KRAS inhibitors

Abstract

This disclosure provides a KRAS inhibitor. Methods for treating cancer using this compound are also provided.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 511,455 filed on 30 June 2023; U.S. Provisional Patent Application No. 63 / 588,239 filed on 5 October 2023; U.S. Provisional Patent Application No. 63 / 551,905 filed on 9 February 2024; and U.S. Provisional Patent Application No. 63 / 655,965 filed on 4 June 2024, each of which is incorporated herein by reference in its entirety.

[0002] This disclosure provides a KRAS inhibitor, and also provides a method for treating cancer using the inhibitor. [Background technology]

[0003] The KRAS oncogene is a member 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 approximately 90% of pancreatic cancers. Single nucleotide substitutions resulting in missense mutations at codons 12 and 13 of the KRAS primary amino acid sequence account for about 40% of KRAS driver mutations in lung adenocarcinoma, and the G12C transversion is the most common activating mutation. KRAS G12C mutations occur in about 13% of lung adenocarcinomas and about 3% of colorectal adenocarcinomas, and are also present in breast, bladder, cervical, ovarian, pancreatic, and uterine cancers. KRAS G12D mutations occur in 28% of all pancreatic ductal adenocarcinoma patients, 13% of all colorectal carcinoma patients, 4% of all non-small cell lung cancer patients, and 3% of all gastric cancer patients. See, for example, Non-Patent Literature 1. Due to the clinical significance of this protein, many attempts have been made to develop RAS inhibitors, but these attempts have been largely unsuccessful. Therefore, drugs that inhibit mutant KRAS are desired. [Prior art documents] [Non-patent literature]

[0004]

Non-Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0005] In some embodiments, the present disclosure provides a compound of formula (I):

Chemical Formula

[0006] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein, Y is either O or SO2; R 1 is either ethynyl or ethyl; R1' is hydrogen, halo, or C 1-3 It is alkyl, R 1’’ is hydrogen; R2 is hydrogen; R 3 It is a halo; R 4 and R 5 They are either the same or different, with hydrogen and C respectively. 1-4 Alkyl, hydroxy, or C 1-4 It is a haloalkyl; R 6 C 1-6 Alkyl, C 3-6 Cycloalkyl, hydroxy C 1-6 Alkyl, Halo C 1-6 Alkyl, hydroxy-halo C 1-6 Alkyl, methylsulfonyl C1-C6 alkyl, or -(CH2) n -A is; Here, A is C 3-6 Cycloalkyl, C 3-7 A cyclic moiety selected from heterocycloalkyl, aryl, heteroaryl, a spiro structure of any of these rings, and a bicyclic structure of any of these rings, where n is 0, 1, 2, or 3; Here, A is C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 3-6 Cycloalkylcarbonyl, hydroxy, halo, cyano, halo C 1-6 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkoxycarbonyl, Halo C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbamates, amides, C 1-4 It is optionally substituted with one or more substituents selected from alkylamides, oxo, and methylsulfonyl; R 7 and R 8 They are either the same or different, and each is hydrogen, hydroxyl, and C 1-6 Alkyl, C 1-6 It is an alkylsulfonyl or halo.

[0007] In some embodiments of formula (I), R 1 is ethynyl. In some embodiments of formula (I), R 1 is ethyl. In some embodiments of formula (I), R 1 is hydrogen. In some embodiments of formula (I), R 1 is halo.

[0008] In some embodiments of formula (I), R 1’’ is halo. In some embodiments of formula (I), R 1’’ is fluoro.

[0009] In some embodiments of formula (I), R 3 is fluoro.

[0010] In some embodiments of formula (I), R 4 and R 5 are both hydrogen. In other embodiments, one of R 4 and R 5 is hydroxy and the other is methyl.

[0011] In some embodiments of formula (I), Y is O. In some embodiments of formula (I), Y is SO2.

[0012] In some embodiments of formula (I), R 1’ is hydrogen. In some embodiments of formula (I), R 1’’ is halo (e.g., fluoro).

[0013] In some embodiments of formula (I), R6 is C 2-6 alkyl, hydroxy C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-halo C 1-6 alkyl, or methylsulfonyl C1-C6 alkyl.

[0014] In some embodiments of formula (I), R 6 is -(CH2) n-A, where n and A are as defined above. In some embodiments, n is 0. In some embodiments, n is 1. A is C 4-6 cycloalkyl, C 3-10 heterocycloalkyl, aryl, heteroaryl, a spiro structure of any of these rings, and a bicyclic structure of any of these rings.

[0015] In some embodiments of formula (I), R 7 and R 8 are hydrogen. In some embodiments, one of R s 7 and R 8 is hydrogen and one is halo.

[0016] In some embodiments, the present disclosure provides a compound of formula (II):

Chemical formula

[0017] In some aspects of equation (II), R 1 is ethynyl. In some aspects of formula (I), R 1 It is ethyl.

[0018] In some embodiments, A is C 1-4Alkyl, C 1-4 Alkylcarbonyl, C 3-6 Cycloalkylcarbonyl, hydroxy, halo, halo C 1-6 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkoxycarbonyl, Halo C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbamates, amides, C 1-4 It is optionally substituted with one or more substituents selected from alkylamides, oxo (=O), and methylsulfonyl groups.

[0019] In some aspects of equation (II), R 3 It is fluoro.

[0020] In some aspects of equation (II), R 4 and R 5 In all cases, R 4 and R 5 One of them is hydroxyl, and the other is methyl or ethyl.

[0021] In some aspects of equation (II), R 4’ and R 5’ In all cases, R 4’ and R 5’ These are all halos.

[0022] In some aspects of equation (II), R 1’ is hydrogen. In some aspects of equation (I), R 1’’ This is a halo (for example, a fluoro).

[0023] In some aspects of equation (II), R 1’’ is a halo. In some aspects of equation (II), R 1’’ It is fluoro.

[0024] In some aspects of equation (II), R6 is C 2-6 Alkyl, hydroxy C1-6 Alkyl, Halo C 1-6 Alkyl, hydroxy-halo C 1-6 It is alkyl, or methylsulfonyl C1-C6 alkyl.

[0025] In some aspects of equation (II), R 6 is, -(CH2) n -A, where n and A are as defined above. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, A is C 4-6 Cycloalkyl, C 3-10 The cyclic moiety is selected from heterocycloalkyl, aryl, heteroaryl, a spiro structure of any of these rings, and a bicyclic structure of any of these rings.

[0026] In some aspects of equation (II), R 7 and R 8 is hydrogen. In some embodiments, R 7 and R 8 One of them is hydrogen, and the other is a halo.

[0027] In some embodiments, this disclosure relates to compounds of formula (III): [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula, R 1 is either ethynyl or ethyl; R 1’ is hydrogen or a halo (e.g., fluoro); R 1’’ is hydrogen, C 2-3 Alkenil, C 1-3 Alkyl, C 2-3 Selected from alkynyl, halo, and hydroxy; R 2 is hydrogen; R 3 is a halo (for example, a fluoro); R 6 C 1-6Alkyl, hydroxy C 1-6 Alkyl, Halo C 1-6 Alkyl, hydroxy-halo C 1-6 Alkyl, methylsulfonyl C1-C6 alkyl, or -(CH2) n -A is; Here, A is C 3-6 Cycloalkyl, C 3-7 A heterocycloalkyl group, a spiro structure of any of these rings, and a cyclic portion selected from any bicyclic structure of these rings, where n is 0, 1, or 2; Here, A is C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 3-6 Cycloalkylcarbonyl, hydroxy, halo, halo C 1-6 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkoxycarbonyl, Halo C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbamates, amides, C 1-4 It is optionally substituted with one or more substituents selected from alkylamides, oxo (=O), and methylsulfonyl; R 7 and R 8 They are either the same or different, with hydrogen and C respectively. 1-6 Alkyl, C 1-6 It is an alkylsulfonyl or halo.

[0028] In some aspects of equation (III), R 1 is ethynyl. In some aspects of formula (I), R 1 It is ethyl.

[0029] In some aspects of equation (III), R 3 It is fluoro.

[0030] In some aspects of equation (III), R 1’ is hydrogen. In some aspects of equation (I), R 1’’This is a halo (for example, a fluoro).

[0031] In some aspects of equation (III), R 1’’ is a halo. In some aspects of equation (III), R 1’’ It is fluoro.

[0032] In some aspects of equation (III), R6 is C 2-6 Alkyl, hydroxy C 1-6 Alkyl, Halo C 1-6 Alkyl, hydroxy-halo C 1-6 It is alkyl, or methylsulfonyl C1-C6 alkyl.

[0033] In some aspects of equation (III), R 6 is, -(CH2) n -A, where n and A are as defined above. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, A is C 4-6 Cycloalkyl, C 3-10 The cyclic moiety is selected from heterocycloalkyl, aryl, heteroaryl, a spiro structure of any of these rings, and a bicyclic structure of any of these rings.

[0034] In some aspects of equation (III), R 7 and R 8 is hydrogen. In some embodiments, R 7 and R 8 One of them is hydrogen, and the other is a halo.

[0035] In some embodiments, the present disclosure relates to a compound of formula (IV): [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula, R 1 is either ethynyl or ethyl; R 1’ is hydrogen or a halo (e.g., fluoro); R1’’ is hydrogen, C 2-3 Alkenil, C 1-3 Alkyl, C 2-3 Selected from alkynyl, halo, and hydroxy; R 2 is hydrogen; R 3 is a halo (for example, a fluoro); R 6 C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Halo C 1-6 Alkyl, hydroxy-halo C 1-6 Alkyl, methylsulfonyl C1-C6 alkyl, or -(CH2) n -A is; Here, A is C 3-6 Cycloalkyl, C 3-7 A heterocycloalkyl group, a spiro structure of any of these rings, and a cyclic portion selected from any bicyclic structure of these rings, where n is 0, 1, or 2; Here, A is C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 3-6 Cycloalkylcarbonyl, hydroxy, halo, halo C 1-6 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkoxycarbonyl, Halo C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbamates, amides, C 1-4 It is optionally substituted with one or more substituents selected from alkylamides, oxo (=O), and methylsulfonyl; R 7 and R 8 They are either the same or different, with hydrogen and C respectively. 1-6 Alkyl, C 1-6 It is an alkylsulfonyl or halo.

[0036] In some aspects of equation (IV), R 1is ethynyl. In some aspects of formula (I), R 1 It is ethyl.

[0037] In some aspects of equation (IV), R 3 It is fluoro.

[0038] In some aspects of equation (IV), R 1’ is hydrogen. In some aspects of equation (I), R 1’’ This is a halo (for example, a fluoro).

[0039] In some aspects of equation (IV), R 1’’ is a halo. In some aspects of equation (IV), R 1’’ It is fluoro.

[0040] In some aspects of equation (IV), R6 is C 2-6 Alkyl, hydroxy C 1-6 Alkyl, Halo C 1-6 Alkyl, hydroxy-halo C 1-6 It is alkyl, or methylsulfonyl C1-C6 alkyl.

[0041] In some aspects of equation (IV), R 6 is, -(CH2) n -A, where n and A are as defined above. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, A is C 4-6 Cycloalkyl, C 3-10 The cyclic moiety is selected from heterocycloalkyl, aryl, heteroaryl, a spiro structure of any of these rings, and a bicyclic structure of any of these rings.

[0042] In some aspects of equation (IV), R 7 and R 8 is hydrogen. In some embodiments, R 7 and R 8 One of them is hydrogen, and the other is a halo.

[0043] In some embodiments, this disclosure relates to compounds of formula (V): [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula, Y is either O or SO2; R 1 and R 1’ These are either the same or different, and are hydrogen, halo, and C respectively. 1-4 Alkyl, C 2-4 Alkenil, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 It is a haloalkoxy; R 2 is hydrogen; R 3 is a halo (for example, a fluoro); R 4 and R 5 They are either the same or different, with hydrogen and C respectively. 1-4 Alkyl or hydroxyl; R 20 is hydrogen and hydroxy C 1-4 Selected from alkyl groups; R 6 C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Halo C 1-6 Alkyl, hydroxy-halo C 1-6 Alkyl, methylsulfonyl C1-C6 alkyl, or -(CH2) n -A is; Here, A is C 3-6 Cycloalkyl, C 3-7 A heterocycloalkyl group, a spiro structure of any of these rings, and a cyclic portion selected from any bicyclic structure of these rings, where n is 0, 1, or 2; Here, A is C 1-4 Alkyl, C 1-4 Alkylcarbonyl, cyano, C 3-6 Cycloalkylcarbonyl, hydroxy, halo, halo C 1-6 Alkyl, C1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkoxycarbonyl, Halo C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbamates, amides, C 1-4 Alkylamide, oxo (=O), hydroxy C 1-4 It is optionally substituted with one or more substituents selected from alkyl and methylsulfonyl groups; R 7 and R 8 They are either the same or different, with hydrogen and C respectively. 1-6 Alkyl, C 1-6 It is an alkylsulfonyl or halo.

[0044] In some aspects of equation (V), R 1 and R 1’ These are either the same or different, and are hydrogen, halo, and C respectively. 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 It is a haloalkoxy.

[0045] In some aspects of equation (V), R 3 It is fluoro.

[0046] In some aspects of equation (V), R 4 and R 5 In all cases, H. In other embodiments, R 4 and R 5 One of them is hydroxyl, and the other is methyl.

[0047] In some aspects of equation (V), Y is O. In some aspects of equation (I), Y is SO2.

[0048] In some aspects of equation (V), R6 is C 2-6 Alkyl, hydroxy C 1-6 Alkyl, Halo C 1-6Alkyl, hydroxy-halo C 1-6 It is alkyl, or methylsulfonyl C1-C6 alkyl.

[0049] In some aspects of equation (V), R 6 is, -(CH2) n -A, where n and A are as defined above. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, A is C 4-6 Cycloalkyl, C 3-10 The cyclic moiety is selected from heterocycloalkyl, aryl, heteroaryl, a spiro structure of any of these rings, and a bicyclic structure of any of these rings.

[0050] In some aspects of equation (V), A is C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 3-6 Cycloalkylcarbonyl, hydroxy, halo, halo C 1-6 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkoxycarbonyl, Halo C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbamates, amides, C 1-4 It is optionally substituted with one or more substituents selected from alkylamides, oxo (=O), and methylsulfonyl groups.

[0051] In some aspects of equation (V), A is C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 3-6 Cycloalkylcarbonyl, hydroxy, halo, halo C 1-6 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkoxycarbonyl, Halo C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbamates, amides, C1-4 Alkylamide, oxo(=O), hydroxy C 1-4 is optionally substituted with one or more substituents selected from alkyl, and methylsulfonyl.

[0052] In some embodiments of formula (V), R 7 and R 8 are hydrogen. In some embodiments, one of R 7 and R 8 is hydrogen and one is halo.

[0053] In some embodiments, the present disclosure provides a compound of formula (VI):

Chemical formula

[0054] In some aspects of equation (VI), R 3 It is fluoro.

[0055] In some aspects of equation (VI), R 4 and R 5 In all cases, R 4 and R 5 One of them is hydroxyl, and the other is methyl or ethyl.

[0056] In some aspects of equation (VI), R 4’ and R 5’In all cases, R 4’ and R 5’ These are all halos.

[0057] In some aspects of equation (VI), R6 is C 2-6 Alkyl, hydroxy C 1-6 Alkyl, Halo C 1-6 Alkyl, hydroxy-halo C 1-6 It is alkyl, or methylsulfonyl C1-C6 alkyl.

[0058] In some aspects of equation (VI), R 6 is, -(CH2) n -A, where n and A are as defined above. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, A is C 4-6 Cycloalkyl, C 3-10 The cyclic moiety is selected from heterocycloalkyl, aryl, heteroaryl, a spiro structure of any of these rings, and a bicyclic structure of any of these rings.

[0059] In some aspects of equation (VI), R 7 and R 8 is hydrogen. In some embodiments, R 7 and R 8 One of them is hydrogen, and the other is a halo.

[0060] In some aspects, this disclosure is, [ka] [ka] [ka] [ka] [ka]

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[0061] In some embodiments, the present disclosure

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[0062] In some aspects, this disclosure is, [ka] The present invention provides compounds selected from the group consisting of the above, or pharmaceutically acceptable salts thereof.

[0063] In some aspects, this disclosure is, [ka] The present invention provides compounds selected from the group consisting of the above, or pharmaceutically acceptable salts thereof.

[0064] In some aspects, this disclosure is, 5-Ethinyl-6-fluoro-4-(8-fluoro-2-(((3R,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalene-2-ol; 5-Ethinyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-1-methyl-3-(methylsulfonyl)octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalene-2-ol; 3-Ethyl-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-ol; 3-Ethyl-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-ol; 4-(4-(3,3-difluoro-5-(hydroxymethyl)piperidine-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(4-(3,3-difluoro-5-(hydroxymethyl)piperidine-1-yl)-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; (S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((3S,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((4aS,7aR)-3-fluoro-1,3-dimethyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((4aS,7aR)-3-fluoro-1,3-dimethyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((3S,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((3S,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; 4-(2-{[(4aS,7aR)-1-[(oxetan-3-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(2S)-3-fluoro-2-hydroxypropyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; Methyl 3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H- (5S)-5-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}pyrrolidine-2-oncyclopenta[b]pyridine-1-yl]methyl}3-hydroxyazetidine-1-carboxylate; 4-(2-{[(4aS,7aR)-1-(oxetan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 1-{3-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]azetidine-1-yl}ethane-1-one; 5-Ethinyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-(tetrahydro-2H-pyran-4-yl)octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalene-2-ol; 4-((4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-yl)tetrahydro-2H-thiopyran-1,1-dioxide 4-(2-{[(4aS,7aR)-1-(cyclopropylmethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(cyclobutylmethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(3-methyloxetane-3-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-cyclobutyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(2R)-3-fluoro-2-hydroxypropyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(1-hydroxycyclobutyl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(2-methyloxetan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(2-methyloxetan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 1-(3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-3-hydroxyazetidine-1-yl)ethane-1-one; 4-(2-{[(4aS,7aR)-1-{[3-(hydroxymethyl)oxetane-3-yl]methyl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; tert-butyl3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}azetidine-1-carboxylate; tert-butyl N-(1-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}cyclopropyl)carbamate; tert-butyl3-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]azetidine-1-carboxylate; 4-(2-{[(4aS,7aR)-1-(2,2-difluoroethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 1-(3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}azetidine-1-yl)ethane-1-one; Methyl 3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}azetidine-1-carboxylate; Methyl 3-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]azetidine-1-carboxylate; N-(1-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}cyclopropyl)acetamide 1-(3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-3-methylazetidine-1-yl)ethane-1-one; 4-(2-{[(4aS,7aR)-1-(2-hydroxyethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-propyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(2-methylpropyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(3,3-difluorocyclobutyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(3,3-dimethylcyclobutyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(2S)-2-hydroxypropyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(2R)-2-hydroxypropyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}oxetan-3-ol; 4-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}pyrrolidine-2-one; (5R)-5-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}pyrrolidine-2-one; 6-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]-2,6-thiaspiro[3,3]heptan-2,2-dione (3aR,6aS)-5-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]-hexahydro-1H-2,6-cyclopenta[c]thiophene-2,2-dione 2-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]-7,6-thiaspiro[3.5]nonane-7,7-dione 4-(2-{[(4aS,7aR)-1-propyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(cyclopropylmethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(2-hydroxyethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-cyclobutyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 4-{2-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]ethyl}piperidine-2,6-dione 4-(2-{[(4aS,7aR)-1-{[1-(methoxymethyl)cyclopropyl]methyl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; tert-butyl3-{2-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]ethyl}azetidine-1-carboxylate; 4-(2-{[(4aS,7aR)-1-{2-oxaspiro[3,3]heptan-6-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 3-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]cyclobutan-1-carboxamide 4-(2-{[(4aS,7aR)-1-{7-oxaspiro[3.5]nonanane-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-{spiro[2,3]hexane-5-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(3-methanesulfonylcyclobutyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-{2-oxaspiro[3.5]nonane-7-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(oxolan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(oxolan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(oxolan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 1-(3-{2-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]ethyl}azetidine-1-yl)propan-1-one; 1-(3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}azetidine-1-yl)propan-1-one; 4-(2-{[(4aS,7aR)-1-[2-(1-cyclopropanecarbonylazetidine-3-yl)ethyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 1-(3-{2-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]ethyl}azetidine-1-yl)-2-methylpropan-1-one; 1-(3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}azetidine-1-yl)-2-methylpropan-1-one; 4-(2-{[(4aS,7aR)-1-[(1-cyclopropanecarbonylazetidine-3-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; Ethyl 3-{2-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]ethyl}azetidine-1-carboxylate; 1-(3-{2-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]ethyl}azetidine-1-yl)ethane-1-one; Methyl 3-{2-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]ethyl}azetidine-1-carboxylate; 1,1,1-Trifluoro-2-methylpropan-2-yl3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}azetidine-1-carboxylate; 1,1,1-Trifluoro-2-methylpropan-2-yl3-{2-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]ethyl}azetidine-1-carboxylate; 4-(2-{[(4aS,7aR)-1-(2-cyclopropylethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(1,4-dioxan-2-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(1,4-dioxan-2-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(1,4-dioxan-2-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(oxolan-3-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[2-(oxan-4-yl)ethyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(oxan-4-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-1,6-thian-1,1-dione 4-(2-{[(4aS,7aR)-1-[(oxolan-2-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(oxolan-2-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(2-cyclobutylethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(oxan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(oxan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 3-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]-1,6-thian-1,1-dione 4-(2-{[(4aS,7aR)-1-{5,8-dioxaspiro[3,4]octan-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 3-{2-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]ethyl}-1,6-thiolan-1,1-dione 3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-1,6-thian-1,1-dione 6-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}piperidine-2-one; 4-(2-{[(4aS,7aR)-1-(3-methanesulfonylpropyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(2-methanesulfonylethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-1,3-oxazolidine-2-one; 5-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}piperidine-2-one; 3-{2-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]ethyl}-1,6-thietan-1,1-dione 4-(2-{[(4aS,7aR)-1-[(3,3-difluorocyclobutyl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; tert-butyl6-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-2-azaspiro[3.3]heptane-2-carboxylate; Ethyl 6-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-2-azaspiro[3.3]heptane-2-carboxylate; 4-(2-{[(4aS,7aR)-1-[(3,3-dimethylcyclobutyl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(oxan-3-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(oxan-3-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(2,2-dimethyl-1,3-dioxan-5-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[2-(oxolan-2-yl)ethyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[2-(oxolan-2-yl)ethyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[2-(oxolan-2-yl)ethyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 5-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-1-methylpyrrolidine-2-one; 5-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-1-methylpyrrolidine-2-one; 5-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-1-methylpyrrolidine-2-one; 4-(2-{[(4aS,7aR)-1-(3,3-dimethoxycyclobutyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(oxetan-3-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(cyclobutylmethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(cyclopropylmethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(oxetan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; tert-butyl N-(3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}cyclobutyl)carbamate; (6R)-4-(2-{[(4aS,7aR)-1-[(oxetan-3-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6R)-4-(2-{[(4aS,7aR)-1-(oxetan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; Ethyl N-(3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}cyclobutyl)carbamate; Methyl N-(3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}cyclobutyl)carbamate; (3R)-1-(2-{[(4aS,7aR)-1-{8-oxabicyclo[3.2.1]octan-3-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-{8-oxabicyclo[3.2.1]octan-3-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-[3-(methoxymethyl)cyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-[(oxolan-2-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; 4-(2-{[(4aS,7aR)-1-(3-hydroxy-3-methylcyclobutyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(3-hydroxy-3-methylcyclobutyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-7-(8-fluoro-3-hydroxynaphthalene-1-yl)pyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(3aR,6aS)-hexahydro-1H-cyclopenta[c]furan-5-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{2,6-dioxaspiro[4.5]decane-9-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(3-methoxy-1-methylcyclobutyl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(3-methoxy-1-methylcyclobutyl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{2,6-dioxaspiro[4.5]decane-9-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(3-hydroxy-3-methylcyclobutyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(3-hydroxy-3-methylcyclobutyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{2,5-dioxaspiro[3,4]octan-7-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[3-(methoxymethyl)cyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(4aS,7aR)-1-[3-(methoxymethyl)cyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; (6S)-4-(2-{[(4aS,7aR)-1-(3-fluorooxan-4-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(2-{[(4aS,7aR)-1-[3-hydroxy-3-(trifluoromethyl)cyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-[3-hydroxy-3-(trifluoromethyl)cyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (6S)-4-(2-{[(4aS,7aR)-1-[3-hydroxy-3-(trifluoromethyl)cyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[3-hydroxy-3-(trifluoromethyl)cyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{[(1R,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-yl]methyl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{1-oxaspiro[4,4]nonanane-3-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{1-oxaspiro[4,4]nonanane-3-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(3-fluorooxan-4-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(3-fluorooxan-4-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(3-fluorooxan-4-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(1,2-thiazole-4-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{8-oxabicyclo[3.2.1]octan-3-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-7-{5'-hydroxy-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-7'-yl}pyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(1S,5R)-6,8-dioxabicyclo[3.2.1]octan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(1S,5R)-6,8-dioxabicyclo[3.2.1]octan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-[6-(2-hydroxypropan-2-yl)-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; (6S)-4-(2-{[(4aS,7aR)-1-{[(1r,3s)-3-hydroxy-3-methylcyclobutyl]methyl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(2R,4r,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(2-{[(4aS,7aR)-1-[(2R,4r,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-{[(1s,3s)-3-methoxycyclobutyl]methyl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (6S)-4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-7-(8-fluoro-3-hydroxynaphthalene-1-yl)pyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{[(1S)-2,2-dimethylcyclopropyl]methyl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(2-{[(4aS,7aR)-1-[3-(hydroxymethyl)cyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (6S)-4-(2-{[(4aS,7aR)-1-[3-(hydroxymethyl)cyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-7-(3-hydroxynaphthalene-1-yl)pyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(oxepand-4-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(2-{[(4aS,7aR)-1-(3-hydroxycyclobutyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (6S)-4-(2-{[(4aS,7aR)-1-(3-hydroxycyclobutyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(2-{[(4aS,7aR)-1-[(oxolan-2-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-[(oxolan-2-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(oxan-4-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(2-hydroxy-2-methylpropyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(oxan-4-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{[(3R)-2,2-difluoro-3-methylcyclopropyl]methyl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(2-{[(4aS,7aR)-1-{[(3R)-2,2-difluoro-3-methylcyclopropyl]methyl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; 4-(2-{[(4aS,7aR)-1-{6-oxaspiro[3,4]octan-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-{6-oxaspiro[3,4]octan-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-{6-oxaspiro[3,4]octan-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]cyclohexane-1-carbonitrile; 4-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]cyclohexane-1-carbonitrile; 4-(2-{[(4aS,7aR)-1-(4-methoxycyclohexyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(4-methoxycyclohexyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-(4-ethynylcyclohexyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(1,4-dioxan-2-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-{7-oxaspiro[3.5]nonanane-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-{1-oxaspiro[3.5]nonane-7-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-{1-oxaspiro[3.5]nonane-7-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-{3-oxaspiro[5,5]undecane-9-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-[(1,4-dioxepane-6-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-{8-oxaspiro[4,5]decane-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-{8-oxaspiro[4,5]decane-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-{8-oxaspiro[4,5]decane-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; (6S)-4-(2-{[(4aS,7aR)-1-{2-oxaspiro[3,3]heptan-6-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; 6-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-[(6S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]-2,6-thiaspiro[3.3]heptane-2,2-dione; (6S)-4-(2-{[(4aS,7aR)-1-{7-oxaspiro[3.5]nonanane-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{2-oxaspiro[3.5]nonanane-7-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(2-{[(4aS,7aR)-1-{[(3R)-2,2-difluoro-3-methylcyclopropyl]methyl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; (6S)-4-(2-{[(4aS,7aR)-1-{6-oxaspiro[3,4]octan-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{7-oxaspiro[3.5]nonanane-2-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(4-methoxycyclohexyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(2R)-2-methyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{2-oxaspiro[3.5]nonanane-7-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-cyclobutyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(2S)-2-methyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (1s,3s)-3-[(4aS,7aR)-4a-({[7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-[(6S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]cyclobutan-1-carbonitriel; (6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (1s,3s)-3-[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-[(6S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]cyclobutan-1-carbonitriel; 6S)-4-(2-{[(4aS,7aR)-1-{[(1s,3s)-3-methoxycyclobutyl]methyl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(2R,4r,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(5-chloro-6-methyl-1H-indazole-4-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(6-chloro-5-methyl-1H-indazole-4-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-propyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-7-(8-fluoro-3-hydroxynaphthalene-1-yl)pyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(2,2-difluorocyclopropyl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 1); (6S)-4-(2-{[(4aS,7aR)-1-[(2,2-difluorocyclopropyl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 2); (6S)-4-(2-{[(4aS,7aR)-1-(3-aminocyclobutyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(oxolan-3-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(2-{[(4aS,7aR)-1-(cyclopropylmethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-{7-Oxaspiro[3.5]nonanane-2-yl}-Octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-chloro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(oxolan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol(diastereomer 1); (6S)-4-(2-{[(4aS,7aR)-1-(oxolan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 2); (3R)-1-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (3R)-1-(2-{[(4aS,7aR)-1-{2-oxaspiro[3,3]heptan-6-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (6S)-4-(2-{[(4aS,7aR)-1-{8-oxabicyclo[3.2.1]octan-3-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 1); (6S)-4-(2-{[(4aS,7aR)-1-{8-oxabicyclo[3.2.1]octan-3-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 2); (3R)-1-(2-{[(4aS,7aR)-1-[(2R,4r,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-3-ol; (6S)-4-(2-{[(4aS,7aR)-1-{2-oxaspiro[4.5]decane-8-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 1); (6S)-4-(2-{[(4aS,7aR)-1-{2-oxaspiro[4.5]decane-8-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 2); (6S)-4-(2-{[(4aS,7aR)-1-{1-oxaspiro[3.5]nonanane-7-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 1); (6S)-4-(2-{[(4aS,7aR)-1-{1-oxaspiro[3.5]nonanane-7-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 2); (6S)-4-(2-{[(4aS,7aR)-1-(oxetan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(3-methyloxetan-3-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(cyclopropylmethyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(2-methoxy-2-methylpropyl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(oxetan-3-yl)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-7-(8-fluoro-3-hydroxynaphthalene-1-yl)pyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-(2H3)methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-{2,5-dioxaspiro[3,4]octan-7-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 1); (6S)-4-(2-{[(4aS,7aR)-1-{2,5-dioxaspiro[3,4]octan-7-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 2); (6S)-4-(2-{[(4aS,7aR)-1-{2-oxaspiro[3,3]heptan-6-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(2R,4r,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; 6-[(4aS,7aR)-4a-({[7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-[(6S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]-2-lambda6-thiaspiro[3,3]heptan-2,2-dione; (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(6'R,7'aS)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidine]-7'a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidine]-7'a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(2R,4r,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-propyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol; (2R,6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol; (2R,6S)-4-(2-{[(4aS,7aR)-1-{2-oxaspiro[3,3]heptan-6-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol; (2R,6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol; (2R,6S)-4-(2-{[(4aS,7aR)-1-[(oxan-4-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol; (2R,6S)-4-(2-{[(4aS,7aR)-1-[(2R,4r,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol; (2R,6S)-4-(2-{[(4aS,7aR)-1-[(2R,4s,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol; (6S)-4-(2-{[(4aS,7aR)-1-[(2R,4s,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 1); (6S)-4-(2-{[(4aS,7aR)-1-[(2R,4s,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (diastereomer 2); The present invention provides compounds selected from the group consisting of the above, or pharmaceutically acceptable salts thereof.

