Tethered heterocyclic inhibitors of KRAS G12C mutant protein and uses thereof

Abstract

The present disclosure provides compounds having activity as inhibitors of G12C mutant KRAS proteins, pharmaceutical compositions comprising the compounds, and methods for treating certain disorders such as cancer, including, but not limited to, lung cancer, pancreatic cancer, and colorectal cancer. In particular, the ... TIFF2025533831001242.tif48170 (wherein the substituents are as indicated) and pharmaceutically acceptable salts thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 413,548, filed October 5, 2022, which is incorporated herein by reference in its entirety for all purposes as if fully set forth herein.

[0002] The present disclosure relates generally to compounds having activity as inhibitors of G12C mutant KRAS protein, pharmaceutical compositions containing the compounds, and uses and methods for treating disorders such as cancer, including, but not limited to, lung cancer, pancreatic cancer, and colorectal cancer. [Background technology]

[0003] The KRAS oncoprotein is a G protein that couples extracellular mitogenic signaling to intracellular growth-promoting responses. KRAS functions as a molecular "on / off" switch, alternating between an inactive GDP-bound state and an active GTP-bound state. The transition between these states is facilitated by guanine nucleotide exchange factors. Mitogenic stimulation can induce GTP binding, which leads to a conformational change that allows KRAS to interact with downstream effector proteins, resulting in cell proliferation. In normal cells, growth-promoting signaling is regulated by the action of GTPase-activating proteins (GAPs), which return KRAS to its GDP-bound, non-proliferative state. KRAS mutations impair the regulated cycling of KRAS between these GDP- and GTP-bound states, resulting in the accumulation of the active GTP-bound state and impaired cell proliferation. See Simanshu et al., Cell 2017, 170, 17-33.

[0004] Attempts to develop inhibitors of mutated KRAS proteins have historically been hampered by the picomolar affinity with which KRAS binds GDP and GTP and the absence of a druggable pocket on the surface of the protein. See Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-851. A covalent inhibitor of the G12C mutant of KRAS, "KRAS G12C These inhibitors inhibit GDP-KRAS G12C This discovery has led to significant new efforts in KRAS inhibitor research, recently leading to the entry of KRAS inhibitors into human clinical trials. While some progress has been made, the search for additional KRAS inhibitors to treat disorders such as cancer remains challenging. G12C There remains a need for inhibitors. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Simanshu et al.,Cell 2017,170,17-33 [Non-patent document 2] Cox et al.,Nat.Rev.Drug Discov.2014,13,828-851 [Non-patent document 3] O'Bryan,JPPharmacol.Res.2019,139,503-511 [Non-patent document 4] Ostrem et al.,Nature 2013,503,548-551 Summary of the Invention [Means for solving the problem]

[0006] One embodiment of the present disclosure is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3 or 4; n is 1 or 2, o is 0, 1, 2, 3 or 4; A is N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy, W is CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy, X is [ka] and Y is N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy; Z is phenyl, heteroaryl having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a bicyclic ring containing a heteroaryl ring having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S fused to a cycloalkyl ring having 5 or 6 total ring atoms or a heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, wherein each of the phenyl, heteroaryl, and bicyclic ring is optionally substituted with 1 to 4 substituents; R 1a , R 1b and R 2 each independently selected from H, D, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~2 Alkylene-OH, C 0~2 Alkylene-C 1~4 Alkoxy, C 0~2 Alkylene-C 1~4 Haloalkoxy, C 0~2 Alkylene-CN, C 0~2 Alkylene-N(R N1 ) C having 2, 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S 1~2 alkylene-heterocycloalkyl, or R 1b and R 2 together with the carbon atoms to which they are attached, [ka] Forming a base, Each R 3 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two adjacent R 3 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms; 1 R 4 and R 5a together with the atoms to which they are attached form an optionally substituted ring having 6 to 10 total ring atoms and 0, 1 or 2 heteroatoms selected from N, O and S, which ring is saturated or unsaturated; When n is 2, the other R 4 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene CN, C 1~3 Alkylene OH, C 1~3 Alkylene-C 1~3 alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, or spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R 5b is C 1~3 Haloalkyl, C 1~4 Alkyl, C 2~3 Alkenyl, C 2~3 Alkynyl, Halo, C 1~3 Alkoxy, C 1~3 thioalkoxy, cycloalkyl having 3 to 7 total ring atoms, cycloalkenyl having 5 to 7 total ring atoms, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, each of the foregoing being independently optionally substituted with 1 to 3 substituents; Each R 6 are independently halo, CN, oxo, C 1~3 Alkyl, C 1~3 Haloalkyl, C0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 Alkoxy, deuterated C 0~3 Alkylene-C 1~3 Alkoxy, C 1~4 Alkylene-N(R N1 ) 2, spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two adjacent R 6 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms, or Y and an adjacent R 6 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms, any of the above fused cycloalkyl rings being optionally substituted with 1 or 2 substituents; or Two non-adjacent R 6 are joined together to form C 1~3 Alkylene bridge or C 1~3 forming an ether bridge, and Each R N1 are independently H or C 1~4 It is alkyl.

[0007] In some cases, [ka] In some cases, [ka] In some cases, A is N. In some cases, n is 1. In some cases, n is 2. In some cases, R 4 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, W is CH.

[0008] In some cases, one R 4 and R 5aare taken together with the atoms to which they are attached to form an optionally substituted ring having 6 to 10 total ring atoms and 0, 1, or 2 heteroatoms selected from N, O, and S, and the ring is saturated. 4 and R 5a together with the atoms to which they are attached form an optionally substituted ring having 6 to 10 total ring atoms and 0, 1, or 2 heteroatoms selected from N, O, and S, and the ring is unsaturated. In some cases, the optionally substituted ring has 6 or 7 total ring atoms. In some cases, the optionally substituted ring has 0 heteroatoms. In some cases, the optionally substituted ring has 1 or 2 heteroatoms selected from N, O, and S. In some cases, the 1 or 2 heteroatoms are each O. In some cases, the 1 or 2 heteroatoms are each N. In some cases, one R 4 and R 5a The ring formed by R together with the atoms to which they are attached is unsubstituted. 4 and R 5a The ring formed by these atoms is C 1~3 Alkyl, C 1~3 Haloalkyl, oxo, halo, CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 and phenyl. In some cases, the cycloalkyl group is substituted with one or two substituents selected from the group consisting of alkoxy, cycloalkyl having 3 to 7 total ring atoms, cycloalkenyl having 5 to 7 total ring atoms, heterocycloalkyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, and phenyl. [ka] In some cases, R 5b is CF3, CF2H, CFH2 or CF2CH3.

[0009] In some cases, X is [ka] In some cases, Y is CH. In some cases, o is 0. In some cases, o is 1. In some cases, R 6 is CH3, CH2F, CHF2, or CF3. In some cases, [ka] is.

[0010] In some cases, Z is heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, and the heteroaryl is optionally substituted with 1 to 4 substituents. In some cases, the heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl. In some cases, the heteroaryl is pyrazolyl or pyridyl. In some cases, the heteroaryl is halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 0~6 Alkylene-N(R N1 )2(in the formula, each R N1 are independently H or C 1~3 alkyl), C with 3 to 6 total ring atoms 0~2 Alkylene-cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0~2 Alkylene-heterocycloalkyl and C 0~2substituted with 1 to 4 substituents each independently selected from the group consisting of alkyl, alkenyl, C 0~6 Alkylene-C 1~3 Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is optionally substituted with 1 to 3 substituents independently selected from deuterium, halo, OH, CH, OCH, and OCD. In some cases, each of the 1 to 4 substituents is independently selected from Cl, F, CN, CH, CD, CHCH, CH(CH), CF, CHF, CHF, CHCHF, CH(CH), CH(CH)CHF, CH(CH)CHF, C(=CH)CHF, OH, CHOH, CHCHOH, CH(CH)CHOH, C(CH)OH, C(CH)CHOH, CHC(CH)OH, OCH, OCD, CHOCH, CHOCD, CHCHOCH, CHFCHOCH, C(CH)CH, C(= ... F2CH2OCH3, CH2CH2OCD3, CH2CH2OCH2CH3, CH2CH2CH2OCH3, CH2CH2CH2OCD3, CH(CH3)CH2OCH3, CH(CH3)CH2OCD3, C(CH3)2CH2OCH3, C(CH3)2CH2OCD3, CH 2CH(CH3)OCH3, CH2CH(CH3)OCD3, CH2C(CH3)2OCH3, CH2C(CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] In some cases, each of the 1 to 4 substituents is independently selected from the group consisting of CH3, CH2CH2OCH3, CH2CH2OCD3, [ka] In some cases, Z is [ka] [ka] [ka] [ka] [ka] In some cases, Z is [ka] is.

