydroxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(pyrrolidin-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidine-3-carbonitrile; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1λ 6 -thiomorpholine-1,1-dione; (9aR)-8-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-octahydropiperazine o[2,1-c]morpholin-4-one; (8aR)-7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(4-methanesulfonylpiperidin-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-N,N-dimethylpiperidine-4-sulfonamide; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-7-azaspiro[3.5]nonan-7-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(piperidin-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{2-azabicyclo[2.2.1]heptan-2-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{8-azabicyclo[3.2.1]octan-8-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{hexahydro-1H-furo[3,4-c]pyrrol-5-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2R)-2-(hydroxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-(hydroxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (8aS)-7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)morpholine-2-carbonitrile; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(3R)-3-ethylmorpholin-4-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]heptan-5-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidine-4-carbonitrile; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidin-3-ol; 7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-7-azaspiro[3.5]nonan-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-4-methylpiperidin-4-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidine-3-carbonitrile isomer 1; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidine-3-carbonitrile isomer 2; 5-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-2-methyl-1λ 6 ,2,5-thiadiazepane-1,1-dione; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(3S)-3-ethylmorpholin-4-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidin-4-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(4-methoxypiperidin-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-8-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-8-methyl-3-azabicyclo[3.2.1]octan-8-ol; (8aS)-7-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-azabicyclo[3.3.1]nonan-9-ol; (3aR,5R,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-5-(difluoromethyl)-octahydrocyclopenta[c]pyrrol-5-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(methoxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-(methoxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[4-(dimethylphosphoryl)piperidin-1-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3aR,5S,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-5-methyl-octahydrocyclopenta[c]pyrrol-5-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[4-(methoxymethyl)piperidin-1-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-azabicyclo[3.1.1]heptan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{9-oxa-3-azabicyclo[4.2.1]nonan-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidin-3-ol; (3R)-1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidin-3-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3S)-1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidin-3-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,4-oxazepan-6-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,4-oxazepan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(6-methoxy-1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(6-methoxy-1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-3-one; 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(1-fluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl]cyclopropane-1-carbonitrile; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2-fluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(2,2-difluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(2,2-difluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 2; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-({1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl}methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(oxane-4-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-7-6fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{8-[(1s,4s)-4-hydroxycyclohexanecarbonyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{8-methanesulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine; 1-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one; 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[6-(hydroxymethyl)-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{6-oxa-3-azabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-(azepan-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (1S,4S)-5-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-3-one; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]heptan-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]heptan-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(1-methyl-octahydro-1H-indol-3a-yl)methoxy]-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{2-methyl-2H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol isomer 1; 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol isomer 2; 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (4R)-4-[(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)amino]pyrrolidin-2-one; 4-[2-({1H,2H,3H,5H,9bH-benzo[a]pyrrolidin-9b-yl}methoxy)-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{2-methyl-2H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[5-hydroxy-2-(propan-2-yl)phenyl]pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(2-cyclobutyl-5-hydroxyphenyl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(2-{bicyclo[1.1.1]pentan-1-yl}-5-hydroxyphenyl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-hydroxy-3-methylpiperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-1-(difluoromethyl)-1,2-dihydropyridin-2-one; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-hydroxy-3-methylpiperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-2-(difluoromethyl)-1,2-dihydroisoquinolin-1-one; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[1-(difluoromethoxy)isoquinolin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-hydroxy-3-methylpiperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-2-(difluoromethyl)-6-(trifluoromethyl)-1,2-dihydroisoquinolin-1-one; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[1-(difluoromethoxy)-6-(trifluoromethyl)isoquinolin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[5-hydroxy-2-(propan-2-yl)phenyl]quinazolin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(2-cyclobutyl-5-hydroxyphenyl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(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)azepan-4-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(2-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(2-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 2; 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)-1,4-oxazepan-6-ol; 1-(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)-3-methylazepan-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazepan-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazepan-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 2; 5-ethyl-6-fluoro-4-(8-fluoro-4-(6-(hydroxymethyl)-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 1-(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)-3-(fluoromethyl)piperidin-3-ol isomer 1; 1-(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)-3-(fluoromethyl)piperidin-3-ol isomer 2; 4-(2-(((4aS,7aR)-1-ethyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethyl-4-(2-(((4aS,7aR)-1-ethyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol; 2-(1-(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)piperidin-3-yl)acetonitrile; 2-(1-(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)-3-methylpiperidin-3-yl)acetonitrile; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-(hydroxymethyl)azepan-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 4-(4-((S)-3-(2,2-difluoroethyl)piperidin-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 6-(difluoromethyl)-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)-1,4-oxazepan-6-ol; 4-(2-(((4aS,7aR)-1-cyclopropyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 2-(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)-1,4-oxazepan-6-yl)acetonitrile isomer 1; 2-(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)-1,4-oxazepan-6-yl)acetonitrile isomer 2; 1-(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)-3-(trifluoromethyl)piperidin-3-ol isomer 1; 1-(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)-3-(trifluoromethyl)piperidin-3-ol isomer 2; 4-(7-(8-ethyl-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)-6-methyl-1,4-oxazepan-6-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(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)-3-azabicyclo[3.2.1]octan-6-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(5-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-chloro-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(5-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 2; 1-(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)-3-methylazepan-3-ol; 4-(4-(3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-(hydroxymethyl)azepan-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 2; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 5-ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 2; 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(6-fluoro-6-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(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)-3-azabicyclo[4.1.0]heptan-1-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane; 3-(difluoromethyl)-1-(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)piperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((3S,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazocane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (3R)-1-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((4aS)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 6-cyclopropyl-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)-1,4-oxazepan-6-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-methyloctahydro-3aH-indol-3a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-methyloctahydro-3aH-indol-3a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; 3-(difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methyloctahydro-1H-cyclopenta[b]pyridine 1-oxide; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-5-methyl-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 4-(2-(((4aS,7aR)-1-cyclopropyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(5-(difluoromethoxy)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3-ol; (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-3-fluoro-1-(methyl-d3)octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-3-fluoro-1-(methyl-d3)octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazocane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((3R,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((3S,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-2-(((4aS,7aR)-1-(methyl-d3)octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (R)-1-(2-((1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolidin-6',1''-cyclopropane]-7a'(7'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3R)-1-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol, and 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the present disclosure provides atropisomers of the compounds of any of the previous embodiments. In certain embodiments, the compounds are stable atropisomers as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0071] Unless otherwise indicated, any atom with unsatisfied valences is assumed to have enough hydrogen atoms to satisfy the valences.

[0072] The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise.

[0073] As used herein, the term "or" is a logical or (i.e., and / or) and does not indicate an exclusive or unless expressly indicated by words such as "either," "otherwise," "alternatively," and words of similar effect.

[0074] As used herein, the phrase "or a pharmaceutically acceptable salt thereof" refers to at least one compound or at least one salt of a compound, or a combination thereof. For example, "a compound of Formula (I) or a pharmaceutically acceptable salt thereof" includes, but is not limited to, a compound of Formula (I), two compounds of Formula (I), a pharmaceutically acceptable salt of a compound of Formula (I), a compound of Formula (I) and one or more pharmaceutically acceptable salts of a compound of Formula (I), and two or more pharmaceutically acceptable salts of a compound of Formula (I).

[0075] The term "C2-C4 alkenyl," as used herein, refers to a group derived from a hydrocarbon containing from 2 to 4 carbon atoms and one double bond.

[0076] 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.

[0077] The term "C1-C6 alkoxy," as used herein, refers to a C1-C6 alkyl group attached to the parent molecular moiety through an oxygen atom.

[0078] The term "C1-C3 alkoxy C1-C3 alkyl," as used herein, refers to a C1-C3 alkoxy group attached to the parent molecular moiety through a C1-C3 alkyl group.

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

[0080] 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.

[0081] The term "C1-C3 alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 3 carbon atoms.

[0082] The term "C1-C6 alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 6 carbon atoms.

[0083] The term "(C1-C6 alkyl)amino," as used herein, refers to R-NH, where R is a C1-C6 alkyl group.

[0084] The term "(C1-C6 alkyl)amino C1-C3 alkyl," as used herein, refers to a (C1-C6 alkyl)amino group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0085] 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.

[0086] The term "C1-C3 alkylene," as used herein, refers to a divalent straight-chain saturated hydrocarbon containing from 1 to 3 carbon atoms.

[0087] The term "haloC1-C3 alkylcarbonyl," as used herein, refers to a haloC1-C3 alkyl group attached to the parent molecular moiety through a carbonyl group. In some embodiments, the haloC1-C3 alkylcarbonyl is -C(O)CF3.

[0088] The term "C2-C4 alkynyl," as used herein, refers to a group derived from a hydrocarbon containing from 2 to 4 carbon atoms and one triple bond.

[0089] The term "C2-C4 alkynyloxy," as used herein, refers to a C2-C4 alkynyl group attached to the parent molecular moiety through an oxygen atom.

[0090] The term "amino," as used herein, refers to --NH.sub.2.

[0091] 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.

[0092] The term "aryl," as used herein, refers to a phenyl group or a bicyclic or tricyclic ring system in which at least one of the rings is a phenyl group. Bicyclic and tricyclic fused ring systems consist of a phenyl group fused to a 4- to 8-membered aromatic or non-aromatic monocyclic or bicyclic fused or spirocyclic ring system. The aryl groups of the present disclosure can be attached to the parent molecular moiety through any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and 2',3'-dihydrospiro(cyclopropane-1,1'-indenyl).

[0093] 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.

[0094] The term "carboxy" as used herein refers to -CO2H.

[0095] The term "carboxy C1-C6 alkyl," as used herein, refers to a C1-C6 alkyl group substituted with one, two, or three carboxy groups.

[0096] The term "cyano," as used herein, refers to --CN.

[0097] The term "cyano C1-C3 alkoxy," as used herein, refers to a C1-C3 alkoxy group substituted by a cyano group.

[0098] The term "C3-C4 cycloalkyl," as used herein, refers to a saturated monocyclic hydrocarbon ring system having 3 or 4 carbon atoms and 0 heteroatoms (e.g., cyclopropyl, cyclobutyl).

[0099] The term "C3-C6 cycloalkyl," as used herein, refers to a saturated monocyclic or bicyclic hydrocarbon ring system having 3 to 6 carbon atoms and 0 heteroatoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentanyl, cyclohexyl).

[0100] The term "C3-C8 cycloalkyl," as used herein, refers to a saturated monocyclic or bicyclic hydrocarbon ring system having 3, 4, 5, 6, 7, or 8 carbon atoms and 0 heteroatoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentanyl). In some embodiments, the C3-C8 cycloalkyl is fused to a heterocyclyl or heteroaryl, as described herein.

[0101] The term "C3-C6 cycloalkyl C1-C6 alkyl," as used herein, refers to a C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) attached to the parent molecular moiety through a C1-C6 alkyl group.

[0102] The term "C3-C6 cycloalkylcarbonyl," as used herein, refers to a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) attached to the parent molecular moiety through a carbonyl group.

[0103] The term "di(C1-C6 alkyl)amino" as used herein refers to -NR z R z’ In the formula, R z and R z’ are the same or different C1 to C6 alkyl groups.

[0104] The term "di(C1-C3 alkyl)aminoC2-C6 alkyl" as used herein means -(C2-C6 alkyl)NR z R z’ In the formula, R z and R z’ are the same or different C1 to C6 alkyl groups.

[0105] The term "dimethylphosphino," as used herein, refers to -P(O)(CH3)2.

[0106] The term "dimethylsulfonamide," as used herein, refers to -S(O)N(CH).

[0107] The terms "halo" and "halogen" as used herein refer to F, Cl, Br, or I.

[0108] The term "halo C1-C3 alkoxy," as used herein, refers to a C1-C3 alkoxy group substituted with one, two, or three halogen atoms.

[0109] The term "haloC1-C3 alkyl," as used herein, refers to a C1-C3 alkyl group substituted with one, two, or three halogen atoms.

[0110] The term "haloC1-C6 alkyl," as used herein, refers to a C1-C6 alkyl group substituted with one, two, or three halogen atoms.

[0111] The term "heteroaryl," as used herein, refers to an aromatic 5- or 6-membered ring in which at least one atom is selected from N, O, and S, and the remaining atoms are carbon. The term "heteroaryl" also includes bicyclic systems in which a heteroaryl ring is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S; and tricyclic systems in which a bicyclic system is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S. A heteroaryl group is attached to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. Representative examples of heteroaryl groups include, but are not limited to, alloxazine, benzo[1,2-d:4,5-d']bisthiazole, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.

[0112] The term "heteroaryl C1-C6 alkyl," as used herein, refers to a heteroaryl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0113] The term "heterocyclyl," as used herein, refers to a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered saturated or partially unsaturated ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" also includes groups in which a heterocyclyl ring is fused to one, two, or three 4- to 6-membered aromatic or non-aromatic carbocyclic rings or monocyclic heterocyclyl groups. The term "heterocyclyl" also includes monocyclic or polycyclic heterocyclyl groups, as described above, that are further substituted with one or more spirocyclic groups attached to the heterocyclyl group through a spirocarbon. Examples of heterocyclyl groups include, but are not limited to, dihydro-1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolidine-6',1''-cyclopropane], hexahydro-2H-1,4-dioxa-2a1-azacyclopenta[cd]pentalenyl, hexahydropyrrolidinyl, indolinyl, morpholinyl, octahydroindolizinyl, octahydroquinolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, thiatanyl, thiolanyl, thienyl, 1,2-dioxanyl, 1,4-dioxanyl, trimethylenyl oxide, thiazolinyl, imidazolidinyl, homopiperazinyl, pyrrolinyl, tetrahydrothiofuranyl, pyranyl, and thiomorpholinyl. The term "4-6 membered heterocyclyl" refers to a "heterocyclyl" group as defined above containing 4, 5 or 6 members in the ring.

[0114] In particular, R 5 is a 5-10 membered monocyclic, bicyclic, or tricyclic ring containing one nitrogen atom and optionally containing 1-3 additional heteroatoms selected from the group consisting of oxygen or nitrogen, the ring contains 0-3 double bonds, and the bicyclic or tricyclic ring may be formed by fusion of an additional ring, or the additional ring may be a spirocyclic ring. c and R dtaken together with the nitrogen atom to which they are attached to form a 5-10 membered monocyclic, bicyclic, or tricyclic ring, optionally containing 1-3 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the bicyclic or tricyclic ring may be formed by fusion of a second ring, or the second ring may be a spiro ring similar to those described in the preceding paragraph.

[0115] The term "heterocyclylC1-C3 alkyl," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0116] The term "heterocyclylC1-C6 alkyl," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0117] The term "hydroxy," as used herein, refers to --OH.

[0118] 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.

[0119] The term "hydroxy C1-C6 alkyl," as used herein, refers to a hydroxy group attached to the parent molecular moiety through a C1-C6 alkyl group.

[0120] The term "methylsulfonyl," as used herein, refers to -S(O)2CH3.

[0121] The term "oxo" as used herein refers to =O.

[0122] The term "tetrahydropyranylcarbonyl," as used herein, refers to a tetrahydropyranyl group attached to the parent molecular moiety through a carbonyl group. The carbonyl can be attached to the tetrahydropyranyl moiety at any suitable position, such as the 1-, 2-, 3-, or 4-position. In one aspect, the carbonyl is attached to the tetrahydropyranyl group at the 4-position.

[0123] A further aspect of the subject matter described herein is the use of the disclosed compounds as radiolabeled ligands for the development of ligand binding assays or for monitoring in vivo adsorption, metabolism, distribution, receptor binding or occupancy, or compound disposition. For example, the compounds described herein can be prepared using radioisotopes, and the resulting radiolabeled compounds can be used to develop binding assays or for metabolic studies. Alternatively, and for the same purpose, the compounds described herein can be converted to radiolabeled forms by catalytic tritiation using methods known to those skilled in the art.

[0124] Certain compounds of the present disclosure exist as stereoisomers.When stereochemistry is not specified, it should be understood that the present disclosure encompasses all stereochemical isomeric forms or mixtures thereof that have the ability to inhibit mutant KRAS.Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products and then separating them, for example, by converting them into diastereomeric mixtures, followed by separation or recrystallization, or by directly separating enantiomers using chromatographic methods or chiral chromatography columns.Starting compounds of specific stereochemistry are commercially available, or can be prepared and resolved by techniques known in the art.

[0125] Certain compounds of the present disclosure exist as atropisomers. The term "atropisomer" refers to a conformational stereoisomer that occurs when rotation around a single bond in a molecule is prevented or significantly retarded as a result of steric interactions with other parts of the molecule, and the substituents on both ends of the single bond are asymmetric (i.e., optical activity occurs without the need for an asymmetric carbon center or stereocenter). If the rotation barrier around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of isomeric species may be possible. Atropisomers are enantiomers (or epimers) that do not have a single asymmetric atom.

[0126] Atropisomers can be considered stable if the barrier to interconversion is high enough to allow the atropisomers to undergo little or no interconversion at room temperature for at least one week. In some embodiments, the atropisomers undergo little or no interconversion at room temperature for at least one year. In some embodiments, the atropisomeric compounds of the present disclosure do not undergo more than about 5% interconversion to their opposite atropisomers at room temperature for one week when the atropisomeric compounds are in substantially pure form, typically in the solid state. In some embodiments, the atropisomeric compounds of the present disclosure do not undergo more than about 5% interconversion to their opposite atropisomers at room temperature (about 25° C.) for one year. In some embodiments, the atropisomeric compounds of the present disclosure are sufficiently stable to undergo no more than about 5% interconversion in aqueous pharmaceutical formulations held at 0° C. for at least one week. The present chemical compounds, pharmaceutical compositions and methods are intended to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of single atropisomers and intermediate mixtures.

[0127] The energy barrier to thermal racemization of atropisomers can be determined by steric hindrance to free rotation of one or more bonds forming the chiral axis. Certain biaryl compounds exhibit atropisomerism when rotation around an intercyclic bond lacking C2 symmetry is restricted. The free energy barrier to isomerization (enantiomerization) is a measure of the stability of the intercyclic bond against rotation. Optical and thermal excitation can promote the racemization of such isomers, depending on electronic and steric factors.

[0128] Ortho-substituted biaryl compounds may exhibit this type of conformational rotational isomerism. Such biaryls are enantiomeric chiral atropisomers, with sp between the aryl rings. 2 -sp 2 The carbon-carbon intercyclic bond has a sufficiently high energy barrier to prevent free rotation, and the substituent W 1 ≠W 2 and W 3 ≠W 4 makes the molecule asymmetric. [ka]

[0129] W 1 :W 3 , W 1 :W 4 and / or W 2 :W 4 , W 2 :W 3 The steric interactions between the two are large enough to make the planar conformation the energy maximum. Two nonplanar, axially chiral enantiomers then exist as atropisomers if their interconversion is slow enough so that they can be isolated without each other. The bold and dashed lines in the diagram shown above indicate moieties or portions of molecules that are sterically restricted due to rotational energy barriers. The bolded portions lie perpendicularly above the plane of the paper, and the dashed portions lie perpendicularly below the plane of the paper. The "flat" portions of the molecules (the left rings of each of the two biaryls shown) lie in the plane of the paper.

[0130] The pharmaceutical compounds of the present disclosure may include one or more pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see, for example, Berge, SM et al., J. Pharm. Sci., 66:1-19 (1977)). Salts can be obtained during the final isolation and purification of the compounds described herein, or by separately reacting a free base functional group of the compound with a suitable acid or by reacting an acidic group of the compound with a suitable base. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like, as well as non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, and calcium, and from non-toxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine.

[0131] Pharmaceutical Composition In another aspect, the present disclosure provides compositions, e.g., pharmaceutical compositions, containing one or a combination of compounds described within this disclosure formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present disclosure can also be administered in combination therapy, i.e., in combination with other agents described herein.

[0132] As used herein, "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. In some embodiments, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0133] The pharmaceutical compositions of the present disclosure can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by those skilled in the art, the route and / or mode of administration will vary depending on the desired results. In some embodiments, the route of administration of the compounds of the present disclosure includes intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral routes of administration, for example, by injection or infusion. The term "parenteral administration," as used herein, refers to a mode of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0134] Sterile injectable solution can be prepared by incorporating the required amount of active compound into suitable solvent with one or combination of the above-listed components as needed, and then sterilizing by microfiltration.Generally, dispersion is prepared by incorporating active compound into sterile vehicle that contains basic dispersion medium and other components required from above-listed.For the preparation of sterile injectable solution, some preparation methods are vacuum drying and freeze-drying (lyophilization), thereby obtaining the powder of active ingredient and any additional desired components from its solution that has been previously sterilized and filtered.

[0135] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils, and injectable organic esters. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0136] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.The use of such media and agents for pharmaceutically active substances is well known in the art.Except insofar as any conventional media or agent is incompatible with the active compound, its use in the pharmaceutical compositions of the present disclosure is contemplated.Auxiliary active compounds can also be incorporated into the composition.

[0137] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The compositions may be formulated as a solution or liquid with an ordered structure suitable for high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of surfactants. In many cases, it is desirable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0138] Alternatively, the compounds of the present disclosure may be administered parenterally, including topical, epidermal, or mucosal routes of administration, such as intranasally, orally, intravaginally, rectally, sublingually, or topically.

[0139] Any pharmaceutical composition contemplated herein can be orally delivered, for example, through any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for manufacturing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable formulation, pharmaceutical compositions according to the present disclosure may contain at least one agent selected from the group consisting of sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0140] Tablets may, for example, be prepared by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient that is suitable for the manufacture of tablets.

[0141] 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 sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersing or wetting agents, such as naturally occurring phosphatides, for example, lecithin; condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecatylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions 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, for example, but not limited to, sucrose, saccharin, and aspartame.

[0142] Oily suspensions can be prepared by suspending at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in a vegetable oil, such as peanut oil, sesame oil, and coconut oil; or 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. To provide a palatable oily suspension, at least one sweetener and / or at least one flavoring agent described herein above can be added to the oily suspension. Oily suspensions can further contain at least one preservative, including, but not limited to, an antioxidant, such as butylated hydroxyanisole and alpha-tocopherol.