[0065] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0066] In some embodiments, the Disclosure provides an oral dosage form comprising a compound described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0067] In some embodiments, the compound is an atropisomer of any of the compounds in the preceding embodiments. In certain embodiments, the compound is a stable atropisomer as described herein. In some embodiments, the compound is a specific diastereomer if the chiral central carbon atom in the structure does not have the stereochemistry shown by the dashed and solid wedge bonds.

[0068] In another aspect, the Disclosure provides a method for treating KRAS G12D-related disorders or disorders associated with KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H in subjects requiring treatment of such disorders, the method comprising administering a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof as defined herein to the subject.

[0069] In another aspect, the Disclosure provides a method for treating cancers susceptible to KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H inhibition in subjects requiring treatment of cancers susceptible to KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H inhibition, the method comprising administering the compounds described herein or pharmaceutically acceptable salts thereof to the subject.

[0070] In some embodiments, the Disclosure provides a method for treating cancer expressing a KRAS mutation and / or KRAS copy number amplification in a subject requiring treatment of such cancer, comprising administering a compound described herein or a pharmaceutically acceptable salt thereof to the subject.

[0071] In some embodiments, the Disclosure provides a method for treating cancers expressing KRAS G13R, Q61R, A146T, A146V, A59G, G12A, G12C, G12D, G12R, G12S, G12V, G13C, G13D, Q61H, Q61K and / or KRAS Q61L mutations, and / or KRAS copy number amplification, in a subject requiring such treatment, comprising administering a compound described herein or a pharmaceutically acceptable salt thereof to said subject.

[0072] In some embodiments, the Disclosure provides methods for treating cancers expressing KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, KRAS A146T, and / or KRAS Q61H mutations in subjects requiring treatment of such cancers, the methods comprising administering the compounds described herein, pharmaceutically acceptable salts of the compounds, compositions, or dosage forms to the subject.

[0073] In some embodiments, the Disclosure provides a method for treating cancers expressing KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H mutations in subjects requiring treatment of cancers expressing KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H mutations, the method comprising administering the compounds described herein or pharmaceutically acceptable salts thereof to the subject.

[0074] In another aspect, the 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 described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein.

[0075] In another embodiment, the Disclosure provides a method for treating cancer in a subject requiring treatment of cancer, comprising administering a compound described herein or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, 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. In some embodiments, the cancer is non-small cell lung cancer.

[0076] In another aspect, the Disclosure provides the compounds described herein or pharmaceutically acceptable salts thereof or pharmaceutically acceptable compositions thereof as defined herein for use in the treatment of diseases or disorders associated with KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and / or KRAS Q61H.

[0077] In another aspect, the Disclosure provides the use of the compounds described herein, or pharmaceutically acceptable salts thereof as defined herein, in the manufacture of a drug for the treatment of cancer.

[0078] In another aspect, the Disclosure provides the use of compounds described herein, as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of agents for inhibiting the activity of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, and / or KRAS Q61H.

[0079] In another aspect, the Disclosure provides the use of compounds described herein, as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of agents for the treatment of diseases or disorders related to KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, and / or KRAS Q61H.

[0080] In some embodiments, the present disclosure provides atropisomers of any of the compounds in the prior embodiments. In certain embodiments, the compound is a stable atropisomer as described herein. [Modes for carrying out the invention]

[0081] The issued U.S. patents, published U.S. patents, international patents, and foreign patent applications, as well as the references, cited herein are incorporated by reference to the same extent as they are specifically and individually indicated to be incorporated by reference.

[0082] Unless otherwise specified, any atom whose valence is not met is assumed to have enough hydrogen atoms to satisfy that valence.

[0083] The singular forms "a," "an," and "the" refer to multiple objects unless otherwise indicated by the context.

[0084] As used herein, the term "or" means logical disjunction (i.e., and / or) and does not mean exclusive disjunction unless explicitly indicated by the terms "either," "otherwise," "either / or," or similar expressions.

[0085] As used herein, the phrase "or a pharmaceutically acceptable salt thereof" refers to at least one compound, or at least one salt of a compound, or a combination thereof.

[0086] As used herein, the term "C2-C4 alkenyl" refers to a group derived from a linear or branched hydrocarbon containing two to four carbon atoms and at least one double bond.

[0087] As used herein, the term "C1-C3 alkoxy" refers to a C1-C3 alkoxy attached to the parent molecule via an oxygen atom. 1-3 This refers to an alkyl group.

[0088] The terms "C1-C4 alkoxy" and "C" as used herein 1-4 "Alkoxy" refers to a C1-C4 alkyl group attached to the parent molecule via an oxygen atom.

[0089] The terms "C1-C4 alkoxy C1-C4 alkyl" and "C" as used herein 1-4 Alkoxy C 1-4 "Alkyl" refers to a C1-C4 alkoxy group attached to the parent molecule via a C1-C4 alkyl group.

[0090] The terms "C1-C4 alkoxycarbonyl" and "C" as used herein 1-4 "Alkoxycarbonyl" refers to a C1-C4 alkoxy group attached to the parent molecule via a carbonyl group.

[0091] Terms used in this specification include "C 1-3 "Alkyl" refers to a group derived from a straight-chain or branched-chain saturated hydrocarbon containing 1 to 3 carbon atoms.

[0092] The terms "C1-C4 alkyl" and "C" as used herein 1-4 "Alkyl" refers to a group derived from a straight-chain or branched-chain saturated hydrocarbon containing 1 to 4 carbon atoms.

[0093] Terms used in this specification include "C 1-6 "Alkyl" refers to a group derived from a straight-chain or branched-chain saturated hydrocarbon containing 1 to 6 carbon atoms.

[0094] As used herein, the term "C2-C6 alkyl" refers to a group derived from a linear or branched saturated hydrocarbon containing 2 to 6 carbon atoms.

[0095] Terms used in this specification include "C 1-4 "Alkylamide" refers to a C1-C4 alkyl group attached to the parent molecule via an amide (-NHC(O)-) group.

[0096] Terms used in this specification include "C 1-4 "Alkylcarbamate" refers to a C1-C4 alkyl group attached to the parent molecule via a carbamate (-NHC(O)O-) group.

[0097] The terms "C1-C4 alkylcarbonyl" and "C" as used herein 1-4 "Alkylcarbonyl" refers to a C1-C4 alkyl group attached to the parent molecule via a carbonyl group.

[0098] Terms used in this specification include "C 1-6 "Alkyl sulfonyl" is S(O)2C 1-6 It refers to.

[0099] As used herein, the term "cyano" refers to -CN.

[0100] The terms "C3-C6 cycloalkyl" and "C" as used herein 3-6"Cycloalkyl" refers to a saturated monocyclic ring system having 3 to 6 carbon atoms and 0 heteroatoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). The term "cycloalkyl" also includes groups in which the cycloalkyl ring is fused to a 3, 4, 5, or 6-membered carbon ring. The term "cycloalkyl" also includes cycloalkyl groups further substituted with one or more spirocyclic groups bonded to the cycloalkyl group via a spirocarbon.

[0101] The terms "C3-C6 cycloalkylcarbonyl" and "C" as used herein 3-6 As used herein, "cycloalkylcarbonyl" refers to a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) bonded to the parent molecule via a carbonyl group.

[0102] As used herein, the term "cyclopropylsulfonyl" refers to -SO2-cyclopropyl.

[0103] As used herein, the term "ethylsulfonyl" refers to -S(O)2CH2CH3.

[0104] Terms used in this specification include "C 3-6A "heterocycloalkyl" refers to a 3, 4, 5, or 6-membered saturated ring containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfonyl (-SO2). The term "heterocycloalkyl" also includes groups in which the heterocycloalkyl ring is fused to a 3, 4, 5, or 6-membered carbocyclic ring and a fused bicyclic structure. The term "heterocycloalkyl" also includes heterocycloalkyl groups further substituted with one or more spirocyclic groups bonded to the heterocycloalkyl group via a spirocarbon. Examples of heterocyclyl groups include, but are not limited to, dihydro-1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrroridine-6',1''-cyclopropane], hexahydro-2H-1,4-dioxa-2a1-azacyclopenta[cd]pentarenyl, hexahydropyrrolidinyl, indolinyl, morpholinyl, octahydroindolidine, octahydroquinolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, 1,2-dioxanyl, 1,3-dioxanyl, 1,4-dioxanyl, triemethylenyl oxide, imidazolidinyl, homopiperazinyl, pyrrolinyl, tetrahydrothiofuranyl, and pyranyl.

[0105] Terms used in this specification include "C 3-7 A "heterocycloalkyl" refers to a saturated ring with 3, 4, 5, 6, or 7 members containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfonyl (-SO2). The term "heterocycloalkyl" also includes groups in which a heterocycloalkyl ring is fused to a 3, 4, 5, or 6-membered carbon ring. The term "heterocycloalkyl" also includes heterocycloalkyl groups that are further substituted with one or more spirocyclic groups bonded to the heterocycloalkyl group via a spirocarbon.

[0106] As used herein, the term "amide" refers to -C(O)NH2.

[0107] As used herein, the term "halo" refers to F, Cl, Br, or I.

[0108] The term "C" as used herein 1-4 A "haloalkoxy" refers to a C1-C4 alkoxy group substituted with one, two, or three halogen atoms.

[0109] The term "halo C" as used herein 1-4 "Alkoxycarbonyl" is a carbon group attached to the parent molecule via a carbonyl group. 1-4 This refers to a haloalkoxy group.

[0110] Terms used in this specification include "C 1-4 "Haloalkyl" and "Halo C 1-4 "Alkyl" refers to a C1-C4 alkyl group substituted with one, two, or three halogen atoms.

[0111] The terms "halo C1-C6 alkyl" and "halo C" as used herein 1-6 "Alkyl" refers to a C1-C6 alkyl group substituted with one, two, or three halogen atoms.

[0112] As used herein, the term "halo-C1-C4 alkylcarbonyl" refers to a halo-C1-C4 alkyl group bonded to the parent molecule via a carbonyl group.

[0113] As used herein, the term "hydroxy" refers to -OH.

[0114] Terms used in this specification include "C 1-4 "Hydroxyalkyl," "C1-C4 hydroxyalkyl," and "hydroxy C1-C4 alkyl" refer to a hydroxyl group bonded to the parent molecule via a C1-C4 alkyl group.

[0115] The terms "hydroxy C1-C6 alkyl" and "hydroxy C" as used herein 1-6 "Alkyl" refers to a hydroxyl group bonded to the parent molecule via a C1-C6 alkyl group.

[0116] The terms "hydroxy-halo C1-C6 alkyl" and "hydroxy-halo C" as used herein 1-6 "Alkyl" refers to a C1-C6 alkyl group substituted with one, two, or three halogen atoms and at least one hydroxyl group.

[0117] As used herein, the term "methylsulfonyl" refers to -S(O)2CH3.

[0118] As used herein, the term "methylsulfonyl C1-C6 alkyl" means C 1-6 This refers to a methylsulfonyl group bonded to the parent molecule via an alkyl group.

[0119] As used herein, the term "oxo" refers to =O.

[0120] An additional 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 kinetics. For example, the compounds described herein can be prepared using radioisotopes, and the resulting radiolabeled compounds can be used for the development of binding assays or for metabolic studies. In addition, and for the same purposes, the compounds described herein can be converted to radiolabeled forms by catalytic tritiation using methods known to those skilled in the art.

[0121] The specific compounds of this disclosure exist as stereoisomers. Where stereochemistry is not specified, it should be understood that this disclosure encompasses all stereoisomeric forms, or mixtures thereof, that have the ability to inhibit mutant KRAS. Therefore, unless otherwise indicated, single stereoisomers of the chemicals of the present invention, as well as enantiomers, racemates, and diastereomer mixtures, are within the scope of the invention. Where the stereochemical configuration of a compound is indicated, the diastereomer or enantiomer excess of that compound is at least 90%.

[0122] Individual stereoisomers of a compound can be prepared synthetically from commercially available starting materials containing chiral centers, or they can be prepared by separation after preparation of a mixture of enantiomer products, for example, conversion to a mixture of diastereomers, followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers by chiral chromatography columns. Starting compounds for specific stereochemistrys are commercially available or can be prepared and divided by techniques known in the art.

[0123] Certain compounds of this disclosure exist as atropisomers. The term “atropisomer” refers to a conformational stereoisomer that arises when rotation around a single bond in a molecule is prevented or significantly delayed as a result of steric interactions with other parts of the molecule, and the substituents at both ends of the single bond are asymmetric (i.e., optical activity arises without the need for an asymmetric carbon center or stereocenter). If the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of the isomeric species may be possible. Atropisomers are enantiomers (or epimers) that do not have a single asymmetric atom.

[0124] An atropisomer can be considered stable if the barrier to interconversion is high enough to allow the atropisomer to undergo little to no interconversion at room temperature for at least one week. In some embodiments, an atropisomer undergoes little to no interconversion at room temperature for at least one year. In some embodiments, the atropisomers of the Disclosure undergo no more than about 5% interconversion to their counterpart atropisomer at room temperature for one week when the atropisomer is in a substantially pure form, which is generally in a solid state. In some embodiments, the atropisomers of the Disclosure undergo no more than about 5% interconversion to their counterpart atropisomer at room temperature (approximately 25°C) for one year. In some embodiments, the atropisomers of the Disclosure are sufficiently stable to undergo only about 5% interconversion in an aqueous pharmaceutical formulation held at 0°C for at least one week. The chemical substance, pharmaceutical composition, and method are defined to include all conceivable atropisomers, such as racemic mixtures, diastereomer mixtures, epimer mixtures, optically pure forms of a single atropisomer, and intermediate mixtures.

[0125] The energy barrier to the thermal racemization of atropisomers can be determined by steric hindrance to the free rotation of one or more bonds forming a chiral axis. Certain biaryl compounds exhibit atropisomerism, where rotation around interring bonds lacking C2 symmetry is restricted. The free energy barrier to isomerization (enantiomerization) is a measure of the stability of the interring bonds with respect to rotation. Optical and thermal excitations can facilitate the racemization of such isomers, depending on electronic and steric factors.

[0126] Ortho-substituted biaryl compounds can exhibit rotational isomerism of this type of conformation. Such biaryls exhibit sp between the aryl rings. 2 -sp 2 The carbon-carbon interannular bond has a sufficiently high energy barrier to prevent free rotation, and the substituent W 1 ≠W 2 and W 3 ≠W4 It is a chiral atropisomer of the enantiomer that makes the molecule asymmetrical. [ka]

[0127] W 1 :W 3 , W 1 :W 4 , and / or W 2 :W 4 , W 2 :W 3 The steric interaction between them is large enough to maximize energy in the planar conformation. Two non-planar axial chiral enantiomers exist as atropisomers if their interconversion is slow enough to isolate them without containing each other. The bold and dashed lines in the figure shown above indicate parts of the molecule that are sterically restricted due to rotational energy barriers. The bold parts are perpendicular to the plane of the paper, and the dashed parts are perpendicular to the plane of the paper. The "planar" parts of the molecule (the left-hand ring in each of the two biaryls shown) are in the plane of the paper.

[0128] The pharmaceutical compounds of this disclosure may comprise one or more pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” means a salt that retains the desired biological activity of the parent compound and does not impart any undesirable toxicological effects (see, for example, Berge, S.M. et al., J. Pharm. Sci., 66:1-19 (1977)). Salts may be obtained during the final isolation and purification of the compounds described herein, or separately by reacting the free basic functional group of the compound with a suitable acid, or by reacting the acidic group of the compound with a suitable base. Examples of acid addition salts include non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphorus, as well as those derived from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, aromatic acids, and aliphatic and aromatic sulfonic acids. Examples of base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, and calcium, as well as non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine.

[0129] Pharmaceutical composition In another aspect, the Disclosure provides compositions, such as pharmaceutical compositions, containing one or a combination of the compounds described herein, formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the Disclosure may also be administered in combination therapy, i.e., in combination with other agents described herein.

[0130] As used herein, “pharmaceutically acceptable carrier” includes all physiologically compatible solvents, dispersions, coatings, antimicrobial and antifungal agents, as well as isotonic and absorption retardants. In some embodiments, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or dermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound may be coated with a substance to protect it from the action of acids and other natural conditions that may inactivate the compound.

[0131] The pharmaceutical compositions of this disclosure can be administered via one or more routes of administration using one or more methods known in the art. As will be understood by those skilled in the art, the route of administration and / or mode of administration will vary depending on the desired outcome. In some embodiments, routes of administration for the compounds of this disclosure include, for example, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral administration routes by injection or infusion. As used herein, the term "parenteral administration" means a mode of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intra-articular, intra-orbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, sub-articular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions.

[0132] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound, along with one or a combination of the components listed above as needed, into a suitable solvent, followed by sterile microfiltration. Generally, dispersion systems are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other required components derived from those listed above. For sterile powders for the preparation of sterile injectable solutions, some preparation methods are vacuum drying and freeze-drying, which yield powders of the active ingredient and any additional desired components from the pre-sterile filtered solution.

[0133] Suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils, and injectable organic esters. Appropriate fluidity may be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0134] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is known in the art. Unless any conventional media or agent is incompatible with the active compound, its use in the pharmaceutical compositions of this disclosure is intended. Co-active compounds may also be incorporated into the compositions.

[0135] Therapeutic compositions typically must be sterile and stable under manufacturing and storage conditions. These compositions can be formulated as solutions or liquids with an ordered structure suitable for high drug concentrations. The carrier may 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. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, maintaining the required particle size in the case of dispersions, and the use of surfactants. In many cases, it is desirable to include isotonic agents, such as sugars, polyhydric alcohols, such as mannitol, sorbitol, or sodium chloride, in the composition. Sustained absorption of injectable compositions can be achieved by including absorption-delaying agents, such as monostearate and gelatin, in the composition.

[0136] Alternatively, the compounds of this disclosure may be administered via parenteral routes, such as topical, dermal, or mucosal routes, such as intranasal, oral, vaginal, rectal, sublingual, or topical.

[0137] Any pharmaceutical composition contemplated herein may be delivered orally, for example, through any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, 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 may be prepared according to any method known in the art for producing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable formulation, the pharmaceutical compositions according to this disclosure may contain at least one agent selected from the group consisting of sweeteners, flavoring agents, colorants, lubricants, antioxidants, and preservatives.

[0138] Tablets may be prepared, for example, by mixing at least one compound and / or at least one pharmaceutically acceptable salt thereof described herein with at least one non-toxic, pharmaceutically acceptable excipient suitable for the manufacture of tablets.

[0139] Aqueous suspensions include, for example, at least one compound and / or at least one pharmaceutically acceptable salt thereof as described herein, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersants or wetting agents such as naturally occurring phosphatides such as lecithin; condensation products of alkylene oxides and fatty acids such as polyoxyethylene stearate; and ethylene oxides and long-chain aliphatic compounds. The aqueous suspension may be prepared by mixing with at least one excipient suitable for the production of an aqueous suspension, including, but not limited to, condensation products with ethanol, such as heptadecathylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative, such as ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetener, not limited to, sucrose, saccharin, and aspartame.

[0140] An oily suspension may be prepared, for example, by suspending at least one compound and / or at least one pharmaceutically acceptable salt thereof described herein in a vegetable oil, such as peanut oil, sesame oil, and coconut oil; or a mineral oil, such as liquid paraffin. The oily suspension may also contain at least one thickener, such as beeswax, hard paraffin, and cetyl alcohol. To provide a palatable oily suspension, at least one of the sweeteners and / or at least one flavoring agent already described herein may be added to the oily suspension. The oily suspension may further contain at least one preservative, such as an antioxidant, such as butylated hydroxyanisole and alpha-tocopherol, but not limited to these.

[0141] Dispersible powders and granules may be prepared, for example, by mixing at least one compound and / or at least one pharmaceutically acceptable salt thereof described herein with at least one dispersant and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersants, wetting agents and suspending agents have already been described. Examples of exemplary preservatives include, but are not limited to, antioxidants such as ascorbic acid. In addition, dispersible powders and granules may also contain at least one excipient, including, but not limited to, sweeteners, flavoring agents and colorants.

[0142] The active compound can be prepared by a controlled-release formulation that protects the compound from rapid release, such as an implant, a transdermal patch, and a microencapsulated delivery system. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods for preparing such formulations are patented or generally known to those skilled in the art. See, for example, Robinson, JR, ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0143] The therapeutic compositions may be administered by medical devices known in the art. For example, in one embodiment, the therapeutic compositions of the present disclosure may be administered by needle-free subcutaneous injection devices such as those disclosed in U.S. Patent No. 5,399,163, U.S. Patent No. 5,383,851, U.S. Patent No. 5,312,335, U.S. Patent No. 5,064,413, U.S. Patent No. 4,941,880, U.S. Patent No. 4,790,824, or U.S. Patent No. 4,596,556. Examples of well-known implants and modules useful to this disclosure include: U.S. Patent No. 4,487,603 disclosing an implantable microinfusion pump for dispensing drugs at a controlled rate; U.S. Patent No. 4,486,194 disclosing a therapeutic device for administering drugs through the skin; U.S. Patent No. 4,447,233 disclosing a drug infusion pump for delivering drugs at a precise infusion rate; U.S. Patent No. 4,447,224 disclosing a variable flow implantable infusion device for continuous drug delivery; U.S. Patent No. 4,439,196 disclosing an osmotic drug delivery system having a multi-chamber compartment; and U.S. Patent No. 4,475,196 disclosing an osmotic drug delivery system. These patents are incorporated herein by reference. Many other such implants, delivery systems, and modules are known to those skilled in the art.

