KRAS inhibitors

Abstract

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

Description

Cross-references to related applications

[0001] This application claims priority to the following U.S. provisional application numbers: 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; the entire contents of all of these applications are incorporated herein by reference. Technical Field

[0002] This disclosure provides information on KRAS inhibitors. It also provides methods for treating cancer using these inhibitors. Background Technology

[0003] KRAS oncogenes are members of the RAS family of GTPases involved in many cellular signaling processes. KRAS mutations are gain-of-function mutations present in up to 30% of all tumors, including up to 90% of pancreatic cancers. Single nucleotide substitutions leading to missense mutations at codons 12 and 13 of the KRAS primary amino acid sequence account for approximately 40% of KRAS-driven mutations in lung adenocarcinoma, 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 duct adenocarcinoma patients, 13% of all colorectal cancer patients, 4% of all non-small cell lung cancer patients, and 3% of all gastric cancer patients. See, for example, https: / / www.mycancergenome.org / content / alteration / kras-g12d / . Due to the clinical significance of this protein, numerous attempts have been made to develop RAS inhibitors, but most of these attempts have been unsuccessful. Therefore, there is a need for agents that inhibit mutant KRAS. Summary of the Invention

[0004] In a first aspect, this disclosure provides a compound having formula (I): Or its pharmaceutically acceptable salt, wherein:

[0005] Z represents bond, O, and NR. e or CR e R f , where R e and Rf Independently hydrogen or C1-C3 alkyl;

[0006] R 1 It is an aryl or heteroaryl group, wherein the aryl and heteroaryl groups are optionally substituted by one, two, three, four or five substituents independently selected from the group consisting of: C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkynyl, C2-C4 alkynoxy, amino, aminoC1-C3 alkyl, cyano, cyanoC1-C3 alkoxy, C3-C8 cycloalkyl (e.g., C3-C4 cycloalkyl) optionally substituted by one, two or three halo groups, halo, haloC1-C3 alkyl, haloC1-C3 alkoxy, hydroxyl, hydroxyC1-C3 alkyl, heteroaryl, heterocyclic and phenyl, wherein the heteroaryl, heterocyclic and phenyl groups are optionally substituted by one, two or three substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, halo and haloC1-C3 alkyl;

[0007] R 2 R 3 and R 7 Independently selected from the group consisting of: hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halogen, halogenated C1-C3 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 and hydroxyl;

[0008] R 4 -NHR 50 or

[0009] in

[0010] R 50 A five-membered ring optionally containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen, wherein the ring is optionally substituted by one or two groups independently selected from C1-C3 alkyl and oxo groups;

[0011] n' can be 0, 1, 2, or 3;

[0012] R 8 R 8' R 9 R 9 '、R 10 R 10' R 13 and R 13'Each is independently selected from the group consisting of: hydrogen, C1-C3 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, halogen, halogen-C1-C3 alkyl, hydroxyl, and hydroxy-C1-C3 alkyl; or

[0013] R 8 and R 9 Together they form C1-C3 alkylene groups; or

[0014] R 8 and R 10 Together they form C1-C3 alkylene groups; or

[0015] R 8 and R 13 Together they form C1-C3 alkylene groups; or

[0016] R 9 and R 13 Together they form C1-C3 alkylene groups; or

[0017] R 10 and R 13 Together they form C1-C3 alkylene groups; or

[0018] R 8 and R 8' Together with the atoms to which it is attached, it forms a three-, four-, or five-membered ring optionally containing an oxygen atom or an SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, and hydroxyl groups; or

[0019] R 9 and R 9' Together with the atoms to which it is attached, it forms a three-, four-, or five-membered ring optionally containing an oxygen atom or an SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, and hydroxyl groups; or

[0020] R 10 and R 10' Together with the atoms to which it is attached, it forms a three-, four-, or five-membered ring optionally containing an oxygen atom or an SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, and hydroxyl groups; or

[0021] R 13 and R 13' Together with the atoms to which it is attached, it forms a three-, four-, or five-membered ring that optionally contains an oxygen atom or an SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogen C1-C3 alkyl, and hydroxyl groups;

[0022] W 1 For CR 11 R 12 NR 17 NR 15” C(O), C(O)NR 15” N(C(O)(CH2)) n OR 15 ), O, CHO, OCH2, SO2, SO2NR 15' Or P(O)CH3; where

[0023] n is 0 or 1;

[0024] R 11 and R 12 Independently selected from the group consisting of: hydrogen, C1-C3 alkoxy, C1-C6 alkoxy, C1-C6 alkyl, C1-C3 alkyl, cyano, dimethylphosphino, dimethylsulfonamide, halogen, hydroxyl, and methanesulfonyl; or

[0025] R 11 and R 12 Together with the atoms to which it is attached, it forms a four- to six-membered ring optionally containing an oxygen atom or an SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, and hydroxyl groups; or

[0026] R 11 and R 13 Together with the atoms to which it is attached, it forms a three-, four-, or five-membered ring optionally containing one or two heteroatoms independently selected from nitrogen and oxygen, wherein the ring optionally contains one or two double bonds, and wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, and hydroxyl groups; or

[0027] R 13 and R 15 Together they form CH2;

[0028] R 15' It is a C1-C3 alkyl or a C1-C6 alkoxy-C1-C6 alkyl;

[0029] R 15” It is hydrogen or C1-C3 alkyl;

[0030] R 17 It is selected from the group consisting of C1-C3 alkyl carbonyl, C3-C6 cycloalkyl carbonyl, halogenated C1-C3 alkyl carbonyl, methanesulfonyl and tetrahydropyranyl carbonyl, wherein the C3-C6 cycloalkyl and tetrahydropyranyl are optionally substituted by one or two independent substituents selected from the group consisting of cyano, halogen and hydroxyl;

[0031] X is O or NR 16 , where R 16 It is hydrogen or C1-C3 alkyl;

[0032] R 5 Selected from the group consisting of: hydrogen, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, carboxyl-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, heterocyclic, heterocyclic-C1-C6 alkyl, hydroxyl-C1-C6 alkyl, NR a R b -C(O)-(C1-C6 alkyl), NR a R b C1-C6 alkyl, wherein the aryl group, the aryl moiety of the aryl C1-C6 alkyl group, the C3-C6 cycloalkyl group, the cycloalkyl moiety of the C3-C6 cycloalkyl C1-C6 alkyl group, the heteroaryl group, the heteroaryl moiety of the heteroaryl C1-C6 alkyl group, the heterocyclic group, and the heterocyclic moiety of the heterocyclic C1-C6 alkyl group are optionally substituted by one, two, three, or four groups independently selected from the following: 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, carboxyl, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino C1-C3 alkyl, halogen, halogen C1-C3 alkoxy, halogen C1-C3 alkyl, heterocyclic, heterocyclic C1-C3 alkyl, hydroxyl, hydroxyl C1-C3 alkyl, nitro, and oxo; wherein the heterocyclic group and the heterocyclic C1-C3 alkyl group are optionally further substituted by one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, halogen, and halogen C1-C3 alkyl; or

[0033] R 5 and R 16 Together with the nitrogen atom to which it is attached, a heterocyclic group optionally substituted by one, two, three, four, or five groups independently selected from the group consisting of: one, two, three, or four groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; and

[0034] R a and R bOne of them 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 alkoxy carbonyl, C1-C3 alkyl carbonyl, aryl C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkyl C1-C6 alkyl.

[0035] In some respects, R 7 It is chlorine.

[0036] In some respects, R 7 For hydrogen.

[0037] In some respects, this disclosure provides a compound of formula (II): Or its pharmaceutically acceptable salt, wherein:

[0038] Z represents bond, O, and NR. e or CR e R f , where R e and R f Independently hydrogen or C1-C3 alkyl;

[0039] R 1 It is an aryl or heteroaryl group, wherein the aryl and heteroaryl groups are optionally substituted by one, two, three, four or five substituents independently selected from the group consisting of: C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkynyl, C2-C4 alkynoxy, amino, aminoC1-C3 alkyl, cyano, cyanoC1-C3 alkoxy, C3-C8 cycloalkyl (e.g., C3-C4 cycloalkyl) optionally substituted by one, two or three halogen groups, halogen, halogen C1-C3 alkyl, halogen C1-C3 alkoxy, hydroxyl, hydroxyC1-C3 alkyl, heteroaryl, heterocyclic and phenyl, wherein the heteroaryl, heterocyclic and phenyl groups are optionally substituted by one, two or three substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, halogen and halogen C1-C3 alkyl;

[0040] R 2 and R 3 Independently selected from the group consisting of: hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halogen, halogenated C1-C3 alkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 and hydroxyl;

[0041] R 4 -NHR 50 or

[0042] in

[0043] R 50 A five-membered ring optionally containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen, wherein the ring is optionally substituted by one or two groups independently selected from C1-C3 alkyl and oxo groups;

[0044] n' is 0, 1, 2, or 3;

[0045] R 8 R 8' R 9 R 9 '、R 10 R 10' R 13 and R 13' Each is independently selected from the group consisting of: hydrogen, C1-C3 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, halogen, halogen-C1-C3 alkyl, hydroxyl, and hydroxy-C1-C3 alkyl; or

[0046] R 8 and R 9 Together they form C1-C3 alkylene groups; or

[0047] R 8 and R 10 Together they form C1-C3 alkylene groups; or

[0048] R 8 and R 13 Together they form C1-C3 alkylene groups; or

[0049] R 9 and R 13 Together they form C1-C3 alkylene groups; or

[0050] R 10 and R 13 Together they form C1-C3 alkylene groups; or

[0051] R 8 and R 8' Together with the atoms to which it is attached, it forms a three-, four-, or five-membered ring optionally containing an oxygen atom or an SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, and hydroxyl groups; or

[0052] R 9 and R 9'Together with the atoms to which it is attached, it forms a three-, four-, or five-membered ring optionally containing an oxygen atom or an SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, and hydroxyl groups; or

[0053] R 10 and R 10' Together with the atoms to which it is attached, it forms a three-, four-, or five-membered ring optionally containing an oxygen atom or an SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, and hydroxyl groups; or

[0054] R 13 and R 13' Together with the atoms to which it is attached, it forms a three-, four-, or five-membered ring that optionally contains an oxygen atom or an SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogen C1-C3 alkyl, and hydroxyl groups;

[0055] W 1 For CR 11 R 12 NR 17 NR 15” C(O), C(O)NR 15” N(C(O)(CH2)) n OR 15 ), O, CHO, OCH2, SO2, SO2NR 15' Or P(O)CH3; where

[0056] n is 0 or 1;

[0057] R 11 and R 12 Independently selected from the group consisting of: hydrogen, C1-C3 alkoxy, C1-C6 alkoxy, C1-C6 alkyl, C1-C3 alkyl, cyano, dimethylphosphino, dimethylsulfonamide, halogen, hydroxyl, and methanesulfonyl; or

[0058] R 11 and R 12 Together with the atoms to which it is attached, it forms a four- or five-membered ring optionally containing an oxygen atom or an SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, and hydroxyl groups; or

[0059] R 11 and R 13Together with the atoms to which it is attached, it forms a three-, four-, or five-membered ring optionally containing one or two heteroatoms independently selected from nitrogen and oxygen, wherein the ring optionally contains one or two double bonds, and wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, and hydroxyl groups; or

[0060] R 13 and R 15 Together they form CH2;

[0061] R 15' It is a C1-C3 alkyl or a C1-C6 alkoxy-C1-C6 alkyl;

[0062] R 15” It is hydrogen or C1-C3 alkyl;

[0063] R 17 It is selected from the group consisting of C1-C3 alkyl carbonyl, C3-C6 cycloalkyl carbonyl, halogenated C1-C3 alkyl carbonyl, methanesulfonyl and tetrahydropyranyl carbonyl, wherein the C3-C6 cycloalkyl and tetrahydropyranyl are optionally substituted by one or two independent substituents selected from the group consisting of cyano, halogen and hydroxyl;

[0064] X is O or NR 16 , where R 16 It is hydrogen or C1-C3 alkyl;

[0065] R 5 Selected from the group consisting of: hydrogen, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, carboxyl-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, heterocyclic, heterocyclic-C1-C6 alkyl, hydroxyl-C1-C6 alkyl, NR a R b -C(O)-(C1-C6 alkyl), NR a R bC1-C6 alkyl, wherein the aryl group, the aryl moiety of the aryl C1-C6 alkyl group, the C3-C6 cycloalkyl group, the cycloalkyl moiety of the C3-C6 cycloalkyl C1-C6 alkyl group, the heteroaryl group, the heteroaryl moiety of the heteroaryl C1-C6 alkyl group, the heterocyclic group, and the heterocyclic moiety of the heterocyclic C1-C6 alkyl group are optionally substituted by one, two, three, or four groups independently 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)aminoC1 -C3 alkyl, amino, aminoC1-C3 alkyl, carboxyl, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoC1-C3 alkyl, halogen, halogenC1-C3 alkoxy, halogenC1-C3 alkyl, heterocyclic, heterocyclicC1-C3 alkyl, hydroxyl, hydroxyC1-C3 alkyl, nitro, and oxo; wherein the heterocyclic group and the heterocyclic C1-C3 alkyl group are optionally further substituted with one, two, or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, halogen, and halogenC1-C3 alkyl; or

[0066] R 5 and R 16 Together with the nitrogen atom to which it is attached, a heterocyclic group optionally substituted by one, two, three, four, or five groups independently selected from the group consisting of: one, two, three, or four groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; and

[0067] R a and R b One of them is selected from hydrogen and C1-C3 alkyl, and the other is selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy carbonyl, C1-C3 alkyl carbonyl, aryl C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkyl C1-C6 alkyl.

[0068] In some aspects, this disclosure provides a compound of formula (II), wherein R 2 It is a methoxy group.

[0069] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 4 -NHR 50 And R 50 It is a five-membered ring that optionally contains one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen, wherein the ring is optionally substituted by one or two groups independently selected from C1-C3 alkyl and oxo groups.

[0070] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 For CR 11 R 12 N(C(O)(CH2)) n OR 15 ), O, SO2, SO2NR 15' Or P(O)CH3, where R 11 R 12 n, R 15 and R 15' As defined above.

[0071] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 For CR 11 R 12 .

[0072] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 For NR 17 .

[0073] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 For NR 15” C(O).

[0074] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 For C(O)NR 15” .

[0075] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 For N(C(O)(CH2) n OR 15 ).

[0076] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 It is O.

[0077] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 It is CH2O.

[0078] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 It is OCH2.

[0079] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 It is SO2.

[0080] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 SO2NR 15' .

[0081] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein W 1 It is P(O)CH3.

[0082] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 4 for in This indicates the connection point with the core of equation (I) or (II).

[0083] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 4 for in This indicates the connection point with the core of equation (II).

[0084] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 2 For hydrogen.

[0085] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 3 It is a halogen group.

[0086] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein: X is O.

[0087] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R5 Departments can freely choose from the following groups: Each ring may optionally be substituted by one, two, or three independently selected groups from the group consisting of: C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkyl, tritated C1-C3 alkyl, C3-C6 cycloalkyl, benzyl, halogen, halogenated C1-C3 alkyl, hydroxyl, hydroxyl-C1-C3 alkyl, and oxoyl; and wherein R c and R d Together with the nitrogen atom to which it is attached, it forms a five- to ten-membered ring, either monocyclic or bicyclic, optionally containing an additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, or three independently selected groups from C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkyl, benzyl, halogen, halogen-C1-C3 alkyl, hydroxyl, hydroxy-C1-C3 alkyl, and oxoyl groups; or R c and R d One of them is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy carbonyl and C1-C3 alkyl carbonyl.

[0088] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 -(C1-C3 alkyl)-R 6 , where R 6 It is a ternary to 6-membered monocyclic 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, wherein each ring system optionally contains one or more nitrogen, oxygen, and / or sulfur atoms, and wherein each ring system is optionally substituted by one to four groups independently selected from the group consisting of C1-C3 alkyl, halogen, oxo, and (4- to 6-membered heterocyclic) C1-C3 alkyl; wherein the heterocyclic portion of the (4- to 6-membered heterocyclic) C1-C3 alkyl is further optionally substituted by a halogen group.

[0089] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 for and Indicates the connection point with X.

[0090] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 for and Indicates the connection point with X.

[0091] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 for Where n is 0, 1, or 2; Each R 20 It is a halogen group; and Indicates the connection point with X.

[0092] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 for Where r is 1 or 2; q is 0, 1 or 2; R x Selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkyl, benzyl, halogen, halogen-C1-C3 alkyl, hydroxyl, hydroxyl-C1-C3 alkyl, and oxo group, and Indicates the connection point with X.

[0093] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 for Where R 21 R is selected from the group consisting of C1-C3 alkyl, tritized C1-C3 alkyl, and C3-C6 cycloalkyl. 22 It is a halogen group; p is 0 or 1; and Indicates the connection point with X.

[0094] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 for in Indicates the connection point with X; p is 0 or 1; R 21 Selected from the group consisting of C1-C3 alkyl, tritized C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 It is a halogen group; p is 0 or 1; and Indicates the connection point with X.

[0095] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 5 for in Indicates the connection point with X.

[0096] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

[0097] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 It is a monocyclic heteroaryl ring containing one, two, or three nitrogen atoms, wherein the ring is optionally substituted by one, two, three, four, or five substituents independently selected from the group consisting of: C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halogen, halogenC1-C3 alkyl, halogenC1-C3 alkoxy, hydroxyl, and hydroxyC1-C3 alkyl.

[0098] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 for in This indicates the connection point with the core of equation (I) or (II).

[0099] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 For C6-C 10 Aryl group, optionally substituted by one, two, three, four or five substituents independently selected from the group consisting of: C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, cyano, C3-C5 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl), halogen, halogen C1-C3 alkyl, hydroxyl and hydroxy C1-C3 alkyl.

[0100] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1It is an aryl or heteroaryl group, wherein the aryl and heteroaryl group is optionally substituted by one, two, three, four or five substituents independently selected from the group consisting of: C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkynyl, C2-C4 alkynoxy, amino, cyano, cyanoC1-C3 alkoxy, C3-C4 cycloalkyl optionally substituted with one or two halogen groups, halogen, halogenC1-C3 alkoxy, 4 to 6-membered heterocyclic group and hydroxyl.

[0101] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 It is a naphthyl group, wherein the naphthyl group is substituted by one, two or three groups independently selected from the group consisting of C2-C4 alkynyl, halogen and hydroxyl groups.

[0102] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 for Where R 53 It is a C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, 4- to 6-membered heterocyclic group or hydroxyl; q is an integer from 0 to 4; and; wherein This indicates the connection point with the core of equation (I) or (II).

[0103] In some aspects, this disclosure provides a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R 1 It is a phenyl group, wherein the phenyl group is substituted by one, two or three groups independently selected from the group consisting of C1-C3 alkyl, C3-C5 cycloalkyl, heterocyclic and hydroxyl groups.

[0104] In some aspects, this disclosure provides a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R 1 It is an isoquinolinyl group, wherein the isoquinolinyl group is substituted with one, two, or three groups independently selected from the group consisting of a C1-C3 alkyl halogen and a C1-C3 alkoxy halogen. In some of these respects, R 1 for Where R 51 It is a halogroup C1-C3 alkyl group; R 52 It is a hydrogen or halogroup C1-C3 alkyl group; and This indicates the connection point with the core of equation (I) or (II).

[0105] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 It is an indole group substituted with a halogenated C1-C3 alkyl group. In some of these respects, R 1 for in This indicates the connection point with the core of equation (I) or (II).

[0106] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 It is an indazole group substituted with one, two, or three substituents selected from C1-C3 alkyl and halogen groups. In some of these respects, R 1 for

[0107] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 for Where R 53 It is a C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, 4- to 6-membered heterocyclic group or hydroxyl; and q is an integer from 0 to 4; R 4 yes as well as R 5 yes in Indicates the connection point with X; p is 0 or 1; R 21 Selected from the group consisting of C1-C3 alkyl, tritized C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 It is a halogen group; p is 0 or 1; in This indicates the connection point with the parent molecule.

[0108] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 for Where R 53 It is a C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, 4- to 6-membered heterocyclic group or hydroxyl; q is an integer from 0 to 4; R 4 yes as well as R 5 yes in Indicates the connection point with X; p is 0 or 1; R 21 Selected from the group consisting of C1-C3 alkyl, tritized C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 It is a halogen group; p is 0 or 1; in This indicates the connection point with the parent molecule.

[0109] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 for Where R 53 It is a C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, 4- to 6-membered heterocyclic group or hydroxyl; q is an integer from 0 to 4; R 4 yes as well as R 5 yes in Indicates the connection point with X; p is 0 or 1; R 21 Selected from the group consisting of C1-C3 alkyl, tritized C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 It is a halogen group; p is 0 or 1; in This indicates the connection point with the parent molecule.

[0110] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 for Where R 53 It is a C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, 4- to 6-membered heterocyclic group or hydroxyl; and q is an integer from 0 to 4; R 4 yes as well as R 5 yes in Indicates the connection point with X; p is 0 or 1; R 21 Selected from the group consisting of C1-C3 alkyl, tritized C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 It is a halogen group; p is 0 or 1; in This indicates the connection point with the parent molecule.

[0111] In some aspects, this disclosure provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 for Where R 53 It is a C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, 4- to 6-membered heterocyclic group or hydroxyl; and q is an integer from 0 to 4; R 4 yes as well as R 5 yes in Indicates the connection point with X; p is 0 or 1; R 21 Selected from the group consisting of C1-C3 alkyl, tritized C1-C3 alkyl, and C3-C6 cycloalkyl; and R 22 It is a halogen group; p is 0 or 1; in This indicates the connection point with the parent molecule.

[0112] In some aspects, this disclosure provides a pharmaceutical composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0113] In some aspects, this disclosure provides an oral dosage form comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0114] In some aspects of this method, the compound is a transisomer of the compound described in any of the foregoing aspects. In other aspects, the compound is a stable transisomer as described herein.

[0115] In another aspect, this disclosure provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with a therapeutically effective amount of a compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0116] In another aspect, this disclosure provides a method for treating cancer in a subject, the method comprising administering to the subject in need a therapeutically effective amount of the compound or pharmaceutical composition of this disclosure or a pharmaceutically acceptable salt thereof.