[0143] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersing agent and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents have already been described above. Exemplary preservatives include, but are not limited to, antioxidants, such as ascorbic acid. Furthermore, dispersible powders and granules can also contain at least one excipient, including, but not limited to, sweeteners, flavoring agents, and coloring agents.

[0144] Active compounds can be prepared with carriers that protect compounds from rapid release, such as controlled release formulations, including implants, transdermal patches, and microencapsulated delivery systems.Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used.Many methods for preparing such formulations are patented or generally known to those skilled in the art.For example, see Robinson, JR, ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0145] Therapeutic compositions can be administered using medical devices known in the art.For example, in one aspect, the therapeutic compositions of the present disclosure can be administered using needleless hypodermic injection devices, such as those disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824 or 4,596,556. Examples of well-known implants and modules useful in the present disclosure include U.S. Pat. No. 4,487,603, which discloses an implantable microinfusion pump for dispensing drugs at a controlled rate; U.S. Pat. No. 4,486,194, which discloses a therapeutic device for administering drugs through the skin; U.S. Pat. No. 4,447,233, which discloses a drug infusion pump for delivering drugs at precise infusion rates; U.S. Pat. No. 4,447,224, which discloses a variable flow rate implantable infusion device for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system with multi-chamber compartments; and U.S. Pat. No. 4,475,196, which discloses an osmotic drug delivery system. These patents are incorporated herein by reference. Many other such implants, delivery systems, and modules are known to those skilled in the art.

[0146] In certain aspects, the compounds of the present disclosure may be administered parenterally, i.e., by injection, including but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intrathecal, intraspinal, epidural, and intrasternal injection and / or infusion.

[0147] In some embodiments, the compounds of the present disclosure can be administered orally, i.e., via gelatin capsules, tablets, hard or soft capsules, or liquid capsules.

[0148] Methods of Use / Treatment of KRAS Inhibitors Administration of a therapeutic agent described herein may include administration of a therapeutically effective amount of the therapeutic agent. The term "therapeutically effective amount," as used herein, refers to, but is not limited to, the amount of a therapeutic agent for treating a condition treatable by administration of a composition comprising a KRAS inhibitor described herein. This amount is sufficient to produce a detectable therapeutic effect or an effect that leads to improvement. The effect may include, by way of example and without limitation, treatment of the conditions listed herein. The precise effective amount for a given subject will depend on the subject's size and health, the nature and extent of the condition being treated, the advice of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration.

[0149] For administration of the compounds described herein, dosages range from about 0.0001 to 100 mg / kg, and more usually 0.01 to 40 mg / kg, of the host body weight. Exemplary treatment regimens entail administration once daily, twice weekly, three times weekly, once every week, once every two weeks, once every three weeks, once every four weeks, once every month, once every three months, or once every three to six months.

[0150] The disclosed compounds potently inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, in another aspect, the present disclosure provides a method of inhibiting tumor metastasis, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of any of the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0151] Ras mutations, including but not limited to KRAS mutations, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to the administration of the disclosed compounds (e.g., in the form of pharmaceutical compositions) to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the disclosed compounds can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, the compounds are useful for treating lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0152] Determining whether a tumor or cancer contains a KRAS mutation can be made 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.

[0153] Methods for detecting KRAS mutations are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, samples are evaluated for KRAS mutations, including by real-time PCR. In real-time PCR, a fluorescent probe specific to the KRAS mutation is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRAS mutations are identified using, for example, direct sequencing of a specific region (e.g., exon 2 and / or exon 3) in the KRAS gene. This technique will identify all possible mutations in the sequenced region.

[0154] Methods for detecting mutations in KRAS proteins are known to those skilled in the art, including, but not limited to, detecting KRAS mutants using binding agents (e.g., antibodies) specific to mutant proteins, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0155] The method for determining whether a tumor or cancer contains a KRAS mutation may use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is taken from a subject having a cancer or tumor. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA. The present disclosure also relates to a method for treating a hyperproliferative disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.In some embodiments, the methods involve treating cancer, such as acute myeloid leukemia, adolescent cancer, childhood adrenal cortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloid leukemia (CRL ... Myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), germinoma, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor Tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma of the neck of unknown primary, midline carcinoma, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), mouth cancer, lip and oral cavity cancer, oropharyngeal cancer, The methods relate to the treatment of cancers such as ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinonasal and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric (stomach) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, 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 virus-induced cancer. In some embodiments, the methods relate to the treatment of non-cancerous hyperproliferative diseases such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)).

[0156] In certain embodiments, the present disclosure relates to a method for treating lung cancer, comprising administering an effective amount of any of the above-described compounds (or a pharmaceutical composition comprising same) to a subject in need thereof. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In other embodiments, the lung cancer is small cell lung cancer. Other lung cancers that can be treated with the disclosed compounds include, but are not limited to, ductal tumors, carcinoid tumors, and undifferentiated carcinomas.Subjects that may be treated with the compounds of the present disclosure or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates, or derivatives of said compounds according to the methods of the present disclosure include, for example, acute myeloid leukemia, acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, tumors, cervical cancer, childhood cancer, chordoma, cardiac 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, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma , hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma of the neck of unknown primary, midline carcinoma, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and Included are subjects diagnosed with oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric (stomach) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular tumor, pharyngeal cancer, thymoma and thymic carcinoma, 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 virus-induced cancers.In some embodiments, subjects treated with compounds of the present disclosure include those diagnosed with a non-cancerous hyperproliferative disease, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)). The present disclosure further provides methods of modulating the activity of a mutant KRAS protein by contacting the protein with an effective amount of a compound of the present disclosure. Modulation can be inhibiting or activating protein activity. In some embodiments, the present disclosure provides methods of inhibiting the activity of a protein by contacting a mutant KRAS protein in solution with an effective amount of a compound of the present disclosure. In some embodiments, the present disclosure provides methods of inhibiting the activity of a mutant KRAS protein by contacting a cell, tissue, or organ expressing the protein of interest. In some embodiments, the present disclosure provides methods of inhibiting the activity of a protein in a subject, including, but not limited to, a rodent and a mammal (e.g., a human), by administering to the subject an effective amount of a compound of the present disclosure. In some embodiments, the percentage of modulation is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the disclosure provides methods of inhibiting KRAS activity in a cell by contacting the cell with an amount of a compound of the disclosure sufficient to inhibit the activity of a KRAS mutant in the cell. In some embodiments, the disclosure provides methods of inhibiting mutant KRAS in a tissue by contacting the tissue with an amount of a compound of the disclosure sufficient to inhibit the activity of mutant KRAS in the tissue. In some embodiments, the disclosure provides methods of inhibiting KRAS in an organism by contacting the organism with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS in the organism. In some aspects, the present disclosure provides methods of inhibiting the activity of KRAS in an animal by contacting the animal with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the animal.In some embodiments, the present disclosure provides methods for inhibiting KRAS, including in a mammal, by contacting the mammal with a compound of the present disclosure in an amount sufficient to inhibit KRAS activity in the mammal. In some embodiments, the present disclosure provides methods for inhibiting KRAS activity in a human by contacting the human with a compound of the present disclosure in an amount sufficient to inhibit KRAS activity in the human. The present disclosure also provides methods for treating diseases mediated by KRAS activity in a subject in need of such treatment. The present disclosure also provides methods of combination therapy in which agents known to regulate other pathways or other components of the same pathway, or overlapping sets of target enzymes, are used in combination with a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate, or derivative thereof. In one embodiment, such therapy includes, but is not limited to, combinations of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy.

[0157] Currently, many chemotherapeutic agents are known in the art and can be used in combination with the compounds of the present disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, antiangiogenic agents, and antiandrogens. In some embodiments, the chemotherapeutic agent is an immuno-oncology (IO) agent that can enhance, stimulate, or upregulate the immune system.

[0158] The compounds described herein can be used in combination with the drugs disclosed herein or other suitable drugs, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure will be co-administered with other drugs such as those described above. When used in combination therapy, the compounds described herein are administered simultaneously with the second drug or separately. This combined administration can include simultaneous administration of the two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate dosage forms. That is, the compounds described herein and any of the drugs described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds disclosed herein and any of the drugs described above can be administered simultaneously, with both drugs being in separate formulations. In another alternative, the compounds disclosed herein can be administered followed by any of the drugs described above, or vice versa. In some embodiments of the separate administration protocol, the compounds disclosed herein and any of the drugs described above are administered within minutes, hours, or days.

[0159] The compounds can be made by methods known in the art, including those described below, and including variations within the skill of one in the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. Any variables used to describe the synthesis of the compounds (e.g., numbered "R" substituents) are intended only to illustrate how the compounds are made and should not be confused with variables used in the claims or other sections of this specification. The following methods are for illustrative purposes and are not intended to limit the scope of the present disclosure. [Example]

[0160] synthesis Abbreviations used herein include the following: AA is ammonium acetate; ACN or MeCN is acetonitrile; BOC or Boc is tert-butoxycarbonyl; BOP is (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate); t-Bu or tBu is tert-butyl; DAST is diethylaminosulfur trifluoride; DCM is dichloromethane; DEA is diethanolamine; DIEA or DIPEA is diisopropylethylamine; DMA is dimethylacetamide; DMAP is N,N-dimethylaminopyridine; DMF is dimethylformamide; DMSO is dimethylsulfate. bis(diphenylphosphino)ferrocene; dppf is 1,1'-bis(diphenylphosphino)ferrocene; EtOAc is ethyl acetate; EtOH is ethanol; h is hour; IPA is isopropanol; LAH is lithium aluminum hydride; LCMS is liquid chromatography-mass spectrometry; MeOH is methanol; hexamethyldisilazide; min is minute; MOM is methoxymethyl; Piv is pivaloyl; SNAr is nucleophilic aromatic substitution; TBAF is tetrabutylammonium fluoride; TEA is triethylamine; TFA is trifluoroacetic acid; THF is tetrahydrofuran; and RT is room temperature or retention time (depending on the situation).

[0161] General Scheme The compounds described herein can be prepared according to the methods outlined in Schemes 1-4 shown below and in the Examples. [ka]

[0162] Preparation of Intermediate 2: tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of commercially available 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (10 g, 39.6 mmol) in DCM (200 mL) at −40° C., DIPEA (20.8 mL, 119 mmol) was added, followed by tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.41 g, 39.6 mmol). The reaction mixture was stirred at −40° C. for 30 minutes. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (120 g silica gel column, 50-80% ethyl acetate / petroleum ether) to give tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (13 g, 30.4 mmol, 77% yield) as a pale yellow solid. MS (ESI) m / z: 428.3 [M+H] + .

[0163] Preparation of Intermediate 3: Ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate [ka] To a stirred solution of ethyl 5-oxopyrrolidine-2-carboxylate (30 g, 191 mmol) and 3-chloro-2-(chloromethyl)prop-1-ene (38.2 g, 305 mmol) in THF (150 mL) at −40° C. under an argon atmosphere, LiHMDS (382 mL, 382 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was then poured into aq. 1 M HCl (50 mL) and the pH was adjusted to 7 at 0° C. The mixture was extracted three times with EtOAc. The combined extracts were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography using COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (petroleum ether / EtOAc = 0 to 50%) to give the title compound ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (15 g, 71.7 mmol, 38% yield) as a yellow oil. The product was confirmed by NMR. 1 H NMR(300MHz,CDCl3)δ=5.12-5.01(m,2H),4.32-4.28(m,1H),4.20(q,J=12.1Hz,2H),3.73(br d,J=15.5Hz,1H),3.06(br d,J=15.5Hz,1H),2.88-2.69(m,1H),2.67-2.54(m,1H),2.54-2.38(m,2H),2.21-2.04(m,1H),1.27(t,J=12.1Hz,3H).

[0164] Preparation of Intermediate 4: Ethyl 2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate [ka] A stirred solution of ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (Intermediate 3, 6 g, 28.7 mmol) in DCM (60 mL)-MeOH (12 mL) was purged with O for 30 minutes at −70° C. Then, N was purged for 30 minutes, and dimethyl sulfide (4.5 mL, 57.3 mmol) was added to the mixture at −70° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure to provide a crude residue, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (120 g column, EtOAc-petroleum ether=0 to 50%) to afford the title compound ethyl 2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (4.7 g, 22.25 mmol, 78% yield) as a yellow oil. 1 H NMR(300MHz,CDCl3)δ=4.24(q,J=7.2Hz,2H),4.13(d,J=18.5Hz,1H),3.57(d,J=18.5Hz,1H),3. 05-2.96(m,2H),2.91-2.72(m,1H),2.54-2.39(m,2H),2.25-2.11(m,1H),1.29(t,J=7.2Hz,3H).

[0165] Preparation of Intermediate 5: (±)-Ethyl (2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate [ka] To a stirred solution of ethyl 2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (Intermediate 4, 4.7 g, 22.25 mmol) in ethanol (30 mL) at 0 °C was added sodium borohydride (0.25 g, 6.68 mmol) in portions. The reaction mixture was stirred at 0 °C for 10 minutes. The reaction was quenched with saturated aqueous NH4Cl (2 mL) and stirred for 30 minutes at 5 °C. The reaction mixture was concentrated under reduced pressure to provide a crude residue, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (40 g column, 0-7% MeOH-DCM) to give (±)-ethyl (2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (2.2 g, 10.32 mmol, 46% yield). Approximately 10% of the other diastereomer is present. 1 H NMR(300MHz,CDCl3)δ=4.71-4.59(m,1H),4.26(q,J=7.2Hz,2H),3.98(dd,J=12.8,5.9Hz,1H),3.12(d,J=12. 8Hz,1H),2.91-2.76(m,1H),2.65-2.39(m,4H),2.16-1.93(m,1H),1.89-1.81(m,1H),1.32(t,J=7.2Hz,3H).

[0166] Preparation of Intermediate 6: Ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate [ka] To a stirred solution of (±)ethyl (2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (Intermediate 5, 4.5 g, 21.10 mmol) in DCM (30 mL) at −70° C. was added DAST (4.2 mL, 31.7 mmol). The reaction mixture was allowed to warm gradually to room temperature over 16 h. The reaction mixture was cooled to 0° C., quenched with MeOH (1.5 mL), and diluted with water (50 mL). The mixture was extracted with DCM (3×). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (40 g column, 55% Pet-ether-EtOAc) to give (±)-ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (2.1 g, 9.76 mmol, 46.2% yield) as a yellow liquid. The compound was purified by chiral supercritical fluid chromatography (SFC) (Column: CHIRALPAK™ IC (Daicel, Japan) (250 × 21 mm, 5 μm); % CO 70%, % co-solvent 30%, 0.2% NH 3 .H 2 O in IPA; flow rate: 70 g / min; back pressure: 100 bar; temperature 40 °C. Peak 1: retention time = 3 min; Peak 2: retention time = 4.3 min. Peak 3: 1 H NMR(300MHz,CDCl3)δ=5.31(dt,J=54.2,4.1Hz,1H),4.30-4.14(m,3H),3.32-3.07(m ,1H),2.87-2.56(m,3H),2.50-2.36(m,1H),2.32-2.05(m,2H),1.29(t,J=7.2Hz,3H).

[0167] Preparation of Intermediate 7: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol [ka] A solution of ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (Intermediate 6, 1 g, 4.65 mmol) in THF (9 mL) was added dropwise to an ice-cold solution of 2.4 M LAH in THF (2.90 mL, 6.97 mmol). The reaction mixture was heated to 70° C. for 4 hours. The reaction mixture was cooled to 0° C. and quenched with water (1.2 mL), 10% NaOH (3 mL), and additional water (3 mL). The reaction mixture was then stirred for 10 minutes and filtered through a diatomaceous earth pad (CELITE™, Sigma Aldrich, St. Louis, MO). The pad was washed with EtOAc. The filtrate was concentrated under reduced pressure and purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (12 g column, 20-60% MeOH-DCM) to provide ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (550 mg, 3.45 mmol, 74% yield) as a colorless liquid. TLC system: 20% MeOH-DCM (Rf: 0.1); 1 H NMR (300 MHz, CDCl) δ = 5.29-5.11 (m, 1H), 3.26 (s, 2H), 3.24-3.13 (m, 2H), 3.13-3.01 (m, 1H), 2.98-2.83 (m, 1H), 2.16-2.08 (m, 1H), 2.06-2.01 (m, 1H), 1.99-1.73 (m, 4H). (No exchangeable OH protons appear.)

[0168] Preparation of Intermediate 8: Ethyl (S)-2-((1-phenylethyl)amino)cyclopent-1-ene-1-carboxylate [ka] To a stirred solution of ethyl 2-oxocyclopentane-1-carboxylate (140.5 g, 900 mmol) and 4 Å molecular sieves in DCM (500 mL) was added (S)-1-phenylethan-1-amine (109 g, 900 mmol) at room temperature. The reaction mixture was stirred under reflux for 1 day. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth pad (CELITE™, Sigma Aldrich, St. Louis, MO), and the filtrate was concentrated under reduced pressure to provide a crude residue, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 4-5% ethyl acetate / petroleum ether to give ethyl (S)-2-((1-phenylethyl)amino)cyclopent-1-ene-1-carboxylate (233 g, 898 mmol, 100% yield). MS (ESI) m / z: 259.8 [M+H] + .

[0169] Preparation of Intermediate 9: Ethyl (S,E)-1-(3-ethoxy-3-oxopropyl)-2-(((S)-1-phenylethyl)imino)cyclopentane-1-carboxylate [ka] To a mixture of zinc(II) chloride (473 mL, 898 mmol) and ethyl acrylate (90 g, 898 mmol) in 2-MeTHF at 0 °C was added dropwise ethyl (S)-2-((1-phenylethyl)amino)cyclopent-1-ene-1-carboxylate (Intermediate 8, 233 g, 898 mmol) in THF (233 mL), and the mixture was stirred at 0 °C for 16 h. The reaction mixture was neutralized with saturated NaOH solution and extracted with EtOAc (3 × 500 mL). The combined extracts were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give ethyl (S,E)-1-(3-ethoxy-3-oxopropyl)-2-(((S)-1-phenylethyl)imino)cyclopentane-1-carboxylate (300 g, 835 mmol, 93% yield) as a colorless oil, which was used for the next step without further purification. MS(ESI)m / z:360.1[M+H] + .

[0170] Preparation of Intermediate 10: Ethyl (4aS)-2-oxooctahydro-4aHcyclopenta[b]pyridine-4a-carboxylate [ka] A mixture of ethyl (S,E)-1-(3-ethoxy-3-oxopropyl)-2-(((S)-1-phenylethyl)imino)-cyclopentane-1-carboxylate (Intermediate 9, 145 g, 403 mmol) and 10% palladium on carbon (35 g, 10% w / w) in ethanol (336 mL) was hydrogenated under 50 PSI of hydrogen at room temperature for 18 hours. The reaction mixture was filtered through a pad of diatomaceous earth (CELITE™, Sigma Aldrich, St. Louis, MO), and the filtrate was concentrated under reduced pressure to give a crude residue that was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 4-5% ethyl acetate / petroleum ether to give ethyl (4aS)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (36 g, 170 mmol, 42.2% yield) as a colorless oil. MS (ESI) m / z: 211.6 [M+H] + .

[0171] Preparation of Intermediate 11: ((4aS,7aR)-Octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol [ka] A solution of ethyl (4aS)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (Intermediate 10, 23.7 g, 112 mmol) in THF (415 mL) was added dropwise to an ice-cold solution of 1 M LAH in THF (258 mL, 258 mmol). The reaction mixture was heated to 70° C. for 4 hours. The reaction mixture was cooled to 0° C. and quenched with water (9.8 mL), 10% NaOH (9 mL), and additional water (27 mL). The reaction mixture was then allowed to warm to room temperature and stirred for 20 minutes. The reaction mixture was filtered through a pad of diatomaceous earth (CELITE™, Sigma Aldrich, St. Louis, MO) and washed with excess EtOAc. The filtrate was dried over NaSO, filtered, and concentrated under reduced pressure to give ((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (17.3 g, 111 mmol, 99% yield) as a white solid, which was used directly for the next step without further purification. MS (ESI) m / z: 156.0 [M+H] + .

[0172] Preparation of Intermediate 12: ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol [ka] A solution of ((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (Intermediate 11, 33.8 g, 218 mmol) in MeOH (335 mL) was cooled to 5 °C, and formaldehyde (51.0 mL, 653 mmol) was added over 5 min, followed by the addition of sodium triacetoxyhydroborate (50.8 g, 239 mmol) in several portions, then stirred at room temperature for 4 h. After 4 h, the reaction mixture was concentrated, diluted with 300 mL of 2-MeTHF, and then washed with saturated aqueous KCO. The aqueous phase was extracted with EtOAc (7x), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to provide the crude residue. The compound was purified by chiral SFC [column: BEH2-ethylpyridine (5 × 25 cm, 5 μm); % CO2 90%, % cosolvent 10%, 0.2% NH4OH in MeOH; flow rate: 300 mL / min; back pressure: 100 bar; temperature 35 °C to give ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (28 g, 166 mmol, 76% yield). 1H NMR (400 MHz, chloroform-d) δ = 3.82 (br d,J=4.4Hz,1H),3.70-3.59(m,2H),2.86(t,J=7.7Hz,1H),2.55-2.46(m,1H),2.41-2.33(m,1H) ,2.33-2.24(m,3H),1.98-1.83(m,2H),1.83-1.72(m,1H),1.68-1.51(m,4H),1.48-1.33(m,3H).

[0173] Preparation of intermediate 13: tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of [(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methanol, HCl salt (Intermediate 7, 5.48 g, 28.0 mmol) in DCM (20 mL) was added approximately 10 g of Na2CO3, and the mixture was stirred at room temperature for 30 minutes. The solid was filtered, and the filtrate was evaporated under reduced pressure at 20 °C to give the free amine, which was dissolved in 1,4-dioxane (100 mL). Next, tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 3, 10 g, 23.35 mmol) and Cs2CO3 (22.82 g, 70.0 mmol) were added to the above solution, and the reaction mixture was heated in a sealed tube at 85 °C for 16 hours. The reaction mixture was filtered through a diatomaceous earth pad (CELITE™, Sigma Aldrich, St. Louis, MO), washed with excess DCM, and the filtrate was concentrated under reduced pressure to give a crude residue that was purified by silica gel column chromatography using a COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (120 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), 80–100% EtOAc-petroleum ether) to give tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7 g, 12.70 mmol, 54.4% yield) as a pale yellow solid. MS(ESI)m / z:553.5(M+H) + .