[0144] In certain embodiments, the compounds of the present disclosure may be administered parenterally, i.e., by injection and / or infusion, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intra-articular, intra-articular, intra-orbital, intracardiac, intra-tracheal, subcutaneous, subepidermal, intra-articular, sub-articular, subarachnoid, intraspinal, epidural, and intrasternal injections and / or infusions.

[0145] In some embodiments, the compounds of the present disclosure may be administered orally, i.e., via gelatin capsules, tablets, hard capsules or soft capsules, or liquid capsules.

[0146] Use / treatment methods of KRAS inhibitors The administration of therapeutic agents described herein may include the administration of a therapeutically effective dose. As used herein, the term “therapeutic dose” refers to, but is not limited to, the amount of therapeutic agent necessary to treat a condition treatable by the administration of a composition containing a KRAS inhibitor described herein. Such a dose is sufficient to produce a detectable therapeutic effect or an effect leading to improvement. Such effects may include, but are not limited to, the treatment of symptoms listed herein. The exact effective dose for a subject depends on the size and health status of the subject, the nature and severity of the symptoms under treatment, the recommendations of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration.

[0147] The disclosed compounds potently inhibit anchorage-independent cell proliferation and therefore have the potential to inhibit tumor metastasis. In another embodiment, the present disclosure provides a method for inhibiting tumor metastasis, comprising administering a pharmaceutical composition comprising an effective amount of any of the compounds disclosed herein and a pharmaceutically acceptable carrier to a subject requiring inhibition of tumor metastasis.

[0148] Ras mutations, including but not limited to KRAS mutations, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, certain embodiments relate to the administration of the disclosed compounds (e.g., in the form of pharmaceutical compositions) to patients requiring treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the compounds of this disclosure may 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 embodiments, the compounds are useful in treating lymphomas such as Hodgkin lymphoma or all subtypes of non-Hodgkin lymphoma.

[0149] The determination of whether a tumor or cancer contains a KRAS mutation can be made by evaluating the nucleotide sequence encoding the KRAS protein, by evaluating the amino acid sequence of the KRAS protein, or by evaluating the characteristics of the putative KRAS mutant protein. The sequence of the wild-type human KRAS protein is known in the art.

[0150] 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 higher-order structure 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 thawing assays, and microarray analysis. In some embodiments, a sample is evaluated for KRAS mutations, for example, by real-time PCR. In real-time PCR, a fluorescent probe specific to KRAS mutations is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRAS mutations are identified, for example, using direct sequencing of a specific region in the KRAS gene (e.g., exon 2 and / or exon 3). This technique identifies all possible mutations within the sequenced region.

[0151] Methods for detecting mutations in the KRAS protein are known to those skilled in the art. These methods include, but are not limited to, the detection of KRAS variants using mutant protein-specific binders (e.g., antibodies), protein electrophoresis and Western blotting, and direct peptide sequencing.

[0152] A method for determining whether a tumor or cancer contains a KRAS mutation can use various samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is taken from a subject having cancer or a tumor. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to become a cell lysate. In some embodiments, the sample is processed to become DNA or RNA. The Disclosure also relates to a method for treating a mammalian hyperproliferative disorder, comprising administering to the mammal a therapeutically effective amount of a compound of the Disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.In some embodiments, the method is used to treat acute myeloid leukemia, adolescent cancer, pediatric adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical malformations, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical malformations, embryonic tumors, germ cell tumors, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, and more. Intestinal cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonic tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, pregnancy trophoblastic tumors, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic cell tumors, pancreatic neuroendocrine tumors, kidney Internal cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, primary obstructive cancer, metastatic upper neck and gonad cancer with tubal carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytic neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cancer, oropharynx The present invention relates to the treatment of cancers such as cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymic cancer and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, abnormal childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancers. In some embodiments, the present invention relates to the treatment of noncancerous hyperproliferative diseases such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)).

[0153] In certain embodiments, the Disclosure relates to a method for treating lung cancer, comprising administering an effective amount of any of the above compounds (or a pharmaceutical composition containing them) to a subject in need. In certain embodiments, lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In other embodiments, lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, tubular tumors, carcinoid tumors, and undifferentiated carcinomas.Subjects that may be treated with the compounds of the Disclosure, or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates, or derivatives of such compounds, according to the methods of the Disclosure, include, for example, acute myeloid leukemia, adolescent cancers, pediatric adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical malformations, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical malformations, embryonic tumors, germ cell tumors, primary lymphoma, cervical cancer, Childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonic tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, pregnancy trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma Tumors, hypopharyngeal cancer, intraocular melanoma, pancreatic cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, primary obstructive cancer, metastatic squamous neck cancer with uterine duct cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytic neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral This includes individuals diagnosed with cancer, lip and oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymic cancer and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, abnormal childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some embodiments, subjects treated with the compounds of the Disclosure may include subjects diagnosed with noncancerous hyperproliferative diseases such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)). The Disclosure further provides a method for modulating the activity of a mutant KRAS protein by contacting the protein with an effective amount of the compounds of the Disclosure. Modulation may involve inhibiting or activating protein activity. In some embodiments, the Disclosure provides a method for inhibiting protein activity by contacting a mutant KRAS protein with an effective amount of the compounds of the Disclosure in solution. In some embodiments, the Disclosure provides a method for inhibiting the activity of a mutant KRAS protein by contacting cells, tissues, or organs expressing the protein of interest. In some embodiments, the Disclosure provides a method for inhibiting the activity of a protein in subjects, including but not limited to rodents and mammals (e.g., humans), by administering an effective amount of the compounds of the Disclosure to the subjects. In some embodiments, the percentage of regulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibition exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the Disclosure provides a method for inhibiting KRAS activity in cells by contacting cells with an amount of the Compound of the Disclosure sufficient to inhibit the activity of the KRAS variant in the cells. In some embodiments, the Disclosure provides a method for inhibiting variant KRAS in tissue by contacting the tissue with an amount of the Compound of the Disclosure sufficient to inhibit the activity of the variant KRAS in the tissue. In some embodiments, the Disclosure provides a method for inhibiting KRAS in an organism by contacting the organism with an amount of the Compound of the Disclosure sufficient to inhibit the activity of the KRAS in the organism. In some embodiments, the Disclosure provides a method for inhibiting KRAS activity in an animal by contacting the animal with a compound of the Disclosure in an amount sufficient to inhibit the activity of KRAS in the animal.In some embodiments, the Disclosure provides a method for inhibiting KRAS, comprising contacting a mammal with a compound of the Disclosure in an amount sufficient to inhibit the activity of KRAS within the mammal. In some embodiments, the Disclosure provides a method for inhibiting KRAS activity within a human by contacting the human with a compound of the Disclosure in an amount sufficient to inhibit the activity of KRAS within the human. The Disclosure provides a method for treating a disease mediated by KRAS activity in a subject requiring such treatment. The Disclosure also provides a method for combination therapy in which a drug or a duplicate set of target enzymes known to modulate other pathways or other components of the same pathway is used in combination with a compound of the Disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative thereof.

[0154] The compounds may be prepared by methods known in the art, including those described below and variations within the scope of the art of those skilled in the art. Some reagents and intermediates are known in the art. Other reagents and intermediates may be prepared by methods known in the art using readily available substances. Any variables used to describe the synthesis of the compounds (e.g., numbered "R" substituents) are intended to illustrate the method of preparing the compounds and should not be confused with variables used in the claims or other sections of this specification. The methods described below are for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0155] synthesis Abbreviations used herein include: AA = ammonium acetate; ACN or MeCN = acetonitrile; BOC or Boc = tert-butoxycarbonyl; BOP = (benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate); t-Bu or tBu = tert-butyl; CDI = carbonyldiimidazole; DAST = diethylaminosulfur trifluoride; DCM = dichloromethane; DEA = diethanolamine; dF(CF3 )ppy is 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine; DIBAL-H is diisobutylaluminum hydride; DIEA or DIPEA is diisopropylethylamine; DMA is dimethylacetamide; DMAP is N,N-dimethylaminopyridine; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; dppf is 1,1'-bis(diphenylphosphin)ferrocene; dtbbpy is 4,4'-di-tert-butyl-2,2'-bipyridine; EtO Ac is ethyl acetate; EtOH is ethanol; h is time; IPA is isopropanol; LAH is lithium aluminum hydride; LCMS is liquid chromatography-mass spectrometry; LDA is lithium diisopropylamide; LiHMDS is lithium bis(trimethylsilyl)amide; MeOH is methanol; min is minute; MOM is methoxymethyl; NaCNBD3 is sodium cyanoborodehydride; PCC is pyridinium chlorochromate; NMP is N-methylpyrrolidone; Piv is pivaloyl; SNA r is an aromatic nucleophilic substitution reaction; PyBOP is (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; SELECTFLUOR is 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-dium ditetrafluoroborate; TBAF is tetrabutylammonium fluoride; TEA is trimethylamine; TFA is trifluoroacetic acid; Tf2O is trifluoromethanesulfonic anhydride; THF is tetrahydrofuran.

[0156] The compounds described herein can be prepared according to the methods described in the following examples. [Examples]

[0157] Preparation of intermediate 1: (S)-2-((1-phenylethyl)amino)cyclopenta-1-ene-1-carboxylate ethyl [ka] (S)-1-phenylethane-1-amine (109 g, 900 mmol) was added at room temperature to a stirred solution of ethyl 2-oxocyclopentane-1-carboxylate (140.5 g, 900 mmol) in DCM (500 mL) and sieved through a 4 Å molecular weight sieve. The reaction mixture was stirred under reflux for 1 day. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth pad (CELITE®, Sigma Aldrich, St. Louis, MO), and the filtrate was concentrated under reduced pressure to provide a crude residue, which was purified by COMBIFLASH® chromatography (Teledyne ISO, Lincoln, NE) (using 4-5% ethyl acetate / petroleum ether) to obtain 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] + .

[0158] Preparation of intermediate 2: (S,E)-1-(3-ethoxy-3-oxopropyl)-2-(((S)-1-phenylethyl)imino)cyclopentane-1-carboxylate ethyl [ka] A mixture of zinc(II) chloride (473 mL, 898 mmol) and ethyl acrylate (90 g, 898 mmol) in 2-MeTHF at 0°C was to be added dropwise with ethyl(S)-2-((1-phenylethyl)amino)cyclopentaene-1-ene-1-carboxylate (intermediate 1, 233 g, 898 mmol) in THF (233 mL), and the mixture was stirred at 0°C for 16 hours. The reaction mixture was neutralized with saturated NaOH solution and extracted with ELISA (3 x 500 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain ethyl(S,E)-1-(3-ethoxy-3-oxopropyl)-2-(((S)-1-phenylethyl)imino)cyclopentane-1-carboxylate (300 g, 835 mmol, yield 93%) as a colorless oily substance, which was used for the next step without further purification. MS(ESI)m / z:360.1[M+H] + .

[0159] Preparation of intermediate 3: (4aS,7aR)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate ethyl [ka] A mixture of ethyl(S,E)-1-(3-ethoxy-3-oxopropyl)-2-(((S)-1-phenylethyl)imino)-cyclopentane-1-carboxylate (145 g, 403 mmol) and 10% carbon-supported palladium (35 g, 10% w / w) in ethanol (336 mL) was hydrogenated at room temperature for 18 hours under 50 PSI of hydrogen. The reaction mixture was passed through a diatomaceous earth pad (CELITE®, Sigma Aldrich, St. Louis, MO) and filtered. The filtrate was concentrated under reduced pressure to obtain the crude residue, which was purified by COMBIFLASH® chromatography (Teledyne ISO, Lincoln, NE) (using 4-5% ethyl acetate / petroleum ether) to obtain a set of diastereomers. This set was further purified by SFC to obtain the desired isomer, ethyl (4aS,7aR)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (36 g, 170 mmol, yield 42.2%), as a colorless oily substance. MS(ESI)m / z: 211.6[M+H]+. Preparative SFC conditions: Column: Lux i-amylose-3 (5um, 250 x 50mm); Flow rate: 300g / min; Eluent: 0.1% NH4OH and 75% CO2 in 25% methanol; Back pressure: 120 bar; Temperature: 40°C.

[0160] Preparation of intermediate 4: ((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol [ka] A solution of ethyl(4aS)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (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 cooled to 0°C and quenched with water (9.8 mL), 10% NaOH (9 mL), and further water (27 mL). Next, the reaction mixture was heated to room temperature and stirred for 20 minutes. The reaction mixture was then mixed with diatomaceous earth pad (CELITE (商標)The solution was filtered through Sigma Aldrich (St. Louis, MO) and washed with excess siRNA. The filtrate was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain ((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol (17.3 g, 111 mmol, 99% yield) as a white solid, which was used directly for the next step without further purification. MS(ESI)m / z:156.0[M+H] + .

[0161] Preparation of intermediate 5: tert-butyl(4aS,7aR)-4a-(hydroxymethyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] A mixture of ((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol (6.21 g, 40.0 mmol) and di-tert-butyl dicarbonate (8.73 g, 40.0 mmol) in THF (100 mL) was stirred at room temperature for 18 hours. The mixture was concentrated. The crude product was subjected to silica gel chromatography and eluted with 20-40% ethyl acetate in hexane to obtain tert-butyl(4aS,7aR)-4a-(hydroxymethyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (8.1 g, 31.7 mmol, yield 79%) as a clear oil. MS(ESI) m / z: 255.9 [M+H] + .

[0162] Preparation of intermediate 6: 4-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4- Il-1,4-oxazepan [ka] 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 at -40°C, DIPEA (1.38 mL, 7.92 mmol) was added, followed by 1,4-oxazepane (0.401 g, 3.96 mmol). The reaction mixture was stirred at -40°C for 30 minutes. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (using a 40g silica gel column and 50-80% ethyl acetate / petroleum ether) to obtain tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.85g, 2.68 mmol, yield 68%) as a pale yellow solid. MS(ESI)m / z:317.2[M+H] + .

[0163] Preparation of intermediate 7: tert-butyl(4aS,7aR)-4a-(((7-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] Lithium bis(trimethylsilyl)amide (8.20 mL, 8.20 mmol) was added to a solution of 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-1,4-oxazepane (2000 mg, 6.31 mmol) and tert-butyl(4aS,7aR)-4a-(hydroxymethyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1771 mg, 6.94 mmol) in anhydrous THF (50 mL), and the mixture was stirred at room temperature for 6 hours. After concentration, the residue was purified with silica gel and eluted with 50%-80% ethyl acetate in hexane to obtain tert-butyl(4aS,7aR)-4a-(((7-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (2.8 g, 5.22 mmol, yield 83%). MS(ESI)m / z:536.3[M+H] + . 1 H NMR(499MHz,DMSO-d6)δ 8.97-8.90(m,1H),4.44-4.21(m,3H),4.14-4.06(m,4H),3.92-3.78(m,3H ),3.73-3.67(m,2H),2.89-2.73(m,1H),2.04(quin,J=5.4Hz,2H),1.87(br d,J=4.2Hz,1H),1.80-1.68(m,3H),1.67-1.57(m,2H),1.47(br d,J=6.8Hz,4H),1.34(br s,9H).

[0164] Preparation of intermediate 8: tert-butyl(4aS,7aR)-4a-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] A solution of tert-butyl(4aS,7aR)-4a-(((7-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1400 mg, 2.61 mmol) in THF (20 mL) is mixed with tripotassium phosphate (3.92 mL, 7.84 mmol) and commercially available ((2-fluoro-6-(methoxymethyl) Xy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethinyl)triisopropylsilane (2008 mg, 3.92 mmol) was added, and the mixture was degassed for 10 minutes. Then methanesulfonate (diadamantyl-n-butylphosphin)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (190 mg, 0.261 mmol) was added. The mixture was degassed for 10 minutes, and the resulting solution was heated at 65°C for 16 hours. The reaction product was diluted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, then concentrated, and the residue was purified by silica gel column elution with 40-80% ethyl acetate in hexane to obtain tert-butyl(4aS,7aR)-4a-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (2.1 g, 2.370 mmol, yield 91%). MS(ESI)m / z:886.9[M+H] + . 1H NMR(499MHz,DMSO-d6)δ 9.17(d,J=2.5Hz,1H),8.11(dd,J=8.8,5.5Hz,1H),7.75(d,J=2.5Hz,1H),7.57(t,J=8.9Hz,1H),7. 34(t,J=2.4Hz,1H),5.37(s,2H),4.51-4.34(m,1H),4.29-4.22(m,1H),4.21-4.06(m,5H),3.94(br s,2H),3.88-3.70(m,3H),3.44(s,3H),2.93-2.74(m,1H),2.16-2.02(m ,2H),1.93-1.83(m,1H),1.82-1.60(m,5H),1.59-1.52(m,1H),1.46(br s,2H),1.35(br d,J=4.3Hz,9H),0.87-0.80(m,18H),0.52(quin,J=7.4Hz,3H).

[0165] Preparation of intermediate 9: tert-butyl(4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] To a solution of tert-butyl(4aS,7aR)-4a-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (2.1 g, 2.370 mmol) in THF (20 mL), TBAF (7.11 mL, 7.11 mmol) was added, and the reaction mixture was heated at 60 °C for 0.7 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 50-80% ethyl acetate in hexane to obtain tert-butyl(4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1.65 g, 2.261 mmol, yield 95%). MS(ESI)m / z:730.5[M+H] + . 1 H NMR(499MHz,DMSO-d6)δ 9.13-9.08(m,1H),8.10(dd,J=9.2,6.0Hz,1H),7.75(d,J=2.5Hz,1H),7.55(t,J=9.0Hz,1H),7.36(d,J=2.1Hz,1H),5.38(s,2H) ,4.43-4.35(m,1H),4.33-4.21(m,2H),4.19-4.10(m,4H),4.06-4.02(m,1H),3.94(t,J=4.4Hz,2H),3.88-3.79(m,1H),3.76(br t,J=5.0Hz,2H),3.45(s,3H),2.89-2.74(m,1H),2.14-2.07(m,2H),1.91-1. 82(m,1H),1.81-1.68(m,3H),1.67-1.59(m,2H),1.57-1.41(m,4H),1.32(br s,9H).

[0166] Preparation of intermediate 10: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol, HCl [ka] To a solution of tert-butyl(4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1.4 g, 1.918 mmol) in MeCN (20 ml), 4N HCl (5 ml, 10.00 mmol) in dioxane was added at room temperature. After stirring for 45 minutes, the reaction mixture was concentrated to obtain 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol, HCl (1.19 g, 1.913 mmol, yield 100%), which was used without further purification. MS(ESI)m / z:586.3[M+H] + . 1H NMR(499MHz,DMSO-d6)δ 9.66(br d,J=2.9Hz,1H),9.18(s,1H),8.85(br d,J=5.8Hz,1H),8.00(dd,J=9.2,5.9Hz,1H),7.53-7.44(m,2H),7.29(d,J=2.2Hz,1H),4.48(br d,J=11.0Hz,1H),4.29-4.17(m,5H),4.10(d,J=4.4Hz,1H),3.97(br t,J=4.4Hz,2H),3.78(br t,J=4.6Hz,2H),3.74-3.65(m,1H),3.49-3.43(m,1H),3.09(br d,J=6.1Hz,1H),2.82(br d,J=5.0Hz,1H),2.13(br s,3H),2.00-1.58(m,9H).

[0167] Example 1-1: 4-(2-{[(4aS,7aR)-1-[(oxetan-3-yl)methyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol [ka] A solution of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol HCl (20 mg, 0.034 mmol), acetate (9.77 μl, 0.171 mmol), oxetane-3-carbaldehyde (2.94 mg, 0.034 mmol), and sodium triacetoxyborate (21.71 mg, 0.102 mmol) in DMSO (2 mL) was stirred at room temperature for 3 hours. The crude material was purified by preparative reverse-phase chromatography under the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25 °C. Mobile phase A: Acetonitrile / water (5:95), with 10 mM ammonium acetate; Mobile phase B: Acetonitrile / water (95:5), with 10 mM ammonium acetate; Gradient = 0 (min) - 24% B, 20-64% B, 20.1-100% B, 24-100% B. Fractionation recovery was initiated by MS (ESI+). The fractions containing the desired product were combined and dried by centrifugal evaporation to isolate 5-ethynyl-6-fluoro-4-(8-fluoro-4-(1,4-oxazepan-4-yl)-2-(((4aS,7aR)-1-(oxetan-3-ylmethyl)octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (13 mg, 0.020 mmol, yield 57.2%). MS(ESI)m / z:656[M+H] + . 1H NMR(500MHz,DMSO-d6)δ 9.10(s,1H),7.97(dd,J=9.1,6.0Hz,1H),7.46(t,J=9.0Hz,1H),7.39(d,J=2.3Hz, 1H),7.19(s,1H),4.62-4.47(m,3H),4.28-4.07(m,8H),4.00-3.92(m,3H),3.77(br t,J=4.8Hz,2H),3.15-3.07(m,1H),2.83(br t,J=7.6Hz,1H),2.72-2.58(m,2H),2.44-2.37(m,1H),2.30(br dd.

[0168] Examples 1-2: 4-(2-{[(4aS,7aR)-1-[(2S)-3-fluoro-2-hydroxypropyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol [ka] A solution of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol, HCl (20 mg, 0.032 mmol), (S)-2-(fluoromethyl)oxirane (4.89 mg, 0.064 mmol), and DIPEA (0.022 mL, 0.129 mmol) in DMSO (2 mL) was stirred at 80 °C for 16 hours. The crude substance was purified by preparative reverse-phase chromatography under the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25 °C. Mobile phase A: Acetonitrile / water (5:95) with 10 mM ammonium acetate; Mobile phase B: Acetonitrile / water (95:5) with 10 mM ammonium acetate; Gradient = 0 (min) - 22%B, 20-62%B, 20.1-100%B, 24-100%B. Fractionation and recovery were initiated by MS (ESI+). The fractions containing the desired product were combined and dried by centrifugal evaporation to isolate 4-(2-{[(4aS,7aR)-1-[(2S)-3-fluoro-2-hydroxypropyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)-5-ethinyl-6-fluoronaphthalene-2-ol (11.3 mg, 0.017 mmol, yield 51.7%). MS(ESI)m / z:662.6[M+H] + . 1H NMR(500MHz,DMSO-d6)δ 9.10(s,1H),7.98(br dd,J=8.6,6.5Hz,1H),7.47(t,J=9.2Hz,1H),7.40(s,1H),7.19(br s,1H),4.61(br d,J=10.7Hz,1H),4.49-4.39(m,1H),4.34(br dd,J=10.1,4.8Hz,1H),4.27-4.10(m,6H),4.02-3.92(m,3H),3.81-3.69(m,4H),2.89(br t,J=7.5Hz,1H),2.36(br s,2H),2.11(br s,2H),1.93-1.83(m,2H),1.77-1.65(m,1H),1.63-1.49(m,7H),1.49-1.41(m,1H),1.36-1.25(m,1H).

[0169] Preparation of intermediate 11: tert-butyl3-(((4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-yl)methyl)3-hydroxyazetidine-1-carboxylate [ka] A solution of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol, HCl (6 mg, 9.64 μmol), tert-butyl1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (3.57 mg, 0.019 mmol), and DIPEA (6.74 μl, 0.039 mmol) in DMSO (2 mL) was stirred at 80 °C for 3 hours. The crude material was purified by preparative reverse-phase chromatography under the following conditions: column: XBridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C. Mobile phase A: Acetonitrile / water (5:95) with 10 mM ammonium acetate; Mobile phase B: Acetonitrile / water (95:5) with 10 mM ammonium acetate; Gradient = 0 (min) - 39% B, 20-79% B, 20.1-100% B, 24-100% B. Fractionation and recovery were initiated by MS (ESI+). The fractions containing the desired product were combined and dried by centrifugal evaporation to obtain tert-butyl3-(((4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-yl)methyl)-3-hydroxyazetidine-1-carboxylate (5.9 mg, 7.43 μmol, yield 77%). MS(ESI)m / z:771.1[M+H] + . 1H NMR(500MHz,DMSO-d6)δ 9.10(s,1H),7.98(dd,J=8.9,6.1Hz,1H),7.47(t,J=9.0Hz,1H),7.40(s,1H),7.18(s,1H),5.51-5.33(m,1H),4.61(br d,J=10.6Hz,1H),4.28-4.09(m,6H),4.01-3.93(m,3H),3.82-3.69(m,5H),3.63-3.52(m,4H),3.04-2.95(m,1H),2.12(br s, 2H), 1.93-1.82 (m, 2H), 1.78-1.68 (m, 1H), 1.62-1.26 (m, 17H).

[0170] Examples 1-3: Methyl 3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-3-hydroxyazetidine-1-carboxylate [ka] To a solution of tert-butyl 3-(((4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-yl)methyl)-3-hydroxyazetidine-1-carboxylate (20 mg, 0.026 mmol) in MeCN (2 mL), HCl (0.5 mL, 2.000 mmol) in dioxane was added at room temperature. After stirring for 10 minutes, the reaction mixture was concentrated to obtain 3-(((4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-yl)methyl)azetidine-3-ol, HCl, which was used without further purification. To a solution of the crude product above in DMSO (1 mL), DIPEA (0.018 mL, 0.104 mmol) and methyl chloroform (4.02 μl, 0.052 mmol) were added. After stirring for 10 minutes, the reaction was quenched with 0.1 mL of MeOH. The crude material was purified by preparative reverse-phase chromatography under the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25 °C. Mobile phase A: Acetonitrile / water (5:95), with 10 mM ammonium acetate; Mobile phase B: Acetonitrile / water (95:5), with 10 mM ammonium acetate; Gradient = 0 (min) - 34% B, 20-64% B, 20.1-100% B, 24-100% B. Fractionation recovery was initiated by MS (ESI+).The fractions containing the desired product were combined and dried by centrifugal evaporation to isolate methyl 3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}3-hydroxyazetidine-1-carboxylate (3.3 mg, 4.22 μmol, yield 16.27%). MS(ESI)m / z:728.9[M+H]. + .