[0011] In some cases, [ka] Z is pyrazolyl or pyridyl, each optionally substituted with 1 to 4 substituents. In some cases, the 1 to 4 substituents on Z are independently CH3, CH2CH2OCH3, CH2CH2OCD3, [ka] In some cases, Z is substituted with two substituents. In some cases, one substituent on Z is CH. In some cases, one substituent on Z is CH and the other substituent on Z is CH, CH, CH, CH, OCH, [ka] In some cases, Z is [ka] In some cases, Z is [ka] is.

[0012] In some cases, the compound of formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0013] Another aspect of the present disclosure is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3 or 4; n is 0, 1 or 2; A is N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy; W 1 and W 2 each independently represents N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 2~3 Alkenyl, CC 2~3 Alkynyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 alkoxy, wherein each of the alkenyl and alkynyl is unsubstituted or substituted with 1 to 3 substituents, and each substituent is independently selected from halo, C 1~3 Haloalkyl, C 0~3 Alkylene OH or C 0~3 Alkylene C 1~4 is an alkoxy; X is a heterocycloalkyl or heterocycloalkenyl, each having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, wherein each of the heterocycloalkyl and heterocycloalkenyl is unsubstituted or substituted with 1 to 3 substituents, and each substituent is independently selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~2 Alkylene OH, C 0~2 Alkylene C 1~3 Alkoxy or C 0~2 is alkylene CN, Z is phenyl, heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or a bicyclic ring; C 5~6 a bicyclic ring containing a heteroaryl having 5 or 6 total ring atoms and 1-3 heteroatoms selected from N, O, and S fused to a cycloalkyl or heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; Each of the phenyl, heteroaryl, and bicyclic ring is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 0~6 Alkylene-N(R N1 )2, C 0~2 Alkylene-C 3~6 Cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0~2 Alkylene-heterocycloalkyl or C 0~2 alkylene-phenyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is independently unsubstituted or substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~2 Alkylene OH, C 1~2 Alkylene-C 1~3 Alkoxy, C 1~3 Deuterated alkoxy, N(R N1 )2, (C=O)C 1~3 Alkyl, C 3~5 cycloalkyl or heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, form a spiro-C 3~5 or two adjacent further substituents together with the atoms to which they are attached form a fused C 3~5 forming a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; Each of the above further substituents of cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently halo or C 1~3 is alkyl, [ka] is C 2~6 Alkylene, C 3~6 alkenylene, heteroalkylene having 2 to 6 total atoms and 1 to 3 heteroatoms selected from N, O, and S, or heteroalkenylene having 3 to 6 total atoms and 1 or 2 heteroatoms selected from N, O, and S; [ka] is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from C 1~3 Alkyl, C 1~3 Haloalkyl, C 2~3 Alkenyl, Halo, CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 4~5 cycloalkenyl, heterocycloalkyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl; or two geminal substituents, together with the atoms to which they are attached, may be oxo, =CH2, spiro-C 3~5 Cycloalkyl, spiro-C 4~5 or two adjacent substituents, taken together with the atoms to which they are attached, form a fused C ring; a spiro-heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or a spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or two adjacent substituents, taken together with the atoms to which they are attached, form a fused C ring; 3~5 Cycloalkyl, fused C 4~5 forming a cycloalkenyl, a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R 1a , R 1b and R 2 each independently selected from H, D, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~2 Alkylene-OH, C 0~2 Alkylene-C 1~4 Alkoxy, C 0~2 Alkylene-C 1~4 Haloalkoxy, C 0~2Alkylene-CN, C 0~2 Alkylene-N(R N1 ) C having 2, 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S 1~2 alkylene-heterocycloalkyl, and R 1b and R 2 together with the carbon atoms to which they are attached, [ka] Forming Each R 3 independently, C 1~3 Alkyl, C 1~3 haloalkyl, [ka] , C 0~3 Alkylene CN, C 0~3 Alkylene OH or C 0~3 Alkylene-C 1~3 Alkoxy or two geminal R 3 together with the atom to which they are attached, form oxo, spiro-C 3~7 Cycloalkyl, spiro-C 4~7 a cycloalkenyl, a spiro-heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a spiro-heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or two adjacent R 3 together with the atoms to which they are attached to form a fused C 3~7 Cycloalkyl, fused C 4~7 form a cycloalkenyl, a fused heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or [ka] is deuterated, Each R 4 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene CN, C 1~3 Alkylene OH or C 1~3 Alkylene-C 1~3 Alkoxy or two geminal R 4 together with the atom to which they are attached, form oxo, spiro-C 3~7 forming a cycloalkyl or a spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R 5 Ha, Halo, C 1~3 Haloalkyl, C 1~6 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~3 Alkoxy, C 1~3 Thioalkyl, C 3~7 Cycloalkyl, C 5~7 cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, each of the foregoing being independently unsubstituted or substituted with 1 to 3 substituents, and each substituent being independently selected from C 1~3 Haloalkyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 Cycloalkyl, C 5~7 cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl; R A1 and R A2 each independently represents H, C 1~3 Alkyl, C 1~3Haloalkyl or C 3~5 is cycloalkyl, and Each R N1 are independently H or C 1~4 It is alkyl.

[0014] In some cases, R 1a , R 1b and R 2 At least one of R is H or D. In some cases, R 1a , R 1b and R 2 Each of R is independently H or D. 1a , R 1b and R 2 Two of them are H and R 1a , R 1b and R 2 One of them is Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~2 Alkylene-OH, C 0~2 Alkylene-C 1~4 Alkoxy, C 0~2 Alkylene-C 1~4 Haloalkoxy, C 0~2 Alkylene-CN, C 0~2 Alkylene-N(R N1 ) C having 2 or 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S 1~2 alkylene-heterocycloalkyl. [ka] In some cases, [ka] is.

[0015] In some cases, m is 0. In some cases, m is 1. In some cases, m is 2. In some cases, each R 3are independently CH3, CH2CH3, CH2F, CHF2, CF3, CN, CH2CN, OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3 or CH2CH2OCH3, or two geminal R 3 together with the atom to which they are attached form oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R 3 together with the atoms to which they are attached form a fused cyclopropyl or fused cyclobutyl. In some cases, m is 0 or m is 1 and R 3 is CH3, CH2F, CHF2, CF3, CN, CH2CN, CH2OH, or CH2OCH3, or m is 2 and two geminal R 3 together with the atoms to which they are attached form a spiro-oxetanyl. In some cases, m is 0 or m is 1 and R 3 is CH3. In some cases, [ka] In some cases, [ka] is.

[0016] In some cases, A is N. In some cases, A is CH, CF, C—Cl, C—CN, C—CH, C—CHF, C—CHF, C—CF, C—OH, C—CHOH, C—OCH, or C—CHOCH. In some cases, n is 0. In some cases, n is 1. In some cases, n is 2. In some cases, each R 4 are independently CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2CH2OH, CH2OCH3 or CH2CH2OCH3, or two geminal R 4together with the atom to which they are attached form oxo, spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl. [ka] is.