[0174] Preparation of intermediate 14: tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] tert-Butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 13, 5 g, 9.07 mmol) in 1,4-dioxane (110 mL) and water (33 mL). To the stirred solution was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (5.12 g, 9.98 mmol) and CsCO (8.87 g, 27.2 mmol), followed by PdCl(dppf) (0.66 g, 0.907 mmol). The reaction mixture was purged with N for 5 minutes and then heated in a microwave reactor at 105 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (80 g silica gel column, 50-100% ethyl acetate / petroleum ether) to give tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.5 g, 3.88 mmol, 43% yield) as a brown solid. MS(ESI)m / z:901.7[M+H] + .

[0175] Preparation of intermediate 15: tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 14, 3.7 g, 4.11 mmol) in DMF (50 mL) was added CsF (6.24 g, 41.1 mmol). The reaction mixture was heated at 50° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.9 g, 3.89 mmol, 95% yield) as a brown liquid, which was used for the next step without further purification. MS (ESI) m / z: 746.6 [M+H] + .

[0176] Preparation of intermediate 16: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol [ka] To a stirred solution of tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 15, 3 g, 4.03 mmol) in EtOH (15 mL) and THF (15 mL) was added NaOH (1 M aqueous solution) (40.3 mL, 40.3 mmol). The reaction mixture was heated at 70 °C for 3 h. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with saturated NH4Cl solution, water, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (24 g silica gel column, 10-20% MeOH / DCM) to give 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol (850 mg, 1.544 mmol, 38.3% yield) as a brown solid. MS (ESI) m / z: 551.4 [M+H] + .

[0177] Preparation of intermediate 17: (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolidine [ka] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol (Intermediate 16, 400 mg, 0.727 mmol) in ACN (10 mL) was added morpholine (76 mg, 0.872 mmol), triethylamine (0.405 mL, 2.91 mmol), and BOP (482 mg, 1.09 mmol). The reaction mixture was heated at 80° C. for 8 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude residue. The crude material was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 40 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), eluting with a gradient of 60-100% EtOAc in petroleum ether. Evaporation of fractions containing the desired product afforded (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolidine (450 mg, 89% yield) as a brown liquid, which was used in the next step without purification. MS (ESI) m / z: 620.6 [M+H] + .

[0178] Example 1-1 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka] To a stirred solution of tert-butyl 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-octahydropyrrolo[3,2-b]pyrrole-1-carboxylate (Intermediate 17, 500 mg, 0.807 mmol) in acetonitrile (5 mL) at 0° C. was added 4 N HCl (0.49 mL, 16.14 mmol in 1,4-dioxane), and the reaction mixture was stirred at room temperature for 1 hour. Volatiles from the reaction mixture were removed under reduced pressure (lower temperature, approximately 30° C.), and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (2 mL) and excess TEA (1 mL) was added. The mixture was concentrated under reduced pressure to give an off-white solid. The crude compound was purified by prep-HPLC (high performance liquid chromatography) [HPLC method: Preparative column: EVO (250 × 30 × 5); Mobile phase A: 10 mM ammonium bicarbonate in water - 9.5 pH; Mobile phase B: acetonitrile; Gradient = 0 (min) - 20%, 8-48%, 13.5-48%, 14-100%, 15-100%, 15.5-20-20%; Temperature: 27 °C; Flow rate: 30.0 mL / min; Detection: 220 and 25 Purification by UV at 4 nm gave 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (50 mg, 0.084 mmol, 10.4% yield). MS (ESI) m / z: 576.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ ppm=10.13(s,1H),9.08(s,1H),7.97(dd,J=5.9,9.1Hz,1H),7.46(t,J=9.0Hz,1H),7.39(d,J=2.5Hz,1H),7.21(d,J=2.3Hz,1H),5.37-5.19( m,1H),4.15-4.11(m,2H),4.05-3.92(m,7H),3.84-3.82(m,4H),3.15- 2.99(m,3H),2.87-2.77(m,1H),2.20-1.98(m,2H),1.93-1.70(m,2H).

[0179] Preparation of intermediate 18: (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolidine [ka] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol (300 mg, 0.545 mmol) in ACN (10 mL) was added 1,4-oxazepane (66.1 mg, 0.654 mmol), DIPEA (0.29 mL, 1.635 mmol), and BOP (362 mg, 0.817 mmol). The reaction mixture was heated at 80° C. for 8 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude residue. The crude material was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 40 g REDISEP™ column (Teledyne ISCO, Lincoln, NE) eluted with a gradient of 60-100% EtOAc in petroleum ether. Evaporation of fractions containing the desired product afforded (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolidine (330 mg, 96% yield) as a brown liquid. MS (ESI) m / z: 634.6 [M+H] + .

[0180] Example 1-2 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka] To a stirred solution of (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolidine (330 mg, 0.521 mmol) in acetonitrile (5 mL) at 0 °C, 4 N HCl (1.3 mL, 5.21 mmol in 1,4-dioxane) was added, and the reaction mixture was stirred at room temperature for 1 hour. Volatiles from the reaction mixture were removed under reduced pressure (lower temperature, approximately 30 °C), and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (2 mL), and excess TEA (1 mL) was added. The mixture was evaporated under reduced pressure to give an off-white solid. The crude compound was purified by Prep-HPLC [HPLC method: Preparative column: Waters XBridge BEH C18 XP (50 × 2.1 mm) 2.5 μm; Mobile phase A: 5:95 acetonitrile:water with 10 mM NH4OAc; Mobile phase B: 95:5 acetonitrile:water with 10 mM NH4OAc; Temperature: 50 °C; Gradient: 0-100% B over 3 min; Flow rate: 1.1 mL / min, Injection 2 conditions: Column: Waters XBridge BEH C18 Purification on XP (50 x 2.1 mm) 2.5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; temperature: 50° C.; gradient: 0-100% B over 3 min; flow rate: 1.1 mL / min gave 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (28 mg, 0.047 mmol, 9.12% yield); MS (ESI) m / z: 590.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm = 1H NMR(400MHz,DMSO-d6)δ 10.27(s,1H),9.10(s,1H),7.98(dd,J=9.2,5.9Hz,1H),7.51-7.36(m,2H),7.18(d,J=2.4Hz,1H),5.55-5.16(m,1H),4.22-4.01(m,6H) ,4.00-3.89(m,3H),3.82-3.72(m,2H),3.19-2.96(m,3H),2.88-2.80(m,1H),2.71-2.69(m,1H),2.20-1.96(m,4H),1.90-1.71(m,3H).

[0181] Preparation of Intermediate 19: 4-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-1,4-oxazepane [ka] To a stirred solution of commercially available 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1 g, 3.96 mmol) in DCM (10 mL) at −40° C. was added DIPEA (1.38 mL, 7.92 mmol), followed by 1,4-oxazepane (0.401 g, 3.96 mmol). The reaction mixture was stirred at −40° C. for 30 minutes. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (40 g silica gel column, 50-80% ethyl acetate / petroleum ether) to give tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.85 g, 2.68 mmol, 68% yield) as a pale yellow solid. MS (ESI) m / z: 317.2 [M+H] + .

[0182] Preparation of intermediate 20: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane [ka] To a stirred solution of ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (0.48 g, 2.84 mmol) in dry THF (9 mL) was added sodium hydride (0.189 g, 4.73 mmol, 60% w / w) at 0 °C and stirred at the same temperature for 1 h. Then, 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (0.75 g, 2.365 mmol) in THF (2 mL) was added at 0 °C. The temperature of the reaction mixture was allowed to rise to room temperature and stirred for 1 h. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 ×). The combined organic extracts were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure to give the crude residue. The crude residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (40 g silica gel column; 70% to 80% EtOAc in petroleum ether as eluent) to give 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (550 mg, 1.222 mmol, 52% yield) as an off-white solid. MS (ESI) m / z: 450.4 [M+H] + .

[0183] Preparation of intermediate 21: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane [ka] To a stirred solution of 4-(7-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (500 mg, 1.111 mmol) in 1,4-dioxane (26 mL), HO (7.5 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (627 mg, 1.222 mmol) and CsCO (1086 mg, 3.33 mmol). The reaction mixture was purged with argon for 5 minutes, and PdCl(dppf) (81 mg, 0.111 mmol) was added. The reaction mixture was again purged with argon for 3 minutes and then heated in a microwave reactor at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 40 g silica gel column with 50-100% ethyl acetate / petroleum ether to give 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (500 mg, 0.625 mmol, 56% yield) as a brown solid. MS (ESI) m / z: 800.4 [M+H] + .

[0184] Preparation of intermediate 22: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane [ka] To a stirred solution of 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)-1,4-oxazepane (0.5 g, 0.625 mmol) in DMF (5 mL) was added CsF (0.95 g, 41.1 mmol). The reaction mixture was heated at 50° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane as a brown liquid, which was used for the next step without further purification. MS(ESI) m / z: 644.3 [M+H] + .

[0185] Examples 1-3 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka] To a stirred solution of 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)-1,4-oxazepane (450 mg, 0.562 mmol) in acetonitrile (5 mL) at 0° C., HCl (4 M in dioxane) (0.703 mL, 2.81 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. Volatiles from the reaction mixture were removed under reduced pressure (lower temperature, approximately 30° C.), and the crude residue was coevaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (2 mL), and excess TEA (1 mL) was added. The mixture was evaporated under reduced pressure to give an off-white solid. The crude compound was purified by Prep-HPLC [HPLC method: Preparative column: YMC ExRS (20 × 250) 5 μm, Mobile phase A: 10 mM ammonium bicarbonate in water - pH 9.5; Mobile phase B: acetonitrile; Gradient = 0 (min) - 50%, 2 - 50%, 15 - 70%, 16 - 70%, 17 - 100%, Temperature: 27 °C; Flow rate: 19 mL / min; Detection: UV at 220 and 254 nm] to give 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (78 mg, 0.127 mmol, 23% yield). MS(ESI)m / z:600.4[M+H] +.1H NMR(400MHz,DMSO-d6)δ ppm=10.16(s,1H),9.10(s,1H),7.98(dd,J=9.2,5.9Hz,1H),7.47(t,J=9.0Hz,1H),7. 40(d,J=2.5Hz,1H),7.18(d,J=2.4Hz,1H),4.46(d,J=10.6Hz,1H),4.23-4.07(m,5H), 4.03-3.91(m,3H),3.81-3.73(m,2H),2.72-2.63(m,1H),2.69-2.59(m,1H),2.25-2.1 4(m,4H),2.14-2.06(m,3H),1.92-1.65(m,3H),1.65-1.49(m,6H),1.47-1.33(m,1H).

[0186] The examples in Table 1 were prepared from the appropriate starting materials according to the procedures described for Example 1-1.

[0187] Examples 1-22 / 1-23, 1-25 / 1-26, 1-42 / 1-43, 1-44 / 1-45, 1-60 / 1-61, 1-62 / 1-63, 1-69 / 1-70, 1-71 / 1-72, 1-73 / 1-74, 1-112 / 1-113, 1-119 / 1-140, 120 / 121, 1-124, 1-125, 1-126 / 1-146, 1-128, 1-130 / 1-131, 1-132 / 1-133, 1-135 / 1-143, 1-136, 1-139, and 1-144 were synthesized as diastereomeric mixtures. The final compounds were purified by Prep-HPLC to give pure diastereomeric mixtures, which were further purified by either chiral HPLC or SFC as indicated to give single diastereomers. In the case of Examples 2-40 / 2-41, chiral SFC separation was performed on commercially available 3-cyanopiperidine, and the racemic fragments of Examples 1-114, 1-116, 1-117, 1-118, 1-138, 1-140, and 1-142 were synthesized and then subjected to chiral SFC separation at the start of the reaction sequence to give single diastereomers. The superscripts appearing after the Example numbers in the tables designate which of the following chiral separation conditions were used: A) CHIRALCEL™ OJ-H (Daicel, Japan) (250 x 21) mm, 5 μm; % CO2: 70%; % co-solvent: 30% 0.2% DEA in IPA; total flow rate: 80.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 240 nm B) CHIRALPAK™ IC (Daicel, Japan) (250 x 21) mm, 5 μm; % CO2: 75%; % co-solvent: 25% 0.2% IPA in methanol; total flow rate: 90.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 220 nm C) CHIRALPAK™ IE (Daicel, Japan) (250 x 30) mm, 5 μm; % CO2: 50%; % co-solvent: 50% 0.2% IPA in methanol; total flow rate: 120.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 254 nm D) CHIRALPAK™ IE (Daicel, Japan) (250 x 30) mm, 5 μm; % CO2: 70%; % co-solvent: 30% 0.2% IPA in methanol; total flow rate: 150.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 220 nm E) CHIRALPAK™ IE (Daicel, Japan) (250 x 30) mm, 5 μm; Mobile phase A:; Mobile phase B: 10 mM ammonium acetate in methanol: 0.07% acetic acid; Flow rate: 30.0 mL / min; Gradient: T / %B: 0 / 100; 32 / 100 F) WHELK-O™ 1(R,R) (Regis Technologies, Morton Grove, IL) (250 x 21) mm, 5 μm; % CO2: 70%; % co-solvent: 0.2% DEA in 30% ACN / IPA; total flow rate: 90.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 220 nm G) LUX™ Cellulose-2 (Phenomenex, Torrance, CA) (250 x 21.5) mm, 5 μm; % CO2: 60%; % cosolvent: 40% 5 mM ammonium acetate in ACN:MEOH (50:50); total flow rate: 80.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 220 nm H) LUX™ Cellulose-1 (Phenomenex, Torrance, CA) (250 x 21.5) mm, 5 μm; % CO2: 50%; % cosolvent: 50% 5 mM ammonium acetate in MEOH; total flow rate: 80.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 220 nm I) LUX™ Cellulose-4 (Phenomenex, Torrance, CA) (250 x 21.5) mm, 5 μm; % CO2: 50%; % cosolvent: 50% 5 mM ammonium MEOH; total flow rate: 70.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 220 nm J) CHIRALPAK™ IG (Daicel, Japan) (250 x 21) mm, 5 μm; % CO2: 75%; % cosolvent: 25% 0.2% ammonia in methanol; total flow rate: 90.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 220 nm K) CHIRALCEL™ OD-H (Daicel, Japan) (250 x 21) mm, 5 μm; % CO2: 80%; % cosolvent: 20% 0.2% ammonia in methanol; total flow rate: 80.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 240 nm

[0188] [Table 1]

[0189] [Table 2]

[0190] [Table 3]

[0191] [Table 4]

[0192] [Table 5]

[0193]

Table 6

[0194]

Table 7

[0195]

Table 8

[0196]

Table 9

[0197]

Table 10

[0198]

Table 11

[0199]

Table 12

[0200]

Table 13

[0201]

Table 14

[0202]

Table 15

[0203] Table 16

[0204]

Table 17

[0205]

Table 18

[0206]

Table 19

[0207] Table 20

[0208] Table 21

[0209] Table 22

[0210] Table 23

[0211] Table 24

[0212] Table 25

[0213] Table 26

[0214] Table 27

[0215] Table 28

[0216] Table 29

[0217] Table 30

[0218] Table 31

[0219] Table 32

[0220] Table 33

[0221] Table 34

[0222] Table 35

[0223] Table 36

[0224] Table 37

[0225] Table 38

[0226] Table 39

[0227] Table 40

[0228] Table 41

[0229] Table 42

[0230] Table 43

[0231] Table 44

[0232] Table 45

[0233] Table 46

[0234] Table 47

[0235] Table 48

[0236] Table 49

[0237] Table 50

[0238] Table 51

[0239] Table 52

[0240] Table 53

[0241] Table 54

[0242] Table 55

[0243] Table 56

[0244] Table 57

[0245] Table 58

[0246] Table 59

[0247] Table 60

[0248] Table 61

[0249] Table 62

[0250] Table 63

[0251] Table 64

[0252] Table 65

[0253] Table 66

[0254] Table 67

[0255] [Table 68]

[0256] [Table 69]

[0257] Preparation of intermediate 116: tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.0 g, 11.67 mmol) and ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (2.17 g, 12.84 mmol) in THF (60 mL) was added 1 M LiHMDS (lithium hexamethyldisilazide) in hexanes (35.0 mL, 35.0 mmol) at 0 °C under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc. The combined organic extracts were washed with water and brine solution, dried over Na2SO4, filtered, and evaporated under reduced pressure to give a crude residue that was purified by silica gel column chromatography using a COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (120 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), 80-100% EtOAc-pet ether) to give tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3 g, 5.35 mmol, 46% yield) as a light brown solid. MS (ESI) m / z: 562.3 [M+H] + .

[0258] Preparation of intermediate 117: tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl-3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.9 g, 1.60 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was added (2-fluoro- 6-(Methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.91 g, 1.76 mmol) and CsCO (1.57 g, 4.81 mmol) were added, followed by PdCl(dppf) (dppf: 1,1'-bis(diphenylphosphino)ferrocene) (0.12 g, 0.16 mmol). The reaction mixture was purged with N for 5 minutes and heated in a microwave reactor at 105 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 40 g silica gel column with 50-100% EtOAc / Pet ether to give tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.8 g, 0.88 mmol, 55% yield) as a brown solid. MS(ESI)m / z:911.5[M+H] + .

[0259] Preparation of intermediate 118: tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.9 g, 1.0 mmol) in DMF (10 mL) was added CsF (1.5 g, 9.88 mmol). The reaction mixture was heated at 50° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.7 g, 0.93 mmol, 94% yield) as a brown oil, which was used for the next step without further purification. MS (ESI) m / z: 755.3 [M+H] + .

[0260] Preparation of intermediate 119: 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol [ka] To a stirred solution of 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-ol (3.5 g, 4.88 mmol) in DMF (40 mL) was added CsF (7.42 g, 48.8 mmol). The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was quenched with water and extracted with EtOAc. The combined layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude compound was triturated with diethyl ether to give 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol (1.8 g, 3.21 mmol, 65.8% yield) as a light brown solid. MS (ESI) m / z: 561.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6, D2O exchange) δ ppm=8.86(d,J=7.0Hz,1H),8.10-8.02(m,1H),7.68(dd,J=8.5,2.5Hz,1H),7.51(td,J=9.0,3.5Hz,1H),7.30(d,J=3.0Hz,1H), 5.38-5.26(m,2H),4.36-4.23(m,2H),3.93(d,J=13.0Hz,1H),3.44-3.36(m,3H),3.19-3.02(m,1H),2.86-2.68(m,2H),2.43(br d,J=10.5Hz,3H),2.01-1.43(m,10H).

[0261] Preparation of intermediate 120: 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol [ka] To a solution of 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol (10.0 g, 17.84 mmol) in 1:2 MeOH-THF (300 mL) was added palladium on carbon (50% humidity; 10.44 g, 9.81 mmol) and the reaction mixture was stirred under a hydrogen bladder for 4 h. The reaction mixture was filtered through a pad of diatomaceous earth (CELITE™, Sigma Aldrich, St. Louis, MO), washed with MeOH (500 mL), and the filtrate was evaporated to give a crude residue which was triturated with PET ether to give 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol (8.6 g, 15.23 mmol, 85% yield) as a light brown solid. MS (ESI) m / z: 565.3 (M+H). + .

[0262] Preparation of intermediate 121: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol [ka] To a stirred suspension of 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol (8.6 g, 15.23 mmol) in acetonitrile (120 mL) was added 6-methyl-1,4-oxazepan-6-ol hydrochloride [Intermediate 75; 2.81 g, 16.75 mmol], PyBOP (11.89 g, 22.85 mmol), and DIPEA (7.98 mL, 45.7 mmol) at room temperature. The reaction mixture was heated at 80 °C for 6 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to give a crude residue, which was diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue that was purified by silica gel column chromatography using a COMBIFLASH™ instrument (120 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), 60-100% EtOAc in petroleum ether) to give 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (6.2 g, 9.15 mmol, 60.1% yield) as a brown solid. MS (ESI) m / z: 678.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δppm=9.55(br s,1H),7.91(dd,J=8.9,6.1Hz,1H),7.68(d,J=1.9Hz,1H),7.44(t,J=9.4Hz,1H),7.22(br d,J=12.4Hz,1H),5.40(s,2H),)5.24-5.12(m,1H),4.45-4.18(m,3H),4.15-3.95(m,3H),3.91-3.68(m,1H),3.64-3.51(m,2H),3 .48(s,3H),3.20-3.11(m,2H),2.87-2.71(m,3H),2.26-2.09(m,2H),1.99(s,3H),1.88-1.44(m,8H),1.20-1.12(m,4H),0.75(br t,J=6.3Hz,3H).

[0263] Preparation of Example 1-134: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol [ka] To a stirred solution of 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (4.5 g, 6.64 mmol) in EtOAc (90 mL) was added 1 M HCl in EtOAc (100 mL, 100 mmol) at 0 °C. The reaction mixture was stirred for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a crude residue, which was dissolved in DCM (200 mL) and neutralized with TEA. The volatiles were removed under reduced pressure, dissolved in DCM, and washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue that was purified by silica gel column chromatography using a COMBIFLASH™ instrument (80 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), 4 to 7% MeOH in DCM) to give 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (3.5 g, 5.43 mmol, 82% yield) as an off-white solid. MS (ESI) m / z: 634.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ ppm=9.96(br s,1H),9.48(d,J=1.5Hz,1H),7.77(dd,J=9.0,6.0Hz,1H),7.42-7.25(m,2H),7.03(dd,J=14.1,2.6Hz,1H),5.17(d,J =11.0Hz,1H),4.54-4.47(m,1H),4.41-4.15(m,3H),4.13-3.82(m,5H),3.63-3.50(m,3H),2.71-2.60(m,1H),2.45(br d,J=0.8Hz,1H),2.25-2.07(m,4H),1.89-1.68(m,2H),1.66-1.46(m,7H ),1.44-1.37(m,1H),1.16(d,J=5.0Hz,3H),0.74(dt,J=7.3,3.3Hz,3H).