[0171] Example 1-4(5S)-5-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}pyrrolidine-2-one [ka] A solution of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (10 mg, 0.017 mmol), (S)-5-(bromomethyl)pyrrolidine-2-one (4.56 mg, 0.026 mmol), and DIPEA (8.95 μl, 0.051 mmol) in DMSO (1 mL) was stirred at 80 °C for 3 days. The crude material was purified by preparative reverse-phase chromatography under the following conditions: column: XBridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C. Mobile phase A: Acetonitrile / water (5:95) with 10 mM ammonium acetate; Mobile phase B: Acetonitrile / water (95:5) with 10 mM ammonium acetate; Gradient = 0 (min) - 36% B, 20-76% B, 20.1-100% B, 24-100% B. Fractionation and recovery were initiated by MS (ESI+). The fractions containing the desired product were combined and dried by centrifugal evaporation to obtain (5S)-5-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}pyrrolidine-2-one (1.8 mg, 2.497 μmol, yield 14.62%). MS(ESI)m / z:683.2[M+H] + . 1H NMR(500MHz,DMSO-d6)δ 9.09(s,1H),8.01-7.93(m,1H),7.51-7.42(m,1H),7.40(d,J=2.5Hz,1H),7.19(d,J=2 .3Hz,1H),4.63-4.51(m,1H),4.33-4.23(m,1H),4.21-4.07(m,4H),4.00-3.88(m,4H) ,3.80-3.73(m,2H),3.70-3.58(m,3H),2.95-2.84(m,1H),2.48-2.36(m,3H),2.35-2. 25(m,1H),2.18-1.97(m,5H),1.78-1.49(m,7H),1.47-1.39(m,1H),1.38-1.26(m,1H).

[0172] Preparation of intermediate 12: tert-butyl(4aS,7aR)-4a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] A mixture of tert-butyl(4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (500 mg, 0.685 mmol) and palladium carbon (10%) (100 mg, 0.094 mmol) in MeOH was filled with an H2 balloon. The reaction mixture was stirred at room temperature for 3 hours. The mixture was filtered and concentrated to obtain tert-butyl(4aS,7aR)-4a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (500 mg, 0.681 mmol, yield 99%), which was used in the next step. MS(ESI)m / z:734.5[M+H] + . 1 H NMR(499MHz,DMSO-d6)δ 9.18(s,1H),7.90(dd,J=9.2,6.0Hz,1H),7.68(d,J=2.8Hz,1H),7.44(t,J=9.4Hz,1H),7.20(d,J=2.6Hz, 1H),5.35(s,2H),4.52-4.22(m,3H),4.20-4.11(m,4H),3.94(t,J=4.6Hz,2H),3.89-3.80(m,1H),3.75(br t,J=5.0Hz,2H),3.44(s,3H),2.91-2.73(m,1H),2.44-2.35(m,1H),2.19(ddd,J=14. 0,7.1,3.0Hz,1H),2.12-2.04(m,2H),1.93-1.67(m,4H),1.67-1.56(m,2H),1.48(br d,J=10.3Hz,4H),1.29(br s,9H),0.75(t,J=7.4Hz,3H).

[0173] Preparation of intermediate 13: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalene-2-ol [ka] To a solution of tert-butyl(4aS,7aR)-4a-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (10 mg, 0.014 mmol) in MeCN (2 ml), 4N HCl (0.5 ml, 0.014 mmol) in dioxane was added at room temperature. After stirring for 10 minutes, the reaction mixture was concentrated, and HCl was removed to obtain 5-ethyl-6-fluoro-4-(8-fluoro-2-(((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (8 mg, 0.014 mmol, 100% yield), which was used without further purification. MS(ESI)m / z:590.2[M+H] + . 1H NMR(500MHz,DMSO-d6)δ 9.16(s,1H),7.95(s,1H),7.76(dd,J=8.8,6.1Hz,1H),7.37-7.30(m,2H),7.03(d,J=2.4Hz,1H),4.33(br dd,J=10.7,7.2Hz,1H),4.20-4.11(m,5H),3.94(br t,J=4.3Hz,3H),3.75(br d,J=5.0Hz,2H),3.11(br d,J=2.6Hz,1H),2.61-2.56(m,1H),2.41-2.33(m,1H),2.18-2.05(m,3H),1.96 -1.89(m,1H),1.83-1.72(m,2H),1.71-1.57(m,4H),1.56-1.46(m,3H),0.73(br t,J=7.4Hz,3H).

[0174] Preparation of intermediate 24: 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol [ka] 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.03 g, 12 mmol) and N-ethyl-N-isopropylpropan-2-amine (6.29 mL, 36.0 mmol) were dissolved in DCM (24 mL), to which 6-methyl-1,4-oxazepan-6-ol·HCl (2.012 g, 12.00 mmol) was added at -40°C. The reaction mixture was warmed to room temperature. After stirring for 1 hour, the reaction mixture was quenched with water and diluted with CHCl3. The organic matter was dried over MgSO4, filtered, and concentrated to obtain a solid. The obtained solid was dissolved in ethyl acetate and stirred for 10 minutes. The solid was recovered and washed with ethyl acetate to obtain 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (3.1 g, 8.93 mmol, yield 74.4%) as an orange solid. 1H NMR(499MHz,DMSO-d6)δ 9.49(br s,1H),5.20(s,1H),4.44-4.32(m,1H),4.25(br d,J=14.8Hz,1H),4.07-3.75(m,4H),3.64-3.48(m,2H),1.16(s,3H).MS(ESI)m / z:348.7[M+H] + .

[0175] Preparation of intermediates 25 and 26: tert-butyl(4aS,7aR)-4a-(((7-chloro-8-fluoro-4-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate and tert-butyl(4aS,7aR)-4a-(((7-chloro-8-fluoro-4-((R)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] To a stirred solution of 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (1.5 g, 4.32 mmol) in tetrahydrofuran (20 mL), tert-butyl(4aS,7aR)-4a-(hydroxymethyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1.214 g, 4.75 mmol) and a THF solution of lithium bis(trimethylsilyl)amide (10.80 mL, 10.80 mmol) were added dropwise at 0°C. The resulting reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with an aqueous saturated NaCl solution and extracted with ethyl acetate (50 mL x 2). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the residue was purified using a silica gel column and eluted with ethyl to isolate 1.5 g of the desired product. This substance was then purified using an SFC column (Chiralpak IG column (5 × 25 cm, 5 μm) used, eluted with 45% MeOH and 0.1% NH4OH in CO2; flow rate = 300 ml / min; detector wavelength = 220 nm; temperature = 45 °C, pressure = 100 bar) to obtain intermediate 25, tert-butyl(4aS,7aR)-4a-(((7-chloro-8-fluoro-4-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate(0 0.69g, 1.219 mmol, yield 28.2%, MS(ESI)m / z:566.3[MH]; and intermediate 26, tert-butyl(4aS,7aR)-4a-(((7-chloro-8-fluoro-4-((R)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (0.57g, 1.007 mmol, yield 23.31%), MS(ESI)m / z:566.3[M+H] + It was isolated.

[0176] Preparation of intermediate 27: tert-butyl(4aS,7aR)-4a-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-4-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] In a solution of THF (10 mL) purged with N2, ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.910 g, 1.775 mmol), tert-butyl(4aS,7aR)-4a-(((7-chloro-8-fluoro-4-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (intermediate 25 g, 0.67 g, 1.184 mmol) and potassium phosphate (1.775 mL, 3.55 mmol), cataCXiumRTM A Palladacycle Gen.3 (0.086 g, 0.118 mmol) was added. The reaction mixture was degassed with N2 for 10 minutes, and the resulting solution was heated at 65°C for 24 hours. The reaction mixture was cooled, filtered through a CELITE® (Sigma-Aldrich, St. Louis, MO) pad, and the filtrate was concentrated under reduced pressure to obtain the crude compound. It was purified by silica gel chromatography and eluted with ethyl acetate to isolate tert-butyl(4aS,7aR)-4a-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1 g, 1.091 mmol, 92% yield). MS(ESI)m / z 917.0. [M+H] + .

[0177] Preparation of intermediate 28: tert-butyl(4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] A mixture of tert-butyl(4aS,7aR)-4a-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1 g, 1.091 mmol) and CsF (1.658 g, 10.91 mmol) in acetonitrile (5 mL) was heated at 65°C for 3 hours. The mixture was then concentrated, and ethyl acetate was added. The mixture was filtered, and the filtrate was washed with water. The organic layer was dried over MgSO4, filtered, and concentrated to obtain tert-butyl(4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (0.65 g, 0.855 mmol, yield 78%). MS(ESI)m / z:760.5[M+H] + .

[0178] Intermediate 29: (S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol, HCl [ka] A mixture of tert-butyl(4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-4-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (0.65 g, 0.855 mmol) and 4M HCl (1 mL, 4.00 mmol) / dioxane in acetonitrile (4 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated to obtain (S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol, HCl (0.56 g, 0.859 mmol, 100% yield). MS(ESI)m / z:616.3[M+H] + .

[0179] Example 1-17: 1-(3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-3-hydroxyazetidine-1-yl)ethane-1-one [ka] To a solution of tert-butyl 3-(((4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-yl)methyl)-3-hydroxyazetidine-1-carboxylate (20 mg, 0.026 mmol) in MeCN (2 mL), HCl (0.5 mL, 2.0 mmol) in dioxane was added at room temperature. After stirring for 10 minutes, the reaction mixture was concentrated to obtain crude 3-(((4aS,7aR)-4a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)octahydro-1H-cyclopenta[b]pyridine-1-yl)methyl)azetidine-3-ol (17 mg, 0.025 mmol, yield 98%), which was used without further purification. To a solution of the crude product above in DMSO (1 mL), DIEA (0.018 mL, 0.104 mmol) and acetic anhydride (4.90 μl, 0.052 mmol) were added. After stirring for 10 minutes, the reaction was quenched with 0.1 mL of MeOH and purified by preparative reverse-phase chromatography under the following conditions: Column: XBridge C18, 19 mm × 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction recovery was initiated by MS (ESI+). The fractions containing the desired product were combined and dried by centrifugal evaporation to isolate 1-(3-{[(4aS,7aR)-4a-({[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-yl]methyl}-3-hydroxyazetidine-1-yl)ethane-1-one (5.6 mg, 7.68 μmol, yield 29.6%). See MS(ESI)m / z:713.8. [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 9.10(s,1H),7.97(dd,J=9.1,6.0Hz,1H),7.46(t,J=9.0Hz,1H),7.40(d,J=2.4Hz,1H),7.19(br d,J=1.7Hz,1H),4.60-4.49(m,1H),4.33-4.25(m,1H),4.15(br d,J=2.1Hz,4H),4.03-3.93(m,4H),3.83-3.70(m,5H),3.55-3.47(m,2H),3.07-2.97(m,1H),2.64-2.57(m,2H),2.11(br d,J=4.7Hz,2H),1.93-1.83(m,1H),1.76-1.45(m,11H),1.45-1.38(m,1H),1.37-1.28(m,1H).

[0180] The compounds in Table 1 were prepared from suitable starting materials according to the procedures described in Examples 1-1, 1-2, 1-3, 1-4 and 1-17.

[0181] Examples 1-16, 1-55, 1-56, 1-70, 1-71, 1-76, 1-77, 1-79, 1-80, 1-95, 1-96, 1-99, 1-100, 1-102, 1-103, 1-131, 1-132, 1-134, 1-135, 1-136, 1-137, 1-141, 1-144, 1-205, 1-214, 1-220, 1-221, 1-323, 1-327, 1-331, 1-332, 1-333, and 1-334 were synthesized as diastereomer mixtures. These were purified by Prep-HPLC to obtain pure diastereomer mixtures, which were further purified by either chiral HPLC or SFC as shown to obtain single diastereomers. The superscript following the example number in the table indicates which of the following chiral separation conditions was used: A. CHIRALPAK™ IC (5 x 25 cm, 5 μm, #406191); BPR pressure: 100 bar; temperature: 35 °C; flow rate: 333 mL / min; mobile phase: CO2 / MeOH:MeCN (1:1) and 0.1% NH4OH (55 / 45); detector wavelength: 220 nm. B.CHIRALPAK™ IC (5 x 25cm, 5μm, #123253); BPR pressure: 100bar; temperature: 35℃; flow rate: 180mL / min; mobile phase: CO2 / MeOH:MeCN (1:1) and 0.1% NH4OH (68 / 32); detector wavelength: 220nm. C. Cellulose-2 (3 × 25 cm, 5 μm, #471467); BPR pressure: 100 bar; Temperature: 35 °C; Flow rate: 160 mL / min; Mobile phase: CO2 / MeOH:MeCN (1:1) and 0.1% NH4OH (55 / 45); Detector wavelength: 220 nm. D. Chiralcel IA, 30 mm × 250 mm, 5 μm particles; flow rate: 100.00 mL / min; column temperature: 50°C. Mobile phase A (CO2) (60%), mobile phase B (MeOH containing 0.1% NH4OH) (40%). Fraction recovery was initiated by UV (220 nm). E. Chiralpak AD-H, 30 mm × 250 mm, 5 μm particles; flow rate: 100.00 mL / min; column temperature: 50°C. Mobile phase A (CO2) (70%), mobile phase B (MeOH / ACN (50:50)) (30%). Fraction recovery was initiated by UV (220 nm). G. Chiralpak AS-H, 30 mm × 250 mm, 5 μm particles; flow rate: 100.00 mL / min; column temperature: 50°C. Mobile phase A (CO2) (80%), mobile phase B (MeOH containing 0.1% DEA) (20%). Fraction recovery was initiated by UV (220 nm). J. Chiralpak IG-H, 19 mm × 200 mm, 5 μm particles; flow rate: 100.00 mL / min; column temperature: 50°C. Mobile phase A (CO2) (60%), mobile phase B (MeOH containing 0.1% DEA) (40%). Fraction recovery was initiated by UV (220 nm). K. Chiralpak OJ, 30 mm × 250 mm, 5 μm particles; flow rate: 100.00 mL / min; column temperature: 35°C. Mobile phase A (CO2) (75%), mobile phase B (IPA containing 0.1% DEA) (40%). Fraction recovery was initiated by UV (220 nm). O. Chiralpak AD-H, 30 mm × 250 mm, 5 μm particles; flow rate: 100.00 mL / min; column temperature: 50°C. Mobile phase A (CO2) (60%), mobile phase B (EtOH containing 0.1% DEA) (40%). Fraction recovery was initiated by UV (220 nm). P. Chiralpak IG-H, 30 mm × 250 mm, 5 μm particles; flow rate: 100.00 mL / min; column temperature: 50°C. Mobile phase A (CO2) (65%), mobile phase B (MeOH containing 0.1% DEA) (35%). Fraction recovery was initiated by UV (220 nm). V.XBridge C18, 19mm × 200mm, 5μm particles; flow rate: 20.00mL / min; column temperature: 25℃. Mobile phase A: acetonitrile / water (5:95), with 10mM ammonium acetate; mobile phase B: acetonitrile / water (95:5), with 10mM ammonium acetate; gradient = 0(min)-21%B, 21-61%B, 100-100%B. Fractionation and recovery were initiated by UV (220nm). W.XBridge C18, 19mm × 200mm, 5μm particles; flow rate: 20.00mL / min; column temperature: 25℃. Mobile phase A: acetonitrile / water (5:95), with 10mM ammonium acetate; mobile phase B: acetonitrile / water (95:5), with 10mM ammonium acetate; gradient = 0(min)-30%B, 30-70%B, 100-100%B. Fractionation and recovery were initiated by UV (220nm). Y.XBridge C18, 30mm × 200mm, 5μm particles; flow rate: 50.00mL / min; column temperature: 25℃. Mobile phase A: acetonitrile / water (5:95), with 10mM ammonium acetate; mobile phase B: acetonitrile / water (95:5), with 10mM ammonium acetate; gradient = 0(min)-25%B, 25-55%B, 100-100%B. Fractionation and recovery were initiated by UV (220nm). Z.XBridge C18, 30mm × 200mm, 5μm particles; flow rate: 50.00mL / min; column temperature: 25℃. Mobile phase A: acetonitrile / water (5:95), with 10mM ammonium acetate; mobile phase B: acetonitrile / water (95:5), with 10mM ammonium acetate; gradient = 0(min)-33%B, 33-63%B, 100-100%B. Fractionation recovery was initiated by UV (220nm). AB.XBridge C18, 19mm x 200mm, 5μm particles; flow rate: 20.00mL / min; column temperature: 25℃. Mobile phase A: acetonitrile / water (5:95), with 10mM ammonium acetate; mobile phase B: acetonitrile / water (95:5), with 10mM ammonium acetate; gradient = 0(min)-20%B, 20-60%B, 100-100%B. Fractionation and recovery were initiated by UV (220nm). AC.XBridge C18, 19mm x 200mm, 5μm particles; flow rate: 20.00mL / min; column temperature: 25℃. Mobile phase A: acetonitrile / water (5:95), with 10mM ammonium acetate; mobile phase B: acetonitrile / water (95:5), with 10mM ammonium acetate; gradient = 0(min)-37%B, 37-75%B, 100-100%B. Fractionation and recovery were initiated by UV (220nm). AJ.XBridge C18, 19mm x 200mm, 5μm particles; flow rate: 20.00mL / min; column temperature: 25℃. Mobile phase A: acetonitrile / water (5:95) with 10mM ammonium acetate; mobile phase B: acetonitrile / water (95:5) with 10mM ammonium acetate; gradient = 0(min)-41%B, 41-76%B, 100-100%B. Fractionation recovery was initiated by UV (220nm). AK.Chiralpak IG-H, 30mm × 250mm, 5μm particles; flow rate: 100.00mL / min; column temperature: 50℃. Mobile phase A (CO2) (60%), mobile phase B (MeOH containing 0.1% DEA) (40%). Fraction recovery was initiated by UV (220nm). AL.XBridge C18, 19mm x 200mm, 5μm particles; flow rate: 20.00mL / min; column temperature: 25℃. Mobile phase A: acetonitrile / water (5:95), with 10mM ammonium acetate; mobile phase B: acetonitrile / water (95:5), with 10mM ammonium acetate; gradient = 0(min)-41%B, 41-71%B, 100-100%B. Fractionation and recovery were initiated by UV (220nm). AM.XBridge C18, 19mm x 200mm, 5μm particles; flow rate: 20.00mL / min; column temperature: 25℃. Mobile phase A: acetonitrile / water (5:95), with 10mM ammonium acetate; mobile phase B: acetonitrile / water (95:5), with 10mM ammonium acetate; gradient = 0(min)-32%B, 32-72%B, 100-100%B. Fractionation recovery was initiated by UV (220nm).

[0182] [Table 1]

[0183] [Table 2]

[0184] [Table 3]

[0185] [Table 4]

[0186] [Table 5]

[0187] [Table 6]

[0188] Table 7

[0189] Table 8

[0190] Table 9

[0191] Table 10

[0192] Table 11

[0193] Table 12

[0194] Table 13

[0195] Table 14

[0196] Table 15

[0197] Table 16

[0198] Table 17

[0199] Table 18

[0200] Table 19

[0201] Table 20

[0202] Table 21

[0203] Table 22

[0204] Table 23

[0205] Table 24

[0206] Table 25

[0207] Table 26

[0208] Table 27

[0209] Table 28

[0210] Table 29

[0211] Table 30

[0212] Table 31

[0213] Table 32

[0214] Table 33

[0215] Table 34

[0216] Table 35

[0217] Table 36

[0218] Table 37

[0219] Table 38

[0220] Table 39

[0221] Table 40

[0222] Table 41

[0223] Table 42

[0224] Table 43

[0225] Table 44

[0226] Table 45

[0227] Table 46

[0228] Table 47

[0229] Table 48

[0230] Table 49

[0231] Table 50

[0232] Table 51

[0233] Table 52

[0234] Table 53

[0235] Table 54

[0236] Table 55

[0237] Table 56

[0238] Table 57

[0239] Table 58

[0240] Table 59

[0241] Table 60

[0242] Table 61

[0243] Table 62

[0244] Table 63

[0245] Table 64

[0246] Table 65

[0247] Table 66

[0248] Table 67

[0249] Table 68

[0250] Table 69

[0251] Table 70

[0252] Table 71

[0253] Table 72

[0254] Table 73

[0255] Table 74

[0256] Table 75

[0257] Table 76

[0258] Table 77

[0259] Table 78

[0260] Table 79

[0261] [Table 80]

[0262] [Table 81]

[0263] [Table 82]

[0264] Preparation of intermediate 30: tert-butyl6-methylene-1,4-oxazepane-4-carboxylate [ka] The intermediate tert-butyl6-methylene-1,4-oxazepane-4-carboxylate was synthesized according to the procedure described in the literature: Bioorg. Med. Chem. Lett. 2019, 29, 2405-2409.

[0265] Preparation of intermediate 31: tert-butyl 6-oxo-1,4-oxazepan-4-carboxylate [ka] To a stirred solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate (6 g, 28.1 mmol) in THF (40 mL) and water (40 mL), sodium metaperiodate (12.03 g, 56.3 mmol) was added, followed by the addition of osmium tetroxide solution (2 mL, 0.141 mmol) in tert-butanol at 0°C. The reaction mixture was stirred at room temperature for 16 hours. Next, the reaction mixture was concentrated to obtain the crude product. The mixture was extracted with ELISA (60 mL x 3). The combined extracts were washed with brine, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (pet. ether / siRNA = 30%) to obtain the title compound tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (2 g, 9.29 mmol, yield 33.0%) as a colorless liquid. 1 H NMR (300MHz, CDCl3) δ ppm=4.02-4.17(m,4H),3.91(brd,J =3.78Hz,2H),3.70(brs,2H)1.45(brs,9H).

[0266] Preparation of intermediates 32a and 32b: tert-butyl(S)-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate and tert-butyl(R)-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate [ka] A stirring solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (2.5 g, 11.61 mmol) in THF (150 mL) was added dropwise to a magnesium methyl chloride solution in THF (46.5 mL, 46.5 mmol) at 0°C. The reaction mixture was stirred for 2 hours. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the product. The racemic compound was purified by SFC chiral separation to obtain isomer-1: tert-butyl(S)-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate (1 g, 4.32 mmol, 37.2% yield) and isomer-2: tert-butyl(R)-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate (1 g, 4.32 mmol, 37.2% yield). [Method; Column / Dimensions: CHIRALPAK (trademark) IG (Daicel, Japan) (250 x 50) mm, 5 μm, %CO2: 60%, Cosolvent: 4M methanolic ammonia in 40% MeOH, Total flow rate: 280.0 g / min, Back pressure: 100 bar, Temperature: 40°C, UV: 205 nm, Retention time = 4.15 min (isomer-1) & Retention time = 6.01 min (isomer-2)]. Isomer-1: 1 H NMR (400MHz, DMSO-d6) δ ppm=4.60-4.66(m,1H),3.48-3.73(m,3H),3.35-3.44(m,2H),3.04-3.20(m,3H),1.41(s,9H),1.02-1.15(m,3H). Isomer-2: 1 H NMR (400MHz, DMSO-d6) δ ppm=4.57 -4.73(m,1H),3.49-3.77(m,3H),3.35-3.48(m,2H),3.06-3.25(m,3H),1.41(s,9H),1.07-1.08(m,3H).

[0267] Preparation of intermediates 33a and 33b: (S)-6-methyl-1,4-oxazepan-6-ol hydrochloride and (R)-6-methyl-1,4-oxazepan-6-ol hydrochloride [ka] To a stirred solution of tert-butyl(S)-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate [intermediate 32a (isomer-1), 1 g, 4.32 mmol] in acetonitrile (10 mL), HCl (4 M in dioxane) (5.40 mL, 21.62 mmol) was added. The resulting reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated and simultaneously evaporated with toluene (twice) to obtain (S)-6-methyl-1,4-oxazepane-6-ol hydrochloride (550 mg, 3.28 mmol, yield 76%) as a white solid. MS(ESI)m / z:132.1[M+H] + .

[0268] To a stirred solution of tert-butyl(R)-6-hydroxy-6-methyl-1,4-oxazepan-4-carboxylate [intermediate 32b (isomer-2), 1 g, 4.32 mmol] in acetonitrile (10 mL), HCl (4 M in dioxane) (5.40 mL, 21.62 mmol) was added. The resulting reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated and simultaneously evaporated with toluene (twice) to obtain (R)-6-methyl-1,4-oxazepan-6-ol hydrochloride (550 mg, 3.28 mmol, yield 76%). MS(ESI)m / z: 132.2[M+H] + .

[0269] Preparation of intermediate 43: 1-(tert-butyl)3-methyl5-oxopiperidine-1,3-dicarboxylate [ka] Under an argon atmosphere, at 0°C, 8.18 g of Dess Martin periodinane (19.28 mmol) was added to a stirred solution of 1-(tert-butyl)3-methyl5-hydroxypiperidine-1,3-dicarboxylate (5 g, 19.28 mmol) in 60 mL of DCM. The reaction mixture was gradually warmed to room temperature over 2 hours. The reaction mixture was then quenched with saturated Na2S2O3 aqueous solution, followed by NaHCO3 solution. The reaction mixture was extracted with DCM, the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using COMBIFLASH® chromatography (Teledyne ISO, Lincoln, NE) (15% solvent-solvent, 40g RediSep® silica gel column; silica gel column) to obtain 1-(tert-butyl)3-methyl5-oxopiperidine-1,3-dicarboxylate (3.9g, 15.16 mmol, 79% yield). 1 ¹H NMR (300 MHz, chloroform-d) δ ppm = 3.95 (s, 2H), 3.85-3.72 (m, 2H), 3.60 (s, 3H), 3.12-2.91 (m, 1H), 2.80-2.48 (m, 2H), 1.46-1.29 (m, 9H).

[0270] Preparation of intermediate 44: 1-(tert-butyl)3-methyl5,5-difluoropiperidine-1,3-dicarboxylate [ka] To a stirred solution of 1-(tert-butyl)3-methyl5-oxopiperidine-1,3-dicarboxylate (1 g, 3.89 mmol) in DCM (20 mL) at -78 °C, DAST (1.027 mL, 7.77 mmol) was added, and the reaction mixture was gradually warmed to room temperature over 3 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution, extracted with DCM, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This residue was purified by silica gel chromatography using COMBIFLASH® chromatography (Teledyne ISO, Lincoln, NE) (15% siRNA, 24 g RediSep® silica gel column; evaporative light scattering detection (ELSD) purification). The fraction containing the product was concentrated to obtain 1-(tert-butyl)3-methyl5,5-difluoropiperidine-1,3-dicarboxylate (750 mg, 2.69 mmol, yield 69.1%). 1 ¹H NMR (300 MHz, chloroform-d) δ ppm = 4.57-4.12 (m, 2H), 3.72 (s, 3H), 3.09-2.66 (m, 3H), 2.60-2.39 (m, 1H), 2.15-1.83 (m, 1H), 1.47 (s, 9H).