[0017] In some cases, [ka] is a C2 alkylene, a C3 alkylene, a C3 alkenylene, or a heteroalkylene having 2 to 4 total atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, [ka] is non-substituted. In some cases, [ka] are CH3, =CH2, oxo, Cl, F, OH, OCH3, [ka] or a combination of the above. [ka] [ka] In some cases, [ka] In some cases, [ka] where p is 0, 1, 2, or 3, and each R 7 are independently CH3, Cl, F, OH, or OCH3, or two geminal R 7together with the atom to which they are attached to form oxo or =CH2, or two adjacent R 7 together with the atoms to which they are attached, [ka] Form.

[0018] In some cases, W 1 is N. In some cases, W 1 is CH. In some cases, W 1 is CF, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2F, C-CHF2, C-CF3, C-CH=CH2, CC(OH)=CH2, C-CH=CH(OH), C-CCH, C-OH, C-CH2OH, C-OCH3 or C-CH2OCH3. In some cases, W 2 is N. In some cases, W 2 is CH. In some cases, W 2 is CF, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2F, C-CHF2, C-CF3, C-CH=CH2, CC(OH)=CH2, C-CH=CH(OH), C-CCH, C-OH, C-CH2OH, C-OCH3 or C-CH2OCH3. In some cases, W 1 is CH, and W 2 is N. In some cases, R 5 is C 1~3 In some cases, R 5 is CF3 or CF2H. In some cases, R 5 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH=CH2, CH=CHCH3, [ka] each of the above is independently unsubstituted or substituted with 1 to 3 substituents, and each substituent is independently selected from C 1~3 Haloalkyl, C 0~6 Alkylene-OH, C 0~6Alkylene-C 1~3 Alkoxy, C 3~7 Cycloalkyl, C 5~7 In some cases, R is independently CH, CF, CFH, CFH, OH, OCH, OCF, CHOH, CHOCH, cyclopropyl, cyclobutyl, or phenyl. In some cases, R is independently CH, CF, CFH, CFH, OH, OCH, OCF, CHOH, CHOCH, cyclopropyl, cyclobutyl, or phenyl. In some cases, R is independently CH, CF, CFH, CFH, OH, OCH, OCF, CHOH, CHOCH, cyclopropyl, cyclobutyl, or phenyl. 5 are Br, Cl, F, OCH3, SCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, [ka] In some cases, W 1 is CH and W 2 is N, and R 5 is CF3, CF2H, or CFH2. In some cases, [ka] [ka] In some cases, [ka] is.

[0019] In some cases, X is [ka] and Y is N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 alkoxy, o is 0, 1, 2, 3, or 4, and each R6 are independently halo, CN, C 1~3 Alkyl, C 2~3 Alkenyl, C 1~3 Haloalkyl, C 0~3 Alkylene-OH, C 0~3 Alkylene-C 1~3 Alkoxy, deuterated C 0~3 Alkylene-C 1~3 Alkoxy or C 1~4 Alkylene-N(R N1 )2 or two geminal R 6 together with the atoms to which they are attached, form oxo, =CH2, spiro-C 3~7 Cycloalkyl, spiro-C 4~7 a cycloalkenyl, a spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a spiro-heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or two adjacent R 6 together with the atoms to which they are attached to form a fused C 3~7 Cycloalkyl, fused C 4~7 a fused heterocycloalkyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or two non-adjacent R 6 are joined together to form C 1~3 Alkylene bridge, C 2~3 Alkenylene bridge, C 1~3 Ether bridge or C 1~3 Form a thioether bridge or connect Y and the adjacent R 6 together with the atoms to which they are attached to form a fused C 3~7 Cycloalkyl, fused C 4~7a cycloalkenyl, a fused heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, wherein any of the above cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~2 Alkylene OH, C 0~2 Alkylene C 1~3 Alkoxy or C 0~2 alkylene CN, and each R N1 are independently H or C 1~4 In some cases, X is alkyl. [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, Y is N. In some cases, Y is CH. In some cases, Y is CF, C—Cl, C—CH3, C—CH2CH3, C—CH2F, C—CHF2, C—CF3, C—OH, C—CH2OH, C—OCH3, or C—CH2OCH3. In some cases, o is 0. In some cases, o is 1. In some cases, o is 2. In some cases, each R 6are independently Br, Cl, F, CN, CH3, CH2F, CHF2, CF3, OH, CH2OH, OCH3, OCD3, CH2OCH3, or CH2N(CH3)2, or two geminal R 6 together with the atom to which they are attached form oxo, ═CH2, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R 6 taken together with the atoms to which they are attached form a fused cyclopropyl, fused cyclobutyl, or fused cyclopentyl, and any of the above spiro and fused rings are unsubstituted or substituted with one or two substituents, and each substituent is independently selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~2 Alkylene OH, C 0~2 Alkylene C 1~3 Alkoxy or C 0~2 alkyleneCN. In some cases, each substituent is independently F, Cl, OH, OCH, OCHCH, or CN. In some cases, two non-adjacent R 6 are joined together to form C 1~3 Alkylene bridge, C 2~3 Alkenylene bridge, C 1~3 Ether bridge or C 1~3 Forms a thioether bridge. In some cases, two non-adjacent R 6 are joined together to form -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2-CH=CH-, or -CH2OCH2-. In some cases, X is [ka] [ka] [ka] In some cases, X is [ka] is.

[0020] In some cases, Z is unsubstituted phenyl or phenyl substituted with 1 to 4 substituents, and each substituent is independently selected from halo, C 0~3 Alkylene CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~4 Alkoxy, C 0~3 Alkylene-C 1~4 thioalkoxy, or [ka] and each R N1 is independently H or CH. In some cases, each substituent is independently F, Cl, CN, OCH, SCH, CHOH, or [ka] In some cases, Z is [ka] is.