[0264] [ka] Scheme 2: Preparation of Compound 2-1 Preparation of intermediate 23: tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of commercially available 7-bromo-2,4-dichloro-8-fluoroquinazoline (15 g, 50.7 mmol) in 1,4-dioxane (150 mL) at 0° C. was added DIPEA (26.6 mL, 152 mmol), followed by tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (12.9 g, 60.8 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (120 g silica gel column, 50-80% ethyl acetate / petroleum ether) to give tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (17 g, 32.4 mmol, 64% yield) as a pale yellow solid. MS (ESI) m / z: 473.3 [M+2] + .

[0265] Preparation of intermediate 24: tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.95 g, 24.80 mmol) in THF (45 mL) at 0 °C, NaH (0.194 g, 4.85 mmol, 60% w / w) was added, and the reaction mixture was stirred at the same temperature for 1 h. To this was added tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9 g, 19.08 mmol) in four portions at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (250 mL × 2). The organic layer was washed with brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue that was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (240 g column, 80-100% EtOAc in petroleum ether) to give tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.5 g, 10.93 mmol, 57% yield). MS (ESI) m / z: 594.5 (M+2). + .

[0266] Preparation of intermediate 25: tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 24, 8 g, 13.46 mmol) in 1,4-dioxane (100 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (6.90 g, 13.46 mmol) and 2 M aqueous potassium phosphate tribasic solution (20.18 mL, 40.4 mmol). The reaction mixture was degassed under argon for 5 minutes, then [1,1'-bis(di-tertbutylphosphino)ferrocene]dichloropalladium(II) (0.877 g, 1.346 mmol) was added, degassed again under argon for 3 minutes, and heated at 50° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue that was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (80 g silica gel column, 50-100% ethyl acetate / petroleum ether) to give tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.5 g, 7.25 mmol, 54% yield) as a brown solid. MS (ESI) m / z: 900.4 [M+H] + .

[0267] Preparation of intermediate 26: tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 25, 3.7 g, 4.11 mmol) in DMF (50 mL) was added CsF (6.24 g, 41.1 mmol). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.9 g, 3.89 mmol, 95% yield) as a brown liquid, which was used for the next step without purification. MS (ESI) m / z: 744.3 [M+H] + .

[0268] Preparation of intermediate 27: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-ol [ka] To a stirred solution of crude tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 26, 3 g, 4.03 mmol) in EtOH (15 mL) and THF (15 mL) was added NaOH (1 M aqueous solution) (40.3 mL, 40.3 mmol). The reaction mixture was heated at 70° C. for 3 h. The reaction mixture was evaporated and the residue was diluted with ethyl acetate. The organic layer was washed with saturated NH4Cl solution, water, brine, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (24 g silica gel column, 10-20% MeOH / DCM) to give 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-ol (850 mg, 1.544 mmol, 38.3% yield) as a brown solid. MS (ESI) m / z: 550.2 [M+H] + .

[0269] Preparation of intermediate 28: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(morpholin-4-yl)quinazoline [ka] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-ol (Intermediate 27, 20 mg, 0.036 mmol) in ACN (1 mL) was added morpholine (3.8 mg, 0.044 mmol), triethylamine (0.020 mL, 0.146 mmol), and BOP (24.4 mg, 0.055 mmol). The reaction mixture was heated at 80° C. for 8 hours. The reaction mixture was evaporated, and the residue was diluted with ethyl acetate. The organic layer was washed with water, then brine, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(morpholin-4-yl)quinazoline (25 mg, crude) as a brown liquid, which was used for the next step without purification. MS (ESI) m / z: 619.3 [M+H] + .

[0270] Example 2-1: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(morpholin-4-yl)quinazoline (Intermediate 28, 200 mg, 0.323 mmol) in ACN (2 mL) at 0 °C, 4 N HCl (2 mL, 65.83 mmol in 1,4-dioxane) was added, and the reaction mixture was stirred at room temperature for 1 hour. Volatiles from the reaction mixture were removed under reduced pressure (lower temperature, approximately 30 °C), and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (5 mL), TEA (1 mL) was added, and then evaporated under reduced pressure to give an off-white solid. The crude compound was purified by Prep-HPLC [HPLC method: Preparative column: YMC EXRS (250 x 20 x 5 microns), Mobile phase A: 10 mM ammonium bicarbonate-9.5 in water; Mobile phase B: acetonitrile:methanol; Gradient = 60-100% B over 20 min; Temperature: 27 °C; Flow rate: 19.0 mL / min; Detection: UV at 220 nm] to give 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (11.9 mg, 0.020 mmol, 6.8% yield). MS (ESI) m / z: 575.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm=7.96(dd,J=9.1,6.0Hz,1H),7.76(d,J=8.6Hz,1H),7.46(t,J=9.0Hz,1H), 7.37(d,J=2.6Hz,1H),7.24(dd,J=8.4,6.8Hz,1H),7.09(d,J=2.3Hz,1H),5.38 -5.19(m,1H),4.13-4.08(m,1H),4.01(dd,J=10.4,4.4Hz,1H),3.88-3.72(m,9 H),3.16-3.00(m,3H),2.88-2.78(m,1H),2.19-1.97(m,3H),1.88-1.73(m,3H).

[0271] Preparation of intermediate 29: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(1,4-oxazepan-4-yl)quinazoline [ka] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-ol (Intermediate 27, 300 mg, 0.546 mmol) in ACN (10 mL) was added 1,4-oxazepane (60.7 mg, 0.600 mmol), DIPEA (0.286 mL, 1.635 mmol), and BOP (362 mg, 0.817 mmol). The reaction mixture was heated at 80° C. for 8 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude residue. The crude material was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (40 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), eluting with a gradient of 60-100% EtOAc in petroleum ether) to give 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(1,4-oxazepan-4-yl)quinazoline (300 mg, 0.474 mmol, 87% yield) as a brown liquid. MS (ESI) m / z: 633.3 [M+H] + .

[0272] Example 2-2: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(1,4-oxazepan-4-yl)quinazoline (Intermediate 29, 300 mg, 0.474 mmol) in acetonitrile (5 mL) at 0 °C, HCl (4 M in dioxane) (0.15 mL, 4.74 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Volatiles from the reaction mixture were removed under reduced pressure (lower temperature, approximately 30 °C), and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (2 mL), excess TEA (1 mL) was added, and evaporated under reduced pressure to give the crude residue. The crude compound was purified by Prep-HPLC [HPLC method: Column: YMC ExRS (20 × 250) 5 μl; Mobile phase A: 10 mM ammonium bicarbonate in HO, pH 9.5; Mobile phase B: ACN; Flow rate: 19 mL / min; Gradient T / %B: 0 / 50, 2 / 50; 15 / 70; 16 / 100 to give 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (59.02 mg, 0.098 mmol, 21% yield). MS (ESI) m / z: 589.40 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 10.23-10.08(m,1H),7.97(dd,J=9.3,5.8Hz,1H),7.83(d,J=9.0Hz,1H),7.46(t,J=9.0Hz,1H),7.36(d,J=2.5Hz,1H),7 .18(dd,J=8.5,7.0Hz,1H),7.07(d,J=2.5Hz,1H),5.35-5.22(m,1H),4.12-3.90(m,8H),3.77(t,J=5.3Hz,2H),3.09(br d,J=13.5Hz,2H),3.02(s,1H),2.83(br d,J=6.5Hz,1H),2.58-2.53(m,1H),2.16-2.08(m,3H),2.08-1.98(m,2H),1.89-1.73(m,3H).

[0273] Preparation of intermediate 30: tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 23, 2.5 g, 5.49 mmol) and ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (Intermediate 12, 1.1 g, 6.59 mmol) in THF (25 mL) was added 1 M LiHMDS (lithium hexamethyldisilazide) in hexanes (5.49 mL, 5.49 mmol) under nitrogen at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3x). The combined organic extracts were washed with water, brine solution, dried over Na2SO4, filtered, and evaporated under reduced pressure to give a crude residue that was purified by silica gel column chromatography using a COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (120 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), 80-100% EtOAc-petroleum ether) to give tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.5 g, 4.14 mmol, 75% yield) as a pale yellow solid. MS (ESI) m / z: 604.2 [M+H] + .

[0274] Preparation of intermediate 31: tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred, degassed solution of tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 30, 2.5 g, 4.14 mmol) in 1,4-dioxane (50 mL) was added 2-fluoro-6-(methoxymeth)- To the reaction mixture was added (2.119 g, 4.14 mmol) of (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.119 g, 4.14 mmol) and 2 M aqueous potassium phosphate tribasic solution (6.20 mL, 12.41 mmol), followed by [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.135 g, 0.207 mmol). The reaction mixture was purged with N for 5 minutes and heated at 50°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using an 80 g silica gel column with 50-100% ethyl acetate / petroleum ether to give tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.0 g, 3.30 mmol, 80% yield) as a brown solid. MS(ESI)m / z:911.2[M+H] + .

[0275] Preparation of intermediate 32: tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-3,8 diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 31, 3.0 g, 3.30 mmol) in DMF (30 mL) was added cesium fluoride (5.01 g, 33.0 mmol) and the mixture was heated at 50° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-3,8 diazabicyclo[3.2.1]octane-8-carboxylate (2.2 g, 2.92 mmol, 89% yield) as a brown liquid, which was used for the next step without further purification. MS (ESI) m / z: 754.3 [M+H] + .

[0276] Preparation of intermediate 33: 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-ol [ka] To a stirred solution of tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-3,8 diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 32, 2.2 g, 2.92 mmol) in ethanol (20 mL) and THF (20 mL) was added NaOH (29.2 mL, 29.2 mmol), and the mixture was stirred at 80 °C for 36 h. The reaction mixture was then diluted with EtOAc (100 mL) and washed with 0.5 N aqueous HCl (150 mL × 3). The aqueous layer was made basic (pH ∼8) with solid NaHCO and extracted with EtOAc (3 × ). The combined organic extracts were washed with water, brine solution, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude compound, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (40 g silica gel column, 10-20% MeOH / DCM) to give 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-ol (1.5 g, 2.68 mmol, 92% yield) as a brown solid. MS (ESI) m / z: 560.2 [M+H] + .

[0277] Preparation of intermediate 34: 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(1,4-oxazepan-4-yl)quinazoline [ka] To a stirred solution of 2-{[(4aS)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3,3-bis(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-ol (Intermediate 33, 255 mg, 0.447 mmol) in ACN (5 mL) was added 1,4-oxazepane (54.2 mg, 0.536 mmol), DIPEA (0.234 mL, 1.340 mmol), and BOP (296 mg, 0.670 mmol). The reaction mixture was heated at 80° C. for 8 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 40 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), eluting with a gradient of 60-100% EtOAc in petroleum ether to give (2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(1,4-oxazepan-4-yl)quinazoline (211 mg, 73% yield) as a brown liquid. MS (ESI) m / z: 643.4 [M+H] + .

[0278] Example 2-3: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka] To a stirred solution of (2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-4-(1,4-oxazepan-4-yl)quinazoline (Intermediate 34, 330 mg, 0.521 mmol) in acetonitrile (5 mL) at 0 °C, 4N HCl (1.3 mL, 5.21 mmol in 1,4-dioxane) was added, and the reaction mixture was stirred at room temperature for 1 hour. Volatiles from the reaction mixture were removed under reduced pressure (lower temperature, approximately 30°C), and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (2 mL), excess TEA (1 mL) was added, and the mixture was evaporated under reduced pressure to give an off-white solid. The crude compound was purified by Prep-HPLC [HPLC Method: Preparative Column: Waters XBridge BEH C18 XP (50 x 2.1 mm) 2.5 μm; Mobile Phase A: 5:95 acetonitrile:water with 10 mM NH4OAc; Mobile Phase B: 95:5 acetonitrile:water with 10 mM NH4OAc; Temperature: 50°C; Gradient: 0-100% B over 3 minutes; Flow Rate: 1.1 mL / min. Injection 2 Conditions: Column: Waters XBridge BEH C18 Purification on XP (50 × 2.1 mm) 2.5 μm; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Temperature: 50 °C; Gradient: 0 to 100% B over 3 min; Flow rate: 1.1 mL / min gave 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (28 mg, 0.047 mmol, 9% yield). MS (ESI) m / z: 599.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ ppm=10.13(s,1H),7.97(dd,J=9.1,6.0Hz,1H),7.84(br d,J=9.0Hz,1H),7.47(t,J=9.0Hz,1H),7.37(d,J=2.5Hz,1H),7.21(br s,1H),7.07(d,J=2.1Hz,1H),4.10-4.05(m,5H),3.94-3.90(m,3H),3.80-3.75(m,2H),3.18-1.16(m,1H).2.84-2 .61(m,3H),2.60-2.53(m,2H),2.38-2.24(m,2H),2.21-2.00(m,2H),1.91(s,2H),1.65-1.50(m,6H),1.24(s,1H).

[0279] The examples in Table 2 were prepared from the appropriate starting materials according to the procedures described for Example 2-1.

[0280] [Table 70]

[0281] [Table 71]

[0282] [Table 72]

[0283] [Table 73]

[0284] [Table 74]

[0285] [Table 75]

[0286] Table 76

[0287] Table 77

[0288] Table 78

[0289] Table 79

[0290] Table 80

[0291] Table 81

[0292] Table 82

[0293] Table 83

[0294] Table 84

[0295] Table 85

[0296] Table 86

[0297] Table 87

[0298] Table 88

[0299] Table 89

[0300] Table 90

[0301]

Table 91

[0302] Table 92

[0303]

Table 93

[0304] Table 94

[0305]

Table 95

[0306] Table 96

[0307] [Table 97]

[0308] [Table 98]

[0309] [Table 99]

[0310] [Table 100]

[0311] [Table 101]

[0312] [ka] Scheme 3: Preparation of Compound 3-1 Preparation of intermediate 35: tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300 mg, 3.03 mmol) in dioxane (8 mL) was added DIPEA (0.476 mL, 2.72 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (193 mg, 0.908 mmol). The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was diluted with ethyl acetate (50 mL) and washed with water (30 mL × 2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (12 g, ISCO column, MeOH / DCM, 0-5%, 20 min) to give tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (415 mg, 0.82 mmol, 90% yield) as a white solid. MS (ESI) m / z 507.0 [M+1] + . 1 H NMR(499MHz,DMSO-d6)δ ppm=8.10(d,J=1.9Hz,1H),4.38(br d,J=10.6Hz,2H),4.25(br s,2H),3.66(m,2H)1.79(m,2H),1.62(m,2H),1.47 s,9H).

[0313] Preparation of Intermediate 36: tert-butyl 3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a degassed solution of tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 35, 1 g, 3.03 mmol) in DMA (80 mL) was added cesium fluoride (5.25 g, 34.6 mmol). The reaction mixture was degassed with nitrogen for 10 minutes and heated in a sealed tube at 88 °C for 5 hours. Water (200 mL) and ethyl acetate (150 mL) were added, and the reaction mixture was stirred for 15 minutes. The separated aqueous layer was extracted with ethyl acetate (2 × 100 mL), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 15-25% ethyl acetate in petroleum ether as eluent to give tert-butyl-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.7 g, 8.77 mmol, 63.4% yield) as a pale yellow solid. MS (ESI) m / z 489.0 [M+1] + .

[0314] Preparation of intermediate 37: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a degassed solution of tert-butyl-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 36, 2.00 g, 4.08 mmol) in anhydrous 1,4-dioxane (20 mL) was added potassium phosphate (1.73 g, 8.17 mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (5.8 g, 12.25 mmol), and PdCl(dppf) (149 mg, 0.204 mmol). The reaction mixture was degassed again and heated at 80 °C for 48 h. After completion of the reaction, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (40 mL), filtered through a bed of diatomaceous earth (CELITE™, Sigma Aldrich, St. Louis, MO), and concentrated under reduced pressure to give the crude product. The residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% ethyl acetate in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 1.74 mmol, 42% yield). 1 H NMR(400MHz,CDCl3):δ ppm=7.76(d,J=1.6Hz,1H),7.20-7.18(d,J=8.8Hz,4H),6.86(dt,J=9.6Hz,4H),6.60(s,1H),6.38(s,1H),4.60(s,3H),4 .39-4.21(m,4H),3.63(s,6H),2.29(s,3H),1.98-1.96(m,6H),1.76-1.63(m,2H),1.49(s,9H)LCMS(ESI)m / z:757.2[M+H] + .

[0315] Preparation of intermediate 38: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8 diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 37, 1.40 g, 1.849 mmol) in anhydrous ACN (15 mL) at 0° C. under nitrogen was added N-iodosuccinimide (0.42 g, 1.849 mmol) and trifluoroacetic acid (0.028 mL, 0.370 mmol). The reaction mixture was allowed to reach room temperature over 1 h. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate (5 mL) and saturated aqueous sodium bicarbonate (4 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. The crude residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% ethyl acetate in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8 diazabicyclo[3.2.1]octane-8-carboxylate (1.42 g, 1.560 mmol, 84% yield) as a pale yellow fluffy solid. LCMS (ESI) m / z: 883.3 [M+H] + .

[0316] Preparation of intermediate 39: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 38, 1.40 g, 1.585 mmol) in anhydrous DMA (10 mL) in a sealed tube under nitrogen was added copper(I) iodide (0.60 g, 3.17 mmol). The reaction mixture was degassed for 10 minutes, after which methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.91 g, 4.76 mmol) was added and the reaction mixture was heated at 90° C. for 12 hours. The reaction progress was monitored by LCMS. The reaction mixture was diluted with diethyl ether (20 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with diethyl ether (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% ethyl acetate in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.85 g, 0.630 mmol, 40% yield) as a pale yellow solid. 1H NMR(400MHz,CDCl3):δ ppm=7.77(s,1H),7.16(d,J=8.8Hz,4H),6.87(dt,J=9.6 and 2.8Hz,4H),6.43(s,1H),4.76-4.72(m,2H),4.59-4.55 (m,2H),3.81(s,6H),2.43(s,3H),1.97-1.82(m,4H),1.97-1.82(m,4H),1.53(s,9H).LCMS(ESI)m / z:825.2[M+H] + .

[0317] Intermediates 40A and 40B: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Intermediate 39 (5.0 g, 6.06 mmol) was subjected to SFC separation (column: CHIRALPAK™ IH (Daicel, Japan) (250 mm x 4.6 mm; 5 μm), mobile phase: 0.25% isopropanol), and peak-1 was eluted at a retention time of 5.85 minutes (2.4 g, 2.90 mmol, 40% yield), and peak-2 was eluted at a retention time of 9.53 minutes (2.4 g, 2.90 mmol, 40% yield). Peak-1 (40A): 1 H NMR(400MHz,CDCl3):δ ppm=7.78(s,1H),7.16(d,J=8.8Hz,4H),6.87(dt,J=9.6 and 2.8Hz,4H),6.43(s,1H),4.76-4.72(m,2H),4.59-4.55( m,2H),3.81(s,6H),2.43(s,3H),1.97-1.82(m,4H),1.97-1.82(m,4H),1.53(s,9H)ppm.LCMS(ESI)m / z:825.2[M+H] + LCMS(ESI) m / z: 825.2 [M+H] + .[α] 23.5 (MeOH=0.10)=+96.00; Peak-2: (40B) 1H NMR(400MHz,CDCl3):δ ppm=7.78(s,1H),7.16(d,J=8.8Hz,4H),6.87(dt,J=9.6 and 2.8Hz,4H),6.43(s,1H),4.76-4.72(m,2H),4.59-4.55( m,2H),3.81(s,6H),2.43(s,3H),1.97-1.82(m,4H),1.97-1.82(m,4H),1.53(s,9H)ppm.LCMS(ESI)m / z:825.2[M+H] + .[α] 23.3 ( MeOH=0.10)=-110.00.

[0318] Preparation of intermediate 41: tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of [(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methanol (Intermediate 40B, 0.205 g, 1.212 mmol) in THF (5 mL) at 0 °C, NaH (0.194 g, 4.85 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To this was added tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 1.212 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice cubes and concentrated under reduced pressure. The crude material was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude material, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (24 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), 0-10% MeOH-DCM) to give tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.70 g, 0.718 mmol, 59.3% yield). MS(ESI)m / z:974.4(M+H) + .

[0319] Preparation of intermediate 42: 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-ol [ka] To a stirred solution of tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 41, 300 mg, 0.308 mmol) in EtOH (4 mL), THF (4 mL) was added sodium hydroxide (1 M aqueous solution) (3.08 mL, 3.08 mmol). The reaction mixture was heated at 70° C. for 18 hours. The reaction mixture was evaporated and the residue was diluted with ethyl acetate. The organic layer was washed with saturated NH4Cl solution, water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (24 g silica gel column, 10-20% MeOH / DCM) to give 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-ol (110 mg, 0.141 mmol, 45.8% yield) as a brown solid. MS (ESI) m / z: 780.5 [M+H] + .

[0320] Preparation of intermediate 43: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] To a stirred solution of 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-ol (Intermediate 42, 20 mg, 0.026 mmol) in ACN (1 mL) was added (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane (2.90 mg, 0.026 mmol), DIPEA (0.013 mL, 0.077 mmol), and BOP (17.01 mg, 0.038 mmol). The reaction mixture was heated at 80° C. for 8 h. The reaction mixture was evaporated, and the residue was diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (20 mg, 0.023 mmol, 89% yield) as a brown liquid, which was used for the next step without purification. MS (ESI) m / z: 875.3 [M+H] + .