[0271] Preparation of intermediates 45a and 45b: tert-butyl 3,3-difluoro-5-(hydroxymethyl)piperidine-1-carboxylate [ka] Under an argon atmosphere, at 0°C, a stirred solution of 1-(tert-butyl)3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate (500 mg, 1.790 mmol) in tetrahydrofuran (10 mL) was mixed with 2 M LAH solution (0.716 mL, 1.432 mmol) in THF. The reaction mixture was gradually warmed to room temperature over 2 hours. The reaction mixture was then quenched with saturated Na2SO4 aqueous solution. The reaction mixture was filtered through a CELITE® (SigmaAldrich, St. Louis, MO) pad, washed with RINKAN (50 mL), and the filtrate was concentrated under reduced pressure to obtain the crude residue. This residue was purified by silica gel column chromatography using COMBIFLASH® chromatography (Teledyne ISO, Lincoln, NE) (60% solvent-solvent, 12 g RediSep® silica gel column, ELSD purification) to obtain racemic tert-butyl 3,3-difluoro-5-(hydroxymethyl)piperidine-1-carboxylate as a colorless liquid. The racemic compound was purified by chiral SFC to obtain tert-butyl 3,3-difluoro-5-(hydroxymethyl)piperidine-1-carboxylate, 45a (150 mg, 0.597 mmol, yield 33.3%) and tert-butyl 3,3-difluoro-5-(hydroxymethyl)piperidine-1-carboxylate, 45b (150 mg, 0.597 mmol, yield 33.3%) as colorless liquids. SFC chiral separation method: Peak-1 (45a): retention time 6.3 min; Peak-2 (45b): retention time 7.7 min; column / dimensions Chiralpak AD-H (250 × 4.6) mm, 5 μm; %CO2: 90%; %cosolvent: 10% 0.2% ammonia in MeOH; total flow rate: 2.0 g / min; back pressure: 100 bar; temperature: 35°C; UV: 200 nm. Peak-1 (45a): 1 H NMR(300MHz,DMSO-d6)δ ppm=4.69(t,J=5.21Hz,1H),4.21-3.82(m,2H),3.41-3.32(m,1H),3.30-3.21(m,1H),3.20-3. 05(m,1H),2.73-2.51(m,1H),2.15-1.99(m,1H),1.85-1.55(m,2H),1.40(s,9H).Peak-2(45b):1 H NMR(300MHz,DMSO-d6)δ ppm=4.69(t,J=5.39Hz,1H),4.20-3.81(m,2H),3.43-3.32(m,1H),3.30-3.21(m,1H),3 .20-3.05(m,1H),2.73-2.51(m,1H),2.15-1.99(m,1H),1.86-1.52(m,2H),1.40(s,9H).

[0272] Preparation of intermediate 46a: (5,5-difluoropiperidine-3-yl)methanol hydrochloride [ka] To an ice-cold solution of tert-butyl 3,3-difluoro-5-(hydroxymethyl)piperidine-1-carboxylate (intermediate 45a, 60 mg, 0.239 mmol) in ethyl acetate (0.5 mL), an siRNA solution in 4 M HCl (0.725 mL, 23.88 mmol) was added under an argon atmosphere at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was further triturated with diethyl ether and dried to obtain (5,5-difluoropiperidine-3-yl)methanol hydrochloride (35 mg, 0.232 mmol, yield 97%). 1 H NMR (300MHz, DMSO-d6) δ ppm=11.02-8.01(brs,2H),4.05-4.01(m,1H)3.73-3.53(m,1H),3.45-3.18(m,3H),2.90-2.67(m,1H),2.33-1.75(m,4H).

[0273] Examples 2-7 were synthesized using this fragment.

[0274] Preparation of intermediate 46b: (5,5-difluoropiperidine-3-yl)methanol hydrochloride [ka] To an ice-cold solution of tert-butyl 3,3-difluoro-5-(hydroxymethyl)piperidine-1-carboxylate (intermediate 45b, 60 mg, 0.239 mmol) in ethyl acetate, an siRNA solution in 4 M HCl (7.25 μL, 0.239 mmol) was added under an argon atmosphere at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was further triturated with diethyl ether and dried to obtain (5,5-difluoropiperidine-3-yl)methanol hydrochloride (35 mg, 0.232 mmol, yield 97%). 1 H NMR(300MHz,DMSO-d6)δ ppm=10.52-8.10(brs,2H),4.05-4.01(m,1H)3.71-3.58(m,1H),3.50-3.34(m,3H),3.31-3.16(m,1H),2.84-2.68(m,1H),2.39-1.78(m,4H).

[0275] Examples 2-7 and 2-8 were synthesized using this fragment.

[0276] Preparation of intermediates 47a and 47b: 1-benzyl-3-ethylpiperidine-3-ol [ka] Under an argon atmosphere, at 0°C, a stirred solution of 1-benzylpiperidine-3-one (1 g, 5.28 mmol) in tetrahydrofuran (5 mL) was mixed with ethylmagnesium bromide solution (42.3 mL, 21.14 mmol) in diethyl ether. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude racemic 1-benzyl-3-ethylpiperidine-3-ol (900 mg, 4.10 mmol, yield 78%). The racemic compound was purified by chiral supercritical fluid chromatography (SFC) to obtain peak-1(47a) 1-benzyl-3-ethylpiperidine-3-ol (375 mg, 1.710 mmol, yield 32.4%) and peak-2(47b) 1-benzyl-3-ethylpiperidine-3-ol (395 mg, 1.801 mmol, yield 34.1%). SFC chiral separation method: Peak-1 retention time: 3.41 min; Peak-2 retention time: 4.98 min; Column / dimensions: Chiralpak AD-H (250 × 50) mm, 5 μm; %CO2: 85%; %cosolvent: 0.2% ammonia in 15% MeOH; Total flow rate: 280.0 g / min; Back pressure: 100 bar; Temperature: 30°C; UV: 220 nm. Peak-1(47a): 1 ¹H NMR (400MHz, chloroform-d) δ ppm = 7.43-7.22 (m, 5H), 3.63-3.54 (s, 2H), 3.41-3.24 (m, 1H), 2.87-2.67 (m, 2H), 2.47-2.31 (m, 2H), 2.21-2.06 (m, 1H), 1.99-1.87 (m, 1H), 1.87-1.74 (m, 1H), 1.70-1.45 (m, 5H) [No exchangeable OH protons appeared]. Peak-2 (47b): 1 ¹H NMR (400MHz, chloroform-d) δ ppm = 7.44-7.24 (m,5H), 3.62-3.54 (s,2H), 3.44-3.21 (m,1H), 2.90-2.68 (m,2H), 2.46-2.30 (m,2H), 2.22-2.05 (m,1H), 2.01-1.86 (m,1H), 1.87-1.74 (m,1H), 1.70-1.46 (m,5H) [No exchangeable OH protons appeared].

[0277] Preparation of intermediate 48a: 3-ethylpiperidine-3-ol [ka] Under an argon atmosphere, at room temperature, a stirred solution of 1-benzyl-3-ethylpiperidine-3-ol (intermediate 47a, 375 mg, 1.710 mmol) in MeOH (4 mL) was mixed with Pd-C (184 mg, 1.733 mmol). The reaction mixture was purged with H2 and stirred under an H2 bladder for 6 hours. The reaction mixture was filtered through a CELITE® (Sigma Aldrich, St. Louis, MO) pad, and the filtrate was concentrated under reduced pressure to obtain crude 3-ethylpiperidine-3-ol (195 mg, 1.512 mmol, yield 88%). MS(ESI) m / z: 130.2 [M+H] + .

[0278] Examples 2-6 and 4-7 were synthesized using this fragment.

[0279] Preparation of intermediate 48b: 3-ethylpiperidine-3-ol [ka] Under an argon atmosphere, at room temperature, a stirred solution of 1-benzyl-3-ethylpiperidine-3-ol (intermediate 47b, 380 mg, 1.733 mmol) in MeOH (4 mL) was mixed with Pd-C (184 mg, 1.733 mmol). The reaction mixture was purged with H2 and stirred under an H2 balloon for 6 hours. The reaction mixture was filtered on a CELITE® (Sigma Aldrich, St. Louis, MO) bed, and the filtrate was concentrated under reduced pressure to obtain crude 3-ethylpiperidine-3-ol (200 mg, 1.548 mmol, yield 89%). MS(ESI) m / z: 130.2 [M+H] + .

[0280] Examples 2-5 and 4-8 were synthesized using this fragment.

[0281] Preparation of intermediate 49a: Ethyl (4aS,7aR)-1-methyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate [ka] To a stirred suspension of NaH (3.79 g, 95 mmol) in THF (100 mL) at 0°C, (4aS,7aR)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate ethyl (10 g, 47.3 mmol) was added, and the reaction mixture was stirred for 30 minutes. Then, MeI (3.85 mL, 61.5 mmol) was added, and the mixture was gradually warmed to room temperature over 2 hours. The reaction mixture was then quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (using 30% ethyl acetate / petroleum ether) to obtain ethyl (4aS,7aR)-1-methyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (7.5 g, 33.0 mmol, yield 69.6%). MS(ESI)m / z:226.2[M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm=4.25(q,J=4.0Hz,2H),4.09(t,J=8.0Hz,1H),2.95(s,3H),2.45-2.35(m,3H),2.25-2.08(m,2H),1.92-1.56(m,5H),1.27(t,J=7.2Hz,3H).

[0282] Preparation of intermediate 49b: Ethyl(4aS,7aR)-1-methyl-3-(methylsulfanyl)-2-oxo-octahydro-1H-cyclopenta[b]pyridine-4a-carboxylate [ka] Under an argon atmosphere at -30°C, a stirred solution of ethyl (4aS,7aR)-1-methyl-2-oxo-octahydro-1H-cyclopenta[b]pyridine-4a-carboxylate (800 mg, 3.55 mmol) in THF (20 mL) was mixed with lithium diisopropylamide (LDA) (2 M THF solution) (2.66 mL, 5.33 mmol), and the reaction mixture was stirred for 15 minutes. Then, a solution of S-methylmethanethiosulfonate (0.517 mL, 5.33 mmol) was added, and the resulting reaction mixture was gradually allowed to return to room temperature over 16 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography using COMBIFLASH® chromatography (Teledyne ISO, Lincoln, NE) (40-60% HCl in petroleum ether, 40g RediSep® column, ELSD purification). The fraction containing the desired product was evaporated to obtain ethyl (4aS,7aR)-1-methyl-3-(methylsulfanyl)-2-oxo-octahydro-1H-cyclopenta[b]pyridine-4a-carboxylate (400 mg, 1.474 mmol, yield 41.5%), and ethyl (4aS,7aR)-1-methyl-3-(methylsulfanyl)-2-oxo-octahydro-1H-cyclopenta[b]pyridine-4a-carboxylate (180 mg, 0.663 mmol, yield approximately 9%, purity 50%) as the major isomer. Major isomer: MS(ESI)m / z:272.2[M+H] + 1 H NMR(300MHz,chloroform-d)δ ppm=4.29-4.13(m,2H),4.09-4.00(m,1H),3.33(dd,J=12.4,5.9Hz,1H),3.02-2.94 (m,3H),2.58-2.52(m,1H),2.42-2.26(m,3H),2.15-1.59(m,6H),1.33-1.22(m,4H).

[0283] Intermediate 50: Preparation of ethyl(4aS,7aR)-3-methanesulfonyl-1-methyl-2-oxo-octahydro-1H-cyclopenta[b]pyridine-4a-carboxylate [ka] Under an argon atmosphere, ethyl (4aS,7aR)-1-methyl-3-(methylsulfanyl)-2-oxo-octahydro-1H-cyclopenta[b]pyridine-4a-carboxylate (main isomer 49b, 10.0 g, 17.84 mmol) was stirred in MeOH (5 mL)-water (5 mL). OXONE® (Sigma Aldrich, St. Louis, MO) (1.99 g, 3.24 mmol) was added to the mixture, and the reaction mixture was stirred at room temperature for 2 hours. Next, volatile substances were removed under reduced pressure, and the crude residue was dissolved in ELISA. The organic layer was washed with water and brine, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain crude ethyl (4aS,7aR)-3-methanesulfonyl-1-methyl-2-oxo-octahydro-1H-cyclopenta[b]pyridine-4a-carboxylate (400 mg, 1.319 mmol, yield 81%). MS(ESI)m / z:304.2 (M+H) + ; 1 H NMR(300MHz,chloroform-d)δ ppm=4.26-4.16(m,2H),4.06-3.89(m,2H),3.36(s,3H),2.99(s,3H),2.72-2.66(m, 1H),2.42-2.26(m,2H),2.20-2.07(m,1H),2.04-1.70(m,4H),1.27(t,J=7.2Hz,3H).

[0284] Intermediate 51: [(4aS,7aR)-3-methanesulfonyl-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methanol [ka] Under an argon atmosphere, at 0°C, a stirred solution of ethyl (4aS,7aR)-3-methanesulfonyl-1-methyl-2-oxo-octahydro-1H-cyclopenta[b]pyridine-4a-carboxylate (260 mg, 0.857 mmol) in THF (5 mL) was mixed with 1 M diisobutylaluminum hydride (DIBAL-H) ​​(8.57 mL, 8.57 mmol) in THF, and the mixture was stirred for a further 4 hours. The reaction mixture was quenched with saturated potassium sodium tartrate solution and extracted with EtOAC. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude residue, which was purified by silica gel column chromatography using COMBIFLASH® chromatography (Teledyne ISO, Lincoln, NE) (40-60% ethyl ether in petroleum ether, 12 g RediSep® column, ELSD purification). The fraction containing the desired product was evaporated to obtain [(4aS,7aR)-3-methanesulfonyl-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methanol (60 mg, 0.243 mmol, yield 28.3%). MS(ESI)m / z:248.2[M+H] + ; 1 H NMR(300MHz,chloroform-d)δ ppm=3.83-3.67(m,1H),3.64(s,2H),3.02-2.82(m,2H),2.82-2.78(m,3H ),2.69-2.59(m,1H),2.31(s,3H),1.95-1.54(m,7H),1.42-1.32(m,2H).

[0285] Examples 2-4 were synthesized using this fragment.

[0286] Preparation of intermediates 52a & 52b: Ethyl (3S,4aS,7aR)-3-fluoro-1-methyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate & Ethyl (3R,4aS,7aR)-3-fluoro-1-methyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate [ka] Under an argon atmosphere, at -78°C, a stirred solution of ethyl (4aS,7aR)-1-methyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (5 g, 22.19 mmol) in tetrahydrofuran (50 ml) was mixed with LDA (16.65 ml, 33.3 mmol). The reaction mixture was stirred at -76°C for 60 minutes. Next, a solution of N-fluorobenzenesulfonimide (8.40 g, 26.6 mmol) in tetrahydrofuran (50 mL) was added to the reaction mixture, and the mixture was slowly warmed to 0°C over 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography using a CombiFlash apparatus (25% ethyl acetate / hexane, 120 g RediSep® column, ELSD purification) to obtain the major isomer ethyl(3S,4aS,7aR)-3-fluoro-1-methyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate, intermediate 52a (1.25 g, 5.14 mmol, yield 23.15%) and the secondary isomer ethyl(3R,4aS,7aR)-3-fluoro-1-methyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate, intermediate 52b (500 mg, 2.055 mmol, yield 9.26%). Major isomer: 1 H-NMR(300MHz,chloroform-d)δ ppm=4.90-4.74(m,1H),4.30-4.18(m,2H),4.08(t,J=8.4Hz,1H),2.97(s,3H),2.72-2.63(m ,1H),2.40-2.28(m,1H),2.23-2.05(m,2H),1.98-1.54(m,5H),1.25(t,J=6.0Hz,3H).Minor isomer: 1H NMR(300MHz,chloroform-d)δ ppm=4.92-4.67(m,1H),4.29-4.08(m,3H),3.06-2.97(s,3H),2.59-2.40(m,1H ),2.38-2.10(m,2H),1.95-1.68(m,2H),1.67-1.40(m,3H),1.36-1.16(m,3H).

[0287] Preparation of intermediate 53a: ((3S,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol [ka] Under an argon atmosphere, at 0°C, a stirring solution of ethyl (3S,4aS,7aR)-3-fluoro-1-methyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (3 g, 12.33 mmol) in tetrahydrofuran (60 mL) was added to a mixture of DIBAL-H (61.7 mL, 61.7 mmol) and the mixture was stirred for 2 hours. The reaction mixture was then quenched with saturated aqueous potassium sodium tartrate and stirred at room temperature for 1 hour. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude ((3S,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol (1.8 g, 9.61 mmol, yield 78%), which was then proceeded to the next step without further purification. 1 ¹H NMR (300MHz, chloroform-d) δ ppm = 5.5-5.0 (m,1H), 3.60-3.40 (m,2H), 3.00-2.85 (m,1H), 2.85-2.71 (m,1H), 2.34 (s,3H), 2.04-1.76 (m,3H), 1.74-1.51 (m,4H), 1.49-1.30 (m,2H).

[0288] Preparation of intermediate 53b: ((3R,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol [ka] Under an argon atmosphere, at 0°C, a stirred solution of ethyl (3R,4aS,7aR)-3-fluoro-1-methyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (800 mg, 3.29 mmol) in THF (20 mL) was mixed with lithium aluminum hydride (499 mg, 13.15 mmol) and heated at 75°C for 4 hours. The reaction mixture was cooled to 0°C and quenched with water (1.2 mL), 10% NaOH (3 mL), and water (3 mL). The reaction mixture was then stirred for a further 10 minutes and filtered through a CELITE® (Sigma Aldrich, St. Louis, MO) pad. The CELITE® pad was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain crude ((3R,4aS,7aR)-3-fluoro-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol (400 mg, 2.136 mmol, yield 65.0%) as a colorless liquid. The crude material was used in the next step without further purification. 1 ¹H NMR (300 MHz, chloroform-d) δ ppm = 4.59-4.52 (m, 2H), 3.20-3.10 (m, 2H), 2.90-2.80 (m, 1H), 2.37-2.24 (m, 1H), 2.26 (s, 3H), 2.22-2.03 (m, 2H), 2.01-1.93 (m, 1H), 1.81-1.71 (m, 2H), 1.51-1.49 (m, 3H). (No interchangeable OH protons were found).

[0289] Preparation of intermediates 54a and 54b: Ethyl(4aS,7aR)-3-fluoro-1,3-dimethyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate: [ka] Under an argon atmosphere, LDA (3.70 mL, 7.40 mmol) was added to a stirred solution of ethyl (3R,4aS,7aR)-3-fluoro-1-methyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (1.2 g, 4.93 mmol) in THF (15 mL) at -78°C. The reaction mixture was stirred at -78°C for 1.5 hours, and then a solution of methyl iodide (0.370 mL, 5.92 mmol) in THF (5 mL) was added dropwise. The reaction mixture was gradually warmed to -20°C over 2 hours, and then maintained at the same temperature for another 0.5 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using COMBIFLASH® chromatography (Teledyne ISO, Lincoln, NE) (15-40% ethyl acetate / petroleum ether, 12g RediSep® column, ELSD purification) to obtain isomer-1, ethyl(4aS,7aR)-3-fluoro-1,3-dimethyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (0.6g, 2.332 mmol, yield 47.3%) and isomer-2, ethyl(4aS,7aR)-3-fluoro-1,3-dimethyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (0.1g, 0.389 mmol, yield 7.88%). Isomer-1: 1 H NMR(300MHz,DMSO-d6)δ ppm=4.17-4.08(m,3H),2.86(d,J=0.7Hz,3H),2.42(d,J=3.2Hz,1H),2.37(d,J=2.2Hz ,1H),2.23-2.26(m,1H),2.01-1.88(m,2H),1.81-1.74(m,1H),1.66-1.50(m,2H),1.39 -1.32(s,3H),1.21(t,J=7.2Hz,3H).Isomer-2: 1H NMR(300MHz,DMSO-d6)δ ppm=4.19-3.89(m,3H),2.87(d,J=0.7Hz,3H),2.86-2.72(m,1H),2.48-2.42(m,2H ),2.40-2.07(m,2H),1.92-1.54(m,3H),1.48-1.31(m,3H),1.19(t,J=7.2Hz,3H).

[0290] Preparation of intermediate 55a: ((4aS,7aR)-3-fluoro-1,3-dimethyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol [ka] 55a Under an argon atmosphere, at 0°C, a stirred solution of ethyl (4aS,7aR)-3-fluoro-1,3-dimethyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (intermediate 54a, 200 mg, 0.777 mmol) in THF (2 mL) was mixed with lithium aluminum hydride (73.8 mg, 1.943 mmol) and heated at 50°C for 4 hours. The reaction mixture was cooled to 0°C and quenched with water (0.6 mL), 10% NaOH (1.2 mL), and water (1.2 mL). The reaction mixture was then stirred for 10 minutes, filtered through a CELITE® (SigmaAldrich, St. Louis, MO) pad, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain ((4aS,7aR)-3-fluoro-1,3-dimethyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol (100 mg, 0.497 mmol, yield 63.9%) as a colorless liquid. 1 ¹H NMR (400MHz, chloroform-d): δ ppm = 3.56 (br d, J=11Hz, 1H), 3.41 (d, J=11Hz, 1H), 2.98-2.72 (m, 1H), 2.37-2.24 (m, 3H), 2.22-2.03 (m, 4H), 2.01-1.93 (m, 1H), 1.91-1.71 (m, 2H), 1.68-1.51 (m, 3H), 1.46-1.31 (m, 3H). (No exchangeable OH protons appeared).

[0291] Preparation of intermediate 55b: ((4aS,7aR)-3-fluoro-1,3-dimethyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol [ka] To a stirred solution of ethyl(4aS,7aR)-3-fluoro-1,3-dimethyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (intermediate 54b, 100 mg, 0.389 mmol) in 10 mL of THF at 0°C, lithium aluminum hydride (36.9 mg, 0.972 mmol) was added and the mixture was slowly heated at 50°C for 4 hours. The reaction mixture was cooled to 0°C and quenched with water (0.5 mL), 10% NaOH (1 mL), and water (1 mL). The reaction mixture was then stirred for 10 minutes, filtered through a CELITE® (SigmaAldrich, St. Louis, MO) pad, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain ((4aS,7aR)-3-fluoro-1,3-dimethyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol (65 mg, 0.323 mmol, yield 83%) as a colorless liquid. 1 ¹H NMR (400MHz, chloroform-d) δ ppm = 3.61 (br d, J=11Hz, 1H), 3.44 (d, J=11Hz, 1H), 2.80-2.79 (m, 1H), 2.35-2.22 (m, 3H), 2.20-2.00 (m, 4H), 1.90-1.93 (m, 1H), 1.88-1.69 (m, 2H), 1.62-1.48 (m, 3H), 1.31-1.24 (m, 3H). (No exchangeable OH protons appeared).

[0292] From suitable starting materials, the compounds listed in Table 2 were prepared according to the procedures described herein. The mixture of diastereomers was purified by either chiral HPLC or SFC as described to obtain a single diastereomer. The superscript following the example number in the table indicates which chiral separation conditions were used (described after the table). Compounds listed as diastereomer 1 or diastereomer 2 but without a superscript were purified under the following general conditions: Column information: X-Select C18 (250 × 20 × 5 nm) Mobile phase A: 10 mm ammonium bicarbonate in Milli-Q water pH 9.5 Mobile phase B: ACN;MeOH (1:1) Flow rate: 20 mL / min.

[0293] [Table 83]

[0294] [Table 84]

[0295] [Table 85]

[0296] [Table 86]

[0297] [Table 87]

[0298] [Table 88]

[0299] [Table 89]

[0300] Table 90

[0301] Table 91

[0302] Table 92

[0303] Table 93

[0304] Table 94

[0305] Table 95

[0306] Table 96

[0307] Table 97

[0308] Table 98

[0309] Table 99

[0310] Table 100

[0311] Table 101

[0312] Table 102

[0313] Table 103

[0314] Table 104

[0315] Table 105

[0316] Table 106

[0317] Table 107

[0318] Table 108

[0319] Table 109

[0320] Table 110

[0321] Table 111

[0322] Table 112

[0323] Table 113

[0324] Table 114

[0325] Table 115

[0326] Table 116

[0327] Table 117

[0328] Table 118

[0329] Table 119

[0330] Table 120

[0331] Table 121

[0332] Table 122

[0333] Table 123

[0334] Table 124

[0335] Table 125

[0336] Table 126

[0337] Table 127

[0338] Table 128

[0339] Table 129

[0340] Table 130

[0341] Table 131

[0342] Table 132

[0343] Table 133

[0344] Table 134

[0345] Table 135

[0346] Table 136

[0347] Table 137

[0348] Table 138

[0349] Table 139

[0350] Table 140

[0351] Table 141

[0352] Table 142

[0353] Table 143

[0354] Table 144

[0355] Table 145

[0356] Table 146

[0357] Table 147

[0358] Table 148

[0359] Table 149

[0360] Table 150

[0361] Table 151

[0362] Preparation of intermediate 66: 7-bromo-5-(methoxymethoxy)-2,3-dihydro-1H-inden-1-one [ka] Under a nitrogen atmosphere at 0°C, 7-bromo-5-hydroxy-2,3-dihydro-1H-inden-1-one (1 g, 4.40 mmol) and DIPEA (1.54 mL, 8.81 mmol) were stirred in dichloromethane (20 mL), to which MOM-Cl (0.401 mL, 5.29 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was then diluted with dichloromethane, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a CombiFlash instrument (24 g RediSep® silica gel column, 10% siRNA-PET ether) to obtain 7-bromo-5-(methoxymethoxy)-2,3-dihydro-1H-inden-1-one (1.1 g, 4.02 mmol, 91% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm=7.22(d,J=2.0Hz,1H),7.18(d,J=2.0Hz,1H),5.32(s,2H),3.39(s,3H),3.02-2.99(m,2H),2.64-2.62(m,2H).

[0363] Preparation of intermediate 67: 7-bromo-5-(methoxymethoxy)-1-methylene-2,3-dihydro-1H-indene: [ka] Under a nitrogen atmosphere at 0°C, a stirring solution of methyltriphenylphosphonium bromide (1.32 g, 3.69 mmol) in methyl tert-butyl ether (8 mL) was mixed with 3 M potassium tert-butoxide in THF (1.5 mL, 2.77 mmol) and stirred for 15 minutes. Next, 7-bromo-5-(methoxymethoxy)-2,3-dihydro-1H-inden-1-one (250 mg, 0.92 mmol) was added to the reaction mixture and the mixture was gradually warmed to room temperature over 1 hour. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash instrument (24g RediSep® silica gel column, 10% siRNA-Pet Ether, ELSD) to obtain 7-bromo-5-(methoxymethoxy)-1-methylene-2,3-dihydro-1H-indene (180 mg, 0.67 mmol, yield 72.5%) as a colorless liquid. 1 H NMR(400MHz,DMSO-d6)δ ppm=7.11(d,J=2.4Hz,1H),7.01(d,J=1.2Hz,1H),5.99-5.98(m,1H),5.09-5 .08(m,1H),5.22(s,2H),3.38(s,3H),2.92-2.89(m,2H),2.80-2.75(m,2H).