[0021] In some cases, Z is a heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 0~6 Alkylene-N(R N1 )2, C 0~2 Alkylene-C 3~6 Cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0~2 Alkylene-heterocycloalkyl or C0~2 alkylene-phenyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is independently unsubstituted or substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~2 Alkylene OH, C 1~2 Alkylene-C 1~3 Alkoxy, C 1~3 Deuterated alkoxy, N(R N1 )2, (C=O)C 1~3 Alkyl, C 3~5 cycloalkyl, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, form spiro-C 3~5 or two adjacent further substituents together with the atoms to which they are attached form a fused C 3~5 forming a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, wherein each of the further substituents of the cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently halo or C 1~3 alkyl, and each R N1 are independently H or C 1~3In some cases, the heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl. In some cases, the heteroaryl is pyrazolyl or pyridyl. In some cases, the heteroaryl is substituted with one or two substituents. In some cases, each substituent is independently selected from Br, Cl, F, CN, CF, CHF, CHF, CHCHF, CHCHF, CH(CHF), CH(CH)CHF, CH(CH)CHF, C(=CH)CHF, OH, CHOH, CHCHOH, CH(CH)CHOH, C(CH)OH, C(CH)CHOH, CHC(CH)OH, NH, CHNH, CHNHCH, CHN(CH), CHCHNH, CHCHNHCH, CHCHN(CH), CH, CHCH, CHCHCHCH, and CH(CH). 1~6 C selected from alkyl, CH=CH2, CH2CH=CH2 and CH=CHCH3 2~6 Alkenyl, OCH3, CH2OCH3, CH2CH2OCH3, CH2CH2OCH2CH3, CH2CH2CH2OCH3, CH(CH3)OCH3, CH(CH3)CH2OCH3, CH(OCH3)CH2OCH3, CH(CH3)(O C selected from CH3)CH2OCH3, C(CH3)2OCH3, C(CH3)2CH2OCH3, CH2CH(CH3)OCH3, CH2(CH3)(OCH3)OCH3, CH2C(CH3)2OCH3 and CH2C(CH3)2OCH3 0~6 Alkylene-C 1~3 is a cycloalkyl selected from alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, or a heterocycloalkyl selected from azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, isoxazolidinyl, and morpholinyl; 1~6 Alkyl, C 2~6 Alkenyl, C0~6 Alkylene-C 1~3 Each of the alkoxy, cycloalkyl, and heterocycloalkyl substituents is independently unsubstituted or substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~2 Alkylene OH, C 1~2 Alkylene-C 1~3 Alkoxy, C 1~3 Deuterated alkoxy, N(R N1 )2, (C=O)C 1~3 Alkyl, C 3~5 cycloalkyl, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, are C 3~5 Form a spiro-cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two adjacent further substituents together with the atoms to which they are attached form a fused C 3~5 Forms a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, each additional substituent is independently D, Br, Cl, F, OH, CH3, CF3, CF2H, CFH2, OCH3, OCD3, CHOCH3, N(CH3)2, (C=O)CH3, oxetanyl, or azetidinyl, or two geminal additional substituents, together with the atoms to which they are attached, form a spiro-oxetanyl or spiroazetidinyl, each of said oxetanyl, azetidinyl, spiro-oxetanyl, and spiro-azetidinyl, independently unsubstituted or substituted with F, CH3, or a combination thereof. In some cases, each additional substituent is independently D, Br, Cl, F, OH, CH3, CF3, CF2H, CFH2, OCH3, OCD3, N(CH3)2, (C=O)CH3, [ka] or two geminal further substituents together with the atoms to which they are attached are [ka] In some cases, each substituent of the heteroaryl of Z is independently Cl, F, CN, CH3, CD3, CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH2CHF2, CH2CH2F, CH(CH2F)2, CH(CH3)CH2F, CH(CH3)CHF2, C(=CH2)CH2F, OH, CH2OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, CH2C(CH3)2OH, OCH3, OCD3, CH2OCH3, CH2OCD3, CH2CH2OCH3, CHFCH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2OCH2CH3, CH2CH2CH2OCH3, CH2CH2CH2OCD3, CH(CH3)OCH3, CH(CH3)CH2OCH3, CH(OCH3)CH2OCH3, CH(CH3)(OCH3)CH2OCH3, CH(CH2F)(CH3)CH2OCD3, CH(CH3)CH2OCD3, C(CH3)2OCH3, C(CH3)2CH2OCH3, C(CH3)2CH2 OCD3, CH2CH(CH3)OCH3, CH2(CH3)(OCH3)OCH3, CH2CH(CH3)OCD3, CH2C(CH3)2OCH3, CH2C(CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] [ka] In some cases, each heteroaryl substituent of Z is independently CH3, C(CH3)2CH2OH, CH2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, [ka] In some cases, each substituent of the heteroaryl of Z is independently CH3, CH2CH2OCH3, [ka] Or any combination of the above.

[0022] In some cases, Z is [ka] [ka] [ka] [ka] [ka] [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] is.

[0023] In some cases, Z is C 5~6A bicyclic ring comprising a heteroaryl having 5 or 6 total ring atoms and 1-3 heteroatoms selected from N, O, and S fused to a cycloalkyl or heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, wherein the bicyclic ring is unsubstituted or substituted with 1-4 substituents, and each substituent is independently selected from halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 0~6 Alkylene-OH or C 0~6 Alkylene-C 1~3 In some cases, Z is alkoxy. [ka] is.

[0024] In some cases, [ka] R 5 is CHF2 or CF3, and X is [ka] where o is 0 or 1, and R 6is CH3, Y is CH or N, and Z is pyrazolyl or pyridyl each substituted with 1 or 2 substituents, and each substituent is independently Cl, F, CN, CH3, CD3, CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH2CHF2, CH2CH2F, CH(CH2F)2, CH(CH3)CH2F, CH(CH3)CHF2, C(=CH2)CH2F, OH, CH2OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, CH2C(CH3)2OH, OCH3, OCD3, CH2OCH3, CH2OCD3, CH2CH2OCH3, CHFCH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH 2OCH2CH3, CH2CH2CH2OCH3, CH2CH2CH2OCD3, CH(CH3)OCH3, CH(CH3)CH2OCH3, CH(OCH3)CH2OCH3, C H(CH3)(OCH3)CH2OCH3, CH(CH2F)(CH3)CH2OCD3, CH(CH3)CH2OCD3, C(CH3)2OCH3, C(CH3)2CH2OCH 3, C(CH3)2CH2OCD3, CH2CH(CH3)OCH3, CH2(CH3)(OCH3)OCH3, CH2CH(CH3)OCD3, CH2C(CH3)2OCH3, CH2C(CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] In some cases, X is [ka] In some cases, [ka] In some cases, [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] is.

[0025] In some cases, the compound of formula (I) is a compound listed in Table A or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (I) is a compound listed in Table B or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (I) is a compound listed in Table A' or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (I) is a compound listed in Table B' or a pharmaceutically acceptable salt thereof.

[0026] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound or salt described herein, such as a compound of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE) and Formula (IIF), or a compound listed in Table A, Table A', Table B, Table B' and Table E, or a pharmaceutically acceptable salt of any of the above, and a pharmaceutically acceptable excipient.

[0027] Yet another aspect of the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or salt described herein, e.g., a compound of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), and Formula (IIF), or a compound listed in Table A, Table A', Table B, Table B', and Table E, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition described herein. In some cases, the subject has one or more cancer cells that express a KRAS G12C mutant protein. In some cases, the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary site, endometrial cancer, mixed cancer type, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, solid tumor, or any combination of the above. In some cases, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, melanoma, solid tumor, or any combination of the above. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is colorectal cancer. In some cases, the cancer is pancreatic cancer. In some cases, the cancer is a solid tumor. In some cases, the subject has a cancer that is determined to have one or more cells that express a KRAS G12C mutant protein prior to administration of the compound, salt or pharmaceutical composition.In some cases, the method further comprises simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an ATR inhibitor, an Aurora kinase A inhibitor, an AKT inhibitor, an arginase inhibitor, a CDK2 inhibitor, a CDK4 / 6 inhibitor, an ErbB family inhibitor, an ERK inhibitor, a FAK inhibitor, an FGFR inhibitor, a glutaminase inhibitor, an IGF-1R inhibitor, a KIF18A inhibitor, a MAT2A inhibitor, an MCL-1 inhibitor, a MEK inhibitor, an mTOR inhibitor, a PARP inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PI3K inhibitor, a PRMT5 inhibitor, a Raf kinase inhibitor, a SHP2 inhibitor, an SOS1 inhibitor, a Src kinase inhibitor, or one or more chemotherapeutic agents.

[0028] Another aspect of the present disclosure provides a compound as described herein, such as a compound of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE) and Formula (IIF) or a compound listed in Table A, Table A', Table B, Table B' and Table E, or a pharmaceutically acceptable salt of any of the above; or a pharmaceutical composition as described herein, for use as a medicament. The present disclosure also provides the use of a compound described herein, such as a compound of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE) and Formula (IIF) or a compound listed in Table A, Table A', Table B, Table B' and Table E or a pharmaceutically acceptable salt of any of the above, or a pharmaceutical composition described herein, for the manufacture of a medicament for treating cancer. In some cases, the disclosure provides compounds such as compounds of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), and Formula (IIF) or compounds listed in Table A, Table A', Table B, Table B', and Table E, or a pharmaceutically acceptable salt of any of the above, or a composition described herein, for use in treating cancer. In some cases, the one or more cancer cells express a KRAS G12C mutant protein in any of the uses described herein. In some cases, the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary site, endometrial cancer, mixed cancer type, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, solid tumor, or any combination thereof. In some cases, prior to administration of the compound, salt, or pharmaceutical composition, the cancer is determined to have one or more cells that express a KRAS G12C mutant protein.