[0321] Example 3-1: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-8 fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] To a stirred solution of 6-(4-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Intermediate 43, 20 mg, 0.023 mmol) in TFA (35.2 μL, 0.457 mmol) at 0° C., triethylsilane (10.95 μL, 0.069 mmol) was added and the reaction mixture was stirred at 40° C. for 16 hours. Volatiles from the reaction mixture were removed under reduced pressure (lower temperature, approximately 30° C.), and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane, triethylamine was added and evaporated under reduced pressure to give an off-white solid. The crude material was purified by preparative LC / MS using the following conditions: Column: Waters XBridge Purification via C18, 19 × 150 mm, 5-μm particles; mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 15–42% B over 23 min, then hold at 100% B for 5 min; flow rate: 20 mL / min gave 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (6 mg, 8.97 μmol, 39.3% yield): MS(ESI) m / z: 635.3, [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ ppm=9.66-8.76(m,1H),7.86(s,1H),6.83(br s,2H),6.50(s,1H),4.60-4.22(m,5H),4.20-4.06(m,1H),3.80-3.52(m,2H),3.17-3.03 (m,1H),2.88-2.69(m,3H),2.37(d,J=1.3Hz,3H),2.05-1.91(m,1H),1.88-1.43(m,12H).

[0322] [ka] Example 4-1: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethylnaphthalen-2-ol Preparation of intermediate 44: 8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol [ka] To a stirred solution of naphthalene-1,3-diol (20 g, 125 mmol), bromoethynyl)triisopropylsilane (34.3 g, 131 mmol), and potassium acetate (24.51 g, 250 mmol) in anhydrous 1,4-dioxane (200 mL) was added dichloro(p-cymene)ruthenium(II) dimer (7.65 g, 12.49 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 12 h. The reaction mixture was cooled to ambient temperature and filtered through diatomaceous earth (CELITE™, Sigma Aldrich, St. Louis, MO). The bed was washed with EtOAc (2 × 100 mL), and the filtrates were combined and concentrated under reduced pressure to give the crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 12-15% ethyl acetate in petroleum ether as the eluent. The pure fractions were concentrated under reduced pressure to give 8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (30 g, 85 mmol, 67.7% yield). LCMS (ESI) m / z: 341.55 [M+H] + .

[0323] Preparation of Intermediate 45: 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol [ka] To a stirred solution of 8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (Intermediate 44, 25 g, 73.4 mmol) in anhydrous DCM (300 mL) under nitrogen was added DIPEA (38.5 mL, 220 mmol) at −10° C. After 10 min, MOM-Cl (6.13 mL, 81 mmol) was added dropwise to the reaction mixture over 20 min under a nitrogen atmosphere. The resulting mixture was stirred at the same temperature for 2 h. The reaction mixture was diluted with 100 mL of DCM and washed with 200 mL of brine. The combined organics were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 5-10% ethyl acetate in petroleum ether as the eluent. The pure fractions were concentrated under reduced pressure to give 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (21 g, 53.5 mmol, 72.9% yield) as a pale yellow oil. LCMS (ESI) m / z: 385.60 [M+H] + .

[0324] Preparation of Intermediate 46: 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pivalate [ka] To a stirred solution of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (Intermediate 45, 20 g, 52.0 mmol), TEA (21.75 mL, 156 mmol), and DMAP (1.271 g, 10.40 mmol) in anhydrous DCM (200 mL) at −10° C. under a nitrogen atmosphere, pivaloyl chloride (12.80 mL, 104 mmol) was added dropwise over 10 minutes. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was then diluted with 200 mL of DCM and washed with brine (200 mL). The organic material was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 10-15% ethyl acetate in petroleum ether as the eluent. The pure fractions were concentrated under reduced pressure to give 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pivalate (23 g, 49.1 mmol, 94% yield) as a pale yellow oil. LCMS (ESI) m / z: 469.2 [M+H] + .

[0325] Preparation of Intermediate 47: 8-Ethynyl-3-(methoxymethoxy)naphthalen-1-yl pivalate [ka] To a stirred solution of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ylpivalate (Intermediate 46, 12 g, 25.6 mmol) in anhydrous DMF (130 mL) at room temperature under a nitrogen atmosphere was added anhydrous CsF (27.2 g, 179 mmol). The reaction mixture was stirred for 2 h. The reaction mixture was diluted with DCM (200 mL) and washed with brine (200 mL). The organic material was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 5-8% ethyl acetate in petroleum ether as the eluent. The pure fractions were concentrated under reduced pressure to give 8-ethynyl-3-(methoxymethoxy)naphthalen-1-ylpivalate (7 g, 20.62 mmol, 81% yield). LCMS(ESI)m / z:313.3[M+H] + .

[0326] Preparation of Intermediate 48: 8-Ethyl-3-methoxymethoxy)naphthalen-1-yl pivalate [ka] To a stirred solution of 8-ethynyl-3-(methoxymethoxy)naphthalen-1-ylpivalate (Intermediate 47, 7 g, 22.41 mmol) in anhydrous methanol (70 mL) was added Pd / C (1.4 g, 13.16 mmol) at 25 °C. The suspension was degassed under reduced pressure and purged with H several times. The mixture was stirred under a H atmosphere (1 atm) at 25 °C for 5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 15-20% ethyl acetate in petroleum ether as the eluent. Pure fractions were concentrated under reduced pressure to give 8-ethyl-3-(methoxymethoxy)naphthalen-1-ylpivalate (6.56 g, 17.83 mmol, 80% yield) as a pale yellow oil. LCMS(ESI)m / z:316.1[M+H] + .

[0327] Preparation of Intermediate 49: 8-Ethyl-3-(methoxymethoxy)naphthalen-1-ol [ka] To a stirred solution of 8-ethyl-3-(methoxymethoxy)naphthalen-1-ylpivalate (Intermediate 48, 10 g, 31.6 mmol) in THF:water:MeOH (5:1:5) under nitrogen at room temperature was added anhydrous LiOH (1.135 g, 47.4 mmol). The resulting mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The reaction mixture was diluted with EtOAc (150 mL) and washed with brine (200 mL). The organic material was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 25-30% ethyl acetate in petroleum ether as the eluent. The pure fractions were concentrated under reduced pressure to give 8-ethyl-3-(methoxymethoxy)naphthalen-1-ol (6 g, 25.8 mmol, 82% yield). LCMS(ESI)m / z:233.2[M+H] + .

[0328] Preparation of Intermediate 50: 8-Ethyl-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate [ka] To a stirred solution of 8-ethyl-3-(methoxymethoxy)naphthalen-1-ol (Intermediate 49, 3 g, 12.92 mmol) and DIPEA (22.50 mL, 129 mmol) in anhydrous dichloromethane (50 mL) at −40 °C under nitrogen, TfO (2.182 mL, 12.92 mmol) was added dropwise. The resulting reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with cold water (500 mL) and extracted with DCM (2 × 500 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue. The crude compound was purified by flash column (Silicagel 100-200) chromatography using 5–10% ethyl acetate in petroleum ether as the eluent. The pure fractions were concentrated under reduced pressure to give 8-ethyl-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (3.5 g, 9.03 mmol, 69.9% yield) as a pale yellow oil. LCMS (ESI) m / z: 365.3 [M+H] + .

[0329] Preparation of Intermediate 51: 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a stirred solution of 8-ethyl-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (Intermediate 50, 7.4 g, 20.31 mmol) in 1,4-dioxane (80 mL) was added bispinacaratoborane (12.89 g, 50.8 mmol) and potassium acetate (5.98 g, 60.9 mmol). The mixture was degassed and purged with nitrogen for 5 minutes, and PdCl(dppf) (1.659 g, 2.031 mmol) was added. The resulting mixture was stirred under nitrogen at 100 °C for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 2-4% ethyl acetate in petroleum ether as the eluent. Pure fractions were concentrated under reduced pressure to give a brown gum, which was again purified by reverse-phase column chromatography using 80% acetonitrile in 0.01% ammonium formate in water as the eluent. Pure fractions were concentrated under reduced pressure to give 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.5 g, 13.10 mmol, 64.5% yield). LCMS (ESI) m / z: 344.2 [M+H] + . 1 H-NMR(400MHz, CDCl3):δ 7.62(dd,J=0.80,8.00Hz,1H),7.36-7.44(m,3H),7.27(t,J=0.40Hz,1H),5.31(s, 2H),3.53(s,3H),3.21(q,J=7.20Hz,2H),1.46(s,12H),1.38(t,J=7.60Hz,3H)ppm.

[0330] Preparation of intermediate 52: tert-butyl (1R,5S)-3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A mixture of Intermediate 30 (550 mg, 0.910 mmol), 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (327 mg, 0.955 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (29.6 mg, 0.045 mmol), and 2.0 M potassium phosphate tribasic (1365 μL, 2.73 mmol) in dioxane (1 mL) under nitrogen was stirred at 50° C. for 18 hours. EtOAc (25 mL) was added to the mixture, and the ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by prep-HPLC (ISCO C18 100 g column, flow rate = 60 mL / min, gradient = 40% A to 100% B in 20 min, A = HO / ACN / TFA (90:10:0.1), B = HO / ACN / TFA (10:90:0.1)). Pure fractions were combined and concentrated. The mixture was diluted with EtOAc (25 mL) and washed with saturated aqueous sodium carbonate (25 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to give tert-butyl (1R,5S)-3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (550 mg, 0.706 mmol, 78% yield) as a tan foam. MS (ESI) m / z: 740.3 [M+H] + .

[0331] Preparation of intermediate 53: 7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-ol [ka] A mixture of tert-butyl (1R,5S)-3-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 52, 550 mg, 0.743 mmol), 1.0 M sodium hydroxide (7433 μL, 7.43 mmol), and EtOH (25 mL) was stirred at 60° C. for 3 days. The mixture was concentrated. The mixture was extracted with EtOAc (25 mL), and the ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by prep-HPLC (ISCO C18 100 g column, flow rate = 60 mL / min, gradient = 20% A to 100% B in 20 min, A = HO / ACN / TFA (90:10:0.1), B = HO / ACN / TFA (10:90:0.1)). Pure fractions were combined and concentrated. The mixture was diluted with EtOAc (15 mL) and washed with saturated aqueous sodium carbonate (15 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to give 7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-ol (287 mg, 0.500 mmol, 67.2% yield) as a white solid. MS (ESI) m / z: 546.4 [M+H] + .

[0332] Example 4-1: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethylnaphthalen-2-ol [ka] To a solution of 7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-ol (Intermediate 52, 20 mg, 0.037 mmol), TEA (25.5 mL, 0.183 mmol) and morpholine (4.79 mg, 0.055 mmol) in ACN (1.0 mL) was added BOP (24.32 mg, 0.055 mmol) and the mixture was stirred at 60° C. for 18 h. The mixture was concentrated to give crude 4-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)morpholine. MS (ESI) m / z: 615.3 [M+H] +A mixture of 4-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)morpholine, triethylsilane (1 drop), water (1 drop), and TFA (1.0 mL) was stirred at room temperature for 1 hour. The mixture was concentrated. The crude product was purified by prep-HPLC (Phenomenex, Luna 5 micron, 30 × 100 mm, flow rate = 40 mL / min, gradient = 0% A to 100% B in 12 min, A = HO / ACN / TFA (90:10:0.1), B = HO / ACN / TFA (10:90:0.1)). The pure fractions were loaded onto an Oasis MCX cation mixed-mode polymer cartridge (150 mg), the cartridge was washed with methanol (30 mL), and the product was eluted with 0.1 N ammonia in methanol (5.0 mL). The ammonia eluate was concentrated. The pure fractions were lyophilized with ACN / HO (1:1, 5 mL) to give 5-ethyl-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-morpholinoquinazolin-7-yl)naphthalen-2-ol (11.75 mg, 0.019 mmol, 50.6% yield) as a white powder. MS (ESI) m / z: 571.4 [M+H] + . 1 H NMR(499MHz,METHANOL-d4)δ 7.83(d,J=7.9Hz,1H),7.62(d,J=8.1Hz,1H),7.37-7.23(m,3H),7.14(d,J=6.5Hz,1H),6.93(d,J=2.6Hz,1H),4.55(dd,J=10.8,6.6Hz ,1H),4.29(dd,J=10.8,6.5Hz,1H),3.98-3.90(m,8H),2.95-2.86(m,1H),2.73-2.63(m,1H),2.48-2.36(m,3H),2.34(s,3H),1.96(br dd,J=10.8,5.3Hz,1H),1.91-1.68(m,8H),1.65-1.54(m,1H),0.91-0.85(m,3H).

[0333] Preparation of intermediate 54: (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-3-one [ka] To a stirred solution of 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3,3-bis(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-ol (30 mg, 0.054 mmol) in ACN (1 mL) was added (1S,4S)-2,5-diazabicyclo[2.2.1]heptan-3-one (6.61 mg, 0.059 mmol), DIPEA (0.0286 mL, 0.164 mmol), and BOP (35.6 mg, 0.080 mmol). The reaction mixture was heated at 80° C. for 8 hours. The reaction mixture was then cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The crude material was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 40 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), eluting with a gradient of 60-100% EtOAc in petroleum ether. Evaporation of the fractions containing the desired product gave (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-3-one (30 mg, 0.046 mmol, 86% yield) as a brown solid. MS (ESI) m / z: 654.3 [M+H] + .

[0334] Example 5-1 (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-3-one [ka] To a stirred solution of (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-3-one (30 mg, 0.046 mmol) in acetonitrile (1 mL) at 0° C. was added 4 N HCl (4 M in dioxane) (0.115 mL, 0.459 mmol), and the reaction mixture was stirred at room temperature for 1 h. Volatiles from the reaction mixture were removed under reduced pressure (lower temperature, approximately 30° C.), and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (2 mL), excess TEA (1 mL) was added, and the mixture was concentrated under reduced pressure to give an off-white solid. The crude compound was purified by prep-HPLC [HPLC method: Column: CHIRALPAK™ IC (Daicel, Japan) (250 mm × 21 mm); Mobile phase A: 0.1% DEA in CAN, Mobile phase B: 0.1% DEA in methanol, Flow rate: 15.0 mL / min, Gradient: T / %B: 0 / 50; 10 / 50] to give (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-3-one (4.1 mg, 6.72 μmol, 14.65% yield) as an off-white solid. MS(ESI)m / z:610.3[M+H] + . 1H NMR(400MHz,DMSO-d6)δ ppm=10.16(s,1H),7.97(dd,J=6.0,9.0Hz,1H),7.75(d,J=8.5Hz,1H),7.46(t,J=8.9Hz,1H),7. 37(d,J=2.8Hz,1H),7.21(t,J=7.4Hz,1H),7.07(d,J=2.3Hz,1H),4.49-4.40(m,1H),4.38-4.21( m,2H),4.11(dd,J=2.3,10.8Hz,1H),3.85(d,J=4.0Hz,1H),3.83-3.78(m,2H),3.56-3.51(m,4H) ,2.82-2.71(m,1H),2.60-2.54(m,1H),2.32-2.17(m,4H),1.90-1.47(m,8H),1.45-1.34(m,1H).

[0335] Preparation of intermediate 56: tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.7 g, 4.11 mmol) in DMF (50 mL) was added CsF (6.24 g, 41.1 mmol). The reaction mixture was heated at 50° C. for 1 h. The reaction mixture was then cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.9 g, 3.89 mmol, 95% yield) as a brown liquid, which was used for the next step without further purification. MS (ESI) m / z: 746.6 [M+H] + .

[0336] Preparation of intermediate 57: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka] To a solution of tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 0.940 mmol) in acetonitrile (5 mL) was added 4 M HCl in dioxane (0.29 mL, 9.40 mmol) at 0 °C, and the mixture was stirred for 1 h. The solvent was then removed under reduced pressure, and the residue was diluted with DCM and neutralized with excess TEA. The organic layer was washed with water and brine solution, then dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (300 mg, 0.50 mmol, 53% yield). MS (ESI) m / z: 601.3 [M+H] + .

[0337] Example 6-1: 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one [ka] To a solution of 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (50 mg, 0.083 mmol) in DCM (2 mL) was added TEA (0.035 mL, 0.250 mmol) and TFAA (0.018 mL, 0.125 mmol) at 0 °C, and the mixture was stirred for 1 h. The reaction mixture was then quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude compound was purified by prep-HPLC. [HPLC method: Preparative column: YMC ExRS (20 × 250) 5 μm, Mobile phase A: 10 mM ammonium bicarbonate-9.5% in water] pH; mobile phase B: acetonitrile:MeOH (1:1); gradient = 0 (min)-60%, 2-65%, 15-85%, 16-70%, 17-100%; temperature: 27 °C; flow rate: 19 mL / min; detection: UV at 220 and 254 nm] to give 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one (15 mg, 0.019 mmol, 23% yield). MS(ESI)m / z:697.2,[M+H] + . 1H NMR(400MHz,DMSO-d6)δ ppm=9.06(s,1H),7.94(dd,J=9.1,5.9Hz,1H),7.44(t,J=9.0Hz,1H),7.35(d,J=2.3Hz,1H),7.17(s,1H),5.40-5.18(m,1H),4.81(br s,1H),4.76-4.62(m,2H),4.59-4.52(m,1H),4.18-4.11(m,1H),4.08-4.02( m,1H),3.91(d,J=6.0Hz,1H),3.79-3.68(m,2H),3.13-3.01(m,4H),2.84(br d,J=6.5Hz,1H),2.17-1.74(m,9H).

[0338] The examples in Table 3 were prepared from the appropriate starting materials according to the procedure described for Example 6-1.

[0339] [Table 102]

[0340] [Table 103]

[0341] [Table 104]

[0342] [Table 105]

[0343] [Table 106]

[0344] [Table 107]

[0345] Preparation of intermediate 58: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazoline [ka] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazoline (150 mg, 0.303 mmol) in DCM (10 mL) was added DIPEA (0.16 mL, 0.910 mmol) and a solution of propylphosphonic anhydride in EtOAc (0.4 mL, 0.61 mmol) at 0° C. After stirring for 15 min at 0° C., 4,4-difluorocyclohexane-1-carboxylic acid (54.8 mg, 0.33 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was then extracted with EtOAc (2x), washed with water and brine solution, dried over sodium sulfate, filtered, and concentrated to give 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazoline (120 mg, 0.18 mmol, 53% yield). MS (ESI) m / z: 642.2 (M+2). + .

[0346] Preparation of intermediate 59: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazoline [ka] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazoline (100 mg, 0.156 mmol) in 1,4-dioxane (5 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (120 mg, 0.234 mmol) and 2 M potassium phosphate, tribasic in water (0.23 mL, 0.468 mmol). The reaction mixture was degassed under argon for 5 min, then [1,1'-bis(di-tertbutylphosphino)ferrocene]dichloropalladium(II) (10.2 mg, 0.016 mmol) was added, and the mixture was again degassed under argon for 3 min and then heated at 50° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue that was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (12 g silica gel column, 2-5% MeOH in DCM) to give 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazoline (126 mg, 0.133 mmol, 85% yield) as a brown solid. MS(ESI)m / z:946.4[M+H] + .

[0347] Preparation of intermediate 60: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazoline [ka] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazoline (126 mg, 0.133 mmol) in DMF (5 mL) was added CsF (202 mg, 1.33 mmol). The reaction mixture was heated at 50 °C for 1 h. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazoline (99 mg, 0.125 mmol, 94% yield) as a light brown liquid, which was used for the next step without purification. MS (ESI) m / z: 790.3 [M+H] + .

[0348] Example 7-1: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazoline (99 mg, 0.125 mmol) in acetonitrile (5 mL) at 0 °C, 4 M HCl in dioxane (5 mL, 2.51 mmol) was added, and the mixture was stirred for 2 h. Volatiles from the reaction mixture were removed under reduced pressure, and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (2 mL), and excess TEA (1 mL) was added. The mixture was concentrated under reduced pressure to give an off-white solid. The crude compound was purified by prep-HPLC [Waters XBridge C18 (Waters Corp., Milford, CT), (250 mm × 19 mm, 5 μm particles); mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 15% B with a 0-minute hold, 15–55% B over 25 minutes, then 100% B for a 5-minute hold; flow rate: 20 mL / min; detection: UV at 220 and 254 nm]. , 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (8.7 mg, 0.012 mmol, 9% yield) was obtained as an off-white solid. MS (ESI) m / z: 746.3 [M+H] + .

[0349] The examples in Table 4 were prepared from the appropriate starting materials according to the procedures described for Examples 6-1 and 7-1.

[0350] [Table 108]

[0351] [Table 109]

[0352] [Table 110]

[0353] [Table 111]

[0354] Preparation of Intermediate 61: tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300 mg, 3.03 mmol) in dioxane (8 mL) was added DIPEA (0.476 mL, 2.72 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (193 mg, 0.908 mmol). The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was diluted with EtOAc (50 mL) and washed with water (30 mL × 2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (12 g, ISCO column, MeOH / DCM, 0-5%, 20 min) to give tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (415 mg, 0.82 mmol, 90% yield) as a white solid. MS (ESI) m / z 507.0 [M+2] + . 1H NMR(499MHz,DMSO-d6)δ ppm=8.10(d,J=1.9Hz,1H),4.38(br d,J=10.6Hz,2H),4.25(br s,2H),3.66(m,2H)1.79(m,2H),1.62(m,2H),1.47 s,9H).

[0355] Preparation of Intermediate 62: tert-butyl 3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a degassed solution of tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 35, 1 g, 3.03 mmol) in DMA (80 mL) was added cesium fluoride (5.25 g, 34.6 mmol). The reaction mixture was degassed with nitrogen for 10 minutes and heated in a sealed tube at 88 °C for 5 hours. Water (200 mL) and EtOAc (150 mL) were added, and the reaction mixture was stirred for 15 minutes. The separated aqueous layer was extracted with EtOAc (2 × 100 mL), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 15-25% EtOAc in petroleum ether as eluent to give tert-butyl-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.7 g, 8.77 mmol, 63.4% yield) as a pale yellow solid. MS (ESI) m / z 489.0 [M+H] + .