[0364] Preparation of intermediate 68: 7'-bromo-5'-(methoxymethoxy)-2',3'-dihydrospiro[cyclopropane-1,1'-indene] [ka] Under a nitrogen atmosphere at 0°C, 0.27 mL (3.34 mmol) of diiodomethane (0.27 mL, 3.34 mmol) was added to a stirred solution of 1 M diethylzinc in hexane (4.01 mL, 4.01 mmol) in dichloromethane (3 mL). Next, 180 mg (0.67 mmol) of 7-bromo-5-(methoxymethoxy)-1-methylene-2,3-dihydro-1H-indene (180 mg, 0.67 mmol) was added to the reaction mixture, and the mixture was gradually warmed to room temperature over 3 hours. The reaction mixture was then quenched with water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (12g RediSep® silica gel column, 5% siRNA-PetEther, ELSD) to obtain 7'-bromo-5'-(methoxymethoxy)-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (120 mg, 0.42 mmol, yield 63.4%) as a colorless liquid. 1H NMR(400MHz,DMSO-d6)δ ppm=6.93-6.91(m,2H),5.15(s,2H),3.36(s,3H),2.92(t,J=8.0Hz,2H),2.04(t,J=8.0Hz,2H),1.54(q,J=4.4Hz,2H),0.75(q,J=4.0Hz,2H).

[0365] Preparation of intermediate 69: 2-(5'-(methoxymethoxy)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-7'-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: [ka] To a stirred solution of 7'-bromo-5'-(methoxymethoxy)-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (110 mg, 0.39 mmol) and bis(pinacolato)diborone (128 mg, 0.51 mmol) in 1,4-dioxane (2.5 mL), potassium acetate (114 mg, 1.17 mmol) was added, and the reaction mixture was purged with argon for 5 minutes. Then, Pd(dppf)Cl2.DCM complex (28.4 mg, 0.039 mmol) was added to the reaction mixture, and it was purged again with argon for 3 minutes. The reaction mixture was heated at 80°C for 16 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (12g RediSep® silica gel column, 5% siRNA-PetEther, ELSD) to obtain 2-(5'-(methoxymethoxy)-2',3'-dihydrospiro[cyclopropane-1,1'-inden]-7'-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg, 0.21 mmol, yield 54.6%) as a colorless liquid. 1 H NMR(400MHz,DMSO-d6)δ ppm=6.94(d,J=2.4Hz,1H),6.91(d,J=2.4Hz,1H),5.11(s,2H),3.35(s,3H),2. 88(t,J=7.6Hz,2H),1.98(t,J=7.6Hz,2H),1.27(s,14H),0.77(q,J=4.0Hz,2H).

[0366] Preparation of intermediate 70: 1,1-dimethoxy-3-(methoxymethyl)cyclobutene [ka] Under a nitrogen atmosphere, at 0°C, a stirring solution of (3,3-dimethoxycyclobutyl)methanol (1.0 g, 6.84 mmol) in DMF (8.0 mL) was prepared, to which NaH (0.328 g, 13.68 mmol) was added and the mixture was stirred for 10 minutes. Then, methyl iodide (1.07 g, 7.52 mmol) was added to the reaction mixture, and the mixture was gradually warmed to room temperature over 2 hours. The reaction mixture was quenched with ice-cold water and extracted with siRNA. The organic layer was separated, dried over Na₂SO₄, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (40 g RediSep® silica gel column, 10% solvent-solvent, ELSD) to obtain 1,1-dimethoxy-3-(methoxymethyl)cyclobutane (830 mg, 5.19 mmol, yield 76%) as a colorless liquid. 1 H NMR (300MHz, DMSO-d6) δ ppm=3.31-3.29(m,2H),3.23(s,3H),3.04(s,3H),3.01(s,3H),2.17-2.15(m,3H),1.75-1.72(m,2H).

[0367] Preparation of intermediate 71: 3-(methoxymethyl)cyclobutan-1-one [ka] At room temperature, 830 mg (5.18 mmol) of 1,1-dimethoxy-3-(methoxymethyl)cyclobutane was stirred in 13 mL of diethyl ether and 1 mL of water. 99 mg (0.52 mmol) of p-toluenesulfonic acid monohydrate was added to this mixture and stirred for 2 hours. The reaction mixture was then quenched with water and extracted with diethyl ether. The organic layer was separated, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain 830 mg (crude) of 1,1-dimethoxy-3-(methoxymethyl)cyclobutane as a colorless crude liquid, which was used in the next step without further purification.

[0368] Preparation of intermediate 72: 3-hydroxy-3-methylcyclobutyl pivalate [ka] Under a nitrogen atmosphere at 0°C, a stirred solution of 3-oxocyclobutyl pivalate (500 mg, 2.94 mmol) in tetrahydrofuran (6 mL) was added to 3M methylmagnesium bromide (1.96 mL, 5.88 mmol) in diethyl ether. The reaction mixture was gradually warmed to room temperature over 2 hours. The reaction mixture was then quenched with saturated NH4Cl solution, filtered through a Celite pad, washed with Â, and the filtrate was extracted with Â. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. This was purified by silica gel column chromatography using a CombiFlash apparatus (12 g RediSep® silica gel column, 60% solvent-solvent, ELSD) to obtain a mixture of 3-hydroxy-3-methylcyclobutyl pivalate diastereomers (270 mg, 1.44 mmol, yield 49.3%). 1 H NMR (300MHz, DMSO-d6) δ ppm=5.11-5.10(m,1H),4.57-4.50(m,1H),2.40-2.35(m,2H),2.04-2.02(m,2H),1.21-1.18(m,3H),1.14-1.10(m,9H).

[0369] Preparation of intermediate 73: 1-methylcyclobutane-1,3-diol [ka] Under a nitrogen atmosphere at room temperature, a stirred solution of 3-hydroxy-3-methylcyclobutyl pivalate (270 mg, 1.45 mmol) in methanol (1.5 mL) and water (1.5 mL) was mixed with NaOH (232 mg, 5.80 mmol) and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude residue, which was diluted with ice water and acidified to approximately pH 5 with 1.5 M HCl. The aqueous layer was extracted with dichloromethane, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a diastereomer mixture of 1-methylcyclobutane-1,3-diol (120 mg, 1.18 mmol, 95% yield).

[0370] Preparation of intermediate 74: 3-hydroxy-3-methylcyclobutan-1-one [ka] Under a nitrogen atmosphere at 0°C, Dess-Martin periodinane (519 mg, 1.22 mmol) was added to a stirred solution of 1-methylcyclobutan-1,3-diol (125 mg, 1.22 mmol) in dichloromethane (3.0 mL). The reaction mixture was gradually warmed to room temperature over 2 hours. The reaction mixture was then filtered through a CELITE pad and concentrated to obtain a crude residue. The crude residue was redissolved in Et2O and filtered again through a CELITE pad. The filtrate was evaporated to dryness under reduced pressure to obtain 3-hydroxy-3-methylcyclobutan-1-one (100 mg, 1.01 mmol, 82% yield) as a colorless liquid, which was used in the next step without further purification.

[0371] Intermediate 76: tert-butyl 6-(hydroxymethyl)-1,4-oxazepan-4-carboxylate [ka] Under a nitrogen atmosphere at 0°C, a stirred solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate (3g, 14.07 mmol) in tetrahydrofuran (30 mL) was mixed with 1M BH3.THF complex (14.07 mL, 14.07 mmol) in tetrahydrofuran and gradually warmed to room temperature over 4 hours. The reaction mixture was then cooled to 0°C, and 3N NaOH aqueous solution (4.69 mL, 14.07 mmol) and hydrogen peroxide (2.16 mL, 21.10 mmol) were added sequentially. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a Biotage apparatus (80g RediSep® silica gel column, 0-60% ethyl acetate in petroleum ether, ELSD) to obtain tert-butyl 6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (2.6g, 10.5 mmol, yield 75%) as a colorless liquid. MS(ESI)m / z:132.2[M+H-Boc] + . 1 H NMR(400MHz,CDCl3)δ ppm=3.99(dd,J=14.8,4.0Hz,1H),3.86-3.57(m,8H),3.34(dd,J=14.8,5.2Hz,1H),3.23-3.17(m,1H),2.20-2.16(m,1H),1.50(s,9H).

[0372] Intermediate 77: tert-butyl 6-formyl-1,4-oxazepane-4-carboxylate [ka] Under a nitrogen atmosphere at room temperature, tert-butyl 6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (2.6 g, 11.24 mmol) was stirred in dichloromethane (40 mL), to which Dess Martin periodinane (9.54 g, 22.48 mmol) was added, and the mixture was stirred for 48 hours. The reaction mixture was then filtered through a CELiTE pad, and the filtrate was basicized with a 10% NaHCO3 aqueous solution. The two-phase mixture was extracted with dichloromethane, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude tert-butyl 6-formyl-1,4-oxazepane-4-carboxylate (3 g, crude) as a white gum-like solid.

[0373] Intermediate 78: 4-(tert-butoxycarbonyl)-1,4-oxazepan-6-carboxylic acid [ka] Under a nitrogen atmosphere at 0°C, tert-butyl 6-formyl-1,4-oxazepane-4-carboxylate (3 g, 13.08 mmol) was stirred in t-BuOH (30 mL) and water (6 mL). Sodium chlorite (1.78 g, 19.63 mmol) and sodium dihydrogen phosphate (2.36 g, 19.63 mmol) were added. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was then filtered, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 4-(tert-butoxycarbonyl)-1,4-oxazepane-6-carboxylic acid (1.5 g, 5.98 mmol, yield 45.7%). MS(ESI)m / z:146.6[M+H-Boc] + .

[0374] Preparation of intermediates 79a and 79b: 4-(tert-butyl)6-methyl-1,4-oxazepan-4,6-dicarboxylate [ka] Under an argon atmosphere at 0°C, a stirred solution of 4-(tert-butoxycarbonyl)-1,4-oxazepane-6-carboxylic acid (1.5 g, 6.12 mmol) in DMF (20 mL) was mixed with K2CO3 (1.69 g, 12.23 mmol) and methyl iodide (0.765 mL, 12.23 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a Biotage apparatus (80g RediSep® silica gel column, 0-30% ethyl acetate in petroleum ether, ELSD) to obtain racemic 4-(tert-butyl)6-methyl1,4-oxazepane-4,6-dicarboxylate (700 mg, 2.63 mmol, yield 43.1%) as a colorless liquid. The racemic compound was purified by chiral SFC to obtain 4-(tert-butyl)6-methyl1,4-oxazepane-4,6-dicarboxylate (300 mg, yield 18.90%) as a colorless liquid and 4-(tert-butyl)6-methyl1,4-oxazepane-4,6-dicarboxylate (300 mg, yield 15.09%) as a colorless liquid. SFC chiral separation method: Peak-1 (79a) retention time 4.5 min; Peak-2 (79b) retention time 6.1 min; Column / dimensions: Lux i-amylose-3 (250 × 4.6) mm, 5 μm; %CO2: 70%; 0.1% NH4OH in 30% MeOH; Total flow rate: 3.0 g / min; Back pressure: 100 bar; Temperature: 40°C; UV: 220 nm. Peak-1: MS (ESI) m / z: 160.2 [M + H-Boc] + . 1 H NMR(400MHz,CDCl3)δ ppm=4.18-3.89(m,2H),3.84-3.46(m,10H),3.33-3.21(m,1H),3.14-2.96( m,1H),1.49(s,9H),0.98-0.91(m,1H).Peak-2:MS(ESI)m / z:160.2[M+H-Boc] + . 1H NMR (400MHz, CDCl3) δ ppm=4.18-3.89(m,2H),3.84-3.46(m,10H),3.33-3.21(m,1H),3.14-2.96(m,1H),1.49(s,9H),0.98-0.91(m,1H).

[0375] Preparation of intermediate 80: tert-butyl 6-(2-hydroxypropan-2-yl)-1,4-oxazepan-4-carboxylate [ka] Under a nitrogen atmosphere at 0°C, 300 mg, 1.16 mmol, intermediate 79a of 4-(tert-butyl)6-methyl-1,4-oxazepane-4,6-dicarboxylate was added to a stirred solution of tetrahydrofuran (5 mL) with 3 M MeMgBr (1.55 mL, 4.63 mmol) in diethyl ether. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a Biotage apparatus (40g RediSep® silica gel column, 0-30% ethyl acetate in petroleum ether, ELSD) to obtain tert-butyl 6-(2-hydroxypropan-2-yl)-1,4-oxazepan-4-carboxylate (250 mg, 0.96 mmol, yield 83%) as a colorless liquid. 1 H NMR (400MHz, CDCl3) δ ppm=3.99-3.85(m,2H),3.82-3.51(m,4H),3.47-3.10(m,2H),2.13-1.97(m,1H),1.49(s,9H),1.29(s,3H),1.23(s,3H).

[0376] Preparation of intermediate 81: 2-(1,4-oxazepan-6-yl)propan-2-ol, HCl [ka] Under a nitrogen atmosphere at 0°C, tert-butyl 6-(2-hydroxypropan-2-yl)-1,4-oxazepan-4-carboxylate (250 mg, 0.96 mmol) in dichloromethane (5 mL) was stirred, to which 4 M HCl (1.21 mL, 4.82 mmol) in 1,4-dioxane was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was then concentrated under reduced pressure, the crude residue was triturated with diethyl ether (5 mL), and dried under reduced pressure to obtain 2-(1,4-oxazepan-6-yl)propan-2-ol and HCl (250 mg) as a colorless gum. MS(ESI)m / z:160.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ ppm=9.24(brs,1H),8.89(brs,1H),4.70(brs,1H),3.89-3.78(m,2H),3.75-3.68(m,1H),3.64-3.55(m,3 H),3.38-3.32(m,1H),3.26-3.17(m,1H),3.09-2.93(m,2H),2.26-2.17(m,1H),1.08(s,3H),1.05(s,3H).

[0377] Preparation of intermediate 92: Ethyl (4aS,7aR)-1-benzyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate [ka] Under an argon atmosphere at 0°C, sodium hydride (0.947 g, 23.67 mmol) was added to a stirred solution of ethyl (4aS,7aR)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (5.00 g, 23.67 mmol) in THF, and the mixture was stirred for 1 hour. Then, (bromomethyl)benzene (5.62 mL, 47.30 mmol) was added at 0°C, and the mixture was stirred for a further 2 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, dried, and purified by silica gel column chromatography using a CombiFlash apparatus (80g RediSep® column, 30% siRNA-petroleum ether) to obtain ethyl (4aS,7aR)-1-benzyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (7g, 23.23 mmol, 98% yield) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ ppm=7.27-7.14(m,5H),4.18-3.92(m,2H),2.37(dd,J=7.9,5.4Hz,2H),2.14 -1.92(m,4H),1.89-1.62(m,4H),1.59-1.40(m,2H),1.27-1.03(m,3H).

[0378] Preparation of intermediate 192a: 2,7-dichloro-8-fluoro-N,N-dimethylpyrido[4,3-d]pyrimidine-4-amine [ka] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.0 g, 7.81 mmol) in DCM (25 mL), dimethylamine hydrochloride (0.57 g, 7.03 mmol) and N,N-diisopropylethylamine (5.43 mL, 31.24 mmol) were added under a nitrogen atmosphere at -40°C. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was then quenched with ice-cold water and extracted with DCM. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (40g RediSep® column, 40% SiO2 in pet ether) to obtain 2,7-dichloro-8-fluoro-N,N-dimethylpyrido[4,3-d]pyrimidine-4-amine (1.24g, 4.77 mmol, 68% yield) as a pale yellow solid. MS(ESI)m / z:261.0[M+H] + .

[0379] Preparation of intermediate 192b: tert-butyl(4aS,7aR)-4a-({[7-chloro-4-(dimethylamino)-8-fluoropyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] Under a nitrogen atmosphere at 0°C, a stirring solution of tert-butyl(4aS,7aR)-4a-(hydroxymethyl)-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1.0 g, 3.92 mmol) in THF (15 mL) was added to a THF solution of 1 M LiHMDS (7.84 mL, 7.84 mmol), and the mixture was stirred at the same temperature for 15 minutes. Next, a THF solution of 2,7-dichloro-8-fluoro-N,N-dimethylpyrido[4,3-d]pyrimidine-4-amine (1.01 g, 3.92 mmol) was added to THF (5 mL), and the mixture was gradually warmed to room temperature over 16 hours. The reaction mixture was then quenched with ice-cold water and extracted with DCM. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a CombiFlash apparatus (40g RediSep® column, 30% SiO2 in petroleum ether) to obtain tert-butyl(4aS,7aR)-4a-({[7-chloro-4-(dimethylamino)-8-fluoropyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1.0g, 2.12 mmol, 54% yield) as a pale yellow solid. MS(ESI)m / z:480.4[M+H] + .

[0380] Preparation of intermediate 93: Ethyl(3S,4aS,7aR)-1-benzyl-3-fluoro-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate [ka] Under an argon atmosphere at -78°C, a stirring solution of ethyl (4aS,7aR)-1-benzyl-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (7 g, 23.23 mmol) in THF was mixed with 2 M LDA (17.42 mL, 34.80 mmol) in THF and stirred for 1 hour. Then, N-fluorobenzenesulfonimide (9.52 g, 30.20 mmol) was gradually added and stirred at the same temperature for a further 2 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (120g RediSep® column, 30% siRNA-petroleum ether) to obtain ethyl (4aS,7aR)-1-benzyl-3-fluoro-2-oxo-octahydro-1H-cyclopenta[b]pyridine-4a-carboxylate (2.4g, 7.50 mmol, 32.4%) as a pale yellow liquid. 1 H NMR(300MHz,CDCl3)δ ppm=7.30-7.12(m,5H),5.05-4.72(m,1H),4.19-3.88(m,3H),2.67-2.44(m,1H ),2.26-1.92(m,4H),1.88-1.55(m,4H),1.21-1.03(m,3H),-0.01-0.08(m,1H).

[0381] Intermediate 94: ((3S,4aS,7aR)-1-benzyl-3-fluorooctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol [ka] Under an argon atmosphere at 0°C, a stirring solution of ethyl (4aS,7aR)-1-benzyl-3-fluoro-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (1.0 g, 3.13 mmol) in THF (10 mL) was added to a THF solution of 2 M LAH (6.26 mL, 12.52 mmol) and stirred at room temperature for 15 hours. The reaction mixture was cooled to 0°C and quenched with water (6 mL), 10% NaOH (12 mL), and water (12 mL). The reaction mixture was then stirred for 10 minutes and filtered through a CELITE pad. The CELITE pad was washed with ELISA. The filtrate was concentrated under reduced pressure to obtain [(3S,4aS,7aR)-1-benzyl-3-fluoro-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methanol (450 mg, 1.709 mmol, yield 54.6%) as a colorless liquid. 1 H NMR(400MHz,chloroform-d)δ ppm=7.48-7.19(m,5H),5.30-5.02(m,1H),3.91-3.79(m,1H),3.76-3.53(m,3H),3.13-2 .89(m,2H),2.56-2.41(m,1H),2.14-1.95(m,2H),1.91-1.53(m,5H),1.45-1.32(m,2H).

[0382] Intermediate 99: (1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxylic acid [ka] The intermediate (1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxylic acid was synthesized according to the procedure in the literature: J.Med.Chem.,2022,65,8948-8960.

[0383] Intermediate 100: (1s,3s)-3-(hydroxymethyl)-1-(trifluoromethyl)cyclobutan-1-ol [ka] Under an argon atmosphere at 0°C, a 1M borane-THF complex (9.78 mL, 9.78 mmol) was added to a stirred solution of (1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutan-1-carboxylic acid (450 mg, 2.45 mmol) in THF (9 mL). The reaction mixture was gradually warmed to room temperature over 16 hours. The reaction mixture was then quenched with MeOH. The reaction mixture was diluted with RINKAN, washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (12 g RediSep® column, 80% RINKAN-petroleum ether, ELSD) to obtain (1s,3s)-3-(hydroxymethyl)-1-(trifluoromethyl)cyclobutan-1-ol (380 mg, 2.24 mmol, yield 91%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ ppm=6.32(s,1H),4.60(t,J=5.39Hz,1H),3.43-3.33(m,2H),2.43-2.30(m,2H),2.14-1.97(m,1H),1.97-1.84(m,2H).

[0384] Intermediate 101: (1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbaldehyde [ka] Under an argon atmosphere at room temperature, a stirred solution of (1s,3s)-3-(hydroxymethyl)-1-(trifluoromethyl)cyclobutan-1-ol (170 mg, 1.00 mmol) in DCM (3 mL) was mixed with PCC (431 mg, 2.00 mmol) and stirred for 4 hours. The reaction mixture was then diluted with DCM, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (12 g RediSep® column, 20% EtOAC-Pet ether, ELSD) to obtain (1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutan-1-carbaldehyde (100 mg, 0.60 mmol, yield 59.5%) as a colorless liquid. 1 H NMR (300MHz, DMSO-d6) δ ppm=9.71(s,1H),6.60(s,1H),4.09(d,J=6.46Hz,1H),3.02-2.82(m,1H),2.76-2.56(m,1H),2.39-2.25(m,2H).

[0385] Examples 5-59, 5-60, 5-110, 5-118, and 5-135 were synthesized using this fragment.

[0386] Intermediate 102: (1s, 3s) 3-hydroxy-3-methylcyclobutane-1-carboxylic acid [ka] The intermediate (1s,3s)-3-hydroxy-3-methylcyclobutane-1-carboxylic acid was synthesized according to the procedure described in International Publication No. 2015005901A1.

[0387] Intermediate 103: (1s,3s)-3-(hydroxymethyl)-1-methylcyclobutan-1-ol [ka] Under an argon atmosphere at 0°C, a stirred solution of (1s,3s)-3-hydroxy-3-methylcyclobutan-1-carboxylic acid (180 mg, 1.38 mmol) in THF (5 mL) was mixed with 1 M BH3.THF (6.92 mL, 6.92 mmol) in THF, and the reaction mixture was gradually warmed to room temperature over 16 hours. The reaction mixture was quenched with MeOH, and volatile substances were removed under reduced pressure. The crude residue was dissolved in ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a CombiFlash apparatus (12 g RediSep® column, 40-60% siRNA-petroleum ether, ELSD) to obtain (1s,3s)-3-(hydroxymethyl)-1-methylcyclobutan-1-ol (120 mg, 1.03 mmol, yield 74.7%) as a colorless liquid. 1 H NMR (300MHz, DMSO-d6) δ ppm=4.85-4.63(m,1H),4.50-4.28(m,1H),3.33(d,J=5.4Hz,2H),1.97-1.81(m,3H),1.67(br d,J=9.3Hz,2H),1.20(s,3H).

[0388] Intermediate 104: (1s,3s)-3-hydroxy-3-methylcyclobutane-1-carbaldehyde [ka] Under an argon atmosphere at room temperature, a stirred solution of (1s,3s)-3-(hydroxymethyl)-1-methylcyclobutan-1-ol (120 mg, 1.03 mmol) in DCM (4 mL) was mixed with PCC (445 mg, 2.07 mmol), and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with DCM, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash instrument (12 g RediSep® column, 30-40% siRNA-petroleum ether, ELSD) to obtain (1s,3s)-3-hydroxy-3-methylcyclobutan-1-carbaldehyde (21 mg, 0.18 mmol, yield 17.80%) as a colorless liquid (the desired product is volatile). ¹H NMR (300 MHz, chloroform-d): δ ppm = 9.75-9.71 (m, ¹H), 2.34-2.21 (m, ⁵H), 1.88-1.77 (m, ¹H), 1.44 (s, ³H).

[0389] Preparation of intermediate 105: 6-chloro-4-fluoro-1H-indazole [ka] Under an argon atmosphere at room temperature, 15 g of 4-chloro-2,6-difluorobenzaldehyde (85.00 mmol) was stirred in 56.60 mL of 1,4-dioxane. Hydrazine monohydrate (11.33 mL, 234.00 mmol) was added to the mixture, and the reaction mixture was stirred at 95°C for 16 hours. The reaction mixture was then cooled to room temperature, and water (400 mL) was added. The precipitate was filtered off, washed with additional water, and dried under vacuum. The solid was dissolved in ethyl acetate and dried over anhydrous Na₂SO₄. The resulting mixture was filtered, and the filtrate was concentrated to obtain 6-chloro-4-fluoro-1H-indazole (12 g, 70.40 mmol, yield 83%) as a grayish-white solid. MS(ESI)m / z: 169.0[MH] + ; 1 H NMR (300MHz, DMSO-d6) δ ppm=13.62-13.45(m,1H), 8.27-8.18(m,1H), 7.54-7.47(m,1H), 7.10-7.04(m,1H).

[0390] Preparation of intermediate 106: 6-chloro-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ka] Under an argon atmosphere at room temperature, 15 g, 88.00 mmol of chloro-4-fluoro-1H-indazole and 12.03 ml, 132.00 mmol of 3,4-dihydro-2H-pyran (12.03 ml, 132.00 mmol) were stirred in 176 mL of DCM, to which 1.67 g, 8.79 mmol of 4-methylbenzenesulfonic acid hydrate was added. The resulting mixture was stirred for 2 hours. The reaction mixture was then quenched with ice-cold water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to produce a crude residue, which was purified by silica gel column chromatography using a CombiFlash apparatus (80 g RediSep® column, 5-10% siRNA-petroleum ether) to obtain 6-chloro-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (12 g, 47.10 mmol, yield 53.6%). MS(ESI)m / z:254.9[M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ ppm=8.28(s,1H),7.80(s,1H),7.16(dd,J=9.8,1.3Hz,1H),5.90(dd,J=9.5,2.1Hz ,1H),3.92-3.69(m,2H),2.46-2.26(m,1H),2.13-1.91(m,1H),1.82-1.43(m,4H).

[0391] Preparation of intermediate 107: 6-chloro-4-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ka] Under an argon atmosphere at -78°C, a stirred solution of 6-chloro-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10 g, 39.30 mmol) in THF (100 mL) was mixed with lithium chloride (1.99 g, 47.10 mmol) and LDA (51.0 mL, 102 mmol). The reaction mixture was stirred at the same temperature for 2 hours, and methyl iodide (3.93 mL, 62.80 mmol) was added. The reaction mixture was stirred for a further 1 hour, diluted with aqueous ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (80g RediSep® column, 0-100% siRNA-petroleum ether) to obtain 6-chloro-4-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.2g, 11.91 mmol, yield 76%). MS(ESI)m / z:269.0[M+H] + .