[0117] In another aspect, this disclosure provides a method for treating a subject in need of such treatment with a KRAS G12D-related condition or a condition related to KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) as defined herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0118] In another aspect, this disclosure provides a method for treating cancers sensitive to the inhibition of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H in a subject of need, the method comprising administering to the subject a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0119] In another aspect, this disclosure provides a method for treating a subject with cancer, 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.

[0120] In another aspect, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for inhibiting KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H.

[0121] In another aspect, this disclosure provides a compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of diseases or conditions associated with KRAS G12A, KRAS G12C, KRAS G12D, KRASG12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H.

[0122] In another aspect, this disclosure provides the use of a compound of formula (I) or (II) as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

[0123] In another aspect, this disclosure provides the use of compounds of formula (I) or (II) as defined herein, or pharmaceutically acceptable salts thereof, for the manufacture of medicaments for the inhibition of the activity of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRASG12S, KRAS G12V, KRAS G13D and / or KRAS Q61H.

[0124] In another aspect, this disclosure provides the use of compounds of formula (I) or (II) as defined herein, or pharmaceutically acceptable salts thereof, for the manufacture of medicaments for the treatment of diseases or conditions associated with KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRASG12S, KRAS G12V, KRAS G13D and / or KRAS Q61H.

[0125] In another aspect, this disclosure provides a compound selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0126] In some respects, this disclosure provides a compound selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0127] In some respects, this disclosure provides a compound selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0128] In some respects, this disclosure provides a compound selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0129] In some respects, this disclosure provides a compound selected from the group consisting of:

[0130] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0131] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0132] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0133] 5-Ethynyl-6-fluoro-4-{8-fluoro-2-[(1-{[(3R)-3-fluoropyrrolidone-1-yl]methyl}cyclopropyl)methoxy]-4-(morpholino-4-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthol;

[0134] 4-[2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0135] 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]naphthol;

[0136] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]oct-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0137] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0138] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]oct-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0139] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0140] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0141] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0142] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[(3R,4S)-3,4-difluoropyrrolidine-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0143] 6-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-2 6-Thia-6-azaspiro[3.3]heptane-2,2-dione;

[0144] 4-[2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0145] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(2-hydroxypropyl-2-yl)pyrrolidine-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0146] (8aR)-7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one;

[0147] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethylpiperidine-4-sulfonamide;

[0148] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(4-methanesulfonylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0149] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0150] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{2,2-difluoro-7-azaspiro[3.5]non-7-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0151] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylonitrile;

[0152] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylonitrile;

[0153] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[2-(hydroxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0154] 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxynitrile isomer 1;

[0155] 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxynitrile isomer 2;

[0156] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0157] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0158] 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]naphthol;

[0159] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0160] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0161] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-methylmorpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0162] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[(3R)-3-ethylmorpholin-4-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0163] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)piperidine-4-carboxynitrile;

[0164] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0165] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0166] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0167] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]hept-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0168] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-ol;

[0169] 5-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-2-methyl-1 6,2,5-Thiazazacycloheptane-1,1-dione;

[0170] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{9-oxa-2-azaspiro[5.5]undecane-2-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0171] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)piperidin-3-ol isomer 1;

[0172] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)piperidin-3-ol isomer 2;

[0173] 1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-({1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl}methoxy)pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-carboxynitrile isomer 1;

[0174] 1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-({1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl}methoxy)pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-carboxynitrile isomer 2;

[0175] 7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-7-azaspiro[3.5]non-2-ol;

[0176] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{hexahydro-1H-furano[3,4-c]pyrrolo-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0177] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{8-azabicyclo[3.2.1]oct-8-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0178] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{2-azabicyclo[2.2.1]hept-2-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0179] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)piperidin-4-ol;

[0180] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(4-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0181] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[3-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0182] 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-ol;

[0183] 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-methyl-3-azabicyclo[3.2.1]oct-8-ol;

[0184] (3aR,5R,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-5-(difluoromethyl)-octahydrocyclopentadieno[c]pyrrolo-5-ol;

[0185] (1R,5S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.1]hept-6-ol;

[0186] 2-[1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)piperidin-3-yl]acetonitrile;

[0187] 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-6-ol;

[0188] 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.3.1]non-9-ol;

[0189] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-4-hydroxypiperidine-3-carboxynitrile isomer 1;

[0190] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-4-hydroxypiperidine-3-carboxynitrile isomer 2;

[0191] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[3-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol isomer 1;

[0192] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[3-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol isomer 2;

[0193] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(methoxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0194] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-(methoxymethyl)morpholin-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0195] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[4-(dimethylphosphoryl)piperidin-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0196] (3aR,5S,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-5-methyl-octahydrocyclopentadieno[c]pyrrolo-5-ol;

[0197] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[4-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0198] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3-carboxynitrile isomer 1;

[0199] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3-carboxynitrile isomer 2;

[0200] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[3-(dimethylphosphoryl)piperidin-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol isomer 1;

[0201] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[3-(dimethylphosphoryl)piperidin-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol isomer 2;

[0202] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol isomer 1;

[0203] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol isomer 2;

[0204] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]hept-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0205] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1,4-azaphosphonane 4-oxide;

[0206] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0207] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0208] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(6-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0209] 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0210] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0211] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-phenol;

[0212] 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-6-ol;

[0213] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0214] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazolidinyl-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0215] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazolidinyl-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0216] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]oct-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0217] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0218] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0219] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0220] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[2-(hydroxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0221] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0222] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(pyrrolidine-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0223] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl}-8-fluoroquinazoline-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0224] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[(3R,4S)-3,4-difluoropyrrolidine-1-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0225] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)piperidine-3-carboxynitrile;

[0226] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(2-hydroxypropyl-2-yl)pyrrolidine-1-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0227] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)- -Thiomorpholine-1,1-dione;

[0228] (9aR)-8-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-octahydropiperazin[2,1-c]morpholin-4-one;

[0229] (8aR)-7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one;

[0230] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(4-methanesulfonylpiperidin-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0231] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-N,N-dimethylpiperidine-4-sulfonamide;

[0232] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-7-azaspiro[3.5]non-7-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0233] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{2,2-difluoro-7-azaspiro[3.5]non-7-yl}-8-fluoroquinazoline-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0234] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(piperidin-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0235] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{2-azabicyclo[2.2.1]hept-2-yl}-8-fluoroquinazoline-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0236] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{8-azabicyclo[3.2.1]oct-8-yl}-8-fluoroquinazoline-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0237] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{hexahydro-1H-furano[3,4-c]pyrrolo-5-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0238] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0239] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0240] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0241] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(2R)-2-(hydroxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0242] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(2S)-2-(hydroxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0243] (8aS)-7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one;

[0244] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)morpholine-2-carboxynitrile;

[0245] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[(3R)-3-ethylmorpholin-4-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0246] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]hept-5-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0247] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(3R)-3-methylmorpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0248] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)piperidine-4-carboxynitrile;

[0249] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)piperidin-3-ol;

[0250] 7-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-7-azaspiro[3.5]non-2-ol;

[0251] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-4-methylpiperidin-4-ol;

[0252] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)piperidine-3-carboxynitrile isomer 1;

[0253] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)piperidine-3-carboxynitrile isomer 2;

[0254] 5-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-2-methyl-1 6,2,5-Thiazazacycloheptane-1,1-dione;

[0255] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[(3S)-3-ethylmorpholin-4-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0256] 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)piperidin-4-ol;

[0257] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(4-methoxypiperidin-1-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0258] 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]oct-8-ol;

[0259] 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-4-yl)-8-methyl-3-azabicyclo[3.2.1]oct-8-ol;

[0260] (8aS)-7-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one;

[0261] 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-3-azabicyclo[3.3.1]non-9-ol;

[0262] (3aR,5R,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-5-(difluoromethyl)-octahydrocyclopentadien[c]pyrrole-5-ol;

[0263] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(3R)-3-(methoxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0264] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(3S)-3-(methoxymethyl)morpholin-4-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0265] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[4-(dimethylphosphoryl)piperidin-1-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0266] (3aR,5S,6aS)-2-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-4-yl)-5-methyl-octahydrocyclopentadien[c]pyrrolo-5-ol;

[0267] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[4-(methoxymethyl)piperidin-1-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0268] 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-3-azabicyclo[3.1.1]hepta-6-ol;

[0269] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{9-oxa-3-azabicyclo[4.2.1]non-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0270] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-4-yl)piperidin-3-ol;

[0271] (3R)-1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)piperidin-3-ol;

[0272] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(6-methyl-1,4-oxazolidinyl-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0273] (3S)-1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-4-yl)piperidin-3-ol;

[0274] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-4-yl)-6-methyl-1,4-oxazetane-6-ol;

[0275] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazetane-6-ol;

[0276] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-1,4-oxazetane-6-ol;

[0277] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-4-yl)-1,4-oxazetane-6-ol;

[0278] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(6-methoxy-1,4-oxazolidinyl-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0279] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(6-methoxy-1,4-oxazacycloheptane-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0280] 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]oct-3-yl}quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine;

[0281] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethylnaphthyl-2-phenol;

[0282] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethylnaphthyl-2-phenol;

[0283] (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]hepta-3-one;

[0284] 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoroethyl-1-one;

[0285] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0286] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[8-(1-fluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0287] 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl]cyclopropane-1-carboxylonitrile;

[0288] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[8-(2-fluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0289] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(2,2-difluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol isomer 1;

[0290] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(2,2-difluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol isomer 2;

[0291] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0292] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0293] 4-(4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoro-2-({1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl}methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0294] 1-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoroethyl-1-one;

[0295] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0296] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[8-(oxacyclohexane-4-carbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0297] 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoroethyl-1-one;

[0298] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0299] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoroquinazoline-7-yl)-5-ethynyl-6-7-6-fluoronaphthyl-2-phenol;

[0300] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{8-[(1s,4s)-4-hydroxycyclohexanecarbonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0301] 1-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoroethyl-1-one;

[0302] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoroquinazoline-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0303] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{8-methanesulfonyl-3,8-diazabicyclo[3.2.1]oct-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0304] 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine;

[0305] 1-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoroethyl-1-one;

[0306] 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolizidine]-7'a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol;

[0307] 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0308] 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-6-ol;

[0309] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol;

[0310] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0311] 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0312] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{6-oxa-3-azabicyclo[3.2.1]oct-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0313] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(6-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0314] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-phenol;

[0315] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0316] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-4-(azacyclohept-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0317] 1-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolizidine]-7'a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0318] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0319] (1S,4S)-5-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]hepta-3-one;

[0320] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthyl-2-phenol;

[0321] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]hept-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0322] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]hept-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0323] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[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-fluoronaphthyl-2-phenol;

[0324] 5-Ethynyl-6-fluoro-4-{8-fluoro-2-[(1-methyl-octahydro-1H-indol-3a-yl)methoxy]-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthol;

[0325] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[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-fluoronaphthyl-2-phenol;

[0326] 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-6-ol isomer 1;

[0327] 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-6-ol isomer 2;

[0328] 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolizidine]-7'a-yl]methoxy}-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0329] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0330] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol;

[0331] (4R)-4-[(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)amino]pyrrolidone-2-one;

[0332] 4-[2-({1H,2H,3H,5H,9bH-benzo[a]pyrrolizin-9b-yl}methoxy)-8-fluoro-4-(1,4-oxazolidinyl-4-yl)quinazolin-7-yl]-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0333] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-4-yl)-6-methyl-1,4-oxazetane-6-ol;

[0334] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0335] 1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazoline-4-yl)-3-methylpiperidin-3-ol;

[0336] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[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-fluoronaphthyl-2-phenol;

[0337] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazetane-6-ol;

[0338] 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-5-methoxy-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0339] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-5-methoxy-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0340] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-(3-hydroxynaphth-1-yl)pyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0341] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[5-hydroxy-2-(prop-2-yl)phenyl]pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0342] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(2-cyclobutyl-5-hydroxyphenyl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0343] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(2-{bicyclo[1.1.1]pent-1-yl}-5-hydroxyphenyl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0344] 5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[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;

[0345] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[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-dihydroisoquinoline-1-one;

[0346] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[1-(difluoromethoxy)isoquinolin-4-yl]-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0347] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[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-dihydroisoquinoline-1-one;

[0348] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[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;

[0349] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol;

[0350] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[5-hydroxy-2-(prop-2-yl)phenyl]quinazolin-4-yl)-3-methylpiperidin-3-ol;

[0351] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(2-cyclobutyl-5-hydroxyphenyl)-8-fluoroquinazoline-4-yl)-3-methylpiperidin-3-ol;

[0352] 4-(4-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthol;

[0353] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptan-4-ol;

[0354] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidine]-7a'(5'H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0355] 5-Ethynyl-6-fluoro-4-(8-fluoro-4-(2-methyl-1,4-oxazacycloheptane-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol isomer 1;

[0356] 5-Ethynyl-6-fluoro-4-(8-fluoro-4-(2-methyl-1,4-oxazacycloheptane-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol isomer 2;

[0357] 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazatecycloheptane-6-ol;

[0358] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazacyclohepta-3-ol;

[0359] 5-Ethynyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazacycloheptane-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol isomer 1;

[0360] 5-Ethynyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazacycloheptane-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol isomer 2;

[0361] 5-Ethyl-6-fluoro-4-(8-fluoro-4-(6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0362] 5-Ethynyl-6-fluoro-4-(8-fluoro-4-(3-methyl-1,4-oxazacycloheptane-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol isomer 1;

[0363] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3-ol isomer 1;

[0364] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3-ol isomer 2;

[0365] 4-(2-(((4aS,7aR)-1-ethyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0366] 5-Ethyl-4-(2-(((4aS,7aR)-1-ethyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthyl-2-phenol;

[0367] 2-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetonitrile;

[0368] 2-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-yl)acetonitrile;

[0369] 5-Ethynyl-6-fluoro-4-(8-fluoro-4-(3-(hydroxymethyl)azacycloheptyl-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol isomer 1;

[0370] 4-(4-((S)-3-(2,2-difluoroethyl)piperidin-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthol;

[0371] 6-(difluoromethyl)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol;

[0372] 4-(2-(((4aS,7aR)-1-cyclopropyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0373] 2-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-yl)acetonitrile isomer 1;

[0374] 2-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-yl)acetonitrile isomer 2;

[0375] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol isomer 1;

[0376] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol isomer 2;

[0377] 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol;

[0378] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol isomer 1;

[0379] 4-(4-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthol;

[0380] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0381] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol;

[0382] 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-6-ol;

[0383] 5-Ethynyl-6-fluoro-4-(8-fluoro-4-(5-methyl-1,4-oxazacycloheptane-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0384] 5-Chloro-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0385] 5-Ethynyl-6-fluoro-4-(8-fluoro-4-(5-methyl-1,4-oxazacycloheptane-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0386] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol isomer 2;

[0387] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazacyclohepta-3-ol;

[0388] 4-(4-(3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0389] 5-ethynyl-6-fluoro-4-(8-fluoro-4-(3-(hydroxymethyl)azacycloheptyl-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol isomer 2;

[0390] 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazetane-6-ol;

[0391] 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazetane-6-ol;

[0392] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-5-methoxy-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-phenol;

[0393] (3R)-1-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0394] (3R)-1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0395] 5-Ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-4-(1,4-oxazacycloheptane-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol isomer 1;

[0396] 5-Ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-4-(1,4-oxazacycloheptane-4-yl)-2-(((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol isomer 2;

[0397] 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0398] (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0399] 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-phenol;

[0400] (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0401] 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthol;

[0402] 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0403] 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0404] 4-(4-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0405] 4-(4-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0406] 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0407] 5-Ethynyl-6-fluoro-4-(8-fluoro-4-(6-fluoro-6-methyl-1,4-oxazacycloheptane-4-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0408] 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[4.1.0]hept-1-ol;

[0409] 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol;

[0410] 1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyridino[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0411] 1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyridino[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0412] 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)-1H-indol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazatecycloheptane;

[0413] 3-(difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol;

[0414] 3-(difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol;

[0415] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((3S,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0416] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0417] (3R)-1-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((4aS)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0418] 6-Cyclopropyl-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol;

[0419] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0420] (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol;

[0421] (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-((1-methyloctahydro-3aH-indol-3a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol;

[0422] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0423] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0424] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0425] (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-((1-methyloctahydro-3aH-indol-3a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol;

[0426] 3-(difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol;

[0427] 3-(difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol;

[0428] (4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphth-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-cyclopentadien[b]pyridine 1-oxide;

[0429] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0430] 5-Ethynyl-6-fluoro-4-(8-fluoro-5-methyl-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0431] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0432] 4-(2-(((4aS,7aR)-1-cyclopropyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-8-fluoro-5-methoxy-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0433] 4-(5-(difluoromethoxy)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0434] (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3-ol;

[0435] (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3-ol;

[0436] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-3-fluoro-1-(methyl-d3)octahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0437] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-3-fluoro-1-(methyl-d3)octahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0438] 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol;

[0439] 5-Ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0440] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((3R,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0441] 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((3S,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-5-methoxy-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0442] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0443] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0444] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0445] 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol;

[0446] 5-Ethynyl-6-fluoro-4-(8-fluoro-5-methoxy-2-(((4aS,7aR)-1-(methyl-d3)octahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-4-(1,4-oxozyne-heptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol;

[0447] (R)-1-(2-((1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolizin-6',1”-cyclopropane]-7a'(7'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol;

[0448] 4-(4-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0449] 4-(4-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-8-fluoro-5-methoxy-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol;

[0450] (3R)-1-(7-(5-chloro-6-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol, and

[0451] 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol; Or its pharmaceutically acceptable salt.

[0452] In some aspects, this disclosure provides transisomers of compounds from any of the foregoing aspects. In some embodiments, the compounds are stable transisomers as described herein. Detailed Implementation

[0453] Unless otherwise stated, it is assumed that any atom with an unsatisfied valence has hydrogen atoms that are sufficient to satisfy the valence.

[0454] Unless the context otherwise indicates, the singular forms “a / an” and “the” include plural references.

[0455] As used herein, the term “or” is a logical disjunction (i.e., and / or) and does not indicate mutually exclusive disjunction unless explicitly indicated by the terms “or,” “unless,” “alternatively,” and similar terms.

[0456] As used herein, the phrase “or a pharmaceutically acceptable salt thereof” means at least one compound, or at least one salt of a compound, or a combination thereof. For example, “a compound having formula (I) or a pharmaceutically acceptable salt thereof” includes, but is not limited to, a compound having formula (I), two compounds having formula (I), a pharmaceutically acceptable salt of a compound having formula (I), a compound having formula (I) and one or more pharmaceutically acceptable salts of compounds having formula (I), and two or more pharmaceutically acceptable salts of compounds having formula (I).

[0457] As used herein, the term "C2-C4 alkenyl" refers to a group derived from a hydrocarbon containing two to four carbon atoms and a double bond.

[0458] As used herein, the term “C1-C3 alkoxy” refers to a C1-C3 alkyl group that is attached to a parent molecule moiety via an oxygen atom.

[0459] As used herein, the term “C1-C6 alkoxy” refers to a C1-C6 alkyl group that is attached to a portion of the parent molecule via an oxygen atom.

[0460] As used herein, the term “C1-C3 alkoxy C1-C3 alkyl” refers to a C1-C3 alkoxy group attached to a portion of the parent molecule via a C1-C3 alkyl group.

[0461] As used herein, the term “C1-C6 alkoxy-C1-C6 alkyl” refers to a C1-C6 alkoxy group attached to a portion of the parent molecule via a C1-C6 alkyl group.

[0462] As used herein, the term “C1-C3 alkoxy carbonyl” refers to a C1-C3 alkoxy group that is attached to the parent molecule via a carbonyl group.

[0463] As used herein, the term "C1-C3 alkyl" refers to a group derived from a straight-chain or branched-chain saturated hydrocarbon containing one to three carbon atoms.

[0464] As used herein, the term "C1-C6 alkyl" refers to a group derived from a straight-chain or branched-chain saturated hydrocarbon containing one to six carbon atoms.

[0465] As used herein, the term (C1-C6 alkyl)amino refers to R-NH, where R is a C1-C6 alkyl group.

[0466] As used herein, the term "(C1-C6 alkyl)aminoC1-C3 alkyl" refers to a (C1-C6 alkyl)amino group that is attached to the parent molecule via a C1-C3 alkyl group.

[0467] As used herein, the term “C1-C3 alkyl carbonyl” refers to a C1-C3 alkyl group attached to a parent molecule via a carbonyl group.

[0468] As used herein, the term "C1-C3 alkylene" refers to a divalent straight-chain saturated hydrocarbon containing one to three carbon atoms.

[0469] As used herein, the term "halogenated C1-C3 alkyl carbonyl" refers to a C1-C3 alkyl group that is attached to a parent molecule moiety via a carbonyl group. In some aspects, the C1-C3 alkyl carbonyl group is -C(O)CF3.

[0470] As used herein, the term "C2-C4 ynyl group" refers to a group derived from a hydrocarbon containing two to four carbon atoms and a triple bond.

[0471] As used herein, the term “C2-C4 alkynyl group” refers to a C2-C4 alkynyl group that is attached to a portion of the parent molecule via an oxygen atom.

[0472] As used in this article, the term "amino" refers to -NH2.

[0473] As used herein, the term "aminoC1-C3 alkyl" refers to an amino group attached to a portion of the parent molecule via a C1-C3 alkyl group.

[0474] As used herein, the term "aryl" refers to a phenyl or bicyclic or tricyclic ring system, wherein at least one of these rings is a phenyl. Bicyclic and tricyclic fused ring systems consist of a phenyl group fused with a four- to eight-membered aromatic or non-aromatic monocyclic or bicyclic fused ring system or a spirocyclic ring system. The aryl groups disclosed herein can be attached to a portion of the parent molecule via any substituted carbon atom in the group. Representative examples of aryl groups include, but are not limited to, dihydroindenyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and 2',3'-dihydrospiro(cyclopropane-1,1'-indenyl).

[0475] As used herein, the term "aryl C1-C6 alkyl" refers to an aryl group attached to a portion of the parent molecule via a C1-C6 alkyl group.

[0476] As used in this article, the term "carboxyl group" refers to -CO2H.

[0477] As used herein, the term "carboxylated C1-C6 alkyl" refers to a C1-C6 alkyl group that is substituted with one, two, or three carboxyl groups.