[0029] Another aspect of the present disclosure is a method for manufacturing a semiconductor device comprising: (a) Formula (Int-AA): [ka] , formula (Int-AB): [ka] , formula (Int-AC): [ka] , formula (Int-AD): [ka] , formula (Int-AE): [ka] , Formula (Int-AF): [ka] , formula (Int-AG) [ka] , Formula (Int-AH): [ka] , formula (Int-AI): [ka] Or the formula (Int-AJ): [ka] or a pharmaceutically acceptable salt of any of the above, or (b) Formula (Int-B): [ka] a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the foregoing; or (c) Formula (Int-C): [ka] a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the foregoing; or (d) Formula (Int-D): [ka] a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the foregoing; or (e) Formula (Int-E): [ka] a compound of the formula (I), a nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the above. providing an intermediate selected from the group consisting of: A is, [ka] and B is C 1~3 Alkylene -CH=CH2 or C 1~3 is alkylene OH, Q is F, Cl, Br, I or an organoborane; m is 0, 1, 2, 3 or 4; o is 0, 1, 2, 3 or 4; halo is F, Cl, Br or I; [ka] is C 2~6 Alkylene, C 3~6 alkenylene, heteroalkylene having 2 to 6 total atoms and 1 to 3 heteroatoms selected from N, O, and S, or heteroalkenylene having 3 to 6 total atoms and 1 or 2 heteroatoms selected from N, O, and S; [ka] is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from C 1~3 Alkyl, C1~3 Haloalkyl, C 2~3 Alkenyl, Halo, CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 4~5 cycloalkenyl, heterocycloalkyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl; or two geminal substituents, together with the atoms to which they are attached, may be oxo, =CH2, spiro-C 3~5 Cycloalkyl, spiro-C 4~5 or two adjacent substituents, taken together with the atoms to which they are attached, form a fused C ring; a spiro-heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or a spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or two adjacent substituents, taken together with the atoms to which they are attached, form a fused C ring; 3~5 Cycloalkyl, fused C 4~5 forming a cycloalkenyl, a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R ZA and R ZB each independently represents a halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 0~6 Alkylene-N(R N1 )2, C 0~2 Alkylene-C 3~6Cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0~2 Alkylene-heterocycloalkyl or C 0~2 alkylene-phenyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is independently unsubstituted or substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~2 Alkylene OH, C 1~2 Alkylene-C 1~3 Alkoxy, C 1~3 Deuterated alkoxy, N(R N1 )2, (C=O)C 1~3 Alkyl, C 3~5 cycloalkyl, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, form spiro-C 3~5 or two adjacent further substituents together with the atoms to which they are attached form a fused C 3~5 forming a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, wherein each of the further substituents of the cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently halo or C 1~3 alkyl, and each R N1 are independently H or C 1~3 Each R is an alkyl. 3 independently, C 1~3 Alkyl, C 1~3haloalkyl, [ka] , C 0~3 Alkylene CN, C 0~3 Alkylene OH or C 0~3 Alkylene-C 1~3 Alkoxy or two geminal R 3 together with the atom to which they are attached, form oxo, spiro-C 3~7 Cycloalkyl, spiro-C 4~7 a cycloalkenyl, a spiro-heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a spiro-heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or two adjacent R 3 together with the atoms to which they are attached to form a fused C 3~7 Cycloalkyl, fused C 4~7 forming a cycloalkenyl, a fused heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; and R 5 Ha, Halo, C 1~3 Haloalkyl, C 1~6 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~3 Alkoxy, C 1~3 Thioalkyl, C 3~7 Cycloalkyl, C 5~7 cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, each of the foregoing being independently unsubstituted or substituted with 1 to 3 substituents, and each substituent being independently selected from C 1~3 Haloalkyl, C 0~6Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 Cycloalkyl, C 5~7 cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, heterocycloalkenyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or phenyl; and Each R 6 are independently Br, Cl, F, CN, CH3, CH2F, CHF2, CF3, OH, CH2OH, OCH3, OCD3, CH2OCH3, or CH2N(CH3)2, or two geminal R 6 together with the atom to which they are attached form oxo, ═CH2, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R 6 taken together with the atoms to which they are attached form a fused cyclopropyl, fused cyclobutyl, or fused cyclopentyl, and any of the above spiro and fused rings are unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~2 Alkylene OH, C 0~2 Alkylene C 1~3 Alkoxy or C 0~2 It is alkylene CN.

[0030] In some cases, B is CHCH=CH or CHCHOH, m is 0 or 1, o is 0 or 1, and halo is Cl; [ka] [ka] and R 3 is CH3 and R 5 is CHF2 or CF3, and R 6is CH3 and R ZA is CH3, and R ZB are CH3, C(CH3)2CH2OH, CH2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, [ka] In some cases, the intermediate is a compound listed in Table INT-A, Table INT-A', Table INT-B, Table INT-C, Table INT-D, Table INT-E, Table INT-F, Table INT, a nitrogen-protected analog of any of the above, or a pharmaceutically acceptable salt of any of the above.

[0031] Yet another aspect of the present disclosure is a process for preparing a compound described herein (e.g., a compound of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), and Formula (IIF) or a compound listed in Table A, Table A', Table B, Table B', and Table E), or a pharmaceutically acceptable salt of any of the foregoing, comprising reacting a compound of Formula (Int-AA), Formula (Int-AB), Formula (Int-AC), Formula (Int-AD), Formula (Int-AE), Formula (Int-AF), Formula (Int-AG), Formula (Int-AH), Formula (Int-AI), Formula (Int-AJ), Formula (Int-B), Formula (Int-C), and a pharmaceutically acceptable salt thereof, to a compound of the present disclosure (e.g., a compound of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), and Formula (IIF) or a compound listed in Table A, Table A', Table B, Table B', and Table E), or a pharmaceutically acceptable salt thereof.

[0032] Further aspects and advantages will become apparent to those skilled in the art upon review of the following detailed description. The following description includes specific examples, embodiments, and examples, with the understanding that the disclosure is illustrative and is not intended to limit embodiments of the disclosure to the specific examples, embodiments, and examples described herein. DETAILED DESCRIPTION OF THE INVENTION

[0033] Disclosed herein are compounds that have activity as inhibitors of G12C mutant KRAS protein, pharmaceutical compositions containing the compounds, and uses and methods of treating disorders such as cancer with the compounds and pharmaceutical compositions described herein.