[0392] Preparation of intermediate 108: 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol [ka] Under an argon atmosphere at room temperature, a stirred solution of 6-chloro-4-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.0 g, 29.80 mmol) in DMSO (104 mL) was mixed with water (10.73 mL, 595.00 mmol) and potassium hydroxide (10.02 g, 179.00 mmol). The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was then cooled to room temperature, diluted with water, acidified with 1.5 M HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (80g RediSep® column, 50-100% siRNA-petroleum ether) to obtain 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol (4g, 15.00 mmol, yield 50.4%) as a pale yellow solid. MS(ESI)m / z:267.0[M+H] + .

[0393] Preparation of intermediate 109: 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yltrifluoromethanesulfonate [ka] Under an argon atmosphere at -78°C, a stirred solution of 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol (1 g, 3.75 mmol) and DIPEA (3.93 mL, 22.50 mmol) in DCM (20 mL) was added to Tf2O (0.95 mL, 5.62 mmol), and the mixture was stirred for a further 1 hour. The reaction mixture was then diluted with DCM. The organic layer was sequentially washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to produce a crude residue, which was purified by silica gel column chromatography using a CombiFlash apparatus (40 g RediSep® column, 10-20% siRNA-petroleum ether). The fraction containing the desired product was evaporated to obtain 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yltrifluoromethanesulfonate (1.20 g, 3.01 mmol, 80% yield). MS(ESI)m / z:398.9[M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ ppm=8.21(s,1H),8.11(s,1H),5.95(dd,J=9.6,2.3Hz,1H),3.93-3.73(m, 2H), 2.42(s, 3H), 2.09-1.95(m, 2H), 1.81-1.65(m, 1H), 1.64-1.54(m, 3H).

[0394] Preparation of intermediate 110: 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole [ka] To a degassed solution of 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yltrifluoromethanesulfonate (1.2 g, 3.01 mmol) in 1,4-dioxane (24 mL), bis(pinacolato)diborone (1.91 g, 7.52 mmol), potassium acetate (0.74 g, 7.52 mmol), and PdCl2 (dppf) (0.22 g, 0.30 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was then filtered through a CELITE pad and concentrated under reduced pressure to produce a crude residue, which was purified by silica gel column chromatography using a CombiFlash apparatus (40 g RediSep® column, 0-10% siRNA-petroleum ether). The fraction containing the desired product was evaporated to obtain 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1 g, 2.65 mmol, yield 88%). MS(ESI)m / z:377.3,[M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ ppm=8.18(s,1H),8.00(s,1H),5.85(dd,J=9.6,2.6Hz,1H),3.91-3.70(m,2H),2.59( s, 3H), 2.43-2.30 (m, 1H), 2.08-1.88 (m, 2H), 1.63-1.53 ​​(m, 3H), 1.42-1.35 (m, 12H).

[0395] Intermediate 126: ((1r,3s)-3-methoxy-3-methylcyclobutyl)methanol [ka] The intermediate ((1r,3s)-3-methoxy-3-methylcyclobutyl)methanol was synthesized according to the procedure in the literature: International Publication No. 2017147102A1.

[0396] Intermediate 127: (1r,3s)-3-methoxy-3-methylcyclobutane-1-carbaldehyde [ka] Under an argon atmosphere at room temperature, 248 mg of PCC (1.15 mmol) was added in three portions at 1-hour intervals to a stirred solution of ((1r,3s)-3-methoxy-3-methylcyclobutyl)methanol (50 mg, 0.38 mmol) in 2 mL of DCM. The reaction mixture was diluted with DCM and filtered through a CELITE pad. Volatile substances were removed under reduced pressure to obtain a crude residue, which was redissolved in diethyl ether and filtered. The filtrate was concentrated under reduced pressure to obtain crude (1r,3s)-3-methoxy-3-methylcyclobutane-1-carbaldehyde (45 mg), which was used in the next step without further purification. 1 H NMR (300MHz, DMSO-d6) δ ppm=9.68(s,1H),3.20(s,3H),2.82-2.56(m,1H),2.39-2.21(m,2H),2.21- 1.91(m,2H),1.30(s,3H).

[0397] Preparation of intermediate 142: tert-butyl(3-((tert-butyldiphenylsilyl)oxy)-2-hydroxypropyl)carbamate [ka] Under a nitrogen atmosphere at 0°C, tert-butyl(chloro)diphenylsilane (75 ml, 288 mmol) was added to a stirred solution of tert-butyl(2,3-dihydroxypropyl)carbamate (50 g, 261 mmol) and imidazole (21.36 g, 314 mmol) in DCM. The reaction mixture was stirred at the same temperature for 16 hours. The reaction mixture was then quenched with ice-cold water and extracted in DCM. The combined organic extract was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. This was purified by silica gel column chromatography using a CombiFlash apparatus (240 g RediSep® column, 40-60% siRNA-petroleum ether) to obtain tert-butyl(3-((tert-butyldiphenylsilyl)oxy)-2-hydroxypropyl)carbamate (100 g, 231 mmol, yield 89%) as a colorless gum-like liquid. MS(ESI)m / z:428.7[MH] + .

[0398] Preparation of intermediate 143: tert-butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-methylene-1,4-oxazepane-4-carboxylate [ka] Under a nitrogen atmosphere at 0°C, a stirred solution of tert-butyl(3-((tert-butyldiphenylsilyl)oxy)-2-hydroxypropyl)carbamate (20 g, 46.6 mmol) in THF (200 mL) was mixed with NaH (4.10 g, 102 mmol, approximately 60% dispersed in mineral oil), followed by the addition of 3-chloro-2-(chloromethyl)propa-1-ene (5.82 g, 46.6 mmol). The resulting reaction mixture was slowly allowed to reach room temperature and stirred for 16 hours. The reaction mixture was cooled to 0°C and quenched with ice water. The biphasic layer was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by reverse-phase silica gel flash chromatography [Redisep 415 gm, C18, 20-40 microns; mobile phase A: 5% ammonium formate in water; mobile phase B: acetonitrile (80-100%, flow rate: 100 ml / min)] to obtain tert-butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-methylene-1,4-oxazepane-4-carboxylate (4.2 g, 8.72 mmol, yield 18.7%). MS(ESI) m / z: 482.2 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ ppm=7.68-7.61(m,4H),7.42-7.35(m,6H),5.02-4.89(m,2H),4.65-4.23(m,3H),4 .03-3.97(m,1H),3.75-3.50(m,4H),2.80-2.79(m,1H),1.46(s,9H),1.05(s,9H).

[0399] Preparation of intermediates 144 and 145: tert-butyl(S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-oxo-1,4-oxazepan-4-carboxylate and tert-butyl(R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-oxo-1,4-oxazepan-4-carboxylate [ka] Under a nitrogen atmosphere at room temperature, tert-butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-methylene-1,4-oxazepane-4-carboxylate (4.2 g, 8.72 mmol) was stirred in a 1:1 THF-water (90 mL) mixture. Potassium osmium(VI) dihydrate (0.16 g, 0.44 mmol) and sodium periodate (4.66 g, 21.80 mmol) were added. The reaction mixture was stirred at the same temperature for 16 hours, and the reaction was quenched by adding ice water. The reaction mixture was diluted with ethyl acetate and stirred for a further 15 minutes. The organic layer was separated, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude residue. This was purified by chiral SFC [Chiral SFC method: Column: (R,R)WHELK-O1 (250×4.6) mm, 5 μm; Solvent: 0.1% TFA in IPA; Co-solvent: 20.0%; Flow rate: 3.0 mL / min; Temperature: 40℃; Pressure: 100.0 bar; Retention time of the first eluted isomer - 3.296 min, Retention time of the second eluted isomer - 3.584 min], and the first eluted isomer - 1 (144) As isomer-1, tert-butyl(S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-oxo-1,4-oxazepan-4-carboxylate (2g, 4.13 mmol, yield 47.4%) was obtained, and as the second isomer-2(145), tert-butyl(R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-oxo-1,4-oxazepan-4-carboxylate (2g, 4.13 mmol, yield 47.4%) was obtained as a colorless gum-like liquid. Isomer-1: MS(ESI)m / z:484.2[M+H] + ; 1 H NMR(400MHz,CDCl3)δ ppm=7.70-7.66(m,4H),7.47-7.40(m,6H),4.49-4.42(m,1H),4.28-4.24(m,2H),4.05-3.97(m,2H ),3.87-3.50(m,5H),3.05-2.99(m,1H),1.47(s,9H),1.08(s,9H).Isomer-2:MS(ESI)m / z:484.2[M+H] + ; 1H NMR(400MHz,CDCl3)δ ppm=7.70-7.66(m,4H),7.47-7.40(m,6H),4.49-4.42(m,1H),4.28-4.24(m,2H),4 .05-3.97(m,2H),3.87-3.50(m,5H),3.05-2.99(m,1H),1.47(s,9H),1.08(s,9H).

[0400] Preparation of intermediates 146 and 147: tert-butyl(2R,6S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate and tert-butyl(2R,6R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-hydroxy-6-methyl-1,4-oxazepan-4-carboxylate [ka] Under a nitrogen atmosphere at 0°C, a stirring solution of tert-butyl(R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-oxo-1,4-oxazepane-4-carboxylate (2 g, 4.13 mmol) in THF (30 mL) was added to a 3M MeMgBr diethyl ether solution (1.79 mL, 5.38 mmol). The reaction mixture was gradually warmed to room temperature and stirred for a further 5 hours. The reaction mixture was then cooled to 0°C, quenched with saturated NH4Cl aqueous solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (40g RediSep® column, 10-15% SiO2-petroleum ether) to obtain tert-butyl(2R,6S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate (550 mg, 1.07 mmol, yield 25.8%) as the first eluted diastereomer-1(146) and tert-butyl(2R,6R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate (250 mg, 0.48 mmol, yield 11.7%) as the second eluted diastereomer-2(147), both as colorless, gum-like liquids. MS(ESI)m / z:500.3[M+H] + .

[0401] Intermediate 148: (2R,6S)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol hydrochloride [ka] Under an argon atmosphere at 0°C, 300 mg, 0.66 mmol of tert-butyl(2R,6S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-hydroxy-6-methyl-1,4-oxazepan-4-carboxylate (300 mg, 0.66 mmol) was stirred in 5 mL of DCM, to which 3.00 mL, 12.01 mmol of 4 M HCl in 1,4-dioxane was added. The resulting reaction mixture was gradually warmed to room temperature and stirred for 16 hours. Volatile substances were removed under reduced pressure, and the residue was triturated with diethyl ether to obtain (2R,6S)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol hydrochloride (75 mg, 0.37 mmol, yield 61.3%) as a colorless liquid. MS(ESI)m / z: 162.2[M+H] + .

[0402] Intermediate 179: (6S)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol [ka] Under an argon atmosphere at -40°C, a stirred solution of commercially available 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (5.0 g, 19.81 mmol) in DCM (100 mL) was mixed with DIPEA (10.38 mL, 59.4 mmol) and (S)-6-methyl-1,4-oxazepan-6-ol hydrochloride (3.98 g, 23.77 mmol). The reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then quenched with water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a CombiFlash apparatus (40g RediSep® column, 50-80% siRNA in petroleum ether) to obtain (6S)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (3.5g, 10.08 mmol, yield 50.9%) as a yellow solid. MS(ESI)m / z:347.2[M+H]+ ; 1 H NMR (400MHz, DMSO-d6) δ ppm=9.48 (br s, 1H), 5.20 (s, 1H), 4.41-4.18 (m, 2H), 4.07-3.73 (m, 4H), 3.64-3.47 (m, 2H), 1.15 (s, 3H).

[0403] Intermediate 181: (6S)-6-[(tert-butyldimethylsilyl)oxy]-4-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl}-6-methyl-1,4-oxazepane [ka] Under an argon atmosphere at 0°C, a stirred solution of (6S)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (7.5 g, 21.60 mmol) in DCM (50 mL) was mixed with 2,6-lutidine (5.01 mL, 43.20 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (7.45 mL, 32.40 mmol). The reaction mixture was then gradually warmed to room temperature over 10 hours. The reaction mixture was quenched with water and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (80g RediSep® column, 50% SiO2-petroleum ether) to obtain (6S)-6-[(tert-butyldimethylsilyl)oxy]-4-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl}-6-methyl-1,4-oxazepane (8.0g, 17.34 mmol, yield 80%) as a grayish-white solid. MS(ESI)m / z:461.2[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ ppm=9.19(s,1H),4.40(d,J=14.4Hz,1H),4.19-3.84(m,5H),3.58-3.47(m,2H),1.22(s,3H),0.57(s,9H),0.06-0.01(m,6H).

[0404] Preparation of intermediate 182: tert-butyl(4aS,7aR)-4a-[({4-[(6S)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-4-yl]-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] Under an argon atmosphere at 0°C, a stirring solution of tert-butyl(4aS,7aR)-4a-(hydroxymethyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1.66 g, 6.50 mmol) in THF (25 mL) was added with NaH (0.52 g, 13.00 mmol) and stirred for 30 minutes. Then, (6S)-6-[(tert-butyldimethylsilyl)oxy]-4-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl}-6-methyl-1,4-oxazepane (3.0 g, 6.50 mmol) was added in small amounts, and the reaction mixture was gradually warmed to room temperature over 2 hours. The reaction was quenched with an ice-cooled saturated NH4Cl solution and extracted with ELISA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a CombiFlash apparatus (80g RediSep® column, 5-20% toluene in DCM) to obtain tert-butyl(4aS,7aR)-4a-[({4-[(6S)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-4-yl]-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (3g, 4.41 mmol, yield 67.8%) as a grayish-white solid. MS(ESI)m / z:680.3[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ ppm=9.16(s,1H),4.53-4.36(m,2H),4.35-4.13(m,4H),4.10-3.87(m,4H),3.69-3.57(m,2H),1.99-1.7 3(m,5H),1.70-1.45(m,6H),1.43-1.31(m,9H),1.32-1.18(m,3H),0.71-0.64(m,9H),0.12-0.02(m,6H).

[0405] Intermediate 183: (6S)-4-(2-{[(4aS,7aR)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-chloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane hydrochloride [ka] Under a nitrogen atmosphere at 0°C, tert-butyl(4aS,7aR)-4a-[({4-[(6S)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-4-yl]-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1.7 g, 2.25 mmol) was stirred in acetonitrile (17 mL) and then 4 M HCl (5.62 mL, 22.49 mmol) in 1,4-dioxane was added. The reaction mixture was slowly allowed to reach room temperature and stirred for 3 hours. Next, volatile substances were removed under reduced pressure to obtain a crude residue, which was triturated with petroleum ether and dried to obtain (6S)-4-(2-{[(4aS,7aR)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-chloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane hydrochloride (1.5 g, 1.90 mmol, yield 84%) as a grayish-white solid. MS(ESI)m / z:580.2[M+H] + .

[0406] Intermediate 185: (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane [ka] (6S)-4-(2-{[(4aS,7aR)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-chloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane (1.5 g, 1.95 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (1.96 mL, 9.73 mmol) were stirred in DMSO (10 mL), to which acetic acid (0.5 mL) and MP-cyanoborohydride (4.5 g, 9.73 mmol) were added. The reaction mixture was then stirred at 60 °C for 16 hours. The reaction mixture was filtered through a CELITE pad and washed with DCM. The combined filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a CombiFlash apparatus (24g RediSep® column, 20-30% siRNA in petroleum ether) to obtain (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-chloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane (0.95g, 1.47 mmol, yield 76%) as a grayish-white solid. MS(ESI)m / z:620.2[M+H] + .

[0407] Intermediate 187: (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane [ka] Under a nitrogen atmosphere at room temperature, (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl- To a moderately stirred solution of 1,4-oxazepane (100 mg, 0.16 mmol), 2-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (synthesized as reported in International Publication No. 2023284881) (113 mg, 0.32 mmol) and 1.5 M tripotassium phosphate aqueous solution (0.24 mL, 0.48 mmol) were added. The reaction mixture was purged with nitrogen, and CataCXium A Pd G3 (11.74 mg, 0.02 mmol) was added. The reaction mixture was again purged with nitrogen, and the mixture was heated under microwave conditions at 85°C for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (12g RediSep® column, 30% ethyl acetate in petroleum ether) to obtain (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane (90 mg, 0.09 mmol, yield 55.1%) as a brown solid. MS(ESI)m / z:808.4[M+H] + .

[0408] Intermediate 188: (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol [ka] Under a nitrogen atmosphere at room temperature, a stirred solution of (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane (90 mg, 0.11 mmol) in DMF (2 mL) was mixed with CsF (85 mg, 0.56 mmol) and stirred for 16 hours. The reaction mixture was quenched with water and extracted with ELISA. The organic layer was separated, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (80 mg, 0.06 mmol, yield 56.4%) as a brown solid. MS(ESI)m / z:694.2[M+H] + .

[0409] Example 16-1(6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol [ka] Example 16-1 Under a nitrogen atmosphere at 0°C, a stirred solution of (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (80 mg, 0.06 mmol) in acetonitrile (2 mL) was mixed with 4 M HCl (0.08 mL, 0.32 mmol) in 1,4-dioxane. The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. After completion, the mixture was purified by preparative HPLC [HPLC method: preparative column: X-Bridge C18 (150 mm × 19 mm × 5 μm); mobile phase A: 5 mm ammonium formate in water, pH -3.5; mobile phase B: acetonitrile; flow rate: 15 mL / min; temperature: 27 °C; detection: UV 220 nm] to obtain (6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (200 mg, 0.33 mmol, yield 86%). MS(ESI)m / z:650.2[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ ppm=10.22-10.21(m,1H),9.46(s,1H),7.78-7.69(m,1H),7.62-7.53(m,1H),7.39(s,1H),7. 28-7.20(m,1H),5.15-5.14(m,1H),4.53-4.43(m,1H),4.39-4.27(m,1H),4.25-4.13(m,2H), 4.11-3.83(m,4H),3.61-3.51(m,2H),3.02-2.99(m,1H),2.63-2.57(m,1H),2.07-1.97(m,1H ),1.80-1.29(m,11H),1.16(s,3H),0.46-0.31(m,2H),0.29-0.21(m,1H),0.20-0.12(m,1H).

[0410] Preparation of intermediate 189: tert-butyl(4aS,7aR)-4a-[({4-[(6S)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-4-yl]-7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] Under a nitrogen atmosphere at room temperature, tert-butyl(4aS,7aR)-4a-[({4-[(6S)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-4-yl]-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (400 mg, 0.59 mmol) To a stirred solution of 1,4-dioxane (5 mL), 2-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (synthesized as reported in International Publication No. 2023284881) (185 mg, 0.53 mmol) and 1.18 mL, 1.76 mmol, of 1.5 M tripotassium phosphate aqueous solution were added. The reaction mixture was then purged with nitrogen, and CataCXium A Pd G3 (42.8 mg, 0.06 mmol) was added. The reaction mixture was again purged with nitrogen and heated under microwave conditions at 85°C for 3 hours. The reaction mixture was quenched with water and extracted with RINKAN. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a CombiFlash apparatus (12g RediSep® column, 20% SiO2 in petroleum ether) to obtain tert-butyl(4aS,7aR)-4a-[({4-[(6S)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-4-yl]-7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (350 mg, 0.37 mmol, yield 62.8%) as a brown solid. MS(ESI)m / z:868.3[M+H] + .

[0411] Preparation of intermediate 190: tert-butyl(4aS,7aR)-4a-[({7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-[(6S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] Under a nitrogen atmosphere at room temperature, a stirred solution of tert-butyl(4aS,7aR)-4a-[({4-[(6S)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-4-yl]-7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (350 mg, 0.40 mmol) in DMF (2 mL) was mixed with CsF (306 mg, 2.02 mmol) and stirred for 16 hours. The reaction mixture was then quenched with water and extracted with ELISA. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a Biotage apparatus (12g RediSep® column, 65% SiO2 in petroleum ether) to obtain tert-butyl(4aS,7aR)-4a-[({7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-[(6S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (240 mg, 0.30 mmol, yield 75%) as a colorless gum-like solid. MS(ESI)m / z:754.3[M+H] + .

[0412] Intermediate 191: (6S)-4-(2-{[(4aS,7aR)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol [ka] Under a nitrogen atmosphere at 0°C, tert-butyl(4aS,7aR)-4a-[({7-[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-[(6S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (250 mg, 0.33 mmol) was stirred in acetonitrile (3 mL) to which 4 M HCl (0.9 mL, 3.6 mmol) in 1,4-dioxane was added. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was then quenched with 10% NaHCO3 aqueous solution and extracted by DCM. The organic layer was separated, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain crude (6S)-4-(2-{[(4aS,7aR)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (200 mg, 0.33 mmol, yield 86%). MS(ESI)m / z:610.3[M+H] + .

[0413] Example 16-2(6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol [ka] Under a nitrogen atmosphere at room temperature, (6S)-4-(2-{[(4aS,7aR)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (30 mg, 0.05 mmol) was stirred in THF-MeOH (1 mL, 4:1 mixture), to which 3-methoxycyclobutan-1-one (7.39 mg, 0.07 mmol), acetic acid (0.01 mL), and sodium borocyanohydride (7.73 mg, 0.12 mmol) were added. The reaction mixture was then stirred at 65°C for 3 hours. After completion, the reaction mixture was purified by preparative HPLC [HPLC method: preparative column: Sunfire C18 (150 mm × 19 mm × 5 μm); mobile phase A: 5 mm ammonium formate in water, pH -3.5; mobile phase B: acetonitrile; flow rate: 15 mL / min; temperature: 27 °C; detection: UV 220 nm] to obtain (6S)-4-(2-{[(4aS,7aR)-1-[(1s,3s)-3-methoxycyclobutyl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(7,8-difluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (3.06 mg, 4.32 μmol, yield 8.8%) as a grayish-white solid. MS(ESI)m / z:694.3[M+H] + ; 1H NMR(400MHz,CD3CN)δ ppm=9.45-9.42(m,1H),7.71-7.66(m,1H),7.50-7.39(m,2H),7.38-7.24(m,1H),4.73-4.63(m,1H),4.60-4. 51(m,1H),4.50-4.33(m,2H),4.09-4.02(m,1H),4.01-3.94(m,1H),3.91-3.78(m,2H),3.70-3.64(m,1H),3.6 0-3.52(m,2H), 3.19-3.08(m,3H), 2.66-2.52(m,2H), 2.46-2.34(m,3H), 2.33-2.26(m,2H), 2.25-2.07(m,2H), 2.06-1.99(m,1H), 1.95-1.87(m,1H), 1.81-1.70(m,2H), 1.70-1.47(m,4H), 1.45-1.41(m,1H), 1.26(s,3H). The two OH protons did not appear.

[0414] Example 17-1(6S)-4-(2-{[(4aS,7aR)-1-propyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol [ka] Under a nitrogen atmosphere, 10% Pd-C (224 mg, 0.210 mmol) was added to a stirred solution of ((6S)-4-(2-{[(4aS,7aR)-1-cyclopropyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol) (290 mg, 0.42 mmol) in THF-MeOH (12 mL, 1:1 mixture). The reaction mixture was purged with hydrogen and stirred under a hydrogen bladder for 16 hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to obtain a crude residue. This residue was purified by preparative HPLC [HPLC method: preparative column: X-Bridge C18 (150 mm × 19 mm × 5 μm); mobile phase A: 5 mm ammonium formate in water; mobile phase B: acetonitrile; flow rate: 15 mL / min; temperature: 27 °C; detection: 220 nm UV] to obtain (6S)-4-(2-{[(4aS,7aR)-1-propyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (99 mg, 0.14 mmol, yield 33.2%) as a grayish-white solid. MS(ESI)m / z: 662.2[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ ppm=10.09-9.80(m,1H),9.48(s,1H),7.77(dd,J=9.1,6.0Hz,1H),7.42-7.27(m,2H),7.03(dd,J=13.8,2.6Hz,1H),5.15(br s,1H),4.62(d,J=10.6Hz,1H),4.41-4.16(m,3H),4.11-3.80(m,4H),3.63-3.49(m,2H),2.94(t,J=7.4Hz,1H),2.46-2.27(m,4H),2.23-2 .06(m,1H),1.90-1.79(m,1H),1.76-1.67(m,1H),1.65-1.30(m,11H),1.16(d,J=5.0Hz,3H),0.82(t,J=7.3Hz,3H),0.74(t,J=7.3Hz,3H).

[0415] Preparation of intermediate 192: tert-butyl(4aS,7aR)-4a-({[4-(dimethylamino)-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] To a stirred solution of tert-butyl(4aS,7aR)-4a-({[7-chloro-4-(dimethylamino)-8-fluoropyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1.0 g, 2.08 mmol) in 1,4-dioxane (5 mL), 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.13 g, 3.13 mmol) and 1.5 M tripotassium phosphate aqueous solution (4.17 mL, 6.25 mmol) were added at room temperature, and the reaction mixture was purged with nitrogen. Next, CataCXium A Pd G3 (0.15 g, 0.21 mmol) was added to the reaction mixture, purged with nitrogen, and heated under microwave conditions at 80°C for 2 hours. The reaction mixture was quenched with water and extracted with toluene. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a Biotage apparatus (40g RediSep® column, 80% SiO2 in petroleum ether) to obtain tert-butyl(4aS,7aR)-4a-({[4-(dimethylamino)-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1.2g, 1.24 mmol, yield 59.5%) as a grayish-white solid. MS(ESI)m / z:678.4[M+H] + .

[0416] Preparation of intermediate 193: tert-butyl(4aS,7aR)-4a-[({7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] Under a nitrogen atmosphere, a stirred solution of tert-butyl(4aS,7aR)-4a-({[4-(dimethylamino)-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-2-yl]oxy}methyl)-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (1.18 g, 1.22 mmol) in DMSO (3 mL) was mixed with 5N sodium hydroxide aqueous solution (2.44 mL, 12.19 mmol), and the reaction mixture was heated at 80 °C for 1 hour. The reaction mixture was then diluted with ice-cold water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a CombiFlash apparatus (12g RediSep® column, 60% siRNA in petroleum ether) to obtain tert-butyl(4aS,7aR)-4a-[({7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (600 mg, 0.82 mmol, yield 67.3%) as a grayish-white solid. MS(ESI)m / z:651.2[M+H] + .