[0478] As used in this article, the term "cyano" refers to -CN.

[0479] As used herein, the term "cyanoC1-C3alkoxy" refers to a C1-C3 alkoxy group substituted with a cyano group.

[0480] As used herein, the term “C3-C4 cycloalkyl” refers to a saturated monocyclic hydrocarbon ring system having three or four carbon atoms and zero heteroatoms (e.g., cyclopropyl, cyclobutyl).

[0481] As used herein, the term “C3-C6 cycloalkyl” refers to a saturated monocyclic or bicyclic hydrocarbon ring system having three to six carbon atoms and zero heteroatoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, bicyclic [1.1.1]pentyl, cyclohexyl).

[0482] As used herein, the term “C3-C8 cycloalkyl” refers to a saturated monocyclic or bicyclic hydrocarbon ring system having three, four, five, six, seven, or eight carbon atoms and zero heteroatoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, bicyclic [1.1.1]pentyl). In some embodiments, the C3-C8 cycloalkyl group is fused to a heterocyclic or heteroaryl group as described herein.

[0483] As used herein, the term “C3-C6 cycloalkyl C1-C6 alkyl” refers to a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) that is attached to the parent molecule via a C1-C6 alkyl group.

[0484] As used herein, the term “C3-C6 cycloalkyl carbonyl” refers to a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) that is attached to the parent molecule via a carbonyl group.

[0485] As used herein, the term "di(C1-C6 alkyl)amino" refers to -NR z R z' , where R z and R z' They are the same or different C1-C6 alkyl groups.

[0486] As used herein, the term "di(C1-C3 alkyl)aminoC2-C6 alkyl" refers to -(C2-C6 alkyl)NR z R z’ , where R z and R z’ They are the same or different C1-C6 alkyl groups.

[0487] As used herein, the term "dimethylphosphinyl" refers to -P(O)(CH3)2.

[0488] As used herein, the term "dimethylsulfonamide" refers to -S(O)2N(CH3)2.

[0489] As used herein, the terms “halogen” and “halogen” refer to F, Cl, Br, or I.

[0490] As used herein, the term "halogenated C1-C3 alkoxy" refers to a C1-C3 alkoxy group substituted with one, two, or three halogen atoms.

[0491] As used herein, the term "halogenated C1-C3 alkyl" refers to a C1-C3 alkyl group substituted with one, two, or three halogen atoms.

[0492] As used herein, the term "halogenated C1-C6 alkyl" refers to a C1-C6 alkyl group substituted with one, two, or three halogen atoms.

[0493] As used herein, the term "heteroaryl" refers to an aromatic five- or six-membered ring in which at least one atom is selected from N, O, and S, and the remaining atoms are carbon. The term "heteroaryl" also includes: bicyclic systems in which the heteroaryl ring is fused with a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S; and tricyclic systems in which the bicyclic system is fused with a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S. The heteroaryl group is partially attached to the parent molecule via any substituted carbon or nitrogen atom in the group. Representative examples of heteroaryl groups include, but are not limited to, cycloazine, benzo[1,2-d:4,5-d']bisthiazol, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothiopheneyl, furanyl, imidazolyl, indazole, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphridinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridinyl, pyrazinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thiophene, thiophene, triazolyl, thiadiazolyl, and triazinyl.

[0494] As used herein, the term "heteroaryl C1-C6 alkyl" refers to a heteroaryl group attached to a portion of the parent molecule via a C1-C6 alkyl group.

[0495] As used herein, the term "heterocyclic group" refers to a quaternary, quinary, hexaternary, heptaternary, octary, nonaternary, decaternary, eleventh, or twelfth member saturated or partially unsaturated ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" also includes groups in which the heterocyclic ring is fused with one, two, or three quaternary to hexaternary aromatic or non-aromatic carbocyclic or monocyclic heterocyclic groups. The term "heterocyclic group" also includes monocyclic or polycyclic heterocyclic groups as described above, further substituted by one or more spirocyclic groups attached to the heterocyclic group via a spirocarbon. Examples of heterocyclic groups include, but are not limited to, dihydro-1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolizin-6',1”-cyclopropane], hexahydro-2H-1,4-dioxa-2a1-azacyclopentadien[cd]cyclopentadienyl, hexahydropyrrolizinyl, dihydroindolyl, morpholinyl, octahydroinzazinyl, octahydroquinazinyl, piperazine, piperidinyl, pyrrolylalkyl, tetrahydrofuranyl, tetrahydropyranyl, oxacyclobutyl, azacyclobutyl, thiatanyl, thiolanyl, thiophenyl, 1,2-dioxylalkyl, 1,4-dioxylalkyl, and triemethylenyl. (oxide), thiazolinyl, imidazoalkyl, peripterinyl, pyrrolinyl, tetrahydrothiofuranyl, pyranyl, and thiomorpholinyl. The term "4 to 6-membered heterocyclic group" refers to those "heterocyclic groups" described above that include four, five, or six members in the ring.

[0496] Specifically, when R 5 When R is a five- to ten-membered monocyclic, bicyclic, or tricyclic ring containing one nitrogen atom and optionally one to three other heteroatoms selected from the group consisting of oxygen or nitrogen, wherein the ring contains zero to three double bonds, the bicyclic or tricyclic ring may be formed by fusion with another ring, or the other ring may be a spirocyclic ring. Similarly, when R c and R d When a five- to ten-membered ring monocyclic, bicyclic, or tricyclic ring is formed together with the nitrogen atom to which it is attached, optionally containing one to three other heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the bicyclic or tricyclic ring may be formed by fusion with a second ring or the second ring may be a spirocyclic ring, similar to that described in the preceding paragraphs.

[0497] As used herein, the term "heterocyclic C1-C3 alkyl" refers to a heterocyclic group attached to a portion of the parent molecule via a C1-C3 alkyl group.

[0498] As used herein, the term "heterocyclic C1-C6 alkyl" refers to a heterocyclic group attached to a portion of the parent molecule via a C1-C6 alkyl group.

[0499] As used in this article, the term "hydroxyl group" refers to -OH.

[0500] As used herein, the term "hydroxy C1-C3 alkyl" refers to a hydroxyl group attached to a portion of the parent molecule via a C1-C3 alkyl group.

[0501] As used herein, the term "hydroxy C1-C6 alkyl" refers to a hydroxyl group attached to a portion of the parent molecule via a C1-C6 alkyl group.

[0502] As used herein, the term "methylsulfonyl" refers to -S(O)2CH3.

[0503] As used in this article, the term "oxo" refers to =O.

[0504] As used herein, the term "tetrahydropyranyl carbonyl" refers to a tetrahydropyranyl group attached to a parent molecule moiety via a carbonyl group. The carbonyl group can be attached to the tetrahydropyranyl moiety at any suitable position (such as the 1-, 2-, 3-, or 4-position). In one instance, the carbonyl group is attached to the tetrahydropyranyl group at the 4-position.

[0505] Another 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 occupation, or compound disposal. For example, the compounds described herein can be prepared using radioisotopes, and the resulting radiolabeled compounds can be used to develop binding assays or for metabolic studies. Alternatively, and for the same purpose, the compounds described herein can be converted to a radiolabeled form by catalytic tritiation using methods known to those skilled in the art.

[0506] Certain compounds disclosed herein exist as stereoisomers. It should be understood that, when no stereochemistry is specified, this disclosure covers all stereochemical isomer forms or mixtures thereof that possess the ability to suppress mutant KRAS. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing a chiral center, or by preparing a mixture of enantiomers followed by separation, such as by converting to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers on a chiral chromatographic column. The starting compounds for a particular stereochemistry are commercially available or can be prepared and resolved using techniques known in the art.

[0507] Some of the compounds disclosed herein exist as transisomers. The term "transisomer" refers to a conformational stereoisomer that occurs when rotation around a single bond in a molecule is prevented or significantly slowed down due to steric interactions with other parts of the molecule, and the substituents at both ends of the single bond are asymmetric (i.e., optically active without the need for an asymmetric carbon center or stereocenter). Separation and isolation of isomeric substances are permitted when the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow. Transisomers are enantiomers (or epimers) without a single asymmetric atom.

[0508] A transisomer can be considered stable if the barrier to interconversion is high enough to allow little or no interconversion to occur at room temperature for at least one week. In some aspects, a transisomer undergoes little or no interconversion at room temperature for at least one year. In some aspects, when the transisomer is in substantially pure form (which is typically solid), the transisomer disclosed herein does not undergo more than about 5% interconversion to its opposite transisomer at room temperature over a period of one week. In some aspects, the transisomer disclosed herein does not undergo more than about 5% interconversion to its opposite transisomer at room temperature (about 25°C) over a period of one year. In some aspects, the transisomer disclosed herein is sufficiently stable to undergo no more than about 5% interconversion at 0°C in the aqueous pharmaceutical formulation in which it is present for at least one week. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible transisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of single transisomers, and intermediate mixtures.

[0509] The energy barrier for the thermal racemization of blocked isomers can be determined by the steric hindrance of the free rotation of one or more bonds forming the chiral axis. Some biaromatic compounds exhibit blocked isomerism, in which rotation around intercyclic bonds lacking C2 symmetry is restricted. The free energy barrier for isomerization (enantiomerization) is a measure of the stability of the intercyclic bonds relative to rotation. Optical and thermal excitations can promote the racemization of such isomers, depending on electronic and steric factors.

[0510] Ortho-substituted biaromatic compounds can exhibit this type of conformation and rotational isomerism. These biaromatic compounds are enantiomers, chiral trans-blocked isomers, where sp... 2 -sp 2 The intercyclic bonds between carbon-carbon rings and aryl rings have sufficiently high energy barriers to prevent free rotation, and the substituents W... 1 ≠W 2 and W 3 ≠W 4 This causes the molecules to be asymmetrical.

[0511] W 1 :W 3 W 1 :W 4 , and / or W 2 :W 4 W 2 :W 3The spatial interactions between them are large enough that the planar conformation is at its energy maximum. When the interconversion of two nonplanar, axially chiral enantiomers is slow enough that they can freely separate from each other, they exist as blocked isomers. The thick and dashed lines in the figures shown above indicate those portions, or parts of the molecule, that are spatially confined due to the rotational energy barrier. The thickened portions are orthogonal above the plane of the page, and the dashed portions are orthogonal below the plane of the page. The 'flat' portions of the molecule (the left ring in each of the two depicted biaryl compounds) are in the plane of the page.

[0512] The pharmaceutical compositions disclosed herein may include one or more pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” is a salt that retains the desired biological activity of the parent compound without conferring any undesirable toxicological effects (see, for example, Berge, SM et al., J. Pharm. Sci., 66:1-19 (1977)). These salts may be obtained during the final isolation and purification of the compounds described herein, or by reacting the free base functional group of the compound alone with a suitable acid, or by reacting the acidic group of the compound with a suitable base. Acid addition salts include salts derived from non-toxic inorganic acids (such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, etc.) and salts derived from non-toxic organic acids (such as aliphatic monocarboxylic acids and aliphatic dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, aromatic acids, aliphatic and aromatic sulfonic acids, etc.). Alkali addition salts include those derived from alkaline earth metals (such as sodium, potassium, magnesium, calcium, etc.) and those derived from non-toxic organic amines (such as N,N′-dibenzylethylenediamine, N-methylglucosamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, etc.). Pharmaceutical Composition

[0513] On the other hand, this disclosure provides compositions, such as pharmaceutical compositions, containing one or more compounds described herein formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of this disclosure may also be administered in combination therapy, i.e., in combination with other pharmaceutical agents as described herein.

[0514] As used herein, "pharmaceutically acceptable carriers" include any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. In some respects, carriers are 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 acids and other natural conditions that may inactivate it.

[0515] The pharmaceutical compositions disclosed herein may 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 understood by those skilled in the art, the route of administration and / or mode will vary depending on the desired outcome. In some aspects, routes of administration for the compounds disclosed herein include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral administration routes, such as by injection or infusion. As used herein, the phrase “parenteral administration” means a method of administration other than enteric and local administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intrabursal, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, spinal, epidural, and intrasternal injections and infusions.

[0516] Sterile injectable solutions can be prepared by incorporating the active compound in the desired amount into a suitable solvent containing one or a combination of the ingredients listed above, followed by sterile microfiltration. Typically, dispersions are prepared by incorporating the active compound into a sterile medium containing an alkaline dispersion medium and the desired other ingredients from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, some methods include vacuum drying and freeze-drying (lyophilization), which produce a powder of the active ingredient plus any other desired ingredient from a previously sterile filtered solution.

[0517] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions disclosed herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils, and injectable organic esters. For example, suitable flowability can be maintained by using coating materials (e.g., lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0518] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. The use of such media and agents as pharmaceutically active substances is known in the art. The use of any conventional media or reagent in the pharmaceutical compositions disclosed herein is considered unless any conventional media or reagent is incompatible with the active compound. Complementary active compounds may also be incorporated into the composition.

[0519] Therapeutic compositions typically must be sterile and stable under manufacturing and storage conditions. Compositions can be formulated as solutions or liquids with an ordered structure suitable for high drug concentrations. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Suitable flowability can be maintained, for example, by using coatings (e.g., lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants. In many cases, it is desirable to include isotonic agents in the composition, such as sugars, polyols (e.g., mannitol, sorbitol), or sodium chloride. Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption (e.g., monostearate and gelatin) in the composition.

[0520] Alternatively, the compounds disclosed herein may be administered via non-parenteral routes, such as topical, epidermal, or mucosal administration, for example, intranasal, oral, vaginal, rectal, sublingual, or topical administration.

[0521] Any pharmaceutical composition considered herein can be delivered orally, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, lozenges, sugar 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 this disclosure may contain at least one agent selected from the group consisting of sweeteners, flavoring agents, coloring agents, modifiers, antioxidants, and preservatives.

[0522] Tablets can be prepared, for example, by mixing at least one compound having formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic, pharmaceutically acceptable excipient suitable for making tablets.

[0523] Aqueous suspensions can be prepared, for example, by mixing at least one compound having formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for making aqueous suspensions, including but not limited to, suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents such as naturally occurring phospholipids such as lecithin; condensation products of alkyl epoxides and fatty acids such as polyoxyethylene stearate; condensation products of ethylene oxides and long-chain aliphatic alcohols such as heptadecanethoxycetyl alcohol; condensation products of ethylene oxides and esters derived from fatty acids and hexitols such as polyoxyethylene sorbitan monooleate; and condensation products of ethylene oxides and esters derived from fatty acids and hexitol anhydrides such as polyvinyl sorbitan monooleate. The aqueous suspension may also contain at least one preservative, such as ethylparaben and n-propylparaben; at least one colorant; at least one flavoring agent; and / or at least one sweetener, including but not limited to sucrose, saccharin and aspartame.

[0524] Oily suspensions can be prepared, for example, by suspending at least one compound having formula (I) and / or at least one pharmaceutically acceptable salt thereof in a vegetable oil (e.g., peanut oil, sesame oil, and coconut oil) or in a mineral oil (e.g., liquid paraffin). Oily suspensions may also contain at least one thickener, 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 above may be added to the oily suspension. Oily suspensions may further contain at least one preservative, including but not limited to, antioxidants such as butylated hydroxyanisole and α-tocopherol.

[0525] Dispersible powders and granules can be prepared, for example, by mixing at least one compound having formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersant and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersants, wetting agents, and suspending agents have been described above. Exemplary preservatives include, but are not limited to, antioxidants such as ascorbic acid. Furthermore, dispersible powders and granules may also contain at least one excipient, including, but not limited to, sweeteners, flavoring agents, and coloring agents.

[0526] The active compound can be prepared with a carrier that prevents rapid release of the compound, such as in 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 commonly known to those skilled in the art. See, for example, Robinson, JR, editor, Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0527] The therapeutic composition can be administered using medical devices known in the art. For example, in one aspect, the therapeutic composition disclosed herein can be administered using a needle-free subcutaneous injection device, 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 that may be used in this disclosure include: U.S. Patent No. 4,487,603, which discloses an implantable microinfusion pump for dispensing drugs at a controlled rate; U.S. Patent No. 4,486,194, which discloses a therapeutic device for administering drugs through the skin; U.S. Patent No. 4,447,233, which discloses a drug infusion pump for delivering drugs at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion device for continuous drug delivery; U.S. Patent No. 4,439,196, which discloses a permeation drug delivery system with multiple compartments; and U.S. Patent No. 4,475,196, which discloses a permeation 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.

[0528] In some respects, the compounds disclosed herein can be administered parenterally, i.e., by injection, including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-occlusal, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and / or infusion.

[0529] In some respects, the compounds disclosed herein can be administered orally, i.e., via gelatin capsules, tablets, hard or soft capsules, or liquid capsules. Uses / treatments of KRAS inhibitors

[0530] The administration of the therapeutic agents described herein may include the administration of a therapeutically effective amount of the therapeutic agent. As used herein, the term "therapeuticly effective amount" means, but is not limited to, the amount of a therapeutic agent that treats a condition by administration of a composition comprising a KRAS inhibitor described herein. This amount is sufficient to demonstrate a detectable therapeutic or improving effect. Effects may include, for example, but not limited to, treatment of the conditions listed herein. The precise effective amount used on a subject will depend on the subject's size and health condition, the nature and extent of the condition being treated, the advice of the treating physician, and the choice of the therapy or combination of therapies used for administration.

[0531] For the administration of the compounds described herein, the dosage ranges from about 0.0001 to 100 mg / kg host body weight and more typically from 0.01 to 40 mg / kg host body weight. Exemplary treatment regimens require administration once daily, twice weekly, three times weekly, once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, once every three months, or once every three to six months.

[0532] The disclosed compounds strongly inhibit anchor-independent cell growth and therefore have the potential to inhibit tumor metastasis. Therefore, in another aspect, this disclosure provides a method for inhibiting tumor metastasis, the method comprising administering to a subject in need an effective amount of a pharmaceutical composition comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0533] Ras mutations, including but not limited to KRAS mutations, have also been identified in hematologic malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, certain aspects involve administering the disclosed compounds (e.g., in the form of pharmaceutical compositions) to patients requiring treatment for hematologic malignancies. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the compounds disclosed in this invention can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other aspects, these compounds can be used to treat lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0534] Determining whether a tumor or cancer contains a KRAS mutation can be done by assessing the nucleotide sequence encoding the KRAS protein, by assessing the amino acid sequence of the KRAS protein, or by assessing the characteristics of a putative KRAS mutant protein. The sequence of the wild-type human KRAS protein is known in the art.

[0535] 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 aspects, KRAS mutation evaluation of samples includes real-time PCR. In real-time PCR, fluorescent probes specific for KRAS mutations are used. When a mutation is present, the probe binds and fluorescence is detected. In some aspects, direct sequencing methods, such as those targeting specific regions of the KRAS gene (e.g., exon 2 and / or exon 3), are used to identify KRAS mutations. This technique will identify all possible mutations in the sequenced region.

[0536] Methods for detecting mutations in the KRAS protein are known to those skilled in the art. These methods include, but are not limited to, detection of KRAS mutants using binding agents (e.g., antibodies) that are specific to the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0537] Methods for determining whether a tumor or cancer contains a KRAS mutation may use a variety of samples. In some aspects, the sample is taken from a subject with a tumor or cancer. In some aspects, the sample is taken from a subject with cancer or a tumor. In some aspects, the sample is a fresh tumor / cancer sample. In some aspects, the sample is a frozen tumor / cancer sample. In some aspects, the sample is a formalin-fixed paraffin-embedded sample. In some aspects, the sample is processed into cell lysates. In some aspects, the sample is processed into DNA or RNA. This disclosure also relates to a method for treating hyperproliferative disorders in mammals, comprising administering to said mammal a therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.In some respects, the methods relate to the treatment of cancers such as acute myeloid leukemia, adolescent cancer, childhood adrenocortical 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, brainstem glioma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumors, atypical teratoma, embryonic tumors, germ cell tumors, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CLL). CML), chronic myelodysplastic disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory glioma, Ewing's sarcoma, extracranial germ cell tumor, gonadal germ cell tumor, ocular cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreas Neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary lesions, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell carcinoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative tumor, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, ... Pharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleural pulmonary 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 bowel cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some aspects, the methods involve treating non-cancerous hyperplastic disorders, such as benign skin hyperplasia (e.g., psoriasis), restenosis, or prostate cancer (e.g., benign prostatic hyperplasia (BPH)).

[0538] In some respects, this disclosure relates to a method for treating lung cancer, the method comprising administering to a subject in need an effective amount of any of the above-described compounds (or pharmaceutical compositions comprising them). In some respects, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In other respects, 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, glandular tumors, carcinoid tumors, and undifferentiated carcinomas.Subjects who may be treated with the compounds disclosed herein or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates, or derivatives of said compounds according to the methods disclosed herein include, for example, subjects already diagnosed with: acute myeloid leukemia, acute myeloid leukemia, juvenile cancer, childhood adrenocortical 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, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, reproductive cell carcinoma. Cellular tumors, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelodysplastic disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory glioma, Ewing's sarcoma, extracranial germ cell tumors, gonadal germ cell tumors, ocular cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer. Cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary lesions, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative tumor, 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). SCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleural pulmonary 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, laryngeal 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 respects, subjects treated with the compounds disclosed herein include those who have been diagnosed with non-cancerous hyperplastic disorders, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate problems (e.g., benign prostatic hyperplasia (BPH)).This disclosure further provides a method for modulating the activity of a mutant KRAS protein by contacting a protein with an effective amount of the disclosed compound. Modulation may be inhibition or activation of protein activity. In some aspects, this disclosure provides a method for inhibiting protein activity by contacting a mutant KRAS protein with an effective amount of the disclosed compound in solution. In some aspects, this disclosure provides a method for inhibiting the activity of a mutant KRAS protein by contacting cells, tissues, or organs expressing the target protein. In some aspects, this disclosure provides a method for inhibiting protein activity in a subject (including, but not limited to, rodents and mammals (e.g., humans)) by administering an effective amount of the disclosed compound to a subject. In some aspects, the percentage of modulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the percentage of inhibition exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, this disclosure provides a method for inhibiting KRAS activity in cells by contacting the cells with an amount of the disclosed compound sufficient to inhibit the activity of KRAS mutants in the cells. In some aspects, this disclosure provides a method for inhibiting mutant KRAS in tissues by contacting the tissues with an amount of the disclosed compound sufficient to inhibit the activity of mutant KRAS in the tissues. In some aspects, this disclosure provides a method for inhibiting KRAS in organisms by contacting the organisms with an amount of the disclosed compound sufficient to inhibit the activity of KRAS in the organisms. In some aspects, this disclosure provides a method for inhibiting KRAS activity in animals by contacting the animals with an amount of the disclosed compound sufficient to inhibit the activity of KRAS in the animals. In some aspects, this disclosure provides a method for inhibiting KRAS included in mammals by contacting the mammals with an amount of the disclosed compound sufficient to inhibit the activity of KRAS in the mammals. In some aspects, this disclosure provides a method for inhibiting KRAS activity in humans by contacting the humans with an amount of the disclosed compound sufficient to inhibit the activity of KRAS in the humans. This disclosure provides methods for treating KRAS-mediated diseases in subjects requiring such treatment. This disclosure also provides methods for combination therapies, wherein agents known to modulate other pathways, or other components of the same pathway, or even overlapping target enzyme groups, are used in combination with compounds of this disclosure or their pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates, or derivatives. In one aspect, such therapies include, but are not limited to, combinations of one or more compounds of this disclosure with chemotherapeutic agents, therapeutic antibodies, and radiotherapy.