[0356] Preparation of intermediate 63: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a degassed solution of tert-butyl-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 36, 2.00 g, 4.08 mmol) in anhydrous 1,4-dioxane (20 mL) was added potassium phosphate (1.73 g, 8.17 mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (5.8 g, 12.25 mmol), and PdCl(dppf) (149 mg, 0.204 mmol). The reaction mixture was degassed again and heated at 80 °C for 48 h. After completion of the reaction, the reaction mixture was cooled to ambient temperature, diluted with EtOAc (40 mL), filtered through a bed of CELITE™ (Sigma Aldrich, St. Louis, MO), and concentrated under reduced pressure to give the crude product. The residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% EtOAc in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 1.74 mmol, 42% yield). 1H NMR(400MHz,CDCl3):δ ppm=7.76(d,J=1.6Hz,1H),7.20-7.18(d,J=8.8Hz,4H),6.86(dt,J=9.6Hz,4H),6.60(s,1H),6.38(s,1H),4.60(s,3H),4 .39-4.21(m,4H),3.63(s,6H),2.29(s,3H),1.98-1.96(m,6H),1.76-1.63(m,2H),1.49(s,9H)LCMS(ESI)m / z:757.2[M+H] + .

[0357] Preparation of intermediate 64: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8 diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 37, 1.40 g, 1.849 mmol) in anhydrous ACN (15 mL) at 0° C. under nitrogen was added N-iodosuccinimide (0.42 g, 1.849 mmol) and trifluoroacetic acid (0.028 mL, 0.370 mmol). The reaction mixture was allowed to reach room temperature over 1 h. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate (5 mL) and saturated aqueous sodium bicarbonate (4 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. The crude residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% EtOAc in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8 diazabicyclo[3.2.1]octane-8-carboxylate (1.42 g, 1.560 mmol, 84% yield) as a pale yellow fluffy solid. LCMS (ESI) m / z: 883.3 [M+H] + .

[0358] Preparation of intermediate 65: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 38, 1.40 g, 1.585 mmol) in anhydrous DMA (10 mL) in a sealed tube under nitrogen was added copper(I) iodide (0.60 g, 3.17 mmol). The reaction mixture was degassed for 10 minutes, after which methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.91 g, 4.76 mmol) was added and the reaction mixture was heated at 90° C. for 12 hours. The reaction progress was monitored by LCMS. The reaction mixture was diluted with diethyl ether (20 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with diethyl ether (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% EtOAc in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.85 g, 0.630 mmol, 40% yield) as a pale yellow solid. 1 H NMR(400MHz,CDCl3):δ ppm=7.77(s,1H),7.16(d,J=8.8Hz,4H),6.87(dt,J=9.6 and 2.8Hz,4H),6.43(s,1H),4.76-4.72(m,2H),4.59-4.55 (m,2H),3.81(s,6H),2.43(s,3H),1.97-1.82(m,4H),1.97-1.82(m,4H),1.53(s,9H).LCMS(ESI)m / z:825.2[M+H] + .

[0359] Intermediates 66 and 67: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Intermediate 65 (5.0 g, 6.06 mmol) was subjected to SFC separation (method information: Column: CHIRALPAK™ IH (Daicel, Japan) (250 mm x 4.6 mm; 5 μm), mobile phase—0.25% isopropanol), peak-1 eluted at retention time=5.85 min (2.4 g, 2.90 mmol, 40% yield), and peak-2 eluted at retention time=9.53 min (2.4 g, 2.90 mmol, 40% yield). Peak-1 (Intermediate 66): 1 H NMR(400MHz,CDCl3):δ ppm=7.78(s,1H),7.16(d,J=8.8Hz,4H),6.87(dt,J=9.6 and 2.8Hz,4H),6.43(s,1H),4.76-4.72(m,2H),4.59-4.55( m,2H),3.81(s,6H),2.43(s,3H),1.97-1.82(m,4H),1.97-1.82(m,4H),1.53(s,9H)ppm.LCMS(ESI)m / z:825.2[M+H] + LCMS(ESI)m / z:825.2[M+H] + [α] 23.5 (MeOH=0.10)=+96.00; Peak-2: (Intermediate 67) 1 H NMR(400MHz,CDCl3):δ ppm=7.78(s,1H),7.16(d,J=8.8Hz,4H),6.87(dt,J=9.6 and 2.8Hz,4H),6.43(s,1H),4.76-4.72(m,2H),4.59-4.55( m,2H),3.81(s,6H),2.43(s,3H),1.97-1.82(m,4H),1.97-1.82(m,4H),1.53(s,9H)ppm.LCMS(ESI)m / z:825.2[M+H] + .[α] 23.3(MeOH=0.10)=-110.00.

[0360] Preparation of intermediate 68: tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of [(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methanol (0.205 g, 1.212 mmol, Intermediate 67) in THF (5 mL) at 0 °C, NaH (0.194 g, 4.85 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To this was added tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 1.212 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice cubes and concentrated under reduced pressure. The crude product was partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude product, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (24 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), 0-10% MeOH-DCM) to give tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.70 g, 0.718 mmol, 59% yield). MS(ESI)m / z:974.4(M+H) + .

[0361] Preparation of intermediate 69: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] To a solution of tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 0.718 mmol) in acetonitrile (5 mL) was added 4 M HCl in dioxane (0.9 mL, 3.59 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The solvent was then removed under reduced pressure, diluted with MeOH, neutralized with excess TEA, and concentrated again under reduced pressure to give 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (410 mg, 0.47 mmol, 57% yield). MS (ESI) m / z: 874.3 (M+H). + .

[0362] Preparation of intermediate 70: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] To a stirred solution of 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.06 mmol) in DCM (10 mL) was added DIPEA (0.03 mL, 0.17 mmol) and a solution of propylphosphonic anhydride in EtOAc (0.03 mL, 0.11 mmol) at 0 °C. After stirring at 0 °C for 15 min, 3,3-difluorocyclobutane-1-carboxylic acid (9.4 mg, 0.07 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with EtOAc, washed with water and brine solution, then dried over sodium sulfate, filtered, and concentrated to give 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (54 mg, 0.05 mmol, 95% yield). MS (ESI) m / z: 992.3 (M+H). + .

[0363] Example 8-1: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] A vial was charged with 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (54 mg, 0.054 mmol)), triethylsilane (8.69 μL, 0.054 mmol), and TFA (4.19 μL, 0.054 mmol). The vial was then sealed and heated at 40° C. for 16 h. Volatiles from the reaction mixture were removed under reduced pressure, and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (2 mL) and excess TEA (1 mL) was added. The mixture was evaporated under reduced pressure to give a crude residue which was purified by prep-HPLC [HPLC method: Preparative column: Column: Waters XBridge Purification by C18, 19 × 150 mm, 5-μm particles; mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 15–47% B over 22 min, then hold at 100% B for 5 min; flow rate: 20 mL / min; detection: UV at 220 and 254 nm gave 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (14.3 mg, 0.018 mmol, 34% yield). MS (electrospray ionization (ESI)) m / z: 752.3 [M+H] + .

[0364] The examples in Table 5 were prepared from the appropriate starting materials according to the procedure described for Example 8-1.

[0365] [Table 112]

[0366] Preparation of Intermediate 71: tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate [ka] The intermediate tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate was synthesized according to literature procedures: Bioorg. Med. Chem. Lett. 2019, 29, 2405-2409.

[0367] Preparation of Intermediate 72 tert-Butyl 6-oxo-1,4-oxazepane-4-carboxylate [ka] To a stirred solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate (6 g, 28.1 mmol) in THF (40 mL) and water (40 mL) was added sodium metaperiodate (12.03 g, 56.3 mmol), followed by the addition of a solution of osmium tetroxide (2 mL, 0.141 mmol) in tert-butanol at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated to give the crude product. The mixture was extracted with EtOAc (60 mL×3). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (pet. ether / EtOAc = 30%) to give the title compound tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (2 g, 9.29 mmol, 33.0% yield) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ ppm=4.02-4.17(m,4H),3.91(br d,J=3.78Hz,2H),3.70(br s,2H)1.45(br s,9H).

[0368] Preparation of intermediates 73 and 74: tert-butyl 6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate [ka] To a stirred solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (2.5 g, 11.61 mmol) in THF (150 mL) was added dropwise a solution of methylmagnesium chloride in THF (46.5 mL, 46.5 mmol) at 0 °C. The reaction mixture was stirred for 2 h. The reaction mixture was then quenched with saturated NH4Cl solution and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the product. The racemate was purified by SFC chiral separation to give Isomer-1: tert-butyl 6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate (1 g, 4.32 mmol, 37.2% yield) and Isomer-2: tert-butyl 6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate (1 g, 4.32 mmol, 37.2% yield). [Method; Column / Dimensions: CHIRALPAK™ IG (Daicel, Japan) (250 × 50) mm, 5 μm, % CO: 60%, % Co-solvent: 4 M methanolic ammonia in 40% MeOH, Total Flow Rate: 280.0 g / min, Back Pressure: 100 bar, Temperature: 40 °C, UV: 205 nm, RT = 4.15 min (Isomer-1) and RT = 6.01 min (Isomer-2)]. Isomer-1: 1 H NMR(400MHz,DMSO-d6)δ ppm=4.60-4.66(m,1H),3.48-3.73(m,3H),3.35-3.44(m,2H),3.04-3.20(m,3H),1.41(s,9H),1.02-1.15(m,3H). Isomer-2: 1 H NMR(400MHz,DMSO-d6)δ ppm=4.57-4.73(m,1H),3.49-3.77(m,3H),3.35-3.48(m,2H),3.06-3.25(m,3H),1.41(s,9H),1.07-1.08(m,3H).

[0369] Preparation of intermediates 75 and 76: 6-methyl-1,4-oxazepan-6-ol [ka] Intermediate 75 (Isomer-1): To a stirred solution of tert-butyl 6-hydroxy-6-methyl-1,4-oxazepan-4-carboxylate (Intermediate 73, 1 g, 4.32 mmol) in acetonitrile (10 mL) was added HCl (4 M in dioxane) (5.40 mL, 21.62 mmol). The resulting reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated and co-evaporated with toluene (twice) to give 6-methyl-1,4-oxazepan-6-ol hydrochloride (550 mg, 3.28 mmol, 76% yield) as a white solid. MS (ESI) m / z: 132.1 [M+H] + .

[0370] Intermediate 76 (Isomer-2): To a stirred solution of tert-butyl 6-hydroxy-6-methyl-1,4-oxazepan-4-carboxylate (Intermediate 74, 1 g, 4.32 mmol) in acetonitrile (10 mL) was added HCl (4 M in dioxane) (5.40 mL, 21.62 mmol). The resulting reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated and co-evaporated with toluene (twice) to give 6-methyl-1,4-oxazepan-6-ol hydrochloride (550 mg, 3.28 mmol, 76% yield). MS (ESI) m / z: 132.2 [M+H] + .

[0371] Intermediate 75 (Isomer-1) was used for the preparation of Examples 1-84, 1-108, 2-70 and 2-74.

[0372] Preparation of intermediates 77 and 78: tert-butyl 6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate [ka] To an ice-cold solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate (1.2 g, 5.63 mmol) in THF (15 mL) was added a borane-tetrahydrofuran complex solution in THF (6.75 mL, 6.75 mmol). The reaction mixture was heated to 25°C and stirred for 3 h. The reaction mixture was then cooled to 0-10°C and treated sequentially with 3N sodium hydroxide (17 mL) and 30% hydrogen peroxide (6 mL). The resulting homogeneous mixture was stirred overnight at room temperature, then treated with hexane (45 mL), and dried over potassium carbonate. The organic layer was decanted from the precipitate, which was washed with dichloromethane. The organic layer was evaporated to give the title compound. The racemate was purified by SFC chiral separation to give isomer-1 (Intermediate 77): tert-butyl 6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (200 mg, 0.865 mmol, 15.37% yield; peak 1), MS(ESI) m / z: 232.1 [M+H] + and Isomer-2 (Intermediate 78): tert-butyl 6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (220 mg, 0.951 mmol, 16.91% yield; Peak 2). MS (ESI) m / z: 132.0 [M-100] + [Method: Flow rate: 3 mL / min, Column name: CHIRALPAK™ IG (Daicel, Japan) (250 x 4.6) mm. 5 μm, Co-solvent: 30% Vial No.: LD8, Co-solvent name: 0.2% ammonia in methanol, Injection volume: 20 μl, Outlet pressure: 100 bar, Temperature: 40°C, Comments: SFC-3G-30%-15MTS-205NM, t R = 2.0 min (isomer-1) and t R = 4.05 min (isomer-2)].

[0373] Preparation of Intermediates 79 and 80: (1,4-Oxazepan-6-yl)methanol [ka] Intermediate 79 (Isomer-1): To a solution of tert-butyl 6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (Intermediate 77, 200 mg, 0.865 mmol) in acetonitrile (2 mL) at 0 °C, 4.0 M hydrochloric acid in dioxane (0.026 mL, 0.865 mmol) was added and the mixture was stirred for 1 h. The reaction mixture was then concentrated and co-evaporated with CAN to give (1,4-oxazepan-6-yl)methanol hydrochloride (130 mg, 0.776 mmol, 90% yield). MS (ESI) m / z: 132.2 [M+H] + .

[0374] Intermediate 80 (Isomer-2): To a solution of tert-butyl 6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (Intermediate 78, 200 mg, 0.865 mmol) in acetonitrile (2 mL) at 0 °C, 4.0 M hydrochloric acid in dioxane (0.026 mL, 0.865 mmol) was added, and the mixture was stirred for 1 h. The reaction mixture was then concentrated and co-evaporated with CAN to give (1,4-oxazepan-6-yl)methanol hydrochloride (110 mg, 0.658 mmol, 76% yield) as a pale yellow solid. MS (ESI) m / z: 132.1 [M+H] + .

[0375] Intermediate 80 (Isomer-2) was used for the preparation of Examples 1-88.

[0376] Preparation of Intermediate 81: tert-butyl 6,6-difluoro-1,4-oxazepane-4-carboxylate [ka] To a stirred solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (200 mg, 0.929 mmol) in DCM (4 mL) was added diethylaminosulfur trifluoride (0.982 mL, 7.43 mmol) at 0 °C, and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then carefully quenched with MeOH followed by water at 0 °C and then concentrated. The crude residue was partitioned between EtOAc and brine. The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated to give tert-butyl 6,6-difluoro-1,4-oxazepane-4-carboxylate (200 mg, 0.843 mmol, 91% yield). 1 H NMR(300MHz,DMSO-d6)δ ppm=3.70-3.95(m,6H),3.46-3.57(m,2H),1.40(s,9H).

[0377] Preparation of Intermediate 82: 6,6-Difluoro-1,4-oxazepane [ka] To a stirred solution of tert-butyl 6,6-difluoro-1,4-oxazepane-4-carboxylate (200 mg, 0.843 mmol) in acetonitrile (3 mL) at 0 °C, HCl 4 M in dioxane (0.256 mL, 8.43 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was then concentrated and coevaporated with toluene to give the product 6,6-difluoro-1,4-oxazepane (100 mg, 0.729 mmol, 87% yield). MS (ESI) m / z: 138.0 [M+H] + .

[0378] Preparation of Intermediates 83 and 84: 3-Methylpiperidin-3-ol [ka] To a stirred solution of 1-benzylpiperidin-3-one (2 g, 10.57 mmol) in tetrahydrofuran (10 mL) was added dropwise a solution of methylmagnesium bromide in dibutyl ether (14.09 mL, 42.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was then slowly quenched with saturated NH Cl solution and extracted with ethyl acetate (150 mL × 2). The organic layer was washed with brine (ca. 200 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give a racemic mixture. The racemic mixture was purified by SFC chiral purification to give 1-benzyl-3-methylpiperidin-3-ol, isomer 1-intermediate 83 (0.57 g, 2.78 mmol, 26.3% yield) and isomer 2-intermediate 84 (0.6 g, 2.92 mmol, 27.7% yield). [Method: Column / Dimensions: CHIRALPAK™ AD-H (Daicel, Japan) (250 x 30) mm, 5 μm, % CO: 80%, % Co-solvent: 0.2% ammonia in 20% methanol, Total flow rate: 130.0 g / min, Back pressure: 100 bar, Temperature: 40°C, UV: 220 nm, RT: 2.5 min (Isomer-1) and 3.4 min (Isomer-2)]. For Isomer-1: 1 H NMR(300MHz,DMSO-d6)δ ppm=7.21-7.36(m,5H),4.16(s,1H),3.31-3.45(m,2H),2.29-2.48(m,1H),2.19(br d,J=10.20Hz,2H),2.02(br d,J=10.58Hz,1H),1.61(br d,J=3.78Hz,1H),1.23-1.53(m,3H),1.10(s,3H).About isomer-2: 1 H NMR(300MHz,DMSO-d6)δ ppm=7.21-7.34(m,5H),4.16(s,1H),3.32-3.38(m,2H),2.35(br s,1H),2.19(br d,J=10.58Hz,2H),2.02(br d,J=10.95Hz,1H),1.61(br s,1H),1.27-1.51(m,3H),1.10(s,3H).

[0379] Preparation of Intermediate 85: 3-Methylpiperidin-3-ol (Isomer-1) [ka] A stirred solution of 1-benzyl-3-methylpiperidin-3-ol (Intermediate 83) (570 mg, 2.78 mmol) in MeOH (10 mL) was purged with nitrogen for 3 minutes, and palladium on carbon, 10% (1182 mg, 1.111 mmol) was added. The resulting reaction mixture was stirred at room temperature under a hydrogen balloon for 5 hours. The reaction mixture was filtered through a CELITE™ (Sigma Aldrich, St. Louis, MO) pad and washed with MeOH (20 mL). The filtrate was evaporated under reduced pressure to give 3-methylpiperidin-3-ol (200 mg, 1.736 mmol, 62.5% yield). MS (ESI) m / z: 116.2 [M+H] + .

[0380] Intermediate 85 was used for the preparation of Examples 1-85, 1-89, 1-95 and 2-72.

[0381] Preparation of Intermediate 86: Ethyl 3-(benzylamino)butanoate [ka] To a stirred solution of benzylamine (5 g, 46.7 mmol) in EtOH (25 mL) at 0 °C was added trans-ethyl crotonate, 96% (6.96 mL, 56.0 mmol) and stirred at 90 °C for 16 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove volatiles. The crude residue was purified via COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (2-5% methanol / DCM, 40 g column) to afford the desired product, ethyl 3-(benzylamino)butanoate (7 g, 31.6 mmol, 67.8% yield). MS (ESI) m / z: 222.2 [M+H] + .

[0382] Preparation of Intermediate 87: 3-(benzylamino)butan-1-ol [ka] To a suspension of LAH (1.831 g, 48.2 mmol) in THF (100 mL) under a nitrogen atmosphere at 0 °C was added dropwise a solution of methyl 3-(benzylamino)butanoate (5 g, 24.12 mmol) in THF (100 mL). The resulting mixture was warmed to room temperature and stirred for 3 h. The reaction was then quenched at 0 °C by the dropwise addition of a small amount of saturated aqueous sodium sulfate, and the mixture was stirred for 1 h. The resulting solid material was removed by filtration, and the organic solution was concentrated to give 3-(benzylamino)butan-1-ol (3.9 g, 13.05 mmol, 54.1% yield). 1 H NMR(300MHz,DMSO-d6)δ ppm=7.36-7.18(m,5H),3.78-3.69(m,1H),3.63-3.31(m,3H),2.75-2.56(m,1H),2.45-2.15(m,1H) ,2.11-1.85(m,1H),1.73-1.52(m,1H),1.48-1.33(m,1H),1.01(d,J=6.4Hz,2H),0.93-0.77(m,1H).

[0383] Preparation of Intermediate 88: 4-Benzyl-5-methyl-1,4-oxazepan-3-one [ka] To a solution of 3-(benzylamino)butan-1-ol (3 g, 16.74 mmol) and triethylamine (4.99 mL, 35.8 mmol) in DCM (50 mL) was added chloroacetyl chloride (1.557 mL, 19.58 mmol) at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was poured into 1N aqueous HCl solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in 2-propanol (20 mL), and potassium hydroxide (0.66 g, 10 mmol) was added to the solution at room temperature. After stirring for 18 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (hexane / ethyl acetate = 100 / 0 to 1 / 1 as eluent) to give 4-benzyl-5-methyl-1,4-oxazepan-3-one (2.6 g, 10.67 mmol, 63.8% yield). MS (ESI) m / z: 220.2 [M+H] + .

[0384] Preparation of intermediates 89 and 90: 4-benzyl-5-methyl-1,4-oxazepane [ka] To a solution of 4-benzyl-5-methyl-1,4-oxazepan-3-one (2.64 g, 12.04 mmol) in THF (48 mL) was added dropwise a borane-tetrahydrofuran complex solution in THF (11.52 mL, 120 mmol) at 0 °C under a nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 3 hours. The reaction was then quenched by the addition of methanol, and the solution was concentrated under reduced pressure. The residual oil was dissolved in methanol (30 mL), and 1 M aqueous sodium hydroxide solution was added at room temperature. The mixture was refluxed for 3 hours, cooled to room temperature, and diluted with water. The resulting solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The racemate was purified by SFC chiral separation to give intermediate 89 (isomer-1): 4-benzyl-5-methyl-1,4-oxazepane (350 mg, 1.7 mmol, 29.16%) as a pale yellow liquid and intermediate 90 (isomer-2): 4-benzyl-5-methyl-1,4-oxazepane (350 mg, 1.7 mmol, 29.16%) as a pale yellow liquid. [Method Column: CHIRALPAK™ IG (Daicel, Japan) (250 × 4.6) mm, 5 μm, Cosolvent: 0.2% ammonia in methanol, Flow rate: 3 mL / min, Cosolvent percentage: 10%, Back pressure: 100, Isomer-1 (RT = 3.07 min) and Isomer-2 (RT = 3.81 min)] MS (ESI) m / z: 206.2 [M+H] + .