[0034] Compound of formula (II) Formula (II): [ka] Provided herein are compounds of the formula: and pharmaceutically acceptable salts thereof, wherein: m is 0, 1, 2, 3 or 4; n is 0, 1 or 2; A is N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy; W 1 and W 2 each independently represents N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 2~3 Alkenyl, CC 2~3 Alkynyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 alkoxy, wherein each of the alkenyl and alkynyl is unsubstituted or substituted with one or more substituents; X is a heterocycloalkyl or heterocycloalkenyl, each having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, wherein each of the heterocycloalkyl and heterocycloalkenyl is unsubstituted or substituted with one or more substituents; Z is phenyl, heteroaryl having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or a bicyclic ring; 5~6 a bicyclic ring comprising a heteroaryl having 5 or 6 total ring atoms and 1-3 heteroatoms selected from N, O, and S fused to a cycloalkyl or heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, wherein each of the phenyl, heteroaryl, and bicyclic ring is unsubstituted or substituted with one or more substituents; [ka] is C 2~6 Alkylene, C 3~6 alkenylene, heteroalkylene having 2 to 6 total atoms and 1 to 3 heteroatoms selected from N, O, and S, or heteroalkenylene having 3 to 6 total atoms and 1 or 2 heteroatoms selected from N, O, and S; [ka] is unsubstituted or substituted with one or more substituents; R 1a , R 1b and R 2 each independently selected from H, D, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~2 Alkylene-OH, C 0~2 Alkylene-C 1~4 Alkoxy, C 0~2 Alkylene-C 1~4 Haloalkoxy, C 0~2 Alkylene-CN, C 0~2 Alkylene-N(R N1) C having 2, 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S 1~2 alkylene-heterocycloalkyl, and R 1b and R 2 together with the carbon atoms to which they are attached, [ka] Forming Each R 3 independently, C 1~3 Alkyl, C 1~3 haloalkyl, [ka] , C 0~3 Alkylene CN, C 0~3 Alkylene OH or C 0~3 Alkylene-C 1~3 Alkoxy and two geminal R 3 together with the atom to which they are attached, form oxo, spiro-C 3~7 Cycloalkyl, spiro-C 4~7 a cycloalkenyl, a spiro-heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a spiro-heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or two adjacent R 3 together with the atoms to which they are attached to form a fused C 3~7 Cycloalkyl, fused C 4~7 forming a cycloalkenyl, a fused heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; Each R 4 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene CN, C 1~3 Alkylene OH or C1~3 Alkylene-C 1~3 Alkoxy or two geminal R 4 together with the atom to which they are attached, form oxo, spiro-C 3~7 forming a cycloalkyl or a spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R 5 Ha, Halo, C 1~3 Haloalkyl, C 1~6 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~3 Alkoxy, C 1~3 Thioalkyl, C 3~7 Cycloalkyl, C 5~7 cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, each of which is independently unsubstituted or substituted with one or more substituents; R A1 and R A2 each independently represents H, C 1~3 Alkyl, C 1~3 Haloalkyl or C 3~5 is cycloalkyl, Each R N1 are independently H or C 1~4 It is alkyl.

[0035] In some cases, R 1a is H or D. In some cases, R 1a is H. In some cases, R 1a is D. In some cases, R 1b is H or D. In some cases, R 1b is H. In some cases, R 1b is D. In some cases, R 2 is H or D. In some cases, R 2 is H. In some cases, R 2is D. In some cases, R 1a , R 1b and R 2 At least one of R is H or D. In some cases, R 1a , R 1b and R 2 At least one of R is H. In some cases, 1a , R 1b and R 2 At least one of is D. In some cases, R 1a , R 1b and R 2 At least two of are independently H or D. In some cases, 1a , R 1b and R 2 At least two of R are H. In some cases, R 1a , R 1b and R 2 At least two of the are D. In some cases, R 1a , R 1b and R 2 Each of R is independently H or D. 1a , R 1b and R 2 Two of them are H and R 1a , R 1b and R 2 One of them is Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~2 Alkylene-OH, C 0~2 Alkylene-C 1~4 Alkoxy, C 0~2 Alkylene-C 1~4 Haloalkoxy, C 0~2 Alkylene-CN, C 0~2 Alkylene-N(R N1 ) C having 2 or 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S 1~2 In some cases, R is an alkylene-heterocycloalkyl. 1a , R 1b and R 2 Each of R is H. In some cases, R 1a , R 1b and R2 Each of the is D. In some cases, R 1a , R 1b and R 2 At least one of the R is a halo. 1a , R 1b and R 2 One of the is a halo. In some cases, R 1a is the halo and R 1b and R 2 Each of R is H. In some cases, R 1a , R 1b and R 2 At least one of R is Br, Cl, or F. In some cases, R 1a , R 1b and R 2 One of R is Br, Cl, or F. In some cases, R 1a is Br, Cl or F, and R 1b and R 2 Each of R is H. In some cases, R 1a , R 1b and R 2 At least one of R is Br or Cl. 1a , R 1b and R 2 One of R is Br or Cl. 1a is Br or Cl, and R 1b and R 2 Each of R is H. In some cases, R 1a , R 1b and R 2 At least one of 1~4 Alkyl or C 1~4 In some cases, R 1a , R 1b and R 2 One of them is C 1~4 Alkyl or C 1~4 In some cases, R 1a , R 1b and R 2 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2F, CHF2, or CF3.1a , R 1b and R 2 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2F, CHF2, or CF3. In some cases, R 1a , R 1b and R 2 At least one of R is CH, CHF, CHF, or CF. 1a , R 1b and R 2 One of R is CH3, CH2F, CHF2, or CF3. In some cases, R 1a , R 1b and R 2 At least one of 1~2 Alkylene-OH, C 0~2 Alkylene-C 1~4 Alkoxy, C 0~2 Alkylene-C 1~4 Haloalkoxy, C 0~2 Alkylene-CN or C 0~2 Alkylene-N(R N1 )2, and each R N1 are independently H or C 1~4 In some cases, each R N1 is independently H or CH. In some cases, each R N1 are independently H. In some cases, R 1a , R 1b and R 2 is CHOH, OCH, CHOCH, OCF, CHOCF, CN, CHCN, NH, N(CH), CHNH, or CHN(CH). 1a , R 1b and R 2 is CH2OH, OCH3, CH2OCH3, OCF3, CH2OCF3, CN, CH2CN, NH2, N(CH3)2, CH2NH2, or CH2N(CH3)2. In some cases, R 1a , R 1b and R 2 At least one of 1~2Alkylene-heterocycloalkyl, where the heterocycloalkyl contains 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, the heterocycloalkyl is aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxathiolidinyl, isoxothiodinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, diazinyl, or morpholinyl. In some cases, the heterocycloalkyl is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In some cases, R 1a , R 1b and R 2 At least one of R is aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidin-1-yl-methyl, piperidin-1-yl-methyl, or morpholin-1-yl-methyl. 1a , R 1b and R 2 is aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidin-1-yl-methyl, piperidin-1-yl-methyl, or morpholin-1-yl-methyl. 1a , R 1b and R 2 is Br, Cl, F, CH3, CH2F, CHF2, CF3, CH2OH, OCH3, CHOCH3, OCF3, CH2OCF3, CN, CH2CN, NH2, N(CH3)2, CH2NH2, CH2N(CH3)2, aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidin-1-yl-methyl, piperidin-1-yl-methyl, or morpholin-1-yl-methyl. 1b and R 2 together with the carbon atoms to which they are attached, [ka] In some cases, R 1a is H. In some cases, R 1b and R2 together with the carbon atoms to which they are attached [ka] In some cases, [ka] In some cases, [ka] In some cases, [ka] In some cases, [ka] is.