[0539] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds disclosed herein. In some aspects, chemotherapeutic agents are selected from the group consisting of: mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. In some aspects, chemotherapeutic agents are immuno-oncology (IO) agents that enhance, stimulate, or upregulate the immune system.

[0540] The compounds described herein may be used in combination with the pharmaceutical agents disclosed herein or other suitable pharmaceutical agents, depending on the condition being treated. Therefore, in some aspects, the one or more compounds disclosed herein will be administered co-administered with other pharmaceutical agents as described above. When used in combination therapy, the compounds described herein are administered simultaneously or alone with a second pharmaceutical agent. This combination administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in different dosage forms, and single administration. That is, the compounds described herein and any pharmaceutical agents described above may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds disclosed herein and any pharmaceutical agents described above may be administered simultaneously, wherein the two pharmaceutical agents are present in separate formulations. In another alternative, the compounds disclosed herein may be administered immediately following any pharmaceutical agent described above, or vice versa. In some aspects of single administration, the compounds disclosed herein and any pharmaceutical agents described above may be administered at intervals of minutes, hours, or days.

[0541] These compounds can be prepared by methods known in the art (including those described below and variations thereof). Some reagents and intermediates are known in the art. Other reagents and intermediates can be prepared using readily available materials by methods known in the art. Any variables used to describe the synthesis of the compounds (e.g., numbered “R” substituents) are intended only to illustrate how the compounds are prepared and should not be confused with the variables used in the claims or other parts of this specification. The following methods are for illustrative purposes and are not intended to limit the scope of this disclosure. synthesis

[0542] The abbreviations used in this document include: for ammonium acetate, AA; for acetonitrile, ACN or MeCN; for tert-butoxycarbonyl, BOC or Boc; for (benzotriazol-1-yloxytris(dimethylamino)hexafluorophosphate), BOP; for tert-butyl, t-Bu or tBu; for diethylaminosulfur trifluoride, DAST; for dichloromethane, DCM; for diethanolamine, DEA; for diisopropylethylamine, DIEA or DIPEA; for dimethylacetamide, DMA; for N,N-dimethylaminopyridine, DMAP; for dimethylformamide, DMF; for dimethyl sulfoxide, DMSO; for 1,1'-bis(diethylamino)acetamide, DMAP; for dimethylformamide, DMF; for dimethyl sulfoxide, DMSO; for 1,1'-bis(diethylamino)acetamide, DMAP; for dimethylformamide, DMF; for dimethyl sulfoxide, DMSO; for 1,1'-bis(diethylamino)acetamide, DMAP; for dimethylformamide, DMF; for dimethyl sulfoxide, DMSO; for dimethylform ... (Phenylenyl)ferrocene, dppf; for ethyl acetate, EtOAc; for ethanol, EtOH; for hours, h; for isopropanol, IPA; for lithium aluminum hydride, LAH; for liquid chromatography-mass spectrometry, LCMS; for methanol, MeOH; for hexamethyldisilamide, HMDS; for minutes, min; for methoxymethyl, MOM; for pivaloyl, Piv; for nucleophilic aromatic substitution, SNAr; for tetrabutylammonium fluoride, TBAF; for triethylamine, TEA; for trifluoroacetic acid, TFA; for tetrahydrofuran, THF; for room temperature or retention time, RT (context will indicate). General Solution

[0543] The compounds described herein can be prepared according to the methods outlined in Schemes 1 to 4 and the examples shown below. Scheme 1: Preparation of compound 1-1 Preparation of intermediate 2: 3-{2,7-dichloro-8-fluoropyridino[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0544] DIPEA (20.8 mL, 119 mmol) was added 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, followed by the addition of 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 min. 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 product was then analyzed by COMBIFLASH. TMThe crude compound was purified by chromatography (Teledyne ISO, Lincoln, Nebraska) (120 g silica gel column, using 50% to 80% ethyl acetate / petroleum ether) to give tert-butyl 3-{2,7-dichloro-8-fluoropyridino[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] + . Preparation of intermediate 3: ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolizidine-7a(5H)-formate

[0545] LiHMDS (382 mL, 382 mmol) was added dropwise 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 150 mL of THF at -40 °C under an argon atmosphere. The reaction mixture was stirred at room temperature for 20 hours. Subsequently, the reaction mixture was poured into 50 mL of 1 M HCl aqueous solution and the pH was adjusted to 7 at 0 °C. The reaction mixture was extracted three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue, which was then subjected to silica gel column chromatography using COMBIFLASH. TM The crude residue was purified by chromatography (Terry Dionesco, Lincoln, Nebraska) (petroleum ether / EtOAc = 0 to 50%) to give the title compound, ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolizidine-7a(5H)-formate, as a yellow oil (15 g, 71.7 mmol, 38% yield). 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). Preparation of intermediate 4: ethyl 2,5-dioxotetrahydro-1H-pyrrolizidine-7a(5H)-formate

[0546] At -70°C, a stirred solution of ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolizidine-7a(5H)-carboxylate (intermediate 3.6 g, 28.7 mmol) in DCM (60 mL) - MeOH (12 mL) was purged with O3 for 30 minutes. Then, the mixture was purged with N2 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. Subsequently, the reaction mixture was concentrated under reduced pressure to obtain a crude residue, which was then analyzed by COMBIFLASH. TM The crude residue was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) (120 g column, EtOAc petroleum ether = 0 to 50%) to give the title compound ethyl 2,5-dioxotetrahydro-1H-pyrrolizidine-7a(5H)-formate (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). Preparation of intermediate 5: (±)-(2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolizidine-7a(5H)-formate ethyl ester

[0547] Sodium borohydride (0.25 g, 6.68 mmol) was added fractionally to a stirred solution of ethyl 2,5-dioxotetrahydro-1H-pyrrolizidine-7a(5H)-carboxylate (intermediate 4, 4.7 g, 22.25 mmol) in ethanol (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The reaction mixture was quenched with 2 mL of saturated aqueous NH4Cl solution and stirred at 5 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was then subjected to COMBIFLASH. TM The crude residue was purified by chromatography (Terry Dionesco, Lincoln, Nebraska) (40 g column, 0–7% MeOH-DCM) to give ethyl (±)(2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolizidine-7a(5H)-carboxylate (2.2 g, 10.32 mmol, 46% yield). Approximately 10% of other diastereomers were present. 1H 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). Preparation of intermediate 6: (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolizidine-7a(5H)-formate ethyl ester

[0548] At -70°C, DAST (4.2 mL, 31.7 mmol) was added to a stirred solution of (±)(2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolizidine-7a(5H)-carboxylic acid ethyl ester (intermediate 5, 4.5 g, 21.10 mmol) in DCM (30 mL). The reaction mixture was gradually heated to room temperature over a period of 16 hours. The reaction mixture was cooled to 0°C and quenched with MeOH (1.5 mL), and diluted with water (50 mL). The mixture was extracted with DCM (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was then subjected to COMBIFLASH. TM The residue was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska, 40 g column, 55% petroleum ether-EtOAc) to give ethyl (±)-(2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolizidine-7a(5H)-carboxylate (2.1 g, 9.76 mmol, 46.2% yield) as a yellow liquid. The compound was further purified by chiral supercritical fluid chromatography (SFC) (column: CHIRALPAK). TM IC (Daicel, Japan) (250×21mm, 5μm); 70% CO2, 30% co-solvent, 0.2% NH3.H2O in IPA; flow rate: 70 g / min; back pressure: 100 bar; temperature: 40℃. Peak 1: retention time = 3 min; Peak 2: retention time = 4.3 min. Peak 2: 1H 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). Preparation of intermediate 7: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methanol

[0549] A solution of (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolizidine-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 (2.90 mL, 6.97 mmol) in THF. The reaction mixture was heated to 70 °C for 4 hours. The reaction mixture was then cooled to 0 °C and quenched with water (1.2 mL), 10% NaOH (3 mL), and an additional 3 mL of water. Subsequently, the reaction mixture was stirred for 10 minutes and passed through a diatomaceous earth mat (CELITE). TM Filtered by Sigma Aldrich, St. Louis, MO. Washed with EtOAc pads. Concentrated the filtrate under reduced pressure and passed through a Combiflash filter. TM Purification by chromatography (Terry Dianesco, Lincoln, Nebraska) (12 g column, 20 to 60% MeOH-DCM) yielded a colorless liquid ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methanol (550 mg, 3.45 mmol, 74% yield). TLC system: 20% MeOH-DCM (Rf: 0.1); 1 ¹H NMR (300 MHz, CDCl₃) 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 were observed). Preparation of intermediate 8: (S)-2-((1-phenylethyl)amino)cyclopent-1-ene-1-carboxylic acid ethyl ester

[0550] At room temperature, ethyl 2-oxocyclopentane-1-carboxylate (140.5 g, 900 mmol) and (S)-1-phenylethyl-1-amine (109 g, 900 mmol) was added to a stirred solution of molecular sieves in DCM (500 mL). The reaction mixture was stirred under reflux for 1 day. The reaction mixture was cooled to room temperature and then passed through a diatomaceous earth pad (CELITE). TM (The Sigma-Aldrich Company in St. Louis, Missouri) filtered and concentrated the filtrate under reduced pressure to obtain a crude residue, which was then passed through a COMBIFLASH filter. TM The crude residue was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) (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] + . Preparation of intermediate 9: (S,E)-1-(3-ethoxy-3-oxopropyl)-2-(((S)-1-phenylethyl)imino)cyclopentane-1-carboxylic acid ethyl ester

[0551] At 0 °C, a mixture of zinc(II) chloride in 2-MeTHF (473 mL, 898 mmol) and ethyl acrylate (90 g, 898 mmol) was added dropwise to THF (233 mL) containing (S)-2-((1-phenylethyl)amino)cyclopent-1-ene-1-carboxylate (intermediate 8, 233 g, 898 mmol), and the mixture was stirred at 0 °C for 16 hours. The reaction mixture was neutralized with saturated NaOH solution and extracted with EtOAc (3 × 500 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give (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 in the next step without further purification. MS(ESI) m / z: 360.1 [M+H] + . Preparation of intermediate 10: (4aS)-2-oxooctahydro-4aH-cyclopentadieno[b]pyridine-4a-carboxylic acid ethyl ester

[0552] At room temperature, a mixture of (S,E)-1-(3-ethoxy-3-oxopropyl)-2-(((S)-1-phenylethyl)imino)-cyclopentane-1-carboxylic acid ethyl ester (intermediate 9, 145 g, 403 mmol) and 10% palladium / carbon (35 g, 10% w / w) in ethanol (336 mL) was hydrogenated for 18 hours at 50 PSI of hydrogen. The hydrogen was then transported via a diatomaceous earth mat (CELITE). TM The reaction mixture was filtered by Sigma-Aldrich, St. Louis, Missouri, and the filtrate was concentrated under reduced pressure to obtain a crude residue, which was then passed through a COMBIFLASH filter. TM The crude residue was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) (using 4-5% ethyl acetate / petroleum ether) to give ethyl (4aS)-2-oxooctahydro-4aH-cyclopentadieno[b]pyridine-4a-carboxylate as a colorless oil (36 g, 170 mmol, 42.2% yield). MS (ESI) m / z: 211.6 [M+H] + . Preparation of intermediate 11: ((4aS,7aR)-octahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methanol

[0553] A solution of (4aS)-2-oxooctahydro-4aH-cyclopentadien[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 (258 mL, 258 mmol) in THF. The reaction mixture was heated to 70 °C for 4 hours. The reaction mixture was then cooled to 0 °C and quenched with water (9.8 mL), 10% NaOH (9 mL), and an additional 27 mL of water. Subsequently, the reaction mixture was warmed to room temperature and stirred for 20 minutes. The mixture was then processed via a diatomaceous earth mat (CELITE). TM The reaction mixture was filtered and washed with excess EtOAc. The filtrate was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give ((4aS,7aR)-octahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methanol (17.3 g, 111 mmol, 99% yield) as a white solid, which was used as is in the next step without further purification. MS (ESI) m / z: 156.0 [M+H] + . Preparation of intermediate 12: ((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadien[b]pyridin-4a-yl)methanol

[0554] A solution of ((4aS,7aR)-naphthyl-4aH-cyclopentadieno[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 minutes, followed by fractional addition of sodium triacetoxyborohydride (50.8 g, 239 mmol), and then stirred at room temperature for 4 hours. After 4 hours, the reaction mixture was concentrated and diluted with 300 mL of 2-MeTHF, followed by washing with a saturated aqueous solution of K₂CO₃. The aqueous phase was extracted with EtOAc (7×), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude residue. The compound was purified by the following chiral SFC [(column: BEH 2-ethylpyridine (5×25cm, 5μm); 90% CO2, 10% co-solvent, 0.2% NH4OH in MeOH; flow rate: 300mL / min; back pressure: 100 bar; temperature 35℃] to give ((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadien[b]pyridin-4a-yl)methanol (28g, 166mmol, 76% yield). ¹H NMR (400MHz, 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). Preparation of intermediate 13: 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-chloro -8-Fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0555] Approximately 10 g of Na₂CO₃ was added to a solution of [(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methanol, HCl salt (intermediate 7, 5.48 g, 28.0 mmol) in DCM (20 mL), 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 a free amine, which was dissolved in 1,4-dioxane (100 mL). Subsequently, 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (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. via diatomaceous earth mats (CELITE) TM (Sigma-Aldrich, St. Louis, Missouri) The reaction mixture was filtered, washed with excess DCM, and the filtrate was concentrated under reduced pressure to give a crude residue, which was then subjected to silica gel column chromatography using COMBIFLASH. TM Chromatography (Terry Dianesco, Lincoln, Nebraska) (120g REDISEP) TM The crude residue was purified by column chromatography (Teledyne ISCO, Lincoln, Nebraska) using 80 to 100% EtOAc-petroleum ether to give a pale yellow solid of 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (7 g, 12.70 mmol, 54.4% yield). MS (ESI) m / z: 553.5 (M+H) + . Preparation of intermediate 14: 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0556] Add 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 13.5 g, 9.07 mmol) to a stirred solution of 1,4-dioxane (110 mL) and water (33 mL). Add ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (5.12 g, 9.98 mmol) and Cs₂CO₃ (8.87 g, 27.2 mmol), followed by PdCl₂ (dppf) (0.66 g, 0.907 mmol). The reaction mixture was purged with N₂ for 5 min, and then heated in a microwave reactor at 105 °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 a crude product, which was then analyzed by COMBIFLASH. TM The crude product was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) (using an 80 g silica gel column and 50 to 100% ethyl acetate / petroleum ether) to give 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.5 g, 3.88 mmol, 43% yield) as a brown solid. MS (ESI) m / z: 901.7 [M+H] + . Preparation of intermediate 15: 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0557] CsF (6.24 g, 41.1 mmol) was added to a stirred solution of 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 14, 3.7 g, 4.11 mmol) in DMF (50 mL). The reaction mixture was heated at 50 °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 a brown liquid, 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.9 g, 3.89 mmol, 95% yield), which was used in the next step without further purification. MS (ESI) m / z: 746.6 [M+H] + . Preparation of intermediate 16: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol

[0558] To a stirred solution of 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 15, 3 g, 4.03 mmol) in EtOH (15 mL) and THF (15 mL), NaOH (1 M aqueous solution) (40.3 mL, 40.3 mmol) was added (40.3 mL, 40.3 mmol). The reaction mixture was heated at 70 °C for 3 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 saturated NH4Cl solution, water, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude compound, which was then subjected to COMBIFLASH. TMThe crude compound was purified by chromatography (Terry Dionesco, Lincoln, Nebraska) (24 g silica gel column, 10-20% MeOH / DCM) to give 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-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] + . Preparation of intermediate 17: (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolizine

[0559] Morpholine (76 mg, 0.872 mmol), triethylamine (0.405 mL, 2.91 mmol), and BOP (482 mg, 1.09 mmol) were added to a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol (intermediate 16, 400 mg, 0.727 mmol) in ACN (10 mL). 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 a crude residue. The residue was then analyzed by COMBIFLASH. TM Chromatography (Terry Dianesco, Lincoln, Nebraska) (40g REDISEP) TM The crude material was purified using a column (Teledyne ISCO, Lincoln, Nebraska, LA) with a gradient of 60-100% EtOAc / petroleum ether. The fraction containing the desired product was evaporated to give a brown liquid (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolizidine (450 mg, 89% yield), which was used directly in the next step without further purification. MS (ESI) m / z: 620.6 [M+H] + . Example 1-1 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol

[0560] At 0 °C, 4N HCl (0.49 mL, 16.14 mmol in 1,4-dioxane) was added to a stirred solution of 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-octahydropyrrolo[3,2-b]pyrrolo-1-carboxylic acid tert-butyl ester (intermediate 17,500 mg, 0.807 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. The volatiles of the reaction mixture were removed under reduced pressure (at a 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 a grayish-white solid. The crude compound was purified by the following preparative HPLC (High Performance Liquid Chromatography) method: [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℃] Flow rate: 30.0 mL / min; Detection: UV at 220 and 254 nm], yielding 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol (50 mg, 0.084 mmol, 10.4% yield). MS (ESI) m / z: 576.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δppm=10.13(s,1H),9.08(s,1H),7.97(dd,J=5.9,9.1 Hz,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). Preparation of intermediate 18: (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolizine

[0561] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol (300 mg, 0.545 mmol) in ACN (10 mL), 1,4-oxazacycloheptane (66.1 mg, 0.654 mmol), DIPEA (0.29 mL, 1.635 mmol), and BOP (362 mg, 0.817 mmol) were added. 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 a crude residue. The residue was then analyzed by COMBIFLASH. TM Chromatography (Terry Dianesco, Lincoln, Nebraska) (40g REDISEP) TMThe crude material was purified using a column (Teledyne ISCO, Lincoln, Nebraska) with a gradient of 60-100% EtOAc / petroleum ether. Evaporation of the fraction containing the desired product yielded a brown liquid (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolizidine (330 mg, 96% yield). MS (ESI) m / z: 634.6 [M+H] + . Example 1-2 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol

[0562] At 0 °C, 4N HCl (1.3 mL, 5.21 mmol in 1,4-dioxane) was added to a stirred solution of (2R,7aS)-7a-[({7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl}oxy)methyl]-2-fluoro-hexahydro-1H-pyrrolizidine (330 mg, 0.521 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. The volatiles of the reaction mixture were removed under reduced pressure (at a 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 a grayish-white solid. The crude compound was purified by the following preparative 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 minutes; Flow rate: 1.1 mL / min. Injection conditions 2: Column: Waters XBridgeBEH C18 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%–100% B for 3 min; Flow rate: 1.1 mL / min, yielding 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol (28 mg, 0.047 mmol, 9.12% yield); MS (ESI) m / z: 590.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm= 1H NMR (400MHz, DMSO-d6) δ10.27(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). Preparation of intermediate 19: 4-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-1,4-oxazacycloheptane

[0563] At -40°C, DIPEA (1.38 mL, 7.92 mmol) was added to a stirred solution of commercially available 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1 g, 3.96 mmol) in 10 mL of DCM, followed by the addition of 1,4-oxazacycloheptane (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 analyzed by COMBIFLASH. TM The mixture was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) (40 g silica gel column, using 50 to 80% ethyl acetate / petroleum ether) to give tert-butyl 3-{2,7-dichloro-8-fluoropyridino[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] + . Preparation of intermediate 20: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane

[0564] Sodium hydride (0.189 g, 4.73 mmol, 60 w / w%) was added to a stirred solution of ((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methanol (0.48 g, 2.84 mmol) in anhydrous THF (9 mL) at 0 °C, and the mixture was stirred for 1 hour at the same temperature. Then, 4-(2,7-dichloro-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (0.75 g, 2.365 mmol) was added to THF (2 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (2X). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The residue was then analyzed by COMBIFLASH. TM The crude residue was purified by chromatography (Terry Dion Esco Corporation, Lincoln, Nebraska) (40 g silica gel column; petroleum ether containing 70% to 80% EtOAc as eluent) to give 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (550 mg, 1.222 mmol, 52% yield) as a grayish-white solid. MS (ESI) m / z: 450.4 [M+H] + . Preparation of intermediate 21: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphth-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane

[0565] Add ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (627 mg, 1.222 mmol) and Cs2CO3 (1086 mg, 3.33 mmol) to a stirred solution of 4-(7-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentane[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (500 mg, 1.111 mmol) in 1,4-dioxane (26 mL) and H2O (7.5 mL) to the stirred solution. The reaction mixture was purged with argon for 5 minutes and PdCl2 (dppf) (81 mg, 0.111 mmol) was added. The reaction mixture was purged with argon again for 3 minutes, followed by heating at 100 °C for 1 hour in a microwave reactor. 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 then subjected to COMBIFLASH. TM The crude product was purified by chromatography (Terry Dionesco, Lincoln, Nebraska) (using a 40 g silica gel column and 50 to 100% ethyl acetate / petroleum ether) to give 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (500 mg, 0.625 mmol, 56% yield) as a brown solid. MS (ESI) m / z: 800.4 [M+H] + . Preparation of intermediate 22: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane

[0566] CsF (0.95 g, 41.1 mmol) was added to a stirred solution of 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (0.5 g, 0.625 mmol) in DMF (5 mL). 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 a brown liquid, 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane, which was used in the next step without further purification. MS (ESI) m / z: 644.3 [M+H] + . Example 1-3 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol

[0567] At 0 °C, HCl (4 M in dioxane) (0.703 mL, 2.81 mmol) was added to a stirred solution of 4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (450 mg, 0.562 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. The volatiles of the reaction mixture were removed under reduced pressure (at a 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 obtain a grayish-white solid. The crude compound was purified by preparative HPLC [HPLC method: preparative column: YMC ExRS (20×250) 5u, mobile phase A: 10mM ammonium bicarbonate in water -9.5 pH; mobile phase B: acetonitrile; gradient = 0 (min) -50%, 2 -50%, 15 -70%, 16 -70%, 17 -100%; temperature: 27℃; flow rate: 19 mL / min; detection: UV at 220 and 254 nm] to give 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol (78 mg, 0.127 mmol, 23% yield). MS(ESI) m / z: 600.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δppm=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),2.2 5-2.14(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).