[0417] Preparation of intermediate 194: tert-butyl(4aS,7aR)-4a-[({7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-[(2R,6S)-6-hydroxy-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] Under a nitrogen atmosphere at 0°C, tert-butyl(4aS,7aR)-4a-[({7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (200 mg, 0.31 mmol) was stirred in acetonitrile (2 mL) to which (2R,6S)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol hydrochloride (91 mg, 0.46 mmol), DIPEA (0.27 mL, 1.54 mmol), and PyBOP (400 mg, 0.77 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a Biotage apparatus (40g RediSep® column, 100% SiO2 in petroleum ether) to obtain tert-butyl(4aS,7aR)-4a-[({7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-[(2R,6S)-6-hydroxy-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (220 mg, 0.23 mmol, yield 76%) as a brown solid. MS(ESI)m / z:794.3[M+H] + .

[0418] Intermediate 195: (2R,6S)-4-(2-{[(4aS,7aR)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol hydrochloride [ka] Under a nitrogen atmosphere at 0°C, tert-butyl(4aS,7aR)-4a-[({7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-[(2R,6S)-6-hydroxy-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (220 mg, 0.23 mmol) was stirred in acetonitrile (3 mL), to which 4M HCl (0.58 mL, 2.33 mmol) in 1,4-dioxane was added. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. Next, volatile substances were removed under reduced pressure to obtain a crude residue, which was triturated with petroleum ether and dried to obtain the hydrochloride salt of (2R,6S)-4-(2-{[(4aS,7aR)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol as a light brown solid. MS(ESI)m / z:650.2[M+H] + .

[0419] Example 18-1(2R,6S)-4-(2-{[(4aS,7aR)-1-{2-oxaspiro[3,3]heptan-6-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol [ka] Under a nitrogen atmosphere at room temperature, (2R,6S)-4-(2-{[(4aS,7aR)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol (25 mg, 0.04 mmol) was stirred in THF-MeOH (0.5 mL, 4:1 mixture), to which 2-oxaspiro[3.3]heptan-6-one (6.47 mg, 0.06 mmol), acetic acid (0.02 mL), and sodium borocyanohydride (7.25 mg, 0.12 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours, and then preparative HPLC was performed [HPLC method: preparative column: X-Bridge]. The sample was purified using C18 (150mm × 19mm × 5μm); mobile phase A: 5mm ammonium bicarbonate in water, pH -3.5; mobile phase B: acetonitrile; flow rate: 15mL / min; temperature: 27℃; detection: UV 220nm) to obtain (2R,6S)-4-(2-{[(4aS,7aR)-1-{2-oxaspiro[3.3]heptan-6-yl}-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol (4.7mg, 5.94μmol, yield 15.4%) as a grayish-white solid. MS(ESI)m / z:746.3[M+H] + ; 1H NMR(400MHz,CD3CN)δ ppm=9.46-9.45(m,1H),7.75(dd,J=9.1,5.9Hz,1H),7.37(d,J=2.6Hz,1H),7.32(t,J=9.4Hz,1H),7.20-7.03(m,1H) ),5.03-4.87(m,1H),4.76-4.68(m,1H),4.66-4.52(m,2H),4.46-4.31(m,1H),4.08-3.98(m,1H),3.93-3.86(m,1H) ,3.68-3.53(m,3H),3.51-3.41(m,2H),3.14-3.13(m,3H),2.72-2.59(m,2H),2.46-2.38(m,2H),2.29-2.23(m,2H),1.93-1.90(m,1H),1.81-1.70(m,4H),1.70-1.45(m,7H),1.46-1.39(m,2H),1.31-1.29(m,3H),0.90-0.75(m,3H). The three OH protons are, 1 It did not appear in 1H NMR.

[0420] Preparation of intermediate 196: tert-butyl 1,5-dioxa-8-azaspiro[2.6]nonane-8-carboxylate [ka] Under an argon atmosphere, a stirring solution of trimethylsulfonium iodide (6.16 g, 30.20 mmol) in DMSO (50 mL) at 0°C was mixed with 60% NaH (1.21 g, 30.20 mmol) in mineral oil and stirred for 10 minutes. Next, a solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (5.0 g, 23.23 mmol) in DMSO (5 mL) was added to the reaction mixture and the mixture was gradually warmed to room temperature over 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude tert-butyl 1,5-dioxa-8-azaspiro[2.6]nonane-8-carboxylate (5.0 g, 21.81 mmol, yield 94%) as a brown liquid. 1H NMR (400MHz, DMSO-d6) δ ppm=3.88-3.80(m,1H),3.77-3.47(m,5H),3.43-3.26(m,2H),2.81-2.59(m,2H),1.41(s,9H).

[0421] Preparation of intermediate 197: tert-butyl 6-(aminomethyl)-6-hydroxy-1,4-oxazepan-4-carboxylate [ka] Under an argon atmosphere, at 0°C, a stirred solution of tert-butyl 1,5-dioxa-8-azaspiro[2.6]nonane-8-carboxylate (1.0 g, 4.36 mmol) in MeOH (5 mL) was mixed with 7 M ammonia in methanol (6.2 mL, 43.60 mmol). The reaction mixture was then slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography using a CombiFlash apparatus (12 g RediSep® column, 0-20% methanol in DCM) to obtain tert-butyl 6-(aminomethyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (400 mg, 1.62 mmol, yield 37.2%) as a colorless liquid. 1 H NMR (400MHz, DMSO-d6) δ ppm=3.83-3.76(m,1H),3.72-3.41(m,7H),2.96-2.82(m,1H),2.81-2.58(m,1H),2.58-2.34(br s,3H),1.48(s,9H).

[0422] Preparation of intermediates 198-1 and 198-2: tert-butyl(5S)-2-oxo-1,7-dioxa-3,10-diazaspiro[4.6]undecane-10-carboxylate and tert-butyl(5R)-2-oxo-1,7-dioxa-3,10-diazaspiro[4.6]undecane-10-carboxylate [ka] Under an argon atmosphere at room temperature, a stirred solution of tert-butyl 6-(aminomethyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (600 mg, 2.44 mmol) in DCM (2 mL) was mixed with DIPEA (1.3 mL, 7.31 mmol) and CDI (592 mg, 3.65 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. This crude residue was purified by silica gel column chromatography using a CombiFlash apparatus (40 g RediSep® column, 25-100% ethyl ether in petroleum ether) to obtain tert-butyl-2-oxo-1,7-dioxa-3,10-diazaspiro[4.6]undecane-10-carboxylate (400 mg, 1.47 mmol, yield 60.3%) as a grayish-white solid. The racemic product was re-purified by chiral SFC [SFC method: preparative column: Lux Cellulose C4 (250 mm × 4.6 mm × 5 μm); cosolvent name: 5 mM ammonium acetate in ACN: methanol (1:1); cosolvent percentage: 30%; flow rate: 3 mL / min; back pressure: 100 bar] to obtain isomer-1(198-1)tert-butyl(S)-2-oxo-1,7-dioxa-3,10-diazaspiro[4.6]undecane-10-carboxylate (170 mg, 0.62 mmol, yield 25.6%) and isomer-2(198-2)tert-butyl(R)-2-oxo-1,7-dioxa-3,10-diazaspiro[4.6]undecane-10-carboxylate (150 mg, 0.55 mmol, yield 22.6%) as colorless liquids. Isomer-1:MS(ESI)m / z:273.2[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ ppm=7.55(s,1H),3.83-3.76(m,2H),3.66-3.50(m,4H),3.50-3.41(m,2H),3.33-3.30(m,1H),3.19 -3.14(m,1H),1.40(s,9H). Isomer-2:MS(ESI)m / z:273.2[M+H] + ;1 H NMR (400MHz, DMSO-d6) δ ppm=7.55(s,1H),3.88-3.72(m,2H),3.68-3.50(m,4H),3.50-3.28(m,3H),3.24-3.09(m,1H),1.40(s,9H).

[0423] Intermediate 199: (5R)-1,7-dioxa-3,10-diazaspiro[4.6]undecane-2-one hydrochloride [ka] Under an argon atmosphere at 0°C, tert-butyl(5R)-2-oxo-1,7-dioxa-3,10-diazaspiro[4.6]undecane-10-carboxylate 198-2 (0.3 g, 1.10 mmol) was stirred in SiO2 (3 mL), to which 1 M HCl (11.02 mL, 11.02 mmol) was added. The reaction mixture was gradually warmed to room temperature over 3 hours. Volatile substances were removed under reduced pressure at low temperature, and the mixture was triturated with diethyl ether to obtain (5R)-1,7-dioxa-3,10-diazaspiro[4.6]undecane-2-one hydrochloride (0.20 g, 0.96 mmol, yield 87%) as a grayish-white solid. MS(ESI)m / z:173.0[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ ppm=7.83(s, 1H), 4.00-3.74(m, 4H), 3.56-3.39(m, 2H), 3.36-3.18(m, 6H).

[0424] Preparation of intermediate 205: tert-butyl(4aS,7aR)-4a-(hydroxymethyl)-2-methyl-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] Nickel(II) chloride ethylene glycol dimethyl ether complex (34.4 mg, 0.16 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (43.9 mg, 0.04 mmol), tris(2-pyridylmethyl)amine (45.5 mg, 0.16 mmol), and tert-butyl(4aS,7aR)-4a-(hydroxymethyl)octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (500 mg, 1.96 mmol) were placed in a 40 mL screw-cap vial and dissolved in 5 mL of 2,2,2-trifluoroethanol. Then, di-tert-butyl peroxide (2.15 mL, 11.75 mmol) was added to the reaction mixture, and the reaction vial was irradiated in a blue LED (427 nm) chamber for 24 hours. The reaction mixture was diluted with DCM, filtered through a CELITE pad, and the filtrate was concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a CombiFlash apparatus (40g RediSep® column, 22% siRNA in petroleum ether) to obtain a diastereomer mixture of tert-butyl(4aS,7aR)-4a-(hydroxymethyl)-2-methyl-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (500 mg, 1.26 mmol, yield 64.5%) as a colorless liquid. MS(ESI)m / z:270.2[M+H] + .

[0425] Preparation of intermediate 230: tert-butyl(4aS,7aR)-4a-[({4-[(6S)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-4-yl]-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] Under an argon atmosphere at room temperature, tert-butyl(4aS,7aR)-4a-[({4-[(6S)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-4-yl]-7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (5.0 g, 7.35 mmol) was stirred in 1,4-dioxane (50 mL) to which 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.91 g, 8.08 mmol) and an aqueous solution of 1.5 M potassium tribase phosphate (14.7 mL, 22.05 mmol) were added. The reaction mixture was purged with argon for 5 minutes, and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.48 g, 0.74 mmol) was added. The reaction mixture was again purged with argon and heated at 95°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography using a CombiFlash apparatus (120g RediSep® column, 50-80% toluene-pet-ether) to obtain tert-butyl(4aS,7aR)-4a-[({4-[(6S)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-4-yl]-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (3.5g, 3.99 mmol, yield 54.2%) as a brown solid. 1H NMR(400MHz,DMSO-d6)δ ppm=9.27(s,1H),7.90(dd,J=9.0,6.0Hz,1H),7.68(d,J=2.5Hz,1H),7.44(t,J=9.3Hz,1 H),7.21-7.16(m,1H),5.34(s,2H),4.65-4.48(m,1H),4.49-4.13(m,6H),4.07-3.80(m, 5H),3.68-3.57(m,2H),2.86-2.69(m,1H),2.42-2.32(m,1H),2.23-2.10(m,2H),1.82-1 .57(m,7H),1.54-1.35(m,6H),1.34-1.15(m,12H),0.76-0.60(m,9H),0.09-0.05(m,6H).

[0426] Preparation of intermediate 231: tert-butyl(4aS,7aR)-4a-[({7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-[(6S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate [ka] Under an argon atmosphere at room temperature, a stirred solution of tert-butyl(4aS,7aR)-4a-[({4-[(6S)-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-4-yl]-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoropyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (3.5 g, 3.99 mmol) in DMF (5 mL) was added and stirred at 65 °C for 2 hours. The reaction mixture was filtered through a CELITE pad and the pad was washed with ELISA. The combined filtrate was concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography using a CombiFlash apparatus (80g RediSep® column, 50-100% toluene-petroleum ether) to obtain tert-butyl(4aS,7aR)-4a-[({7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-[(6S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (2.7g, 3.53 mmol, yield 89%) as a pale yellow solid. MS(ESI)m / z:764.3[M+H] + ;

[0427] Intermediate 233: (6S)-4-(2-{[(4aS,7aR)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol [ka] Under an argon atmosphere at 0°C, tert-butyl(4aS,7aR)-4a-[({7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-4-[(6S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine-2-yl}oxy)methyl]-octahydro-1H-cyclopenta[b]pyridine-1-carboxylate (2.7 g, 3.53 mmol) was stirred in HCl (35 mL) to which 1 M HCl / HCl (70.7 mL, 70.70 mmol) was added. The reaction mixture was gradually warmed to room temperature over 3 hours. Volatile substances were removed under reduced pressure at low temperature, dissolved in DCM, and basicized with triethylamine. The DCM layer was sequentially washed with saturated NaHCO3 solution, followed by brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude (6S)-4-(2-{[(4aS,7aR)-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol (2.0 g, 3.23 mmol, yield 91%) as a yellow solid. MS(ESI)m / z:620.2[M+H] + .

[0428] Examples 26-1 and 26-2: (6S)-4-(2-{[(4aS,7aR)-1-[(2R,4s,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepane -6-ol and (6S)-4-(2-{[(4aS,7aR)-1-[(2R,4r,6S)-2,6-dimethyloxan-4-yl]-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-6-methyl-1,4-oxazepan-6-ol

change

[0429] Preparation of intermediate 237: 6-chloro-4-fluoro-1H-indazole [ka] Under an argon atmosphere at room temperature, a stirring solution of 4-chloro-2,6-difluorobenzaldehyde (15 g, 85.0 mmol) in 1,4-dioxane (56.6 mL) was mixed with hydrazine monohydrate (11.33 mL, 234.0 mmol), and the reaction mixture was stirred at 95°C for 16 hours. The reaction mixture was then cooled to room temperature, and water was added. The resulting precipitate was filtered, washed with water, and dried under vacuum. The solid was diluted with siRNA, dried over anhydrous Na₂SO₄, and concentrated to obtain 6-chloro-4-fluoro-1H-indazole (12 g, 70.40 mmol, yield 83%) as a grayish-white solid. MS(ESI)m / z: 169.0[MH] + ; 1 H NMR (300MHz, DMSO-d6) δ ppm=13.62-13.45(m,1H), 8.27-8.18(m,1H), 7.54-7.47(m,1H), 7.10-7.04(m,1H).

[0430] Preparation of intermediate 238: 6-chloro-4-fluoro-1-(oxan-2-yl)-1H-indazole [ka] Under an argon atmosphere at room temperature, 15 g, 88.0 mmol of 6-chloro-4-fluoro-1H-indazole and 12.0 mL, 132.0 mmol of 3,4-dihydro-2H-pyran were stirred in 176 mL of DCM, to which 1.67 g, 8.79 mmol of 4-methylbenzenesulfonic acid hydrate was added. The resulting mixture was stirred for 2 hours. The reaction mixture was then quenched with ice-cold water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. This crude residue was purified by silica gel column chromatography using a CombiFlash apparatus (80 g RediSep® column, 5-10% siRNA-pet.-ether) to obtain 6-chloro-4-fluoro-1-(oxan-2-yl)-1H-indazole (12 g, 47.1 mmol, yield 53.6%) as a pale yellow solid. MS(ESI)m / z:254.9[M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ ppm=8.28(s,1H),7.80(s,1H),7.16(dd,J=9.8,1.3Hz,1H),5.90(dd,J=9.5,2.1Hz ,1H),3.92-3.69(m,2H),2.46-2.26(m,1H),2.13-1.91(m,1H),1.82-1.43(m,4H).

[0431] Preparation of intermediate 239: 6-chloro-4-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole [ka] Under an argon atmosphere at -78°C, a stirred solution of 6-chloro-4-fluoro-1-(oxan-2-yl)-1H-indazole (10 g, 39.3 mmol) in THF (100 mL) was mixed with lithium chloride (1.99 g, 47.10 mmol) and a 2 M solution of LDA in THF (51.0 mL, 102.0 mmol). The reaction mixture was stirred at the same temperature for 2 hours, after which methyl iodide (3.93 mL, 62.8 mmol) was added. The reaction mixture was stirred for a further 1 hour. The reaction mixture was then diluted with NH4Cl solution and extracted with siRNA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (80g RediSep® column, 0-100% siRNA-pet-ether) to obtain 6-chloro-4-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole (3.2g, 11.91 mmol, yield 76%) as a brown semi-solid. MS(ESI)m / z:269.0[M+H] + .

[0432] Preparation of intermediate 239-1: 6-chloro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-ol [ka] Under an argon atmosphere at room temperature, a stirred solution of 6-chloro-4-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole (8.0 g, 29.8 mmol) in DMSO (104 mL) was mixed with water (10.7 mL, 595.0 mmol) and potassium hydroxide (10.0 g, 179.0 mmol). The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was then cooled to room temperature, diluted with water, acidified with 1.5 N HCl aqueous solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (80g RediSep® column, 50-100% siRNA-pet-ether) to obtain 6-chloro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-ol (4g, 15.0 mmol, yield 50.4%) as a pale yellow solid. MS(ESI)m / z:267.0[M+H] + .

[0433] Preparation of intermediate 240: 6-chloro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yltrifluoromethanesulfonate [ka] Under an argon atmosphere at -78°C, a stirred solution of 6-chloro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-ol (1 g, 3.75 mmol) and DIPEA (3.93 mL, 22.50 mmol) in DCM (20 mL) was mixed with Tf2O (0.95 mL, 5.62 mmol) and stirred for 1 hour. The reaction mixture was then diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography using a CombiFlash apparatus (40 g RediSep® column, 10-20% siRNA-PET-Ether). The fraction containing the desired product was evaporated to obtain 6-chloro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yltrifluoromethanesulfonate (1.2 g, 3.01 mmol, 80% yield) as a colorless solid. MS(ESI)m / z:398.9[M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ ppm=8.21(s,1H),8.11(s,1H),5.95(dd,J=9.6,2.3Hz,1H),3.93-3.73(m, 2H), 2.42(s, 3H), 2.09-1.95(m, 2H), 1.81-1.65(m, 1H), 1.64-1.54(m, 3H).

[0434] Preparation of intermediate 241: 6-chloro-5-methyl-1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole [ka] Under an argon atmosphere, 6-chloro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yltrifluoromethanesulfonate (1.2 g, 3.01 mmol) in 1,4-dioxane (24 mL) was stirred, to which bis(pinacolato)diborone (1.91 g, 7.52 mmol) and potassium acetate (0.74 g, 7.52 mmol) were added. The reaction mixture was purged with argon, and PdCl2 (dppf) (0.22 g, 0.30 mmol) was added. The reaction mixture was again purged with argon and stirred at 100°C for 16 hours. The reaction mixture was then filtered through a Celite pad and concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography using a CombiFlash apparatus (40 g RediSep® column, 0-10% siRNA-PET-ether). The fraction containing the desired product was evaporated to obtain 6-chloro-5-methyl-1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1 g, 2.65 mmol, yield 88%) as a colorless solid. MS(ESI)m / z:377.3[M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ ppm=8.18(s,1H),8.00(s,1H),5.85(dd,J=9.6,2.6Hz,1H),3.91-3.70(m,2H),2.59( s, 3H), 2.43-2.30 (m, 1H), 2.08-1.88 (m, 2H), 1.63-1.53 ​​(m, 3H), 1.42-1.35 (m, 12H).

[0435] biological activity KRAS G12D RAF disruption assay Recombinant GMPPNP-loaded KRAS G12D (5 nM) was treated with assay buffer (50 mM Tris pH 7.5, 100 mM NaCl, 1 mM MgCl2, 1 mM DTT, 100 ug / ml BSA) at room temperature for 20 minutes. Recombinant GST-RAF1 RBD (9 nM) was added, followed by SA-Tb (0.25 nM), and the reaction mixture was incubated for 3 hours. Homogeneous time-resolved fluorescence (HTRF) signals were measured (PerkinElmer Envision), and the signal ratio (λ) was measured. em 520 / λ em Calculate 495) and IC 50 The values ​​were calculated from the dose-response curve.

[0436] KRAS G12D nucleotide exchange assay Recombinant GDP-loaded KRAS G12D (20 nM) was treated with the compound in assay buffer (10 mM Hepes pH 7.4, 150 mM NaCl, 5 mM MgCl2, 0.0025% Igepal-CA630, 0.05% BSA, 1 mM DTT, 0.5 nM SA-Tb) at room temperature for 20 minutes. BIODIPY-labeled GDP (400 nM) and recombinant SOS (10 nM) were added, and the reaction mixture was incubated for 30 minutes. HTRF signals were measured (PerkinElmer Envision), and the signal ratio (λ) was calculated. em 520 / λ em Calculate 495) and IC 50 The values ​​were calculated from the dose-response curve.

[0437] IC for the compounds described herein 50 The values ​​are shown in Table 6.

[0438] [Table 152]

[0439] [Table 153]

[0440] [Table 154]

[0441] [Table 155]

[0442] [Table 156]

[0443] [Table 157]

[0444] [Table 158]

[0445] [Table 159]

[0446] [Table 160]

[0447] [Table 161]

[0448] Cell proliferation assay Cell lines were purchased from ATCC and cultured according to the provider's recommendations. Cell lines used: HPAC (ATCC, CRL-2119); NCI-H727 (ATCC, CRL-5815); GP2D (Millipore / Sigma, 95090714); H358 (ATCC, CRL-5807). Cells were seeded at 200–750 cells / well in 384-well plates (Greiner3B). This density was previously measured to show a linear response over 5 days of culture (37°C / 5%CO2, 80% humidity). After an overnight recovery culture, compounds dissolved in DMSO were added to the wells using acoustic dispensing at a volume of 1 / 400 of the culture medium. Camptothecin (5 μM) was added to each plate as a positive control. At the end of the 4-day treatment period, CellTiter-Glo® (Promega Corp.) was added, and the signal was detected using a reader adapted to the luminescence mode. The results were normalized as the inhibition rate against DMSO-treated cells [inhibition rate = (1 - (test - mean positive control) / (mean DMSO - mean positive control)) * 100]. The curves were analyzed using nonlinear regression analysis and fitted to a standard four-parameter hyperbola. IC 50 The values ​​are shown in Table 7 and are reported as the concentration of the compound that reduced the signal by 50% compared to a control treated with DMSO alone. Blank spaces indicate that the compound was not tested against a specific mutant / cell line.

[0449] [Table 162]

[0450] [Table 163]

[0451] [Table 164]

[0452] [Table 165]

[0453] [Table 166]

[0454] [Table 167]

[0455] [Table 168]

[0456] pERK immunofluorescence assay Cells (2000-5000 per well) were seeded in a 384-well plate (Revvity6057602) and incubated overnight. Cells were treated with a compound (2 hours) and fixed with paraformaldehyde (4%) for 15 minutes. Cells were washed three times (PBS), permeabilized for 15 minutes (0.1% TritonX100), and then washed three times (PBS). Cells were blocked at room temperature for 1 hour (5% normal goat serum, 0.2M glycine, PBS) and then incubated overnight at 4°C with pERK antibody (CST-4370S, 1:250). Cells were washed three times with PBS and stained at room temperature for 1 hour with anti-rabbit secondary antibody (Invitrogen A-11034, 1:1000), Hoechst33342 (Invitrogen H3570, 1:1000), and CellMask (Invitrogen H32721, 1:15000). Cells were washed three times (PBS) before imaging (Opera Phenix). The mean pERK intensity per cell was measured, and IC50 was obtained from the dose-response curve. 50 The values ​​were calculated. The IC50 values ​​are shown in Table 8.

[0457] [Table 169]

[0458] Cellular KRAS:RAF disruption assay Using the BiBRET vector (Promega), a stable cell line (HEK293T) was constructed as shown, and RAF1 and mutant or wild-type KRAS were co-expressed. The modified cell line was suspended in culture medium (OptiMEM, 4% FBS), plated in a 384-well plate (8000 cells / well), and allowed to stand for 1.5 hours. The cells were treated with the compound for 24 hours according to the manufacturer's instructions, and NanoBRET NanoGlo substrate (Promega) was added. The NanoBRET signal was measured (PerkinElmer Envision), and the signal ratio (λ) was calculated. em 618 / λ em The 460) value was calculated, and the IC50 value was calculated from the dose-response curve. The IC50 values ​​are shown in Table 9.

[0459] [Table 170]

[0460] The specific compounds in this disclosure have desirable pharmacodynamic and pharmacokinetic properties, such as enhanced systemic exposure upon oral administration.

[0461] It should be understood that the section on modes for carrying out the invention, rather than the section on summary and abstract of the invention, is intended to be used to interpret the claims. The section on summary and abstract of the invention may show one or more, but not all, exemplary modes of the disclosure contemplated by the inventors, and is not intended to limit the scope of the disclosure and the appended claims in any way.

[0462] This disclosure has been described above using functional construction blocks that exemplify the implementation of the specified functions and their relationships. The boundaries of these functional construction blocks are arbitrarily defined herein for the convenience of the description. Alternative boundaries may be defined, provided that the specified functions and their relationships are adequately performed.

[0463] The foregoing description of the specified embodiments is intended to fully illustrate the general nature of the disclosure, and others can easily modify and / or adapt such specific embodiments to various uses by applying knowledge within the scope of the art, without excessive experimentation and without departing from the general concepts of the disclosure. Therefore, such adaptations and modifications are intended to be within the meaning and scope of the equivalents of the disclosed embodiments, based on the teachings and guidance presented herein. It should be understood that the expressions and terminology used herein are for illustrative purposes, not limitation, so that they can be interpreted by those skilled in the art in light of the teachings and guidance provided herein.

[0464] The breadth and scope of this disclosure should not be limited by any of the exemplary embodiments described above, but should be defined solely by the following claims and equivalents.

Claims

【Request Item 1】 【Chemistry 1】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, which is a pharmaceutically acceptable salt. 【Request Item 3】 【Chemistry 2】 A compound according to claim 1, selected from the group consisting of the following. 【Request Item 4】 【Chemistry 3】 The compound according to claim 3. 【Request Item 5】 【Chemistry 4】 The compound according to claim 3. 【Request Item 6】 【Chemistry 5】 The compound according to claim 3. 【Request Item 7】 【Transformation 6】 The compound according to claim 3. 【Request Item 8】 【Chemistry 7】 The compound according to claim 3. 【Request Item 9】 【Transformation 8】 The compound according to claim 3. 【Request Item 10】 【Chemistry 9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. 【Request Item 11】 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. 【Request Item 12】 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. 【Request Item 13】 【Chemistry 12】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. 【Request Item 14】 【Chemistry 13】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. 【Request Item 15】 【Chemistry 14】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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