[0036] In some cases, m is 0; [ka] In some cases, m is 1. In some cases, m is 2. In some cases, m is 3. In some cases, m is 4. In some cases, [ka] is deuterated. In some cases, [ka] is fully deuterated. In some cases, [ka] In some cases, at least one R 3 is C 1~3 Alkyl or C 1~3 In some cases, at least one R 3is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, at least one R 3 is CH3, CH2CH3, CF3, CHF2, or CH2F. In some cases, at least one R 3 is CH3. In some cases, m is 1 or 2, and each R 3 is CH3. In some cases, m is 1 and R 3 is CF, CHF, or CHF. In some cases, at least one R 3 teeth, [ka] and R A1 and R A2 each independently represents H, C 1~3 Alkyl, C 1~3 Haloalkyl or C 3~5 In some cases, m is 1 and R 3 teeth, [ka] In some cases, R A1 and R A2 is independently H, CH, CHF, CHF, CF, CHCH, CHCHCH, CH(CH), cyclopropyl, or cyclobutyl. [ka] In some cases, [ka] In some cases, [ka] In some cases, at least one R 3 teeth, [ka] In some cases, at least one R 3 teeth, [ka] In some cases, at least one R 3 is C 0~3 alkyleneCN. In some cases, at least one R 3 is CN, CHCN, or CHCHCN. In some cases, at least one R 3 is CN or CHCN. In some cases, m is 1 and R 3 is CN or CHCN. In some cases, at least one R 3 is C 0~3 Alkylene OH or C 0~3 Alkylene-C 1~3 In some cases, at least one R 3 is OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3. In some cases, m is 1 and R 3 is OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3. In some cases, two geminal R 3 together with the atom to which they are attached form an oxo (=O). In some cases, two geminal R 3 are C groups having, together with the atoms to which they are attached, 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S. 3~7 Form a spiro-cycloalkyl or spiro-heterocycloalkyl. In some cases, the spiro-cycloalkyl is spiro-cyclopropyl, spiro-cyclobutyl, or spiro-cyclopentyl. In some cases, the spiro-heterocycloalkyl is spiro-azetidinyl, spiro-oxetanyl, spiro-pyrrolidinyl, spiro-imidazolidinyl, spiro-pyrazolidinyl, or spiro-tetrahydrofuranyl. In some cases, two geminal R 3together with the atoms to which they are attached form spiro-cyclopropyl, spiro-cyclobutyl, spiro-cyclopentyl, spiro-azetidinyl, spiro-oxetanyl, spiro-pyrrolidinyl, spiro-imidazolidinyl, spiro-pyrazolidinyl, or spiro-tetrahydrofuranyl. In some cases, two geminal R 3 together with the atoms to which they are attached form spiro-C having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S. 4~7 In some cases, two vicinal R 3 are, together with the atoms to which they are attached, a fused C ring having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. 3~7 In some cases, two vicinal R 3 together with the atom to which they are attached form a fused cyclopropyl, fused cyclobutyl, fused cyclopentyl, or fused cyclohexyl. In some cases, two adjacent R 3 together with the atoms to which they are attached to form a fused cyclopropyl or fused cyclobutyl. In some cases, each R 3 are independently CH3, CH2CH3, CF3, CHF2, CH2F, [ka] , CN, CH2CN, OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3 or CH2CH2OCH3, or two geminal R 3 together with the atom to which they are attached form oxo (=O), spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R 3 together with the atoms to which they are attached form a fused cyclopropyl or fused cyclobutyl. In some cases, m is 0 or m is 1 and R 3is CH3, CH2F, CHF2, CF3, CN, CH2CN, CH2OH, or CH2OCH3, or m is 2 and two geminal R 3 together with the atom to which they are attached form a spiro-oxetanyl. In some cases, m is 0 or m is 1 and R 3 is CH3. In some cases, [ka] [ka] In some cases, [ka] In some cases, [ka] is.

[0037] In some cases, A is N, CH, or CC 1~3 In some cases, A is N. In some cases, A is CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 In some cases, A is alkoxy. In some cases, A is CH. In some cases, A is CF, C-Cl, or C-CN. In some cases, A is C-halo or C-CN. In some cases, A is CF or C-Cl. In some cases, A is CF. In some cases, A is C-CN. In some cases, A is CC 1~3 Alkyl or CC 1~3In some cases, A is C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, or C-CH2F. In some cases, A is C-CH3, C-CH2F, C-CHF2, or C-CF3. In some cases, A is C-CH3. In some cases, A is C-CH2F, C-CHF2, or C-CF3. In some cases, A is CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 In some cases, A is C—OH, C—CH2OH, C—CH2CH2OH, C—OCH3, C—CH2OCH3, or C—CH2CH2OCH3. In some cases, A is C—OH, C—CH2OH, C—OCH3, or C—CH2OCH3. In some cases, A is CH, CF, C—Cl, C—CN, C—CH3, C—CH2F, C—CHF2, C—CF3, C—OH, C—CH2OH, C—OCH3, or C—CH2OCH3. In some cases, A is N, CH, CF, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, C-CH2F, C-OH, C-CH2OH, C-CH2CH2OH, C-OCH3, C-CH2OCH3, or C-CH2CH2OCH3. In some cases, A is N, CH, CF, C-Cl, C-CN, C-CH3, C-CF3, C-CHF2, C-CH2F, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3. In some cases, A is N, CH, or C-CH3. In some cases, n is 0. In some cases, n is 1. In some cases, n is 2. In some cases, at least one R 4 is C 1~3 Alkyl or C 1~3 In some cases, at least one R 4 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, at least one R 4 is CH3. In some cases, one R 4is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, n is 2 and each R 4 is independently CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, n is 1 and R 4 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, n is 1 and R 4 is CH3. In some cases, at least one R 4 is C 0~3 alkyleneCN. In some cases, at least one R 4 is CN or CHCN. In some cases, n is 1 and R 4 is CN or CHCN. In some cases, at least one R 4 is C 1~3 Alkylene OH or C 1~3 Alkylene-C 1~3 In some cases, at least one R 4 is CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3. In some cases, n is 1 and R 4 is CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3. In some cases, two geminal R 4 together with the atom to which they are attached form an oxo (=O). In some cases, two geminal R 4 together with the atoms to which they are attached, C 3~7 In some cases, the spiro-cycloalkyl is spiro-cyclopropyl, spiro-cyclobutyl, or spiro-cyclopentyl. In some cases, the spiro-cycloalkyl is spiro-cyclopropyl or spiro-cyclobutyl. In some cases, two geminal R 4are taken together with the atoms to which they are attached to form a spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, the spiro-heterocycloalkyl is spiro-oxetanyl or spiro-tetrahydrofuranyl. In some cases, the spiro-heterocycloalkyl is spiro-oxetanyl. In some cases, two geminal R 4 together with the atoms to which they are attached form spirocyclopropyl, spirocyclobutyl, or spiro-oxetanyl. In some cases, each R 4 are independently CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2CH2OH, OCH3, CH2OCH3, CH2CH2OCH3, or two geminal R 4 together with the atom to which they are attached form oxo, spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl. In some cases, each R 4 are independently CH3, CH2CH3, CH2CH2CH3, CH2F, CN, CH2CN, CH2OH, CH2CH2OH, CH2OCH3, or two geminal R 4 and together with the atom to which they are attached form a spirocyclopropyl. In some cases, each R 4 are independently CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, or two geminal R 4 and together with the atom to which they are attached form oxo, spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl. [ka] In some cases, [ka] In some cases, [ka] is.