[0568] Prepare the examples in Table 1 using appropriate starting materials according to the procedure described for Example 1-1.

[0569] 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 compound was purified by preparative HPLC to obtain a pure diastereomer mixture, which was further purified by chiral HPLC or SFC as described to obtain a single diastereomer. In Examples 2-40 / 2-41, commercially available 3-cyanoperpiperidine was subjected to chiral SFC separation, and in Examples 1-114, 1-116, 1-117, 1-118, 1-138, 1-140, and 1-142, racemic fragments were synthesized and then chiral SFC separation was performed after the start of the reaction process to obtain a single diastereomer. The superscript following the example number in the table indicates which of the following chiral separation conditions was used: A) CHIRALCEL TM OJ-H (Dairuc Industries, Ltd., Japan) (250×21) mm, 5 μm; CO2%: 70%; Cosolvent%: 30%; 0.2% DEA in IPA; Total flow rate: 80.0 g / min; Back pressure: 100 bar; Temperature: 35℃; UV: 240 nm B)CHIRALPAK TM IC (Dairuc Industries, Ltd., Japan) (250×21) mm, 5 μm; CO2%: 75%; Cosolvent%: 25%; 0.2% IPA in methanol; Total flow rate: 90.0 g / min; Back pressure: 100 bar; Temperature: 35℃; UV: 220 nm C)CHIRALPAK TM IE (Dairuc Industries, Ltd., Japan) (250×30) mm, 5 μm; CO2%: 50%; Cosolvent%: 50%; 0.2% IPA in methanol; Total flow rate: 120.0 g / min; Back pressure: 100 bar; Temperature: 35℃; UV: 254 nm D)CHIRALPAK TMIE (Dairuc Industries, Ltd., Japan) (250×30) mm, 5 μm; CO2%: 70%; Cosolvent%: 30%; 0.2% IPA in methanol; Total flow rate: 150.0 g / min; Back pressure: 100 bar; Temperature: 35℃; UV: 220 nm E)CHIRALPAK TM IE (Dairuc Industries, Ltd., Japan) (250×30) 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 TM 1 (R,R) (Regis Technologies, Morton Grove, IL) (250 x 21) mm, 5 μm; CO2%: 70%; Cosolvent%: 30% of 0.2% DEA in ACN / IPA; Total flow rate: 90.0 g / min; Back pressure: 100 bar; Temperature: 35 °C; UV: 220 nm G)LUX TM Cellulose-2 (Phenomenex, Torrance, CA) (250×21.5) mm, 5 μm; CO2%: 60%; Co-solvent%: 40% 5 mM ammonium acetate in ACN:MEOH (50:50); Total flow rate: 80.0 g / min; Back pressure: 100 bar; Temperature: 35℃; UV: 220 nm H)LUX TM Cellulose-1 (Phenomenex, Torrance, CA) (250 x 21.5 mm), 5 μm; CO2%: 50%; Co-solvent%: 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 TM Cellulose-4 (Phenomenex, Torrance, CA) (250 x 21.5 mm), 5 μm; CO2%: 50%; Co-solvent%: 50% 5 mM ammonium in MEOH; Total flow rate: 70.0 g / min; Back pressure: 100 bar; Temperature: 35 °C; UV: 220 nm J)CHIRALPAK TMIG (Dairuc Industries, Ltd., Japan) (250×21) mm, 5 μm; CO2%: 75%; Cosolvent%: 25% of 0.2% ammonia in methanol; Total flow rate: 90.0 g / min; Back pressure: 100 bar; Temperature: 35℃; UV: 220 nm K)CHIRALCEL TM OD-H (Dairuc Industries, Ltd., Japan) (250×21) mm, 5 μm; CO2%: 80%; Cosolvent%: 20% of 0.2% ammonia in methanol; Total flow rate: 80.0 g / min; Back pressure: 100 bar; Temperature: 35℃; UV: 240 nm Table 1 Preparation of intermediate 116: 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0570] At 0 °C under nitrogen, tert-butyl 3-{2,7-dichloro-8-fluoropyridino[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-cyclopentadien[b]pyridin-4a-yl)methanol (2.17 g, 12.84 mmol) in THF (60 mL) were added to a stirred solution. The reaction mixture was heated to room temperature and stirred for 15 hours. 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, dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain a crude residue, which was then subjected to silica gel column chromatography using COMBIFLASH. TM Chromatography (Terry Dianesco, Lincoln, Nebraska) (120g REDISEP) TM The crude residue was purified by column chromatography (Teledyne ISCO, Lincoln, Nebraska) using 80 to 100% EtOAc-petroleum ether to give a light brown solid of 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3 g, 5.35 mmol, 46% yield). MS (ESI) m / z: 562.3 (M+H) + . Preparation of intermediate 117: 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0571] Add ((2-fluoro-6-) to a stirred solution of 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.9 g, 1.60 mmol) in 1,4-dioxane (9 mL) and water (3 mL) (2-fluoro-6-) (Methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (0.91 g, 1.76 mmol) and Cs₂CO₃ (1.57 g, 4.81 mmol) were added, followed by the addition of PdCl₂ (dppf) (dppf: 1,1'-bis(diphenylphosphino)ferrocene) (0.12 g, 0.16 mmol). The reaction mixture was purged with N₂ for 5 min and heated in a microwave reactor at 105 °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 a crude product, which was then analyzed by COMBIFLASH. TM The crude product was purified by chromatography (Terry Dionesco, Lincoln, Nebraska, Inc.) (using a 40 g silica gel column and 50 to 100% EtOAc / petroleum ether) to give a brown solid, tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.8 g, 0.88 mmol, 55% yield). MS (ESI) m / z: 911.5 [M+H] + . Preparation of intermediate 118: 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0572] CsF (1.5 g, 9.88 mmol) was added to a stirred solution of 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.9 g, 1.0 mmol) in DMF (10 mL). The reaction mixture was heated at 50 °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 a brown oily 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.7 g, 0.93 mmol, 94% yield), which was used in the next step without further purification. MS (ESI) m / z: 755.3 [M+H] + . Preparation of intermediate 119: 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol

[0573] CsF (7.42 g, 48.8 mmol) was added to a stirred solution of 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphth-1-yl]pyrido[4,3-d]pyrimidin-4-ol (3.5 g, 4.88 mmol) in DMF (40 mL). The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude compound was ground with diethyl ether to give 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-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] + ; 1 H NMR (400MHz, DMSO-d6, D2O exchange) δppm=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). Preparation of intermediate 120: 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol

[0574] Palladium / carbon (50% wet; 10.44 g, 9.81 mmol) was added to a solution of 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol (10.0 g, 17.84 mmol) in 1:2 MeOH-THF (300 mL), and the reaction mixture was stirred under hydrogen atmosphere for 4 hours. The mixture was then subjected to a diatomaceous earth mat (CELITE). TM The reaction mixture was filtered, washed with MeOH (500 mL), and the filtrate was evaporated to give a crude residue. This crude residue was ground with petroleum ether to give 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-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) + . Preparation of intermediate 121: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol

[0575] At room temperature, 6-methyl-1,4-oxazacycloheptan-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) were added to a stirred suspension of 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-ol (8.6 g, 15.23 mmol) in acetonitrile (120 mL). The reaction mixture was heated at 80 °C for 6 hours. Subsequently, the reaction mixture was 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 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue, which was then subjected to silica gel column chromatography using COMBIFLASH. TM Instrument (120g REDISEP)TM The crude residue was purified by column chromatography (Teledyne ISCO, Lincoln, Nebraska) in petroleum ether (60-100% EtOAc) to give 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol (6.2 g, 9.15 mmol, 60.1% yield) as a brown solid. MS (ESI) m / z: 678.3 [M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ ppm=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). Preparation Example 1-134: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol

[0576] At 0 °C, EtOAc (100 mL, 100 mmol) containing 1 M HCl was added to a stirred solution of 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol (4.5 g, 6.64 mmol) in EtOAc (90 mL). The reaction mixture was stirred for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to obtain 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 a saturated aqueous solution of NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue, which was then subjected to silica gel column chromatography using COMBIFLASH. TM Instrument (80g REDISEP) TM The crude residue was purified by column chromatography (Teledyne ISCO, Lincoln, Nebraska) in DCM at 4–7% MeOH to give a grayish-white solid, 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol (3.5 g, 5.43 mmol, 82% yield). MS (ESI) m / z: 634.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δppm=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). Preparation of intermediate 23: 3-(7-bromo-2-chloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0577] DIPEA (26.6 mL, 152 mmol) was added 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), followed by the addition of 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 text abruptly ends here, so the translation stops as well.) TM The crude compound was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) (120 g silica gel column, using 50 to 80% ethyl acetate / petroleum ether) to give tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazoline-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] + . Preparation of intermediate 24: 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0578] At 0 °C, NaH (0.194 g, 4.85 mmol, 60 w / w%) was added to a solution of 3-(7-bromo-2-chloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.95 g, 24.80 mmol) in THF (45 mL), and the reaction mixture was stirred at the same temperature for 1 hour. At 0 °C, 3-(7-bromo-2-chloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (9 g, 19.08 mmol) was added part-by-part (4 parts) to this reaction mixture. The reaction mixture was heated to room temperature and stirred for 16 hours. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (250 mL x 2). The organic layer was washed with a brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue, which was then subjected to COMBIFLASH.TM The crude residue was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) (240 g column, 80-100% EtOAc in petroleum ether) to give 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-bromo-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.5 g, 10.93 mmol, 57% yield). MS (ESI) m / z: 594.5 (M+2) + . Preparation of intermediate 25: 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0579] Add ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (6.90 g, 13.46 mmol) and 2M tripotassium phosphate aqueous solution (20.18 mL, 40.4 mmol) to a stirred solution of 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-bromo-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (intermediate 24.8 g, 13.46 mmol) in 1,4-dioxane (100 mL) to a stirred solution. The reaction mixture was degassed under argon for 5 minutes, followed by the addition of [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (0.877 g, 1.346 mmol), and degassed again under argon for 3 minutes. The mixture was then 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 obtain a crude residue, which was then subjected to COMBIFLASH. TMThe crude residue was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) (80 g silica gel column, using 50 to 100% ethyl acetate / petroleum ether) to give 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (7.5 g, 7.25 mmol, 54% yield) as a brown solid. MS (ESI) m / z: 900.4 [M+H] + . Preparation of intermediate 26: 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0580] CsF (6.24 g, 41.1 mmol) was added to a stirred solution of 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 25, 3.7 g, 4.11 mmol) in DMF (50 mL). The reaction mixture was heated at 50 °C for 1 h. 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 a crude product, 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.9 g, 3.89 mmol, 95% yield), which was used in the next step without further purification. MS (ESI) m / z: 744.3 [M+H] + . Preparation of intermediate 27: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazolin-4-ol

[0581] To a stirred solution of the crude product 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3(methoxymethoxy)naphth-1-yl]-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 26, 3 g, 4.03 mmol) in EtOH (15 mL) and THF (15 mL), NaOH (1 M aqueous solution) (40.3 mL, 40.3 mmol) was added. The reaction mixture was heated at 70 °C for 3 hours. The reaction mixture was evaporated, and the residue was diluted with ethyl acetate. The organic layer was washed with saturated NH4Cl solution, water, and brine, and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give the crude compound, which was then analyzed by COMBIFLASH. TM The crude compound was purified by chromatography (Terry Dionesco, Lincoln, Nebraska) (24 g silica gel column, 10-20% MeOH / DCM) to give 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazoline-4-ol (850 mg, 1.544 mmol, 38.3% yield) as a brown solid. MS (ESI) m / z: 550.2 [M+H] + . Preparation of intermediate 28: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(morpholin-4-yl)quinazolin

[0582] Morpholine (3.8 mg, 0.044 mmol), triethylamine (0.020 mL, 0.146 mmol), and BOP (24.4 mg, 0.055 mmol) were added to a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazoline-4-ol (intermediate 27, 20 mg, 0.036 mmol) in ACN (1 mL). 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, followed by brine, and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a crude product, 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(morpholin-4-yl)quinazoline (25 mg, crude product), which was used in the next step without further purification. MS (ESI) m / z: 619.3 [M+H] + . Example 2-1: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol

[0583] At 0 °C, 4N HCl (2 mL, 65.83 mmol in 1,4-dioxane) was added to a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(morpholin-4-yl)quinazoline (intermediate 28, 200 mg, 0.323 mmol) in ACN (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. The volatiles of the reaction mixture were removed under reduced pressure (at a 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), and TEA (1 mL) was added, followed by evaporation under reduced pressure to give a grayish-white solid. The crude compound was purified by preparative HPLC [HPLC method: preparative column: YMC EXRS (250×20×5 μm), mobile phase A: 10 mM ammonium bicarbonate in water -9.5; mobile phase B: acetonitrile:methanol; gradient = 60-100% B for 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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol (11.9 mg, 0.020 mmol, 6.8% yield). MS (ESI) m / z: 575.1, [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm=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=2.3H z,1H),5.38-5.19(m,1H),4.13-4.08(m,1H),4.01(dd,J=10.4,4.4Hz,1H),3.88-3.7 2(m,9H),3.16-3.00(m,3H),2.88-2.78(m,1H),2.19-1.97(m,3H),1.88-1.73(m,3H). Preparation of intermediate 29: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(1,4-oxazetane-4-yl)quinazolino

[0584] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazoline-4-ol (intermediate 27, 300 mg, 0.546 mmol) in ACN (10 mL), 1,4-oxazacycloheptane (60.7 mg, 0.600 mmol), DIPEA (0.286 mL, 1.635 mmol), and BOP (362 mg, 0.817 mmol) were added. 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 a crude residue. The residue was then analyzed by COMBIFLASH. TM Chromatography (Terry Dianesco, Lincoln, Nebraska) (40g REDISEP) TM The crude compound was purified by column chromatography (Teledyne ISCO, Lincoln, Nebraska) using a gradient of 60-100% EtOAc / petroleum ether to give a brown liquid 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(1,4-oxazetane-4-yl)quinazoline (300 mg, 0.474 mmol, 87% yield). MS (ESI) m / z: 633.3 [M+H] + . Example 2-2: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazolidinyl-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol

[0585] At 0 °C, HCl (4 M in dioxane) (0.15 mL, 4.74 mmol) was added to a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(1,4-oxazetane-4-yl)quinazoline (intermediate 29, 300 mg, 0.474 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. The volatiles of the reaction mixture were removed under reduced pressure (at a 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 obtain the crude residue. The crude compound was purified by preparative HPLC [HPLC method: column: YMC ExRS (20×250) 5u; mobile phase A: 10mM ammonium bicarbonate in H2O, pH 9.5; mobile phase B: ACN; flow rate: 19mL / min; gradient T / % B: 0 / 50, 2 / 50; 15 / 70; 16 / 100, to give 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-(1,4-oxazolidinyl-heptane-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthol (59.02 mg, 0.098 mmol, 21% yield). MS (ESI) m / z: 589.40 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.23-10.08(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). Preparation of intermediate 30: 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-bromo-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0586] At 0 °C under nitrogen, tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazoline-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-cyclopentadieno[b]pyridin-4a-yl)methanol (intermediate 12, 1.1 g, 6.59 mmol) in THF (25 mL) were added to a stirred solution. The reaction mixture was heated to room temperature and stirred for 15 hours. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain a crude residue, which was then subjected to silica gel column chromatography using COMBIFLASH. TM Chromatography (Terry Dianesco, Lincoln, Nebraska) (120g REDISEP) TM The crude residue was purified by column chromatography (Teledyne ISCO, Lincoln, Nebraska) using 80 to 100% EtOAc-petroleum ether to give a pale yellow solid of 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-bromo-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.5 g, 4.14 mmol, 75% yield). MS (ESI) m / z: 604.2 (M+H) + . Preparation of intermediate 31: 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphth-1-yl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0587] Add ((2-fluoro-6-(methoxy)) to a degassed, stirred solution of 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 30, 2.5 g, 4.14 mmol) in 1,4-dioxane (50 mL) Methoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (2.119 g, 4.14 mmol) and 2M tripotassium phosphate aqueous solution (6.20 mL, 12.41 mmol) were added, followed by the addition of [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.135 g, 0.207 mmol). The reaction mixture was purged with N2 for 5 min and heated at 50 °C for 18 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 the crude product, which was then analyzed by COMBIFLASH. TM The crude product was purified by chromatography (Terry Dionesco, Lincoln, Nebraska) (using an 80 g silica gel column and 50 to 100% ethyl acetate / petroleum ether) to give 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.0 g, 3.30 mmol, 80% yield) as a brown solid. MS (ESI) m / z: 911.2 [M+H] + . Preparation of intermediate 32: 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0588] Cesium fluoride (5.01 g, 33.0 mmol) was added to a stirred solution of 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl-1-yl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 31, 3.0 g, 3.30 mmol) in DMF (30 mL), and the mixture was heated at 50 °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 a brown liquid, 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.2 g, 2.92 mmol, 89% yield), which was used in the next step without further purification. MS (ESI) m / z: 754.3 [M+H] + Preparation of intermediate 33: 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadien[b]pyridin-4a-yl]methyl ⇌}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazoline-4-ol

[0589] To a stirred solution of 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 32, 2.2 g, 2.92 mmol) in ethanol (20 mL) and THF (20 mL), NaOH (29.2 mL, 29.2 mmol) was added, and the mixture was stirred at 80 °C for 36 hours. The reaction mixture was then diluted with EtOAc (100 mL) and washed with 0.5 N HCl aqueous solution (150 mL × 3). The aqueous layer was prepared alkaline (pH approximately 8) with solid NaHCO3 and extracted with EtOAc (3X). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude compound, which was then analyzed by COMBIFLASH. TMThe crude compound (Terry Dionesco, Lincoln, Nebraska) was purified by chromatography (40 g silica gel column, 10-20% MeOH / DCM) to give 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazoline-4-ol (1.5 g, 2.68 mmol, 92% yield) as a brown solid. MS (ESI) m / z: 560.2 [M+H] + . Preparation of intermediate 34: 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)quinazolino

[0590] To a stirred solution of 2-{[(4aS)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3,3-bis(methoxymethoxy)naphth-1-yl]-8-fluoroquinazoline-4-ol (intermediate 33, 255 mg, 0.447 mmol) in ACN (5 mL), 1,4-oxazacycloheptane (54.2 mg, 0.536 mmol), DIPEA (0.234 mL, 1.340 mmol), and BOP (296 mg, 0.670 mmol) were added. 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 a crude residue, which was then subjected to COMBIFLASH. TM Chromatography (Terry Dianesco, Lincoln, Nebraska) (40g REDISEP) TM The crude compound was purified by column chromatography (Teledyne ISCO, Lincoln, Nebraska) using a gradient of 60-100% EtOAc / petroleum ether to give a brown liquid (2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)quinazoline (211 mg, 73% yield). MS (ESI) m / z: 643.4 [M+H] + . Example 2-3: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol

[0591] At 0°C, 4N was added to a stirred solution of (2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoro-4-(1,4-oxazacycloheptane-4-yl)quinazoline (intermediate 34, 330 mg, 0.521 mmol) in acetonitrile (5 mL). 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. The volatiles of the reaction mixture were removed under reduced pressure (at a 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 a grayish-white solid. The crude compound was purified by the following preparative HPLC method: [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 minutes; flow rate: 1.1 mL / min. Injection 2 conditions: column: Waters XBridge BEH...] C18 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%-100% B, over 3 min; Flow rate: 1.1 mL / min, yielding 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazolidinyl-4-yl)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol (28 mg, 0.047 mmol, 9% yield). MS (ESI) m / z: 599.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δppm=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).