[0385] Preparation of Intermediates 91 and 92: 5-Methyl-1,4-oxazepane [ka] Intermediate 91 (Isomer-1): To a stirred solution of 4-benzyl-5-methyl-1,4-oxazepane (350 mg, 1.705 mmol) in 1,2-dichloroethane (5 mL) was added 1-chloroethyl chloroformate (2437 mg, 17.05 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and completely concentrated. The crude mixture was redissolved in MeOH (5 mL) and refluxed for 1 h. The reaction mixture was cooled to room temperature and completely concentrated to give 5-methyl-1,4-oxazepane (150 mg, 1.302 mmol, 76% yield) as a viscous liquid. MS (ESI) m / z: 116.2 [M+H]+.

[0386] Intermediate 92 (Isomer-2): To a stirred solution of 4-benzyl-5-methyl-1,4-oxazepane (350 mg, 1.705 mmol) in 1,2-dichloroethane (5 mL) was added 1-chloroethyl chloroformate (2437 mg, 17.05 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and completely concentrated. The crude material was dissolved in MeOH (5 mL) and refluxed for 1 h. The reaction mixture was cooled to room temperature and completely concentrated to give 5-methyl-1,4-oxazepane (140 mg, 1.216 mmol, 71.3% yield) as a viscous liquid. MS (ESI) m / z: 116.1 [M+H]+.

[0387] Intermediate 91 (Isomer-1) was used for the preparation of Examples 1-93 and 1-96.

[0388] Preparation of intermediates 93 and 94: tert-butyl 1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate and tert-butyl 2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate [ka] To a stirred solution of 4,6-dihydro-1h-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (2 g, 9.56 mmol) in DMF (20 mL) was added cesium carbonate (6.23 g, 19.12 mmol) and iodomethane (1.195 mL, 19.12 mmol) at room temperature, and the mixture was stirred for 16 h. The reaction mixture was then poured into water and extracted with EtOAc (50 × 3). The organic layer was washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a mixture of regioisomers. The mixture of regioisomers was separated by SFC [Conditions Column / Dimensions: CHIRALPAK™ OZ-H (Daicel, Japan) (250 x 30) mm, 5 μm, % CO: 90%, % Co-solvent: 10% 5 mM ammonium acetate in ACN:MeOH (50:50), Total Flow Rate: 150.0 g / min, Back Pressure: 100 bar, Temperature: 40 °C, UV: 220 nm] to give regioisomer-1 (Intermediate 93) (t R = 3 min) (0.2 g, 0.896 mmol, 9.37% yield) Regioisomer-2 (Intermediate 94) (t R = 4.37 min)] (0.8 g, 3.58 mmol, 37.5% yield, regioisomer-2).

[0389] Intermediate 93, tert-butyl 1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate: 1 H NMR(400MHz,CDCl3)δ ppm=7.28-7.20(m,1H),4.62-4.30(m,4H),3.84(d,J=2.5Hz,3H),1.53(d,J=2.5Hz,9H).

[0390] Intermediate 94, tert-butyl 2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate: 1 H NMR(400MHz, CDCl3)δ ppm=7.22-7.04(m,1H),4.63-4.31(m,4H),3.92(s,3H),1.53(d,J=2.0Hz,9H).

[0391] Preparation of Intermediate 95: 1-Methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole [ka] To a stirred solution of tert-butyl 1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (100 mg, 0.448 mmol) in acetonitrile (5 mL) at 0 °C, HCl (4 M in dioxane) (1.120 mL, 4.48 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 h. Volatiles from the reaction mixture were removed under reduced pressure to give 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (50 mg, 0.406 mmol, 91% yield) as an off-white solid. MS (ESI) m / z: 124.1 [M+H]+.

[0392] Preparation of Intermediate 96: 2-Methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole [ka] To a stirred solution of tert-butyl 2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (100 mg, 0.448 mmol) in acetonitrile (2 mL) at 0 °C, HCl (4 M in dioxane) (1.120 mL, 4.48 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 h. Volatiles from the reaction mixture were removed under reduced pressure to give 2-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (45 mg, 0.365 mmol, 82% yield) as a colorless liquid. MS (ESI) m / z: 124.2 [M+H]+.

[0393] Preparation of Intermediate 97: Methyl 4-amino-6-chloro-2-methoxypyridine-3-carboxylate [ka] To a stirred solution of 6-chloro-3-iodo-2-methoxypyridin-4-amine (prepared as described in WO 2010 / 093849 and WO 2022 / 040267) (25 g, 88 mmol) in MeOH (450 mL) was added triethylamine (36.7 mL, 264 mmol) and dppf (4.87 g, 8.79 mmol), followed by palladium(II) acetate (0.986 g, 4.39 mmol). The reaction mixture was purged with N for 5 minutes, and the reaction mixture was stirred in an autoclave at 60° C. under 2.5 kg of CO gas pressure for 16 hours. The reaction mixture was cooled to room temperature and filtered through a pad of CELITE™ (Sigma Aldrich, St. Louis, MO), and the pad was washed with methanol. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 120 g silica gel column with 30-35% ethyl acetate / petroleum ether to give methyl 4-amino-6-chloro-2-methoxypyridine-3-carboxylate (16 g, 73.9 mmol, 84% yield) as a white solid. MS (ESI) m / z: 217.1 [M+H] + .

[0394] Preparation of Intermediate 98: Methyl 4-amino-6-chloro-5-fluoro-2-methoxypyridine-3-carboxylate [ka] To a stirred solution of methyl 4-amino-6-chloro-2-methoxypyridine-3-carboxylate (19 g, 88 mmol) in ACN (400 mL) was added SELECTFLUOR™ (Air Products, Allentown, PA) (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) (31.1 g, 88 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then evaporated under reduced pressure to give the crude product. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 120 g silica gel column with 0-10% ethyl acetate / petroleum ether to give methyl 4-amino-6-chloro-5-fluoro-2-methoxypyridine-3-carboxylate (3 g, 11.95 mmol, 13.62% yield) as a white solid. MS(ESI)m / z:235.1[M+H] + .

[0395] Preparation of Intermediate 99: Methyl 6-chloro-5-fluoro-2-methoxy-4-{[(2,2,2-trichloroacetyl)carbamoyl]amino}pyridine-3-carboxylate [ka] To a stirred solution of methyl 4-amino-6-chloro-5-fluoro-2-methoxypyridine-3-carboxylate (9.5 g, 40.5 mmol) in THF (150 mL) was added trichloroacetyl isocyanate (6.28 mL, 52.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give methyl 6-chloro-5-fluoro-2-methoxy-4-{[(2,2,2-trichloroacetyl)carbamoyl]amino}pyridine-3-carboxylate (17.84 g, 40.5 mmol, 100% yield) as a white solid, which was used in the subsequent step without further purification. MS (ESI) m / z: 424.1 [M+H] + .

[0396] Preparation of Intermediate 100: 7-chloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine-2,4-diol [ka] To a stirred solution of methyl 6-chloro-5-fluoro-2-methoxy-4-{[(2,2,2-trichloroacetyl)carbamoyl]amino}pyridine-3-carboxylate (16 g, 37.8 mmol) in MeOH (200 mL) was added a 7N solution of ammonia (270 mL, 1891 mmol) in methanol slowly over 30 minutes. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the solid was washed with methanol (200 mL) and dried under vacuum to give 7-chloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine-2,4-diol (9 g, 36.3 mmol, 96% yield) as a white solid, which was used in the subsequent step without further purification. MS (ESI) m / z: 246.1 [M+H] + .

[0397] Preparation of Intermediate 101: 2,4,7-trichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine [ka] POCl3 (133 mL, 1425 mmol) followed by DIPEA (24.89 mL, 143 mmol) was added to 7-chloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine-2,4-diol (7 g, 28.5 mmol). The reaction mixture was heated at 90 °C for 2 hours. The reaction mixture was then evaporated, and the residue was dissolved in ethyl acetate. This was added to a cooled saturated solution of sodium bicarbonate and stirred for 10 minutes. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2,4,7-trichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine (8.05 g, 28.5 mmol, 100% yield) as a pale yellow solid. MS (ESI) m / z: 284.0 [M+H] + .

[0398] Preparation of Intermediate 102: 4-{2,7-dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl}-1,4-oxazepane [ka] To a stirred solution of 2,4,7-trichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine (1.5 g, 5.31 mmol) in DCM (20 mL) at −40° C. was added DIPEA (1.85 mL, 10.62 mmol), followed by 1,4-oxazepane (0.537 g, 5.31 mmol). The reaction mixture was slowly allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was treated with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (40 g silica gel column, 50-80% ethyl acetate / pet ether) to give 4-{2,7-dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl}-1,4-oxazepane (1.2 g, 3.46 mmol, 65.1% yield) as a pale yellow solid. MS (ESI) m / z: 347.0 [M+H] + .

[0399] Preparation of intermediate 103: (2R,7aS)-7a-({[7-chloro-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl]oxy}methyl)-2-fluoro-hexahydro-1H-pyrrolidine [ka] To a solution of [(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methanol (220 mg, 1.383 mmol) and 4-{2,7-dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl}-1,4-oxazepane (400 mg, 1.152 mmol) in THF (5 mL) was added LiHMDS (1 M in THF) (3.46 mL, 3.46 mmol) at 0 °C, and the reaction mixture was stirred for 1 h. The reaction mixture was then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated to give a crude residue that was purified by silica gel column chromatography using CombiFlash chromatography (24 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), 80-100% EtOAc-petroleum ether) to give (2R,7aS)-7a-({[7-chloro-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl]oxy}methyl)-2-fluoro-hexahydro-1H-pyrrolidine (400 mg, 0.851 mmol, 73.9% yield) as a brown solid. MS (ESI) m / z: 470.1 [M+H] + .

[0400] Preparation of intermediate 104: (2R,7aS)-2-fluoro-7a-[({8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-hexahydro-1H-pyrrolidine [ka] To a stirred solution of (2R,7aS)-7a-({[7-chloro-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl]oxy}methyl)-2-fluoro-hexahydro-1H-pyrrolidine (400 mg, 0.851 mmol) in 1,4-dioxane (11 mL) and water (3.5 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (436 mg, 0.851 mmol) and CsCO (832 mg, 2.55 mmol), followed by PdCl(dppf) (62.3 mg, 0.085 mmol). The reaction mixture was purged with N2 for 5 minutes and heated in a microwave reactor for 1 hour at 105° C. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 24 g silica gel column with 50-100% ethyl acetate / petroleum ether to give (2R,7aS)-2-fluoro-7a-[({8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-hexahydro-1H-pyrrolidine (220 mg, 0.268 mmol, 31.5% yield) as a brown solid. MS (ESI) m / z: 820.3 [M+H] + .

[0401] Preparation of intermediate 105: (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolidine [ka] To a stirred solution of (2R,7aS)-2-fluoro-7a-[({8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-hexahydro-1H-pyrrolidine (220 mg, 0.268 mmol) in DMF (3 mL) was added CsF (408 mg, 2.68 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolidine (130 mg, 0.196 mmol, 73.0% yield) as a brown liquid, which was used in the subsequent step without further purification. MS (ESI) m / z: 664.3 [M+H] + .

[0402] Example 9-1: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka] To a stirred solution of (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolidine (130 mg, 0.196 mmol) in acetonitrile (2 mL) at 0 °C, 4 N HCl (2 mL, 65.8 mmol in 1,4-dioxane) was added, and the reaction mixture was stirred at room temperature for 1 h. Volatiles from the reaction mixture were removed under reduced pressure (lower temperature, approximately 30 °C), and the crude residue was co-evaporated with 1,4-di...

Claims

1. Formula (I): 【Chemical 1】 (In the formula, Z is a bond, O, or NR ｅ or CR ｅ R ｆ and R ｅ and R ｆ are independently hydrogen or C １ ~C ３ is alkyl; R １ is aryl or heteroaryl, and the aryl and the heteroaryl are C ２ ~C ４ Alkenyl, C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, C ２ ~C ４ Alkynyl, C ２ ~C ４ Alkynyloxy, amino, amino C １ ~C ３ Alkyl, cyano, cyano C １ ~C ３ C optionally substituted with alkoxy, 1, 2 or 3 halo groups ３ ~C ８ Cycloalkyl, halo, haloC １ ~C ３ Alkyl, haloC １ ~C ３ Alkoxy, hydroxy, hydroxy C １ ~C ３ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, heteroaryl, heterocyclyl, and phenyl, wherein said heteroaryl, heterocyclyl, and phenyl are selected from the group consisting of C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, halo and haloC １ ~C ３ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl; R ２ , R ３ and R ７ is hydrogen, C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, cyano, halo, haloC １ ~C ３ Alkyl, —C(O)NH ２ , -C(O)NH(C １ ~C ３ alkyl), -C(O)N(C １ ~C ３ alkyl) ２ and hydroxy; R ４ is -NHR ５０ , or 【Chemistry 2】 and R ５０ is a five-membered ring optionally containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen, said ring being １ ~C ３ optionally substituted with 1 or 2 groups independently selected from alkyl and oxo; n' is 0, 1, 2 or 3; R ８ , R ８’ , R ９ , R ９’ , R １０ , R １０’ , R １３ and R １３’ are each independently hydrogen, C １ ~C ３ Alkoxy, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ３ Alkyl, C ３ ~C ６ Cycloalkyl, cyano, halo, haloC １ ~C ３ Alkyl, hydroxy and hydroxy C １ ~C ３ alkyl; or R ８ and R ９ Let's join together and １ ~C ３ forming an alkylene; or R ８ and R １０ Let's join together and １ ~C ３ forming an alkylene; or R ８ and R １３ Let's join together and １ ~C ３ forming an alkylene; or R ９ and R １３ Let's join together and １ ~C ３ forming an alkylene; or R １０ and R １３ Let's join together and １ ~C ３ forming an alkylene; or R ８ and R ８’ together with the atoms to which they are attached, optionally an oxygen atom or SO ２ forming a 3, 4 or 5 membered ring containing a C １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; or R ９ and R ９’ together with the atoms to which they are attached, optionally an oxygen atom or SO ２ forming a 3, 4 or 5 membered ring containing a C １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; or R １０ and R １０’ together with the atoms to which they are attached, optionally an oxygen atom or SO ２ forming a 3, 4 or 5 membered ring containing a C １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; or R １３ and R １３’ together with the atoms to which they are attached, optionally an oxygen atom or SO ２ forming a 3, 4 or 5 membered ring containing a C １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; W １ is CR １１ R １２ , N.R. １７ , N.R. １５’’ C(O), N(C(O)(CH ２ ) ｎ OR １５ ), O, SO ２ , S.O. ２ NR １５’ or P(O)CH ３ and n is 0 or 1; R １１ and R １２ is hydrogen, C １ ~C ３ Alkoxy, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ３ independently selected from the group consisting of alkyl, cyano, dimethylphosphino; dimethylsulfonamido, halo, hydroxy, and methylsulfonyl; or R １１ and R １２ together with the atoms to which they are attached, optionally an oxygen atom or SO ２ forming a 4- to 6-membered ring containing a C １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; or R １１ and R １３ together with the atoms to which they are attached form a 3-, 4-, or 5-membered ring optionally containing one or two heteroatoms independently selected from nitrogen and oxygen, said ring optionally containing one or two double bonds, and said ring is １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; or R １３ and R １５ Let's get together and CH ２ Forming; R １５’ is C １ ~C ３ Alkyl or C １ ~C ６ Alkoxy C １ ~C ６ is alkyl; R １５’’ is hydrogen or C １ ~C ３ is alkyl; R １７ is C １ ~C ３ Alkylcarbonyl, C ３ ~C ６ Cycloalkylcarbonyl, haloC １ ~C ３ is selected from the group consisting of alkylcarbonyl, methylsulfonyl, and tetrahydropyranylcarbonyl, ３ ~C ６ cycloalkyl and said tetrahydropyranyl are optionally substituted with one or two substituents independently selected from the group consisting of cyano, halo, and hydroxy; X is O or NR １６ and R １６ is hydrogen or C １ ~C ３ is alkyl; R ５ is hydrogen, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, aryl, aryl C １ ~C ６ Alkyl, carboxy C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkyl C １ ~C ６ Alkyl, di(C １ ~C ３ Alkyl)amino C ２ ~C ６ Alkyl, haloC １ ~C ６ Alkyl, heteroaryl, heteroaryl C １ ~C ６ Alkyl, heterocyclyl, heterocyclyl C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, NR ａ R ｂ -C(O)-C １ ~C ６ alkyl), NR ａ R ｂ C １ ~C ６ alkyl, said aryl, said aryl C １ ~C ６ the aryl portion of alkyl, ３ ~C ６ cycloalkyl, the C ３ ~C ６ Cycloalkyl C １ ~C ６ the cycloalkyl portion of the alkyl, the heteroaryl, the heteroaryl C １ ~C ６ the heteroaryl portion of alkyl, the heterocyclyl, the heterocyclyl C １ ~C ６ The heterocyclyl portion of the alkyl is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, deuterated C １ ~C ３ Alkyl, C ３ ~C ６ cycloalkyl, (C １ ~C ６ alkyl)amino, (C １ ~C ６ Alkyl)amino C １ ~C ３ Alkyl, Amino, Amino C １ ~C ３ Alkyl, carboxy, cyano, di(C １ ~C ６ alkyl)amino, di(C １ ~C ６ Alkyl)amino C １ ~C ３ Alkyl, halo, haloC １ ~C ３ Alkoxy, HaloC １ ~C ３ Alkyl, heterocyclyl, heterocyclyl C １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ optionally substituted with 1, 2, 3 or 4 groups independently selected from alkyl, nitro and oxo; said heterocyclyl and said heterocyclyl C １ ~C ３ The heterocyclyl portion of the alkyl is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, halo and haloC １ ~C ３ is optionally further substituted with one, two, or three groups independently selected from the group consisting of alkyl; or R ５ and R １６ together with the nitrogen atom to which they are attached, １ ~C ３ Alkoxy, C １ ~C ３ Alkoxyalkyl, C １ ~C ３ Alkyl, Amino, Amino C １ ~C ３ Alkyl, hydroxy and hydroxy C １ ~C ３ forming a heterocyclic group optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from the group consisting of 1, 2, 3, or 4 groups independently selected from the group consisting of alkyl; and R ａ and R ｂ One of the groups is hydrogen and C １ ~C ３ alkyl, and the other is selected from the group consisting of hydrogen, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxycarbonyl, C １ ~C ３ Alkylcarbonyl, Aryl C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and C ３ ~C ６ Cycloalkyl C １ ~C ６ alkyl) or a pharmaceutically acceptable salt thereof.

2. R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

3. R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is hydrogen.

4. Formula (II): 【Chemistry 3】 (In the formula, Z is a bond, O, or NR ｅ or CR ｅ R ｆ and R ｅ and R ｆ are independently hydrogen or C １ ~C ３ is alkyl; R １ is aryl or heteroaryl, and the aryl and the heteroaryl are C ２ ~C ４ Alkenyl, C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, C ２ ~C ４ Alkynyl, C ２ ~C ４ Alkynyloxy, amino, amino C １ ~C ３ Alkyl, cyano, cyano C １ ~C ３ C optionally substituted with alkoxy, 1, 2 or 3 halo groups ３ ~C ８ Cycloalkyl, halo, haloC １ ~C ３ Alkyl, haloC １ ~C ３ Alkoxy, hydroxy, hydroxy C １ ~C ３ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, heteroaryl, heterocyclyl, and phenyl, wherein said heteroaryl, heterocyclyl, and phenyl are selected from the group consisting of C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, halo and haloC １ ~C ３ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl; R ２ and R ３ is hydrogen, C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, cyano, halo, haloC １ ~C ３ Alkyl, —C(O)NH ２ , -C(O)NH(C １ ~C ３ alkyl), -C(O)N(C １ ~C ３ alkyl) ２ and hydroxy; R ４ is -NHR ５０ , or 【Chemistry 4】 and R ５０ is a five-membered ring optionally containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen, said ring being １ ~C ３ optionally substituted with 1 or 2 groups independently selected from alkyl and oxo; n' is 0, 1, 2 or 3; R ８ , R ８’ , R ９ , R ９’ , R １０ , R １０’ , R １３ and R １３’ are each independently hydrogen, C １ ~C ３ Alkoxy, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ３ Alkyl, C ３ ~C ６ Cycloalkyl, cyano, cyano C １ ~C ３ Alkyl, halo, haloC １ ~C ３ Alkyl, hydroxy and hydroxy C １ ~C ３ alkyl; or R ８ and R ９ Let's join together and １ ~C ３ forming an alkylene; or R ８ and R １０ Let's join together and １ ~C ３ forming an alkylene; or R ８ and R １３ Let's join together and １ ~C ３ forming an alkylene; or R ９ and R １３ Let's join together and １ ~C ３ forming an alkylene; or R １０ and R １３ Let's join together and １ ~C ３ forming an alkylene; or R ８ and R ８’ together with the atoms to which they are attached, optionally an oxygen atom or SO ２ forming a 3, 4 or 5 membered ring containing a C １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; or R ９ and R ９’ together with the atoms to which they are attached, optionally an oxygen atom or SO ２ forming a 3, 4 or 5 membered ring containing a C １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; or R １０ and R １０’ together with the atoms to which they are attached, optionally an oxygen atom or SO ２ forming a 3, 4 or 5 membered ring containing a C １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; or R １３ and R １３’ together with the atoms to which they are attached, optionally an oxygen atom or SO ２ forming a 3, 4 or 5 membered ring containing a C １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; W １ is CR １１ R １２ , N.R. １７ , N.R. １５’’ C(O), N(C(O)(CH ２ ) ｎ OR １５ ), O, SO ２ , S.O. ２ NR １５’ or P(O)CH ３ and n is 0 or 1; R １１ and R １２ is hydrogen, C １ ~C ３ Alkoxy, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ３ independently selected from the group consisting of alkyl, cyano, dimethylphosphino; dimethylsulfonamido, halo, hydroxy, and methylsulfonyl; or R １１ and R １２ together with the atoms to which they are attached, optionally an oxygen atom or SO ２ forming a 4- or 5-membered ring containing a C １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; or R １１ and R １３ together with the atoms to which they are attached form a 3-, 4-, or 5-membered ring optionally containing one or two heteroatoms independently selected from nitrogen and oxygen, said ring optionally containing one or two double bonds, and said ring is １ ~C ３ Alkyl, halo, haloC １ ~C ３ optionally substituted with two groups selected from the group consisting of alkyl and hydroxy; or R １３ and R １５ Let's get together and CH ２ Forming; R １５’ is C １ ~C ３ Alkyl or C １ ~C ６ Alkoxy C １ ~C ６ is alkyl; R １５’’ is hydrogen or C １ ~C ３ is alkyl; R １７ is C １ ~C ３ Alkylcarbonyl, C ３ ~C ６ Cycloalkylcarbonyl, haloC １ ~C ３ is selected from the group consisting of alkylcarbonyl, methylsulfonyl, and tetrahydropyranylcarbonyl, ３ ~C ６ cycloalkyl and said tetrahydropyranyl are optionally substituted with one or two substituents independently selected from the group consisting of cyano, halo, and hydroxy; X is O or NR １６ and R １６ is hydrogen or C １ ~C ３ is alkyl; R ５ is hydrogen, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, aryl, aryl C １ ~C ６ Alkyl, carboxy C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkyl C １ ~C ６ Alkyl, di(C １ ~C ３ Alkyl)amino C ２ ~C ６ Alkyl, haloC １ ~C ６ Alkyl, heteroaryl, heteroaryl C １ ~C ６ Alkyl, heterocyclyl, heterocyclyl C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, NR ａ R ｂ -C(O)-C １ ~C ６ alkyl), NR ａ R ｂ C １ ~C ６ alkyl, said aryl, said aryl C １ ~C ６ the aryl portion of alkyl, ３ ~C ６ cycloalkyl, the C ３ ~C ６ Cycloalkyl C １ ~C ６ the cycloalkyl portion of the alkyl, the heteroaryl, the heteroaryl C １ ~C ６ the heteroaryl portion of alkyl, the heterocyclyl, the heterocyclyl C １ ~C ６ The heterocyclyl portion of the alkyl is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, deuterated C １ ~C ３ Alkyl, C ３ ~C ６ cycloalkyl, (C １ ~C ６ alkyl)amino, (C １ ~C ６ Alkyl)amino C １ ~C ３ Alkyl, Amino, Amino C １ ~C ３ Alkyl, carboxy, cyano, di(C １ ~C ６ alkyl)amino, di(C １ ~C ６ Alkyl)amino C １ ~C ３ Alkyl, halo, haloC １ ~C ３ Alkoxy, HaloC １ ~C ３ Alkyl, heterocyclyl, heterocyclyl C １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ and optionally substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of alkyl, nitro, and oxo; said heterocyclyl and said heterocyclyl C １ ~C ３ The heterocyclyl portion of the alkyl is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, halo and haloC １ ~C ３ is optionally further substituted with one, two, or three groups independently selected from the group consisting of alkyl; or R ５ and R １６ together with the nitrogen atom to which they are attached, １ ~C ３ Alkoxy, C １ ~C ３ Alkoxyalkyl, C １ ~C ３ Alkyl, Amino, Amino C １ ~C ３ Alkyl, hydroxy and hydroxy C １ ~C ３ forming a heterocyclic group optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from the group consisting of 1, 2, 3, or 4 groups independently selected from the group consisting of alkyl; and R ａ and R ｂ One of the groups is hydrogen and C １ ~C ３ alkyl, and the other is selected from hydrogen, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxycarbonyl, C １ ~C ３ Alkylcarbonyl, Aryl C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and C ３ ~C ６ Cycloalkyl C １ ~C ６ alkyl) or a pharmaceutically acceptable salt thereof.