[0592] Prepare the examples in Table 2 using appropriate starting materials according to the procedure described for Example 2-1. Table 2 Preparation of intermediate 35: 3-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0593] DIPEA (0.476 mL, 2.72 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (193 mg, 0.908 mmol) were added to a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300 mg, 3.03 mmol) in dioxane (8 mL). The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a 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 solution was analyzed by COMBIFLASH. TMThe residue was purified by chromatography (Terry Dion Isco, Lincoln, Nebraska) (12 g, ISCO column, MeOH / DCM, 0-5%, 20 min) to give tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazoline-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) δppm = 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), 1.47s, 9H). Preparation of intermediate 36: 3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0594] Cesium fluoride (5.25 g, 34.6 mmol) was added to a degassed solution of 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 35, 1 g, 3.03 mmol) in DMA (80 mL). The reaction mixture was degassed with nitrogen for 10 min and heated in a sealed tube at 88 °C for 5 h. Water (200 mL) and ethyl acetate (150 mL) were added, and the reaction mixture was stirred for 15 min. The separated aqueous layer was extracted with ethyl acetate (2 x 100 mL), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The solution was analyzed by COMBIFLASH. TM Chromatography (Triadian Isco, Lincoln, Nebraska) purified the residue using 15-25% ethyl acetate / 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] + . Preparation of intermediate 37: 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-carboxylic acid tert-butyl ester

[0595] To a degassed solution of 3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 36, 2.00 g, 4.08 mmol) in anhydrous 1,4-dioxane (20 mL), potassium phosphate (1.73 g, 8.17 mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyl-2-yl)pyridine-2-amine (5.8 g, 12.25 mmol) and PdCl2 (dppf) (149 mg, 0.204 mmol) were added. The reaction mixture was degassed again and heated at 80 °C for 48 hours. After the reaction was complete, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (40 mL), and passed through a diatomaceous earth bed (CELITE). TM The crude product was obtained by filtration and concentration under reduced pressure by Sigma-Aldrich, St. Louis, Missouri. It was then processed using a COMBIFLASH filter. TM The residue was purified by chromatography (Terry Dionesco, Lincoln, Nebraska) using 30% ethyl acetate / 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): δppm=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), 4.6 0(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] + . Preparation of intermediate 38: 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-carboxylic acid tert-butyl ester

[0596] Under nitrogen atmosphere at 0 °C, N-iodosuccinimide (0.42 g, 1.849 mmol) and trifluoroacetic acid (0.028 mL, 0.370 mmol) were added to a stirred solution of 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-carboxylic acid tert-butyl ester (intermediate 37, 1.40 g, 1.849 mmol) in anhydrous ACN (15 mL). The reaction mixture was allowed to reach room temperature for one hour. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate solution (5 mL) and saturated aqueous sodium bicarbonate solution (4 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a crude residue. (The solution was then analyzed using COMBIFLASH.) TM Chromatography (Terry Dion Esco, Lincoln, Nebraska) purified the crude residue using 30% ethyl acetate / 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 flocculent solid. LCMS (ESI) m / z: 883.3 [M+H] + . Preparation of intermediate 39: 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0597] Under nitrogen atmosphere in a sealed tube, copper iodide (I) (0.60 g, 3.17 mmol) was added to a stirred solution of 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). The reaction mixture was degassed for 10 min, followed by the addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.91 g, 4.76 mmol) and heating at 90 °C for 12 h. 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 obtain a crude residue. This residue was then processed using COMBIFLASH. TM The crude compound was purified by chromatography (Terry Dionesco, Lincoln, Nebraska) using 30% ethyl acetate / 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): δppm=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] + . Intermediates 40A and 40B: 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] tert-butyl octane-8-carboxylate

[0598] Intermediate 39 (5.0 g, 6.06 mmol) underwent SFC separation (column: CHIRALPAK). TMIH (Dairuc Industries, Ltd., Japan) (250 mm × 4.6 mm; 5 μm), mobile phase: 0.25% isopropanol), wherein 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 (40A): 1 H NMR (400MHz, CDCl3): δppm=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) 1 H NMR (400MHz, CDCl3): δppm=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. Preparation of intermediate 41: 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0599] At 0 °C, NaH (0.194 g, 4.85 mmol) was added to a solution of [(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methanol (intermediate 40B, 0.205 g, 1.212 mmol) in 5 mL of THF, and the mixture was stirred at room temperature for 30 min. At 0 °C, (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1 g, 1.212 mmol) was added to this mixture, and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice and concentrated under reduced pressure. The crude product was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate, filtered, and concentrated to obtain a crude product, which was then subjected to COMBIFLASH. TM Chromatography (Terry Dianesco, Lincoln, Nebraska) (24g REDISEP) TM The crude product was purified by column chromatography (Teledyne ISCO, Lincoln, Nebraska) from 0 to 10% MeOH-DCM to give 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.70 g, 0.718 mmol, 59.3% yield). MS (ESI) m / z: 974.4 (M+H) + . Preparation of intermediate 42: 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazoline-4-ol

[0600] Sodium hydroxide (1M aqueous solution) (3.08 mL, 3.08 mmol) was added to a stirred solution of 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 41, 300 mg, 0.308 mmol) in EtOH (4 mL), THF (4 mL). 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, and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound, which was then subjected to COMBIFLASH. TM The crude compound was purified by chromatography (Terry Dionesco, Lincoln, Nebraska) (24 g silica gel column, 10-20% MeOH / DCM) to give 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazoline-4-ol (110 mg, 0.141 mmol, 45.8% yield) as a brown solid. MS (ESI) m / z: 780.5 [M+H] + . Preparation of intermediate 43: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]oct-3-yl}quinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0601] Add (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) to a stirred solution of 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazoline-4-ol (intermediate 42, 20 mg, 0.026 mmol) in ACN (1 mL) to a stirred solution. Heat the reaction mixture at 80 °C for 8 hours. Evaporate the reaction mixture and dilute the residue 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 a crude product, 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]oct-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), which was used in the next step without further purification. MS (ESI) m / z: 875.3 [M+H] + . Example 3-1: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]oct-3-yl}quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0602] At 0 °C, triethylsilane (10.95 μl, 0.069 mmol) was added to a stirred solution of 6-(4-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[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), and the reaction mixture was stirred at 40 °C for 16 h. The volatiles of the reaction mixture were removed under reduced pressure (at a lower temperature, about 30 °C), and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane and triethylamine was added, followed by evaporation under reduced pressure to obtain a grayish-white solid. The crude material was purified by preparative LC / MS under the following conditions: column: Waters XBridge C18, 19 × 150 mm, 5 μm particles; mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 15–42% B for 23 min, followed by holding at 100% B for 5 min; flow rate: 20 mL / min, yielding 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]oct-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) δppm=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). Example 4-1: Preparation intermediate 44 of 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethylnaphthyl-2-phenol: 8-((triisopropylsilyl)ethynyl)naphth-1,3-diol

[0603] Under a nitrogen atmosphere, 7.65 g (12.49 mmol) of dichloro(p-isopropyltoluene)ruthenium(II) dimer was added 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). The mixture was stirred at 110 °C for 12 hours. The reaction mixture was cooled to ambient temperature and subjected to diatomaceous earth (CELITE) treatment. TM Filtered by Sigma-Aldrich, St. Louis, Missouri. Washed bed with EtOAc (2 × 100 mL), filtrates combined and concentrated under reduced pressure to give crude residue. Purified crude by rapid column chromatography (silica 100-200 mesh) using 12-15% ethyl acetate / petroleum ether as eluent. Concentrated the pure fraction 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] + . Preparation of intermediate 45: 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-phenol

[0604] DIPEA (38.5 mL, 220 mmol) was added to a stirred solution of 8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (intermediate 44, 25 g, 73.4 mmol) in anhydrous DCM (300 mL) at -10 °C under nitrogen atmosphere. After 10 minutes, MOM-Cl (6.13 mL, 81 mmol) was added dropwise to the reaction mixture over a nitrogen atmosphere for 20 minutes. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with 100 mL of DCM and washed with 200 mL of brine. The combined organic matter was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by rapid column chromatography (silica 100-200 mesh) using 5-10% ethyl acetate / petroleum ether as eluent. The fraction was concentrated under reduced pressure to give 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-phenol (21 g, 53.5 mmol, 72.9% yield), a pale yellow oil. LCMS (ESI) m / z: 385.60 [M+H] + . Preparation of intermediate 46: 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl ester of pivalic acid

[0605] Under a nitrogen atmosphere at -10°C, tervapotranol (12.80 mL, 104 mmol) was added dropwise to a stirred solution of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-phenol (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) for 10 minutes. The 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 200 mL of brine. The organic matter was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude residue. The crude product was purified by rapid column chromatography (silica 100-200 mesh) using 10-15% ethyl acetate / petroleum ether as eluent. The fraction was concentrated under reduced pressure to give 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl ester of pivalic acid (23 g, 49.1 mmol, 94% yield), a pale yellow oil. LCMS (ESI) m / z: 469.2 [M+H] + . Preparation of intermediate 47: 8-ethynyl-3-(methoxymethoxy)naphthalene-1-yl ester of pivalic acid

[0606] Anhydrous CsF (27.2 g, 179 mmol) was added to a stirred solution of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl ester of pivalic acid (intermediate 46, 12 g, 25.6 mmol) in anhydrous DMF (130 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours. The reaction mixture was diluted with DCM (200 mL) and washed with brine (200 mL). The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The crude product was purified by rapid column chromatography (silica 100-200 mesh) using 5-8% ethyl acetate / petroleum ether as eluent. The purified fraction was concentrated under reduced pressure to give 8-ethynyl-3-(methoxymethoxy)naphth-1-yl ester of pivalic acid (7 g, 20.62 mmol, 81% yield). LCMS(ESI) m / z: 313.3 [M+H] + . Preparation of intermediate 48: 8-ethyl-3-methoxymethoxy)naphthalene-1-yl ester of pivalic acid

[0607] Pd / C (1.4 g, 13.16 mmol) was added to a stirred solution of 8-ethynyl-3-(methoxymethoxy)naphth-1-yl pivalate (intermediate 47.7 g, 22.41 mmol) in anhydrous methanol (70 mL) at 25 °C. The suspension was degassed under reduced pressure and purified several times with H2. The mixture was stirred for 5 hours at 25 °C under an H2 atmosphere (1 atm). The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude residue. The crude substance was purified by rapid column chromatography (silica 100 to 200 mesh) using 15-20% ethyl acetate / petroleum ether as eluent. The purified fraction was concentrated under reduced pressure to give 8-ethyl-3-(methoxymethoxy)naphth-1-yl pivalate (6.56 g, 17.83 mmol, 80% yield) as a pale yellow oil. LCMS (ESI) m / z: 316.1 [M+H] + . Preparation of intermediate 49: 8-ethyl-3-(methoxymethoxy)naphthol-1-phenol

[0608] Anhydrous LiOH (1.135 g, 47.4 mmol) was added to a stirred solution of 8-ethyl-3-(methoxymethoxy)naphth-1-yl ester of pivalic acid (intermediate 48, 10 g, 31.6 mmol) in THF:water:MeOH (5:1:5) at room temperature under nitrogen. 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 matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The crude substance was purified by rapid column chromatography (silica 100-200 mesh) using 25-30% ethyl acetate / petroleum ether as eluent. The purified fraction was concentrated under reduced pressure to give 8-ethyl-3-(methoxymethoxy)naphth-1-phenol (6 g, 25.8 mmol, 82% yield). LCMS(ESI) m / z: 233.2 [M+H] + . Preparation of intermediate 50: 8-ethyl-3-(methoxymethoxy)naphthalene-1-yl trifluoromethanesulfonic acid ester

[0609] Under nitrogen atmosphere at -40°C, Tf₂O (2.182 mL, 12.92 mmol) was added dropwise to a stirred solution of 8-ethyl-3-(methoxymethoxy)naphthol (intermediate 49, 3 g, 12.92 mmol) and DIPEA (22.50 mL, 129 mmol) in anhydrous dichloromethane (50 mL). The resulting reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was diluted with cold water (500 mL) and extracted with DCM (2 x 500 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude residue. The crude compound was purified by rapid column chromatography (silica gel 100-200) using 5-10% ethyl acetate / petroleum ether as eluent. The fraction was concentrated under reduced pressure to give 8-ethyl-3-(methoxymethoxy)naphthalene-1-yl trifluoromethanesulfonic acid (3.5 g, 9.03 mmol, 69.9% yield), a pale yellow oil. LCMS (ESI) m / z: 365.3 [M+H] + . Preparation of intermediate 51: 2-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[0610] Bispinacolatoborane (12.89 g, 50.8 mmol) and potassium acetate (5.98 g, 60.9 mmol) were added to a stirred solution of 8-ethyl-3-(methoxymethoxy)naphth-1-yl trifluoromethanesulfonate (intermediate 50, 7.4 g, 20.31 mmol) in 1,4-dioxane (80 mL). The mixture was degassed and purged with nitrogen for 5 min, and PdCl2 (dppf) (1.659 g, 2.031 mmol) was added. The mixture was stirred at 100 °C under nitrogen for 3 h. 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 Na2SO4, and concentrated under reduced pressure to give a crude residue. The crude product was purified by rapid column chromatography (silica 100-200 mesh) using 2-4% ethyl acetate / petroleum ether as eluent. The purified fraction was concentrated under reduced pressure to give a brown gel, which was further purified by reversed-phase column chromatography using 80% acetonitrile / 0.01% ammonium formate aqueous solution as eluent. The purified fraction was concentrated under reduced pressure to give 2-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (4.5 g, 13.10 mmol, 64.5% yield). LCMS (ESI) m / z: 344.2 [M+H] + . 1 H-NMR (400MHz, CDCl3): δ7.62(dd,J=0.80,8.00Hz,1H),7.36-7.44(m,3H),7.27(t,J=0.40Hz,1 H), 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. Preparation of intermediate 52: (1R,5S)-3-(7-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0611] At 50 °C and under nitrogen, a mixture of intermediate 30 (550 mg, 0.910 mmol), 2-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (327 mg, 0.955 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (29.6 mg, 0.045 mmol), and 2.0 M tripotassium phosphate (1365 μl, 2.73 mmol) in dioxane (1 mL) was stirred 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 preparative HPLC (ISCO C18 100g column, flow rate = 60 mL / min, gradient = 40% A to 100% B over 20 min, A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)). The pure fraction was separated and concentrated. The mixture was diluted with EtOAc (25 mL) and washed with saturated sodium carbonate aqueous solution (25 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to give (1R,5S)-3-(7-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (550 mg, 0.706 mmol, 78% yield), which was a light brown foam. MS (ESI) m / z: 740.3 [M+H] + . Preparation of intermediate 53: 7-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)quinazolin-4-ol

[0612] At 60 °C, a mixture of (1R,5S)-3-(7-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 52, 550 mg, 0.743 mmol), 1.0 M sodium hydroxide (7433 μl, 7.43 mmol), and EtOH (25 mL) was stirred 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 preparative HPLC (ISCO C18 100g column, flow rate = 60 mL / min, gradient = 20% A to 100% B over 20 min, A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)). The pure fraction was separated and concentrated. The mixture was diluted with EtOAc (15 mL) and washed with saturated aqueous sodium carbonate solution (15 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to give 7-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadien[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] + . Example 4-1: 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethylnaphthyl-2-phenol

[0613] BOP (24.32 mg, 0.055 mmol) was added to a solution of 7-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[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), and the mixture was stirred at 60 °C for 18 hours. The mixture was concentrated to give the crude product 4-(7-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[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)naphth-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[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 then concentrated. The crude product was purified by preparative HPLC (Phenomenex, Luna 5 μm, 30 × 100 mm, flow rate = 40 mL / min, gradient = 0% A to 100% B over 12 min, A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)). The purified fraction was loaded onto an Oasis MCX cationic mixed-mode polymer filter cartridge (150 mg), washed with methanol (30 mL), and eluted with 0.1 N ammonia / methanol (5.0 mL). The ammonia eluent was concentrated. The purified product was lyophilized with ACN / H₂O (1:1, 5 mL) to give 5-ethyl-4-(8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopentadieno[b]pyridin-4a-yl)methoxy)-4-(N-morpholinyl)quinazolin-7-yl)naphthol (11.75 mg, 0.019 mmol, 50.6% yield) as a white powder. MS (ESI) m / z: 571.4 [M+H] + . 1H NMR (499MHz, methanol-d4) δ7.83(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,3 H), 1.96 (brdd, J = 10.8, 5.3Hz, 1H), 1.91-1.68 (m, 8H), 1.65-1.54 (m, 1H), 0.91-0.85 (m, 3H). Preparation of intermediate 54: (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazolin-4- (2,2,1)-2,5-diazabicyclo[2.2.1]hepta-3-one

[0614] To a stirred solution of 2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3,3-bis(methoxymethoxy)naphth-1-yl]-8-fluoroquinazoline-4-ol (30 mg, 0.054 mmol) in ACN (1 mL), (1S,4S)-2,5-diazabicyclo[2.2.1]hepta-3-one (6.61 mg, 0.059 mmol), DIPEA (0.0286 mL, 0.164 mmol), and BOP (35.6 mg, 0.080 mmol) were added. 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 obtain a crude residue. This residue was then processed using COMBIFLASH. TM Chromatography (Terry Dianesco, Lincoln, Nebraska) (40g REDISEP) TMThe crude material was purified using a column (Teledyne ISCO, Lincoln, Nebraska) with a gradient of 60-100% EtOAc / petroleum ether. Evaporation of the fraction containing the desired product yielded (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazoline-4-yl)-2,5-diazabicyclo[2.2.1]hepta-3-one (30 mg, 0.046 mmol, 86% yield). MS (ESI) m / z: 654.3 [M+H] + . Example 5-1: (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]hepta-3-one

[0615] At 0 °C, 4N HCl (4M in dioxane) (0.115 mL, 0.459 mmol) was added to a stirred solution of (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]hepta-3-one (30 mg, 0.046 mmol) in acetonitrile (1 mL) (0.115 mL, 0.459 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The volatiles of the reaction mixture were removed under reduced pressure (at a lower temperature, about 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 then concentrated under reduced pressure to give a grayish-white solid. The crude compound was purified by the following preparative HPLC [HPLC method: column: CHIRALPAK]. TMIC (Dairuc Industries, Ltd., 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], yielding a grayish-white solid (1S,4S)-5-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]hepta-3-one (4.1 mg, 6.72 μmol, 14.65% yield). MS (ESI) m / z: 610.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm=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). Preparation of intermediate 56: 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0616] CsF (6.24 g, 41.1 mmol) was added to a stirred solution of 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphthyl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.7 g, 4.11 mmol) in DMF (50 mL). 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 a brown liquid, 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.9 g, 3.89 mmol, 95% yield), which was used in the next step without further purification. MS (ESI) m / z: 746.6 [M+H] + . Preparation of intermediate 57: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl 6-Fluoronaphth-2-phenol

[0617] At 0 °C, dioxane (0.29 mL, 9.40 mmol) containing 4 M HCl was added to a solution of 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (700 mg, 0.940 mmol) in acetonitrile (5 mL), and the mixture was stirred for 1 hour. 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, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol (300 mg, 0.50 mmol, 53% yield). MS (ESI) m / z: 601.3 [M+H] + . Example 6-1: 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoroethyl-1-one

[0618] At 0 °C, TEA (0.035 mL, 0.250 mmol) and TFAA (0.018 mL, 0.125 mmol) were added to a solution of 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoropyridino[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol (50 mg, 0.083 mmol) in DCM (2 mL), and the mixture was stirred for 1 hour. 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 preparative HPLC as follows: [HPLC method: preparative column: YMC] ExRS(20×250) 5u, mobile phase A: 10mM ammonium bicarbonate in water -9.5pH; mobile phase B: acetonitrile:MeOH (1:1); gradient = 0 (min) -60%, 2 -65%, 15 -85%, 16 -70%, 17 -100%; temperature: 27℃; flow rate: 19mL / min; detection: UV at 220 and 254nm], to obtain 1-[3-( 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoroethyl-1-one (15 mg, 0.019 mmol, 23% yield). MS (ESI) m / z: 697.2, [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm=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).

[0619] Prepare the examples in Table 3 using appropriate starting materials according to the procedure described for Example 6-1. Table 3 Preparation of intermediate 58: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-bromo-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazolino

[0620] At 0 °C, DIPEA (0.16 mL, 0.910 mmol) and a solution of propylphosphonic anhydride in EtOAc (0.4 mL, 0.61 mmol) were added to a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-bromo-4-{3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoroquinazoline (150 mg, 0.303 mmol) in DCM (10 mL). After stirring at 0 °C for 15 min, 4,4-difluorocyclohexane-1-carboxylic acid (54.8 mg, 0.33 mmol) was added, and the reaction mixture was heated to room temperature and stirred for 16 h. The reaction mixture was then extracted with EtOAc(2X), washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-bromo-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazoline (120 mg, 0.18 mmol, 53% yield). MS (ESI) m / z: 642.2 (M+2) + . Preparation of intermediate 59: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphth-1-yl]quinazolin

[0621] Add ((2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-bromo-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazoline (100 mg, 0.156 mmol) and 2M tripotassium phosphate aqueous solution (0.23 mL, 0.468 mmol) to a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-7-bromo-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazoline (100 mg, 0.156 mmol) in 1,4-dioxane (5 mL) to a stirred solution. The reaction mixture was degassed under argon for 5 minutes, followed by the addition of [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) chloride (10.2 g, 0.016 mmol), and the mixture was again degassed under argon for 3 minutes, followed by heating at 50 °C for 16 hours. 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, which was then subjected to COMBIFLASH. TM The residue was purified by chromatography (Terry Dionesco, Lincoln, Nebraska) (12 g silica gel column, using 2-5% MeOH in DCM) to give a brown solid 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphth-1-yl]quinazoline (126 mg, 0.133 mmol, 85% yield). MS (ESI) m / z: 946.4 [M+H] + . Preparation of intermediate 60: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazolino

[0622] CsF (202 mg, 1.33 mmol) was added to a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(prop-2-yl)silyl]ethynyl}naphth-1-yl]quinazoline (126 mg, 0.133 mmol) in DMF (5 mL). 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 a light brown liquid, 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-8-fluoroquinazoline (99 mg, 0.125 mmol, 94% yield), which was used directly in the next step without purification. MS (ESI) m / z: 790.3 [M+H] + . Example 7-1: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol

[0623] At 0 °C, dioxane (5 mL, 2.51 mmol) containing 4 M HCl was added to a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]-8-fluoroquinazoline (99 mg, 0.125 mmol) in acetonitrile (5 mL), and the mixture was stirred for 2 hours. The volatiles of the reaction mixture were removed under reduced pressure, and the crude residue was evaporated along with the 1,4-dioxane. Subsequently, the crude residue was dissolved in 1,4-dioxane (2 mL) and excess TEA (1 mL) was added. The mixture was concentrated under reduced pressure to give a grayish-white solid. The crude compound was purified using the following preparative HPLC method [Waters XBridge C18 (Waters Corp., Milford, CT), (250 mm × 19 mm, 5 μm particles); mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water containing 10 mM ammonium acetate; gradient: hold at 15% B for 0 min, 15%–55% B for 25 min, then at 100% B. B. Hold at 5 min; flow rate: 20 mL / min; detection: UV at 220 and 254 nm. This yielded a grayish-white solid, 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazoline-7-yl)-5-ethynyl-6-fluoronaphthyl-2-phenol (8.7 mg, 0.012 mmol, 9% yield). MS (ESI) m / z: 746.3 [M+H]. + .

[0624] Prepare the examples in Table 4 using appropriate starting materials according to the procedures described for Examples 6-1 and 7-1. Table 4 Preparation of intermediate 61: 3-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0625] DIPEA (0.476 mL, 2.72 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (193 mg, 0.908 mmol) were added to a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300 mg, 3.03 mmol) in dioxane (8 mL). The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a 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 solution was analyzed by COMBIFLASH. TM The residue was purified by chromatography (Terry Dion Isco, Lincoln, Nebraska) (12 g, ISCO column, MeOH / DCM, 0-5%, 20 min) to give tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazoline-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] + . 1 H NMR (499MHz, DMSO-d6) δppm = 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), 1.47s, 9H). Preparation of intermediate 62: 3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0626] Cesium fluoride (5.25 g, 34.6 mmol) was added to a degassed solution of 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 35, 1 g, 3.03 mmol) in DMA (80 mL). The reaction mixture was degassed with nitrogen for 10 min and heated in a sealed tube at 88 °C for 5 h. Water (200 mL) and EtOAc (150 mL) were added, and the reaction mixture was stirred for 15 min. The separated aqueous layer was extracted with EtOAc (2 x 100 mL), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by the following: COMBIFLASH TMChromatography (Terry Dion Esco, Lincoln, Nebraska), using 15-25% EtOAc / petroleum ether as eluent, yielded a pale yellow solid of tert-butyl 3-(7-bromo-6-chloro-2,8-difluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.7 g, 8.77 mmol, 63.4% yield). MS (ESI) m / z 489.0 [M+1] + . Preparation of intermediate 63: 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-carboxylic acid tert-butyl ester

[0627] To a degassed solution of 3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate 36, 2.00 g, 4.08 mmol) in anhydrous 1,4-dioxane (20 mL), potassium phosphate (1.73 g, 8.17 mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridine-2-amine (5.8 g, 12.25 mmol) and PdCl2 (dppf) (149 mg, 0.204 mmol) were added. The reaction mixture was degassed again and heated at 80 °C for 48 hours. After the reaction was complete, the reaction mixture was cooled to ambient temperature, diluted with EtOAc (40 mL), and purified by CELITE. TM The crude product was obtained by bed filtration (Sigma-Aldrich, St. Louis, Missouri) and concentration under reduced pressure. The residue was purified by the following: COMBIFLASH TM Chromatography (Terry Dionesco, Lincoln, Nebraska) using 30% EtOAc / petroleum ether yielded 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-carboxylic acid tert-butyl ester (1.5 g, 1.74 mmol, 42% yield). 1H NMR (400MHz, CDCl3): δppm=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), 4.6 0(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] + . Preparation of intermediate 64: 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-carboxylic acid tert-butyl ester

[0628] Under nitrogen atmosphere at 0 °C, N-iodosuccinimide (0.42 g, 1.849 mmol) and trifluoroacetic acid (0.028 mL, 0.370 mmol) were added to a stirred solution of 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-carboxylic acid tert-butyl ester (intermediate 37, 1.40 g, 1.849 mmol) in anhydrous ACN (15 mL). The reaction mixture was allowed to reach room temperature for one hour. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate solution (5 mL) and saturated aqueous sodium bicarbonate solution (4 mL). The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a crude residue. The crude residue was purified by the following process: COMBIFLASH TM Chromatography (Terry Dionesco, Lincoln, Nebraska) using 30% EtOAc / petroleum ether yielded 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 flocculent solid. LCMS (ESI) m / z: 883.3 [M+H] + . Preparation of intermediate 65: 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] tert-butyl octane-8-carboxylate

[0629] Under nitrogen atmosphere in a sealed tube, copper iodide (I) (0.60 g, 3.17 mmol) was added to a stirred solution of 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). The reaction mixture was degassed for 10 min, followed by the addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.91 g, 4.76 mmol) and heating at 90 °C for 12 h. 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 obtain a crude residue. This residue was then processed using COMBIFLASH. TM The crude compound was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) using 30% EtOAc / 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): δppm=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] + . Intermediates 66 and 67: 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] tert-butyl octane-8-carboxylate

[0630] Intermediate 65 (5.0 g, 6.06 mmol) was separated by SFC (method information: column: CHIRALPAK). TM IH (Dairuc Industries, Ltd., Japan) (250 mm × 4.6 mm; 5 μm), mobile phase: 0.25% isopropanol), wherein 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): δppm=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): δppm=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. Preparation of intermediate 68: 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0631] At 0 °C, NaH (0.194 g, 4.85 mmol) was added to a solution of [(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methanol (0.205 g, 1.212 mmol, intermediate 67) in THF (5 mL), and the mixture was stirred at room temperature for 30 min. At 0 °C, (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1 g, 1.212 mmol) was added to this mixture, and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice and concentrated under reduced pressure. The crude product was partitioned between EtOAc and water. The organic layer was dried with sodium sulfate, filtered, and concentrated to obtain a crude product, which was then subjected to COMBIFLASH. TM Chromatography (Terry Dianesco, Lincoln, Nebraska) (24g REDISEP) TM The crude product was purified by column chromatography (Teledyne ISCO, Lincoln, Nebraska) from 0 to 10% MeOH-DCM to give 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.70 g, 0.718 mmol, 59% yield). MS (ESI) m / z: 974.4 (M+H) + . Preparation of intermediate 69: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoroquinazoline-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0632] At 0 °C, dioxane (0.9 mL, 3.59 mmol) containing 4 M HCl was added to a solution of 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (700 mg, 0.718 mmol) in acetonitrile (5 mL). The reaction mixture was heated 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-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoroquinazoline-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) + . Preparation of intermediate 70: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazoline-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0633] At 0 °C, DIPEA (0.03 mL, 0.17 mmol) and EtOAc (0.03 mL, 0.11 mmol) containing propylphosphonic anhydride solution were added to a stirred solution of 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]oct-3-yl}-8-fluoroquinazoline-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.06 mmol) in DCM (10 mL). 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 heated to room temperature and stirred for 16 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazoline-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) + . Example 8-1: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0634] A vial was filled with 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazoline-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 hours. The volatiles of the reaction mixture were removed under reduced pressure, and the crude residue was co-evaporated with 1,4-dioxane. Subsequently, the crude residue was dissolved in 1,4-dioxane (2 mL) and excess TEA (1 mL) was added. The mixture was evaporated under reduced pressure to obtain the crude residue, which was purified by the following preparative HPLC method: [HPLC method: preparative column: column: Waters XBridge C18, 19 × 150 mm, 5 μm particles; mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 15-47% B for 22 min, then at 100%...] B, held at 220 nm for 5 minutes; flow rate: 20 mL / min; detection: UV at 220 and 254 nm, yielded 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopentadieno[b]pyridin-4a-yl]methoxy}-6-chloro-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazoline-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] + .

[0635] Prepare the examples in Table 5 using appropriate starting materials according to the procedure described for Example 8-1. Table 5 Preparation of intermediate 71: tert-butyl 6-methylene-1,4-oxazetane-4-carboxylate

[0636] According to the literature procedure: Bioorg. Med. Chem. Lett. 2019, 29, 2405-2409, the intermediate tert-butyl 6-methylene-1,4-oxazetane-4-carboxylate was synthesized. Preparation of intermediate 72: tert-butyl 6-oxo-1,4-oxazetane-4-carboxylate

[0637] Sodium periodate (12.03 g, 56.3 mmol) was added to a stirred solution of 6-methylene-1,4-oxazacycloheptan-4-carboxylate (6 g, 28.1 mmol) in THF (40 mL) and water (40 mL) at 0 °C, followed by the addition of tert-butanol (2 mL, 0.141 mmol) containing osmium tetroxide. The reaction mixture was stirred at room temperature for 16 hours. Subsequently, the reaction mixture was concentrated to give a 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 then subjected to COMBIFLASH. TM The crude residue was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) (petroleum ether / EtOAc = 30%) to give the title compound tert-butyl 6-oxo-1,4-oxazetane-4-carboxylate (2 g, 9.29 mmol, 33.0% yield) as a colorless liquid. 1 H NMR (300MHz, CDCl3) δppm = 4.02-4.17 (m, 4H), 3.91 (br d, J = 3.78Hz, 2H), 3.70 (br s, 2H) 1.45 (br s, 9H). Preparation of intermediates 73 and 74: tert-butyl 6-hydroxy-6-methyl-1,4-oxazacycloheptane-4-carboxylate

[0638] At 0 °C, tert-butyl 6-oxo-1,4-oxazacycloheptan-4-carboxylate (2.5 g, 11.61 mmol) was added dropwise to a stirred solution of methyl magnesium chloride in 150 mL of THF (46.5 mL, 46.5 mmol). The reaction mixture was stirred for 2 hours. 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. Racemic compounds were purified by chiral separation using SFC to yield isomer-1: tert-butyl 6-hydroxy-6-methyl-1,4-oxazacycloheptane-4-carboxylate (1 g, 4.32 mmol, 37.2% yield) and isomer-2: tert-butyl 6-hydroxy-6-methyl-1,4-oxazacycloheptane-4-carboxylate (1 g, 4.32 mmol, 37.2% yield). [Method: Column / Size: CHIRALPAK] TMIG (Japan Daicel Co., Ltd.) (250×50)mm, 5μm, CO2%: 60%, cosolvent%: 40% 4M MeOH containing methanol and ammonia, total flow rate: 280.0g / min, back pressure: 100 bar, temperature: 40℃, UV: 205nm, RT=4.15min (isomer-1) and RT=6.01min (isomer-2)]. Isomer-1: 1 H NMR (400MHz, DMSO-d6) δppm=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) δppm=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). Preparation of intermediates 75 and 76: 6-methyl-1,4-oxazacycloheptane-6-ol

[0639] Intermediate 75 (Isomer-1): HCl (4M in dioxane) (5.40 mL, 21.62 mmol) was added to a stirred solution of tert-butyl 6-hydroxy-6-methyl-1,4-oxazacycloheptane-4-carboxylate (Intermediate 73, 1 g, 4.32 mmol) in acetonitrile (10 mL). The resulting reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated and co-evaporated with toluene (twice) to give 6-methyl-1,4-oxazacycloheptane-6-ol hydrochloride as a white solid (550 mg, 3.28 mmol, 76% yield). MS (ESI) m / z: 132.1 [M+H] + .

[0640] Intermediate 76 (Isomer-2): HCl (4M in dioxane) (5.40 mL, 21.62 mmol) was added to a stirred solution of tert-butyl 6-hydroxy-6-methyl-1,4-oxazacycloheptane-4-carboxylate (Intermediate 74, 1 g, 4.32 mmol) in acetonitrile (10 mL). The resulting reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated and co-evaporated with toluene (twice) to give 6-methyl-1,4-oxazacycloheptane-6-ol hydrochloride (550 mg, 3.28 mmol, 76% yield). MS (ESI) m / z: 132.2 [M+H] + .

[0641] Intermediate 75 (isomer-1) was used to prepare Examples 1-84, 1-108, 2-70 and 2-74. Preparation of intermediates 77 and 78: tert-butyl 6-(hydroxymethyl)-1,4-oxazetane-4-carboxylate

[0642] A solution of tert-butyl 6-methylene-1,4-oxazacycloheptan-4-carboxylate (1.2 g, 5.63 mmol) in ice-cold THF (15 mL) was added to a solution of a borane-tetrahydrofuran complex in THF (6.75 mL, 6.75 mmol). The reaction mixture was heated to 25 °C and stirred for 3 hours. 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 and washed with dichloromethane. The organic layer was evaporated to give the title compound. The racemic compound was purified by chiral separation using SFC to give isomer-1 (intermediate 77): tert-butyl 6-(hydroxymethyl)-1,4-oxazacycloheptane-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-oxazacycloheptan-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] TMIG (Dairuc Corporation, Japan) (250×4.6)mm, 5μm, cosolvent: 30% vial N°: LD8, cosolvent name: 0.2% ammonia-methanol, injection volume: 20μl, outlet pressure: 100 bar, temperature: 40℃, remarks: SFC-3G-30%-15MTS-205NM, t R = 2.0 minutes (isomer-1) and t R = 4.05 minutes (isomer-2)]. Preparation of intermediates 79 and 80: (1,4-oxazacycloheptane-6-yl)methanol

[0643] Intermediate 79 (Isomer-1): At 0 °C, dioxane (0.026 mL, 0.865 mmol) containing 4.0 M hydrochloric acid was added to a solution of tert-butyl 6-(hydroxymethyl)-1,4-oxazacycloheptane-4-carboxylate (Intermediate 77, 200 mg, 0.865 mmol) in acetonitrile (2 mL), and the mixture was stirred for 1 hour. The reaction mixture was then concentrated and co-evaporated with CAN to give (1,4-oxazacycloheptane-6-yl)methanol hydrochloride (130 mg, 0.776 mmol, 90% yield). MS (ESI) m / z: 132.2 [M+H] + .

[0644] Intermediate 80 (Isomer-2): At 0 °C, dioxane (0.026 mL, 0.865 mmol) containing 4.0 M hydrochloric acid was added to a solution of tert-butyl 6-(hydroxymethyl)-1,4-oxazacycloheptane-4-carboxylate (Intermediate 78, 200 mg, 0.865 mmol) in acetonitrile (2 mL), and the mixture was stirred for 1 hour. The reaction mixture was then concentrated and co-evaporated with CAN to give (1,4-oxazacycloheptane-6-yl)methanol hydrochloride as a pale yellow solid (110 mg, 0.658 mmol, 76% yield). MS (ESI) m / z: 132.1 [M+H] + .

[0645] Intermediate 80 (isomer-2) was used to prepare Examples 1-88. Preparation of intermediate 81: tert-butyl 6,6-difluoro-1,4-oxazacycloheptane-4-carboxylate

[0646] At 0 °C, tert-butyl trifluoride (0.982 mL, 7.43 mmol) was added to a stirred solution of 6-oxo-1,4-oxazacycloheptan-4-carboxylate (200 mg, 0.929 mmol) in DCM (4 mL), and the reaction mixture was stirred at 25 °C for 16 hours. Subsequently, the reaction mixture was carefully quenched with MeOH at 0 °C, followed by the addition of water and concentration. The crude residue was partitioned between EtOAc and brine. The organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and concentrated to give tert-butyl 6,6-difluoro-1,4-oxazacycloheptan-4-carboxylate (200 mg, 0.843 mmol, 91% yield). 1 H NMR (300MHz, DMSO-d6) δppm=3.70-3.95 (m, 6H), 3.46-3.57 (m, 2H), 1.40 (s, 9H). Preparation of intermediate 82: 6,6-difluoro-1,4-oxazacycloheptane

[0647] At 0 °C, a stirred solution of tert-butyl 6,6-difluoro-1,4-oxazacycloheptan-4-carboxylate (200 mg, 0.843 mmol) in acetonitrile (3 mL) was added to dioxane (0.256 mL, 8.43 mmol) containing 4 M HCl, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated and co-evaporated with toluene to give the product 6,6-difluoro-1,4-oxazacycloheptanane (100 mg, 0.729 mmol, 87% yield). MS (ESI) m / z: 138.0 [M+H] + . Preparation of intermediates 83 and 84: 3-methylpiperidin-3-ol

[0648] At 0 °C, dibutyl ether (14.09 mL, 42.3 mmol) containing methyl magnesium bromide solution was added dropwise to a stirred solution of 1-phenylmethylpiperidin-3-one (2 g, 10.57 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at 0 °C for 2 hours. Subsequently, the reaction mixture was slowly quenched with saturated NH4Cl solution and extracted with ethyl acetate (150 mL × 2). The organic layer was washed with brine (approximately 200 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a racemic mixture. The racemic mixture was purified by chiral purification using SFC to give 1-phenylmethyl-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 / Size: CHIRALPAK] TM AD-H (Dairu Industries, Ltd., Japan) (250×30) mm, 5 μm, CO2%: 80%, co-solvent%: 20% methanol containing 0.2% ammonia, total flow rate: 130.0 g / min, back pressure: 100 bar, temperature: 40℃, UV: 220 nm, RT = 2.5 min (isomer-1) and 3.4 min (isomer-2)]. Isomer-1: 1 ¹H NMR (300MHz, DMSO-d⁶) δppm = 7.21–7.36 (m, 5H), 4.16 (s, 1H), 3.31–3.45 (m, 2H), 2.29–2.48 (m, 1H), 2.19 (brd, J = 10.20 Hz, 2H), 2.02 (brd, J = 10.58 Hz, 1H), 1.61 (brd, J = 3.78 Hz, 1H), 1.23–1.53 (m, 3H), 1.10 (s, 3H). Isomer-2: 1 HNMR (300MHz, DMSO-d6) δppm=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). Preparation of intermediate 85: 3-methylpiperidin-3-ol (isomer-1)

[0649] 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 10% palladium / carbon (1182 mg, 1.111 mmol) was added. The resulting reaction mixture was stirred under a hydrogen balloon at room temperature for 5 hours. The reaction mixture was then subjected to CELITE chromatography. TM (Sigma-Aldrich, St. Louis, Missouri) The solution was filtered through a 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] + .

[0650] Intermediate 85 was used to prepare Examples 1-85, 1-89, 1-95 and 2-72. Preparation of intermediate 86: ethyl 3-(phenylmethylamino)butyrate

[0651] Ethyl trans-butenoate (96.96 mL, 56.0 mmol) was added to a stirred solution of benzylamine (5 g, 46.7 mmol) in EtOH (25 mL) at 0 °C, and the mixture was stirred at 90 °C for 16 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove volatiles. The solution was then analyzed via COMBIFLASH. TM The crude residue was purified by chromatography (Terry Dionesco, Lincoln, Nebraska, 2-5% methanol / DCM, 40 g column) to give the desired product, ethyl 3-(phenylmethylamino)butyrate (7 g, 31.6 mmol, 67.8% yield). MS (ESI) m / z: 222.2 [M+H] + . Preparation of intermediate 87: 3-(phenylmethylamino)but-1-ol

[0652] At 0 °C under a nitrogen atmosphere, a solution of methyl 3-(phenylmethylamino)butyrate (5 g, 24.12 mmol) in THF (100 mL) was added dropwise to a suspension of LAH (1.831 g, 48.2 mmol) in THF (100 mL). The resulting mixture was heated to room temperature and stirred for 3 hours. Subsequently, a small amount of saturated aqueous sodium sulfate solution was added dropwise at 0 °C to quench the reactants, and the mixture was stirred for 1 hour. The resulting solids were removed by filtration, and the organic solution was concentrated to give 3-(phenylmethylamino)but-1-ol (3.9 g, 13.05 mmol, 54.1% yield). 1H NMR (300MHz, DMSO-d6) δppm=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). Preparation of intermediate 88: 4-phenylmethyl-5-methyl-1,4-oxazetane-3-one

[0653] At 0 °C, chloroacetyl chloride (1.557 mL, 19.58 mmol) was added to a solution of 3-(phenylmethylamino)but-1-ol (3 g, 16.74 mmol) and triethylamine (4.99 mL, 35.8 mmol) in DCM (50 mL), and the mixture was stirred for one hour. The reaction mixture was poured into a 1 N HCl aqueous 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. (Surveyed via COMBIFLASH) TM The crude compound was purified by chromatography (Terry Dionesco, Lincoln, Nebraska) (hexane / ethyl acetate = 100 / 0 to 1 / 1 as eluent) to give 4-benzyl-5-methyl-1,4-oxazacycloheptan-3-one (2.6 g, 10.67 mmol, 63.8% yield). MS (ESI) m / z: 220.2 [M+H] + . Preparation of intermediates 89 and 90: 4-phenylmethyl-5-methyl-1,4-oxazacycloheptane

[0654] At 0 °C under a nitrogen atmosphere, a solution of boranetetrahydrofuran complex in THF (11.52 mL, 120 mmol) was added dropwise to a solution of 2.64 g (12.04 mmol) of 4-phenylmethyl-5-methyl-1,4-oxazacycloheptan-3-one in 48 mL of THF. The mixture was heated to room temperature and stirred for 3 hours. Subsequently, the reactants were quenched by adding methanol and the solution was concentrated under reduced pressure. The remaining oily substance was dissolved in methanol (30 mL) and 1 M sodium hydroxide aqueous 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. Racemic compounds were purified by chiral separation using SFC to yield intermediate 89 (isomer-1): 4-phenylmethyl-5-methyl-1,4-oxazacycloheptane (350 mg, 1.7 mmol, 29.16%), a pale yellow liquid, and intermediate 90 (isomer-2): 4-phenylmethyl-5-methyl-1,4-oxazacycloheptane (350 mg, 1.7 mmol, 29.16%), also a pale yellow liquid. [Method column name: CHIRALPAK] TM IG (Dairuc Industries, Ltd., Japan) (250×4.6) mm, 5 μm, cosolvent: methanol containing 0.2% ammonia, 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] + . Preparation of intermediates 91 and 92: 5-methyl-1,4-oxazacycloheptane

[0655] Intermediate 91 (Isomer-1): At room temperature, 1-chloroethyl chloroformate (2437 mg, 17.05 mmol) was added to a stirred solution of 4-benzyl-5-methyl-1,4-oxazacycloheptane (350 mg, 1.705 mmol) in 1,2-dichloroethane (5 mL). 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 a gel-like liquid of 5-methyl-1,4-oxazacycloheptane (150 mg, 1.302 mmol, 76% yield). MS (ESI) m / z: 116.2 [M+H]+.

[0656] Intermediate 92 (Isomer-2): At room temperature, 1-chloroethyl chloroformate (2437 mg, 17.05 mmol) was added to a stirred solution of 4-benzyl-5-methyl-1,4-oxazacycloheptane (350 mg, 1.705 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and completely concentrated. The crude product 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-oxazacycloheptane (140 mg, 1.216 mmol, 71.3% yield) as a colloidal liquid. MS (ESI) m / z: 116.1 [M+H]+.

[0657] Intermediate 91 (isomer-1) was used to prepare Examples 1-93 and 1-96. Preparation of intermediates 93 and 94: 1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-formate tert-butyl ester and 2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-formate tert-butyl ester

[0658] At room temperature, cesium carbonate (6.23 g, 19.12 mmol) and methyl iodide (1.195 mL, 19.12 mmol) were added to a stirred solution of 4,6-dihydro-1h-pyrrolo[3,4-c]pyrazole-5-carboxylate (2 g, 9.56 mmol) in DMF (20 mL), and the mixture was stirred for 16 hours. The reaction mixture was then poured into water and extracted with EtOAc (50 × 3). The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a mixture of regioisomers. The mixture of regioisomers was separated by the following: SFC [condition column / size: CHIRALPAK] TM OZ-H (Dairuc Industries, Ltd., Japan) (250×30) mm, 5 μm, CO2%: 90%. Cosolvent%: 10% ACN:MeOH (50:50) containing 5 mM ammonium acetate, total flow rate: 150.0 g / min, back pressure: 100 bar; temperature: 40 °C, UV: 220 nm]. Regiomeric isomer-1 (intermediate 93) (tR = 3 min) (0.2 g, 0.896 mmol, 9.37% yield), regiomeric isomer-2 (intermediate 94) (tR = 3 min ... R =4.37 minutes (0.8 g, 3.58 mmol, 37.5% yield, regiomeric isomer-2).