5. R ４ is -NHR ５０ and R ５０ is a five-membered ring optionally containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen, said ring being １ ~C ３ 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two groups independently selected from alkyl and oxo.

6. W １ is CR １１ R １２ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein

7. W １ is NR １７ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein

8. W １ is NR １５’’ (C(O)) or a pharmaceutically acceptable salt thereof.

9. W １ is N(C(O)(CH ２ ) ｎ OR １５ 5. The compound according to claim 1, wherein R is a methyl group or a pharmaceutically acceptable salt thereof.

10. W １ The compound according to any one of claims 1 to 4, wherein is O, or a pharmaceutically acceptable salt thereof.

11. W １ is SO ２ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein

12. W １ is SO ２ NR １５’ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein

13. W １ is P(O)CH ３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein

14. R ４ teeth, 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 and 【Chemistry 8】 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein represents a linkage point to the core of formula (I) or (II).

15. R ４ teeth, 【Chemistry 9】 and 【Chemistry 10】 15. The compound of claim 4 or 14, or a pharmaceutically acceptable salt thereof, wherein represents the point of attachment to the core of formula (II).

16. R ２ The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

17. R ３ The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein is halo.

18. 18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein X is O.

19. R ５ teeth, 【Chemistry 11】 wherein each ring is C １ ~C ３ Alkoxy, C １ ~C ３ Alkoxy C １ ~C ３ Alkyl, C １ ~C ３ Alkyl, deuterated C １ ~C ３ Alkyl, C ３ ~C ６ Cycloalkyl, benzyl, halo, haloC １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of alkyl and oxo; R ｃ and R ｄ together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, said ring being １ ~C ３ Alkoxy, C １ ~C ３ Alkoxy C １ ~C ３ Alkyl, C １ ~C ３ Alkyl, benzyl, halo, haloC １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ optionally substituted with one, two, or three groups independently selected from alkyl and oxo; or R ｃ and R ｄ One of the groups is hydrogen and C １ ~C ３ alkyl, and the other is selected from hydrogen, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxycarbonyl and C １ ~C ３ alkylcarbonyl) 19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

20. R ５ is -(C １ ~C ３ alkyl)-R ６ and R ６ is a 3-6 membered monocyclic ring system, an 8 or 9 membered bicyclic fused saturated ring system, a 10 membered tricyclic saturated ring system or a 12 membered tetracyclic saturated ring system, each ring system optionally containing one or more nitrogen, oxygen and / or sulfur atoms, and each ring system is selected from the group consisting of C １ ~C ３ Alkyl, halo, oxo and (4-6 membered heterocyclyl)C １ ~C ３ and the (4- to 6-membered heterocyclyl)C is optionally substituted with 1 to 4 groups independently selected from the group consisting of alkyl. １ ~C ３ 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl portion of the alkyl is further optionally substituted with a halo group.

21. R ５ teeth, 【Chemistry 12】 and 【Chemistry 13】 21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein represents the point of attachment to X.

22. R ５ teeth, 【Chemistry 14】 and 【Chemistry 15】 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein: represents the point of attachment to X.

23. R ５ teeth, 【Chemistry 16】 wherein n is 0, 1 or 2; Each R ２０ is a halo; and 【Chemistry 17】 represents the point of attachment to X) 21. The compound according to any one of claims 1 to 20, wherein:

24. R ５ teeth, 【Chemistry 18】 wherein r is 1 or 2; q is 0, 1, or 2; R ｘ is C １ ~C ３ Alkoxy, C １ ~C ３ Alkoxy C １ ~C ３ Alkyl, C １ ~C ３ Alkyl, benzyl, halo, haloC １ ~C ３ Alkyl, hydroxy, hydroxy C １ ~C ３ selected from the group consisting of alkyl and oxo, and 【Chemistry 19】 indicates the point of attachment to X) 21. The compound according to any one of claims 1 to 20, wherein:

25. R ５ teeth, 【Chemistry 20】 (In the formula, R ２１ is C １ ~C ３ Alkyl, deuterated C １ ~C ３ Alkyl and C ３ ~C ６ cycloalkyl; R ２２ is halo; p is 0 or 1; and 【Chemical 21】 indicates the point of attachment to X) 21. The compound according to any one of claims 1 to 20, wherein:

26. R ５ teeth, 【Chemical 22】 (In the formula, 【Chemical 23】 represents the point of attachment to X; p is 0 or 1; R ２１ is C １ ~C ３ Alkyl, deuterated C １ ~C ３ Alkyl and C ３ ~C ６ cycloalkyl; and R ２２ is halo; p is 0 or 1; and 【Chemistry 24】 indicates the point of attachment to X) 21. The compound according to any one of claims 1 to 20, wherein:

27. R ５ teeth, 【Chemistry 25】 and 【Chemical 26】 21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: represents the point of attachment to X.

28. 28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

29. R １ is a monocyclic heteroaryl ring containing 1, 2 or 3 nitrogen atoms, said ring being １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, Amino, Amino C １ ~C ３ Alkyl, cyano, C ３ ~C ４ Cycloalkyl, halo, haloC １ ~C ３ Alkyl, haloC １ ~C ３ Alkoxy, hydroxy and hydroxy C １ ~C ３ 29. The compound of any one of claims 1 to 28, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl.

30. R １ teeth, 【Chemical 27】 and 【Chemical Formula 28】 30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein: denotes the point of attachment to the core of formula (I) or (II).

31. R １ is C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, Amino, Amino C １ ~C ３ Alkyl, cyano, C ３ ~C ５ Cycloalkyl, halo, haloC １ ~C ３ Alkyl, hydroxy and hydroxy C １ ~C ３ C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl ６ ~C １０ 29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, which is aryl.

32. R １ is aryl or heteroaryl, and the aryl and heteroaryl are C ２ ~C ４ Alkenyl, C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, C ２ ~C ４ Alkynyl, C ２ ~C ４ Alkynyloxy, amino, cyano, cyano C １ ~C ３ C optionally substituted with alkoxy, 1 or 2 halo groups ３ ~C ５ Cycloalkyl, halo, haloC １ ~C ３ Alkyl, haloC １ ~C ３ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkoxy, 4- to 6-membered heterocyclyl, and hydroxy.

33. R １ is naphthyl, and said naphthyl is C ２ ~C ４ 33. The compound of any one of claims 1 to 27 or 32, or a pharmaceutically acceptable salt thereof, substituted with one, two, or three groups independently selected from the group consisting of alkynyl, halo, and hydroxy.

34. R １ teeth, 【Chemical 29】 (In the formula, R ５３ is C １ ~C ３ Alkyl, halo, haloC １ ~C ３ Alkyl, haloC １ ~C ３ alkoxy, 4- to 6-membered heterocyclyl, or hydroxy; q is an integer from 0 to 4; and 【Chemistry 30】 indicates the point of attachment to the core of formula (I) or (II) 34. The compound according to any one of claims 1 to 29 or 31 to 33, or a pharmaceutically acceptable salt thereof, wherein:

35. R １ is phenyl, said phenyl being C １ ~C ３ Alkyl, C ３ ~C ５ 33. The compound of any one of claims 1 to 28 or 32, or a pharmaceutically acceptable salt thereof, substituted with one, two, or three groups independently selected from the group consisting of cycloalkyl, heterocyclyl, and hydroxy.

36. R １ is isoquinolinyl, said isoquinolinyl being haloC １ ~C ３ Alkyl and haloC １ ~C ３ 33. The compound of any one of claims 1 to 28 or 32, or a pharmaceutically acceptable salt thereof, substituted with one, two, or three groups independently selected from the group consisting of alkoxy.

37. R １ teeth, 【Chemical 31】 (In the formula, R ５１ is Halo C １ ~C ３ alkyl; R ５２ is hydrogen or haloC １ ~C ３ is alkyl; and 【Chemical 32】 indicates the point of attachment to the core of formula (I) or (II) 37. The compound of claim 36, wherein:

38. R １ is Halo C １ ~C ３ 33. The compound of any one of claims 1 to 28 or 32, or a pharmaceutically acceptable salt thereof, which is an indolyl substituted with alkyl.

39. R １ is C １ ~C ３ 33. The compound of any one of claims 1 to 28 or 32, or a pharmaceutically acceptable salt thereof, which is indazolyl substituted with 1, 2 or 3 substituents selected from alkyl and halo.

40. 【Catalog 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical Formula 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemical 44】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

41.

45. 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemical 54】 【Chemistry 55】 41. The compound of claim 40, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

42.

56. 【Chemical 57】 【Chemistry 58】 【Chemical Formula 59】 【Chemistry 60】 【Hua 61】 【Hua 62】 【Chemistry 63】 【Hua 64】 【Chemistry 65】 【Hua 66】 【Hua 67】 【Chemistry 68】 【Chemical Formula 69】 【Chemistry 70】 5. The compound of claim 4, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

43. 【Catalog 71】 【Chemical 72】 【Chemical 73】 [Chemical 74] 【Chemistry 75】 【Chemical Formula 76】 【Chemical 77】 【Chemical 78】 【Chemical 79】 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 【Chemistry 83】 【Chemistry 84】 【Chemistry 85】 【Chemistry 86】 【Hua 87】 【Hua 88】 【Chemistry 89】 41. The compound of claim 40, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

44. 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(1-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}cyclopropyl)methoxy]-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; 4-[2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-[8-fluoro-4-(morpholin-4-yl)-2-({1-[(piperidin-1-yl)methyl]cyclopropyl}methoxy)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 6-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2λ ６ -thia-6-azaspiro[3.3]heptane-2,2-dione; 4-[2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (8aR)-7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethylpiperidine-4-sulfonamide; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(4-methanesulfonylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[2-(hydroxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile isomer 1; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile isomer 2; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-[8-fluoro-2-({1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl}methoxy)-4-[(3R)-3-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(3R)-3-ethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]heptan-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol; 5-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-methyl-1λ ６ , 2,5-thiadiazepane-1,1-dione; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{9-oxa-2-azaspiro[5.5]undecan-2-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol isomer 1; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol isomer 2; 1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl}methoxy)pyrido[4,3-d]pyrimidin-4-yl]piperidine-3-carbonitrile isomer 1; 1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl}methoxy)pyrido[4,3-d]pyrimidin-4-yl]piperidine-3-carbonitrile isomer 2; 7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-7-azaspiro[3.5]nonan-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{hexahydro-1H-furo[3,4-c]pyrrol-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{8-azabicyclo[3.2.1]octan-8-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{2-azabicyclo[2.2.1]heptan-2-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(4-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[3-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-methyl-3-azabicyclo[3.2.1]octan-8-ol; (3aR,5R,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5-(difluoromethyl)-octahydrocyclopenta[c]pyrrol-5-ol; (1R,5S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.1]heptan-6-ol; 2-[1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl]acetonitrile; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.3.1]nonan-9-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-hydroxypiperidine-3-carbonitrile isomer 1; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-hydroxypiperidine-3-carbonitrile isomer 2; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[3-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[3-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 2; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(methoxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-(methoxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[4-(dimethylphosphoryl)piperidin-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3aR,5S,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5-methyl-octahydrocyclopenta[c]pyrrol-5-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[4-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3-carbonitrile isomer 1; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3-carbonitrile isomer 2; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[3-(dimethylphosphoryl)piperidin-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[3-(dimethylphosphoryl)piperidin-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 2; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 2; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]heptan-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(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)-4-methyl-1,4-azaphosphinane 4-oxide; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[6-(hydroxymethyl)-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[6-(hydroxymethyl)-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[2-(hydroxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(pyrrolidin-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidine-3-carbonitrile; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1λ ６ -thiomorpholine-1,1-dione; (9aR)-8-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-octahydropiperazino[2,1-c]morpholin-4-one; (8aR)-7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(4-methanesulfonylpiperidin-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-N,N-dimethylpiperidine-4-sulfonamide; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-7-azaspiro[3.5]nonan-7-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(piperidin-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{2-azabicyclo[2.2.1]heptan-2-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{8-azabicyclo[3.2.1]octan-8-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{hexahydro-1H-furo[3,4-c]pyrrol-5-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2R)-2-(hydroxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-(hydroxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (8aS)-7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)morpholine-2-carbonitrile; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(3R)-3-ethylmorpholin-4-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]heptan-5-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidine-4-carbonitrile; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidin-3-ol; 7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-7-azaspiro[3.5]nonan-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-4-methylpiperidin-4-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidine-3-carbonitrile isomer 1; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidine-3-carbonitrile isomer 2; 5-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-2-methyl-1λ ６ , 2,5-thiadiazepane-1,1-dione; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[(3S)-3-ethylmorpholin-4-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidin-4-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(4-methoxypiperidin-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-8-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-8-methyl-3-azabicyclo[3.2.1]octan-8-ol; (8aS)-7-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-azabicyclo[3.3.1]nonan-9-ol; (3aR,5R,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-5-(difluoromethyl)-octahydrocyclopenta[c]pyrrol-5-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(methoxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-(methoxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[4-(dimethylphosphoryl)piperidin-1-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3aR,5S,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-5-methyl-octahydrocyclopenta[c]pyrrol-5-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[4-(methoxymethyl)piperidin-1-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-azabicyclo[3.1.1]heptan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{9-oxa-3-azabicyclo[4.2.1]nonan-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidin-3-ol; (3R)-1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidin-3-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3S)-1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)piperidin-3-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,4-oxazepan-6-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,4-oxazepan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(6-methoxy-1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(6-methoxy-1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-3-one; 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(1-fluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl]cyclopropane-1-carbonitrile; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2-fluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(2,2-difluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(2,2-difluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 2; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-({1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl}methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(oxane-4-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-7-6fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{8-[(1s,4s)-4-hydroxycyclohexanecarbonyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{8-methanesulfonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoroquinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine; 1-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,2,2-trifluoroethan-1-one; 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[6-(hydroxymethyl)-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{6-oxa-3-azabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-(azepan-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-(5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (1S,4S)-5-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-3-one; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]heptan-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]heptan-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(1-methyl-octahydro-1H-indol-3a-yl)methoxy]-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{2-methyl-2H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol isomer 1; 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol isomer 2; 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (4R)-4-[(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)amino]pyrrolidin-2-one, 4-[2-({1H,2H,3H,5H,9bH-benzo[a]pyrrolidin-9b-yl}methoxy)-8-fluoro-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{2-methyl-2H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[5-hydroxy-2-(propan-2-yl)phenyl]pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(2-cyclobutyl-5-hydroxyphenyl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(2-{bicyclo[1.1.1]pentan-1-yl}-5-hydroxyphenyl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-hydroxy-3-methylpiperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-1-(difluoromethyl)-1,2-dihydropyridin-2-one; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-hydroxy-3-methylpiperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-2-(difluoromethyl)-1,2-dihydroisoquinolin-1-one; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[1-(difluoromethoxy)isoquinolin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-hydroxy-3-methylpiperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-2-(difluoromethyl)-6-(trifluoromethyl)-1,2-dihydroisoquinolin-1-one; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[1-(difluoromethoxy)-6-(trifluoromethyl)isoquinolin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[5-hydroxy-2-(propan-2-yl)phenyl]quinazolin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(2-cyclobutyl-5-hydroxyphenyl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(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)azepan-4-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(2-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(2-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 2; 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)-1,4-oxazepan-6-ol; 1-(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)-3-methylazepan-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazepan-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazepan-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 2; 5-ethyl-6-fluoro-4-(8-fluoro-4-(6-(hydroxymethyl)-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 1-(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)-3-(fluoromethyl)piperidin-3-ol isomer 1; 1-(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)-3-(fluoromethyl)piperidin-3-ol isomer 2; 4-(2-(((4aS,7aR)-1-ethyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethyl-4-(2-(((4aS,7aR)-1-ethyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol; 2-(1-(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)piperidin-3-yl)acetonitrile; 2-(1-(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)-3-methylpiperidin-3-yl)acetonitrile; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-(hydroxymethyl)azepan-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 4-(4-((S)-3-(2,2-difluoroethyl)piperidin-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 6-(difluoromethyl)-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)-1,4-oxazepan-6-ol; 4-(2-(((4aS,7aR)-1-cyclopropyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 2-(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)-1,4-oxazepan-6-yl)acetonitrile isomer 1; 2-(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)-1,4-oxazepan-6-yl)acetonitrile isomer 2; 1-(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)-3-(trifluoromethyl)piperidin-3-ol isomer 1; 1-(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)-3-(trifluoromethyl)piperidin-3-ol isomer 2; 4-(7-(8-ethyl-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)-6-methyl-1,4-oxazepan-6-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(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)-3-azabicyclo[3.2.1]octan-6-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(5-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-chloro-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(5-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 2; 1-(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)-3-methylazepan-3-ol; 4-(4-(3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-(hydroxymethyl)azepan-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 2; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 1; 5-ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol isomer 2; 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-(6-fluoro-6-methyl-1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(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)-3-azabicyclo[4.1.0]heptan-1-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane; 3-(difluoromethyl)-1-(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)piperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((3S,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazocane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (3R)-1-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((4aS)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 6-cyclopropyl-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)-1,4-oxazepan-6-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-methyloctahydro-3aH-indol-3a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-methyloctahydro-3aH-indol-3a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; 3-(difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methyloctahydro-1H-cyclopenta[b]pyridine 1-oxide; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-5-methyl-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 4-(2-(((4aS,7aR)-1-cyclopropyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-8-fluoro-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(5-(difluoromethoxy)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3-ol; (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-3-fluoro-1-(methyl-d3)octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-3-fluoro-1-(methyl-d3)octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazocane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((3R,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((3S,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-2-(((4aS,7aR)-1-(methyl-d3)octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (R)-1-(2-((1′H,3′H,5′H-dispiro[cyclopropane-1,2′-pyrrolidin-6′,1″-cyclopropane]-7a′(7′H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (3R)-1-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; and 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol or a pharmaceutically acceptable salt thereof.

45. 45. A pharmaceutical composition comprising a compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

46. 45. An oral dosage form comprising a compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

47. 45. A method of inhibiting KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H in a subject in need thereof, comprising administering to the subject a compound, composition or dosage form according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof.

48. 45. A method of treating a cancer susceptible to KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H inhibition in a subject in need thereof, comprising administering to the subject a compound, composition or dosage form according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof.

49. 45. A method of treating a cancer expressing a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H mutation in a subject in need thereof, comprising administering to the subject a compound, composition or dosage form according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof.

50. 45. A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound, composition or dosage form according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof.

51. 51. The method of claim 50, wherein the cancer is pancreatic cancer, colorectal cancer, lung cancer, gastric cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, uterine cancer, or a combination thereof.

52. 52. The method of claim 51, wherein the cancer is non-small cell lung cancer.

Images