[0659] Intermediate 93, 1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-tert-butyl formate: 1 H NMR (400MHz, CDCl3) δppm=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).

[0660] Intermediate 94, 2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-tert-butyl formate: 1 H NMR (400MHz, CDCl3) δppm = 7.22-7.04 (m, 1H), 4.63-4.31 (m, 4H), 3.92 (s, 3H), 1.53 (d, J = 2.0Hz, 9H). Preparation of intermediate 95: 1-Methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

[0661] At 0 °C, HCl (4 M in dioxane) (1.120 mL, 4.48 mmol) was added to a stirred solution of 1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylic acid tert-butyl ester (100 mg, 0.448 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at 0 °C for 1 hour. The volatiles of 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, yield 91%) as a grayish-white solid. MS (ESI) m / z: 124.1 [M+H]+. Preparation of intermediate 96: 2-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

[0662] At 0 °C, HCl (4 M in dioxane) (1.120 mL, 4.48 mmol) was added to a stirred solution of 2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester (100 mg, 0.448 mmol) in acetonitrile (2 mL), and the reaction mixture was stirred at 0 °C for 1 hour. The volatiles of the reaction mixture were removed under reduced pressure to give 2-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride as a colorless liquid (45 mg, 0.365 mmol, 82% yield). MS (ESI) m / z: 124.2 [M+H]+. Preparation of intermediate 97: Methyl 4-amino-6-chloro-2-methoxypyridine-3-carboxylate

[0663] Triethylamine (36.7 mL, 264 mmol) and dppf (4.87 g, 8.79 mmol) were added to a stirred solution of 6-chloro-3-iodo-2-methoxypyridin-4-amine (prepared as described in WO 2010 / 093849 and WO 2022 / 040267) in MeOH (450 mL), followed by palladium(II) acetate (0.986 g, 4.39 mmol). The reaction mixture was purged with N2 for 5 min and stirred in an autoclave at 60 °C under 2.5 kg CO gas pressure for 16 h. The reaction mixture was cooled to room temperature and analyzed by CELITE. TM (Sigma-Aldrich, St. Louis, Missouri) Pad filtration and pad washing with methanol. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then filtered through a COMBIFLASH filter. TM The crude product was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) (using a 120 g silica gel column and 30% to 35% ethyl acetate / petroleum ether) to give methyl 4-amino-6-chloro-2-methoxypyridine-3-carboxylate as a white solid (16 g, 73.9 mmol, 84% yield). MS (ESI) m / z: 217.1 [M+H] + . Preparation of intermediate 98: Methyl 4-amino-6-chloro-5-fluoro-2-methoxypyridine-3-carboxylate

[0664] SELECTFLUOR was added to a stirred solution of methyl 4-amino-6-chloro-2-methoxypyridine-3-carboxylate (19 g, 88 mmol) in ACN (400 mL). TM (Air Products, Allentown, PA) (bis(tetrafluoroborate)-1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane ester) (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 product was analyzed by COMBIFLASH. TM The crude compound was purified by chromatography (Terry Dion Esco, Lincoln, Nebraska) (120 g silica gel column, using 0 to 10% ethyl acetate / petroleum ether) to give methyl 4-amino-6-chloro-5-fluoro-2-methoxypyridine-3-carboxylate as a white solid (3 g, 11.95 mmol, 13.62% yield). MS (ESI) m / z: 235.1 [M+H]+ . Preparation of intermediate 99: 6-chloro-5-fluoro-2-methoxy-4-{[(2,2,2-trichloroacetyl)carbamoyl]amino} Methyl pyridine-3-carboxylate

[0665] 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), trichloroacetyl isocyanate (6.28 mL, 52.6 mmol) was added. 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 without further purification. MS (ESI) m / z: 424.1 [M+H] + . Preparation of intermediate 100: 7-chloro-8-fluoro-5-methoxypyrido[4,3-d]pyridine-2,4-diol

[0666] Over a 30-minute period, 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 slowly added to a stirred solution of 7N ammonia (270 mL, 1891 mmol in methanol). 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 without further purification. MS (ESI) m / z: 246.1 [M+H] + . Preparation of intermediate 101: 2,4,7-trichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine

[0667] POCl3 (133 mL, 1425 mmol), followed by DIPEA (24.89 mL, 143 mmol), was added to 7-chloro-8-fluoro-5-methoxypyridano[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 sodium bicarbonate solution and stirred for 10 minutes. The organic layer was washed with brine, dri...

Claims

1. A compound having formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is a bond, O, NR e or CR e R f , where R e and R f are independently hydrogen or C1-C3 alkyl; R 1 is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkynyl, C2-C4 alkynyloxy, amino, aminoC1-C3 alkyl, cyano, cyanoC1-C3 alkoxy, C3-C8 cycloalkyl optionally substituted with one, two or three halo groups, halo, haloC1-C3 alkyl, haloC1-C3 alkoxy, hydroxy, hydroxyC1-C3 alkyl, heteroaryl, heterocyclyl and phenyl, wherein the heteroaryl, heterocyclyl and phenyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, halo and haloC1-C3 alkyl; R 2 , R 3 and R 7 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 hydroxyl; R 4 NHR 50 or in R 50 is a five-membered ring optionally containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen, wherein the ring is optionally substituted with one or two 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' each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, halo, halo C1-C3 alkyl, hydroxyl and hydroxy C1-C3 alkyl; or R 8 and R 9 together to form a C1-C3 alkylene group; or R 8 and R 10 together to form a C1-C3 alkylene group; or R 8 and R 13 together to form a C1-C3 alkylene group; or R 9 and R 13 together to form a C1-C3 alkylene group; or R 10 and R 13 together to form a C1-C3 alkylene group; or R 8 and R 8' Together with the atoms to which it is attached, it forms a three-, four- or five-membered ring optionally containing an oxygen atom or a SO2 group, wherein 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 9 and R 9' Together with the atoms to which it is attached, it forms a three-, four- or five-membered ring optionally containing an oxygen atom or a SO2 group, wherein 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 10 and R 10' Together with the atoms to which it is attached, it forms a three-, four- or five-membered ring optionally containing an oxygen atom or a SO2 group, wherein 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 13' Together with the atoms to which they are attached, they form a three-, four- or five-membered ring optionally containing an oxygen atom or a SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl and hydroxy; W 1 CR 11 R 12 NR 17 NR 15” C(O), N(C(O)(CH2) n OR 15 )、O、SO2、SO2NR 15' or P(O)CH3; n is 0 or 1; R 11 and R 12 independently selected from the group consisting of hydrogen, C1-C3 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C1-C3 alkyl, cyano, dimethylphosphino, dimethylsulfonamide, halide, hydroxyl and methylsulfonyl; or R 11 and R 12 Together with the atoms to which it is attached, it forms a four to six membered ring optionally containing an oxygen atom or a SO2 group, wherein 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 11 and R 13 together with the atoms to which they are attached, form a three, four or five membered ring optionally containing one or two heteroatoms independently selected from nitrogen and oxygen, wherein the ring optionally contains one or two double bonds, and wherein 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 Together they form CH2; R 15' is C1-C3 alkyl or C1-C6 alkoxy C1-C6 alkyl; R 15” is hydrogen or C1-C3 alkyl; R 17 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 , where R 16 is hydrogen or C1-C3 alkyl; R 5 Selected from the group consisting of: hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di(C1-C3 alkyl)amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-(C1-C6 alkyl), NR a R b C1-C6 alkyl, wherein the aryl, the aryl portion of the arylC1-C6 alkyl, the C3-C6 cycloalkyl, the cycloalkyl portion of the C3-C6 cycloalkylC1-C6 alkyl, the heteroaryl, the heteroaryl portion of the heteroarylC1-C6 alkyl, the heterocyclyl, the heterocyclyl portion of the heterocyclylC1-C6 alkyl are optionally substituted with one, two, three or four groups independently selected from the following: C1-C3 alkoxy, C1-C3 alkyl, deuterated C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C6 alkyl)amino, (C1-C6 alkyl)aminoC1-C3 alkyl, amino, aminoC1-C3 alkyl, carboxyl, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoC1-C3 alkyl, halo, haloC1-C3 alkoxy, haloC1-C3 alkyl, heterocyclyl, heterocyclylC1-C3 alkyl, hydroxyl, hydroxyC1-C3 alkyl, nitro and oxo; wherein the heterocyclyl and the heterocyclyl moiety of the heterocyclylC1-C3 alkyl are further optionally substituted with one, two or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, halo and haloC1-C3 alkyl; or R 5 and R 16 together with the nitrogen atom to which it is attached, forms a heterocyclic group optionally substituted with one, two, three, four or five groups independently selected from the group consisting of: one, two, three or four groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxyl and hydroxyC1-C3 alkyl; and R a and R b One of them 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.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 For chlorine.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 For hydrogen.

4. A compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: Z is a bond, O, NR e or CR e R f , where R e and R f are independently hydrogen or C1-C3 alkyl; R 1 is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of C2-C4 alkenyl, C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkynyl, C2-C4 alkynyloxy, amino, aminoC1-C3 alkyl, cyano, cyanoC1-C3 alkoxy, C3-C8 cycloalkyl optionally substituted with one, two or three halo groups, halo, haloC1-C3 alkyl, haloC1-C3 alkoxy, hydroxy, hydroxyC1-C3 alkyl, heteroaryl, heterocyclyl and phenyl, wherein the heteroaryl, heterocyclyl and phenyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, halo and haloC1-C3 alkyl; R 2 and R 3 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 hydroxyl; R 4 NHR 50 or in R 50 is a five-membered ring optionally containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen, wherein the ring is optionally substituted with one or two 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' each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, cyano C1-C3 alkyl, halo, halo C1-C3 alkyl, hydroxyl and hydroxy C1-C3 alkyl; or R 8 and R 9 together to form a C1-C3 alkylene group; or R 8 and R 10 together to form a C1-C3 alkylene group; or R 8 and R 13 together to form a C1-C3 alkylene group; or R 9 and R 13 together to form a C1-C3 alkylene group; or R 10 and R 13 together to form a C1-C3 alkylene group; or R 8 and R 8' Together with the atoms to which it is attached, it forms a three-, four- or five-membered ring optionally containing an oxygen atom or a SO2 group, wherein 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 9 and R 9' Together with the atoms to which it is attached, it forms a three-, four- or five-membered ring optionally containing an oxygen atom or a SO2 group, wherein 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 10 and R 10' Together with the atoms to which it is attached, it forms a three-, four- or five-membered ring optionally containing an oxygen atom or a SO2 group, wherein 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 13' Together with the atoms to which they are attached, they form a three-, four- or five-membered ring optionally containing an oxygen atom or a SO2 group, wherein the ring is optionally substituted with two groups selected from the group consisting of C1-C3 alkyl, halo, haloC1-C3 alkyl and hydroxy; W 1 CR 11 R 12 NR 17 NR 15” C(O), N(C(O)(CH2) n OR 15 )、O、SO2、SO2NR 15' or P(O)CH3; n is 0 or 1; R 11 and R 12 independently selected from the group consisting of hydrogen, C1-C3 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C1-C3 alkyl, cyano, dimethylphosphino, dimethylsulfonamide, halide, hydroxyl and methylsulfonyl; or R 11 and R 12 Together with the atoms to which it is attached, it forms a four- or five-membered ring optionally containing an oxygen atom or a SO2 group, wherein 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 11 and R 13 together with the atoms to which they are attached, form a three, four or five membered ring optionally containing one or two heteroatoms independently selected from nitrogen and oxygen, wherein the ring optionally contains one or two double bonds, and wherein 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 Together they form CH2; R 15' is C1-C3 alkyl or C1-C6 alkoxy C1-C6 alkyl; R 15” is hydrogen or C1-C3 alkyl; R 17 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 , where R 16 is hydrogen or C1-C3 alkyl; R 5 Selected from the group consisting of: hydrogen, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl, aryl, aryl C1-C6 alkyl, carboxy C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, di(C1-C3 alkyl)amino C2-C6 alkyl, halo C1-C6 alkyl, heteroaryl, heteroaryl C1-C6 alkyl, heterocyclyl, heterocyclyl C1-C6 alkyl, hydroxy C1-C6 alkyl, NR a R b -C(O)-(C1-C6 alkyl), NR a R b C1-C6 alkyl, wherein the aryl, the aryl portion of the arylC1-C6 alkyl, the C3-C6 cycloalkyl, the cycloalkyl portion of the C3-C6 cycloalkylC1-C6 alkyl, the heteroaryl, the heteroaryl portion of the heteroarylC1-C6 alkyl, the heterocyclyl, the heterocyclyl portion of the heterocyclylC1-C6 alkyl are optionally substituted with one, two, three or four groups independently 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)aminoC1-C6 alkyl -C3 alkyl, amino, aminoC1-C3 alkyl, carboxyl, cyano, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoC1-C3 alkyl, halo, haloC1-C3 alkoxy, haloC1-C3 alkyl, heterocyclyl, heterocyclylC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, nitro and oxo; wherein the heterocyclyl and the heterocyclyl moiety of the heterocyclylC1-C3 alkyl are further optionally substituted with one, two or three groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, halo and haloC1-C3 alkyl; or R 5 and R 16 together with the nitrogen atom to which it is attached, forms a heterocyclic group optionally substituted with one, two, three, four or five groups independently selected from the group consisting of: one, two, three or four groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyalkyl, C1-C3 alkyl, amino, aminoC1-C3 alkyl, hydroxyl and hydroxyC1-C3 alkyl; and R a and R b One of them is selected from hydrogen and C1-C3 alkyl, and the other is selected from 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.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 4 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, wherein the ring is optionally substituted with one or two groups independently selected from C1-C3 alkyl and oxo.

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

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

8. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein W 1 NR 15” (C(O).

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein W 1 N(C(O)(CH2) n OR 15 ).

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

11. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein W 1 For SO2.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein W 1 For SO2NR 15 '.

13. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein W 1 It is P(O)CH3.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 4 for in represents the point of attachment to the core of formula (I) or (II).

15. The compound according to claim 4 or 14 or a pharmaceutically acceptable salt thereof, wherein R 4 for in represents the point of attachment to the core of formula (II).

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

17. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein R 3 It is a halogen group.

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

19. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from the group consisting of: wherein each ring is optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, tritiated C1-C3 alkyl, C3-C6 cycloalkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl and oxo; and wherein R c and R d together with the nitrogen atom to which it is attached, form a five to ten membered monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, wherein the 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, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl and oxo; or R c and R d One of the groups 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.

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R 5 -(C1-C3 alkyl)-R 6 , where R 6 is a three- to six-membered monocyclic ring system, an eight- or nine-membered bicyclic fused saturated ring system, a ten-membered tricyclic saturated ring system, or a twelve-membered tetracyclic saturated ring system, wherein each ring system optionally contains one or more nitrogen, oxygen, and / or sulfur atoms, and wherein 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- to 6-membered heterocyclyl)C1-C3 alkyl; wherein the heterocyclyl portion of the (4- to 6-membered heterocyclyl)C1-C3 alkyl is further optionally substituted with a halo group.

21. The compound according to claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein R 5 for and Indicates the connection point with X.

22. A compound as claimed in any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein R 5 for and Indicates the connection point with X.

23. A compound as claimed in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 5 for Where n is 0, 1, or 2; Each R 20 is a halo group; and Indicates the connection point with X.

24. A compound as claimed in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein R 5 for Where 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 Indicates the connection point with X.

25. A compound as claimed in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein R 5 for Where R 21 is selected from the group consisting of C1-C3 alkyl, tritiated C1-C3 alkyl and C3-C6 cycloalkyl, R 22 is a halogen group; p is 0 or 1; and Indicates the connection point with X.

26. A compound as described in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 5 for in represents the connection point with X; p is 0 or 1; R 21 Selected from the group consisting of C1-C3 alkyl, tritiated C1-C3 alkyl and C3-C6 cycloalkyl; and R 22 is a halogen group; p is 0 or 1; and Indicates the connection point with X.

27. A compound as described in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 5 for in Indicates the connection point with X.

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

29. A compound as described in any one of claims 1 to 28, wherein R 1 is a monocyclic heteroaryl ring containing one, two or three nitrogen atoms, wherein the ring is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C4 cycloalkyl, halo, haloC1-C3 alkyl, haloC1-C3 alkoxy, hydroxy and hydroxyC1-C3 alkyl.

30. A compound as described in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R 1 for in represents the point of attachment to the core of formula (I) or (II).

31. A compound as described in any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 1 C6-C 10 Aryl, which is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of C1-C3 alkoxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, cyano, C3-C5 cycloalkyl, halo, haloC1-C3 alkyl, hydroxy and hydroxyC1-C3 alkyl.

32. A compound as described in any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 1 is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one, two, three, four or five 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-C5 cycloalkyl optionally substituted with one or two halo groups, halo, haloC1-C3 alkyl, haloC1-C3 alkoxy, 4 to 6 membered heterocyclyl and hydroxy.

33. A compound as described in any one of claims 1 to 27 and 32, or a pharmaceutically acceptable salt thereof, wherein R 1 is naphthyl, wherein the naphthyl is substituted by one, two or three groups independently selected from the group consisting of C2-C4 alkynyl, halo and hydroxy.

34. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 29 and 31 to 33, wherein R 1 for Where R 53 is C1-C3 alkyl, halo, halo C1-C3 alkyl, halo C1-C3 alkoxy, 4-membered to 6-membered heterocyclic group or hydroxyl; q is an integer from 0 to 4; and represents the point of attachment to the core of formula (I) or (II).

35. A compound as described in any one of claims 1 to 28 and 32, or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, wherein the phenyl is substituted by one, two or three groups independently selected from the group consisting of C1-C3 alkyl, C3-C5 cycloalkyl, heterocyclyl and hydroxy.

36. A compound as described in any one of claims 1 to 28 and 32, or a pharmaceutically acceptable salt thereof, wherein R 1 isoquinolinyl, wherein the isoquinolinyl is substituted by one, two or three groups independently selected from the group consisting of halo C1-C3 alkyl and halo C1-C3 alkoxy.

37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 1 for Where R 51 is a halogen C1-C3 alkyl group; R 52 is hydrogen or halogen C1-C3 alkyl; and wherein represents the point of attachment to the core of formula (I) or (II).

38. A compound as described in any one of claims 1 to 28 and 32, or a pharmaceutically acceptable salt thereof, wherein R 1 It is an indolyl group substituted by a halogen C1-C3 alkyl group.

39. A compound as described in any one of claims 1 to 28 and 32, or a pharmaceutically acceptable salt thereof, wherein R 1 is indazolyl substituted by one, two or three substituents selected from C1-C3 alkyl and halogen.

40. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

41. The compound of claim 40, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

42. The compound of claim 4, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

43. The compound of claim 40, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

44. A compound selected from the group consisting of: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]oct-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]oct-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2 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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-4-{2,2-difluoro-7-azaspiro[3.5]non-7-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]hept-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-methyl-1 6,2,5-Thiadiazepane-1,1-dione; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{9-oxa-2-azaspiro[5.5]undec-2-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-4-{8-azabicyclo[3.2.1]oct-8-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{2-azabicyclo[2.2.1]hept-2-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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]hept-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-azaphosphane 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]hept-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]hept-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-pyrrolizin-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-pyrrolizin-7a-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}-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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{8-oxa-3-azabicyclo[3.2.1]oct-3-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-4-{6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1 6-Thiomorpholine-1,1-dione; (9aR)-8-(2-{[(2R,7aS)-2-Fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-7-azaspiro[3.5]non-7-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{2,2-difluoro-7-azaspiro[3.5]non-7-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-4-{2-azabicyclo[2.2.1]hept-2-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{8-azabicyclo[3.2.1]oct-8-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]hept-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-2-methyl-1 6,2,5-Thiadiazepane-1,1-dione; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{9-oxa-3-azabicyclo[4.2.1]non-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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]oct-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-ethylnaphthol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-(morpholin-4-yl)quinazolin-7-yl)-5-ethylnaphthol; (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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[8-(1-fluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[8-(2-fluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-4-[8-(2,2-difluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-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]oct-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-pyrrolizin-7a-yl]methoxy}-4-[8-(4,4-difluorocyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-[8-(oxane-4-carbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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-pyrrolizin-7a-yl]methoxy}-4-[8-(3,3-difluorocyclobutanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-4-{8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-7-6-fluoronaphthalene-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{8-[(1s,4s)-4-hydroxycyclohexanecarbonyl]-3,8-diazabicyclo[3.2.1]oct-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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{8-methanesulfonyl-3,8-diazabicyclo[3.2.1]oct-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'-pyrrolizine]-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-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{6-oxa-3-azabicyclo[3.2.1]oct-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-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'-pyrrolizine]-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-pyrrolizin-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-pyrrolizin-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]hept-5-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizin-7a-yl]methoxy}-8-fluoro-4-{2-oxa-5-azabicyclo[4.1.0]hept-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'-pyrrolizine]-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]pyrrolizin-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]hept-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-pyrrolizin-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-pyrrolizin-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]hept-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'-pyrrolizine]-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'-pyrrolizine]-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'-pyrrolizine]-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-pyrrolizin-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]hept-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-pyrrolizin-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-pyrrolizin-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]oct-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-pyrrolizin-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-pyrrolizin-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'-pyrrolizine]-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'-pyrrolizine]-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]hept-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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]hept-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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-pyrrolizin-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]hept-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-pyrrolizin-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]hept-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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]hept-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]hept-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-oxazoctan-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-pyrrolizin-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-pyrrolizin-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-oxazoctan-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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-pyrrolizin-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'-pyrrolizine-6',1"-cyclopropyl]-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]hept-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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]hept-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-pyrrolizin-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. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

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

47. 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, the method comprising administering to the subject a compound, composition or dosage form as described in any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof.

48. A method of treating a cancer sensitive to inhibition of 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 compound, composition or dosage form as described in any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof.

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

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

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

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

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