[0038] In some cases, [ka] is not replaced. In some cases, [ka] is substituted with 1 to 4 substituents. In some cases, each of the 1 to 4 substituents is independently selected from C 1~3 Alkyl, C 1~3 Haloalkyl, C 2~3 Alkenyl, Halo, CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 4~5 cycloalkenyl, heterocycloalkyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, phenyl, or two geminal substituents, taken together with the atoms to which they are attached, may be oxo, =CH2, spiro-C 3~5 Cycloalkyl, spiro-C 4~5 or two adjacent substituents, together with the atoms to which they are attached, form a fused C ring; a spiro-heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or a spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or two adjacent substituents, together with the atoms to which they are attached, form a fused C ring; 3~5 Cycloalkyl, fused C 4~5Forms a cycloalkenyl, a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, each substituent independently is selected from C 1~3 Alkyl, C 1~3 Haloalkyl, C 2~3 Alkenyl, Halo, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 or two geminal substituents, together with the atoms to which they are attached, form oxo or =CH2, or two adjacent substituents, together with the atoms to which they are attached, form a fused C 3~5 Forms a cycloalkyl or a fused heterocycloalkyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, each C 1~3 The alkyl substituents are independently CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2. In some cases, each C 1~3 The alkyl substituent is CH3. In some cases, each C 1~ The 3 haloalkyl substituents are independently CF, CHF, or CHF. In some cases, each C 2~3 The alkenyl substituents are independently CH=CH2, CH=CHCH3, or CH2CH=CH2. In some cases, each halo substituent is independently Cl or F. In some cases, each C 0~3 The alkylene OH substituents are independently OH, CHOH, or CHCHOH. In some cases, each C 0~3 Alkylene-C 1~3 The alkoxy substituents are independently OCH, OCHCH, CHOCH, or CHOCHCH. In some cases, each C 3~5 The cycloalkyl substituents are independently cyclopropyl, cyclobutyl, or cyclopentyl. In some cases, each C 4~5The cycloalkenyl substituents are independently cyclobutenyl or cyclopentenyl. In some cases, each heterocycloalkyl substituent is independently oxetanyl, tetrahydrofuranyl, aziridinyl, or azetidinyl. In some cases, each spiro-cycloalkyl substituent is independently spiro-cyclopropyl or spiro-cyclobutyl. In some cases, each spiro-cycloalkenyl is spiro-cyclobutenyl. In some cases, each spiro-heterocycloalkyl is independently spiro-oxetanyl, spiro-tetrahydrofuranyl, spiro-aziridinyl, or spiro-azetidinyl. In some cases, each fused cycloalkyl substituent is independently fused cyclopropyl or fused cyclobutyl. In some cases, each fused cycloalkenyl is fused cyclobutenyl. In some cases, each fused heterocycloalkyl is independently a fused oxetanyl, a fused tetrahydrofuranyl, a fused aziridinyl, or a fused azetidinyl. [ka] each of the one to four substituents is independently CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH=CH2, CH=CHCH3, CH2CH=CH2, Cl, F, OH, CH2OH, CH2CH2OH, OCH3, OCH2CH3, CHOCH3, CHOCH2CH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, aziridinyl or azetidinyl, or two gemina In some cases, aryl substituents, taken together with the atoms to which they are attached, form a spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, spiro-aziridinyl, or spiro-azetidinyl, or two adjacent substituents, taken together with the atoms to which they are attached, form a fused cyclopropyl, fused cyclobutyl, fused oxetanyl, fused tetrahydrofuranyl, fused aziridinyl, or fused azetidinyl. [ka] each of the 1 to 4 substituents is independently CH3, ═CH2, oxo, Cl, F, OH, OCH3, [ka] In some cases, [ka] is C 2~6 alkylene, C 2~6 Alkylene is unsubstituted or substituted with 1 to 4 substituents. [ka] is a C2 alkylene, which is unsubstituted or substituted with 1 to 4 substituents. [ka] In some cases, [ka] is a C alkylene, which is unsubstituted or substituted with 1 to 4 substituents. [ka] In some cases, [ka] is C 4~6 alkylene, C 4~6 Alkylene is unsubstituted or substituted with 1 to 4 substituents. [ka] where p is 0, 1, 2, or 3, and each R 7 are independently CH3, Cl, F, OH, or OCH3, or two geminal R 7together with the atom to which they are attached to form oxo or =CH2, or two adjacent R 7 together with the atoms to which they are attached, [ka] In some cases, [ka] In some cases, [ka] is C 3~6 alkenylene, C 3~6 Alkenylene is unsubstituted or substituted with 1 to 4 substituents. [ka] is a C3 alkenylene, which is unsubstituted or substituted with 1 to 4 substituents. [ka] In some cases, [ka] is C 4~6 alkenylene, C 4~6 Alkenylene is unsubstituted or substituted with 1 to 4 substituents. [ka] where p is 0, 1, 2, or 3, and each R 7 are independently CH3, Cl, F, OH, OCH3, [ka] In some cases, [ka] is heteroalkylene having 2 to 6 total atoms and 1 to 3 heteroatoms selected from N, O, and S. In some cases, the heteroalkylene has 2 to 4 total atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, [ka] is heteroalkylene having two total atoms and one heteroatom selected from N, O, and S. In some cases, [ka] In some cases, the heteroalkylene has a total of 3 atoms and one heteroatom selected from N, O, and S. In some cases, [ka] In some cases, the heteroalkylene has a total of 4 atoms and one heteroatom selected from N, O, and S. In some cases, [ka] In some cases, [ka] In some cases, [ka] In some cases, [ka] is heteroalkenylene having 3 to 6 total atoms and 1 to 3 heteroatoms selected from N, O, and S. In some cases, [ka] [ka] In some cases, [ka] In some cases, [ka] is.

[0039] In some cases, [ka] is a tether having 2 to 6 total atoms and 0, 1, or 2 heteroatoms selected from NO and S, forming a ring of formula (II) having 6 to 10 total atoms, the tether being unsubstituted or substituted. [ka] is saturated. In some cases, [ka] is unsaturated. In some cases, [ka] has a total of 2 atoms, forming a ring with a total of 6 ring atoms. [ka] has 3 total atoms, forming a ring with 7 total ring atoms. [ka] has a total of 4 atoms, forming a ring with a total of 8 ring atoms. [ka] has a total of 5 atoms, forming a ring with a total of 9 ring atoms. [ka] has a total of 6 atoms, forming a ring with a total of 10 ring atoms. [ka] has 0 heteroatoms. In some cases, [ka] has 1 or 2 heteroatoms selected from N, O and S. In some cases, [ka] has one or two oxygen atoms. In some cases, [ka] is the ether. In some cases, [ka] is a polyether. In some cases, [ka] has one or two nitrogen atoms. In some cases, [ka] forms a cyclic amide (i.e., a lactam). In some cases, [ka] forms a cyclic amine. In some cases, [ka] is not replaced. In some cases, [ka] is substituted with 1 or 2 substituents, and each substituent is independently 1~3 Alkyl, C 1~3 Haloalkyl, Halo, CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 Alkoxy, C 3~7 Cycloalkyl, C 5~7 Cycloalkenyl, heterocycloalkyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, phenyl, or two geminal substituents which, together with the atoms to which they are attached, form an oxo. In some cases, [ka] is.

[0040] In some cases, W 1 is N. In some cases, W 1 is CH. In some cases, W 1 is C-halo or C-CN. In some cases, W 1 is CF, C—Cl, or C—Br. In some cases, W 1 is CF, C—Cl, or C—CN. In some cases, W 1 CC 1~3 Alkyl or CC 1~3 In some cases, W is a haloalkyl. 1 is C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2 or C-CH2F. In some cases, W 1 is C-CH3, C-CH2CH3, C-CH2F, C-CHF2 or C-CF3. In some cases, W 1 is C-CH3 or C-CH2CH3. In some cases, W 1 CC 2~3 Alkenyl or CC 2~3and alkynyl, wherein each of the alkenyl and alkynyl is unsubstituted or substituted with one or more substituents. In some cases, each of the alkenyl and alkynyl is unsubstituted. In some cases, each of the alkenyl and alkynyl is substituted with 1 to 3 substituents, and each substituent is independently selected from halo, C 1~3 Haloalkyl, C 0~3 Alkylene OH or C 0~3 Alkylene C 1~4 In some cases, W 1 is C-CH=CH2, CC(OH)=CH2, C-CH=CH(OH) or C-CCH. In some cases, W 1 CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 In some cases, W 1 is C—OH, C—CH2OH, C—CH2CH2OH, C—OCH3, C—CH2OCH3, or C—CH2CH2OCH3. In some cases, W 1 is C-OH, C-CH2OH, C-OCH3 or C-CH2OCH3. In some cases, W 1 is CH, CF, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, C-CH2F, C-OH, C-CH2OH, C-CH2CH2OH, C-OCH3, C-CH2OCH3 or C-CH2CH2OCH3. In some cases, W 1 is CH, CF, C—Cl, C—CN, C—CH3, C—CH2CH3, C—OH, C—CH2OH, C—OCH3, or C—CH2OCH3. In some cases, W 1 is CF, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2F, C-CHF2, C-CF3, C-CH=CH2, CC(OH)=CH2, C-CH=CH(OH), C-CCH, C-OH, C-CH2OH, C-OCH3 or C-CH2OCH3. In some cases, W 2 is N. In some cases, W 2 is CH. In some cases, W2 is C-halo or C-CN. In some cases, W 2 is CF, C—Cl, or C—Br. In some cases, W 2 is CF, C—Cl, or C—CN. In some cases, W 2 CC 1~3 Alkyl or CC 1~3 In some cases, W is a haloalkyl. 2 is -CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, or C-CH2F. In some cases, W 2 is C-CH3, C-CH2CH3, C-CH2F, C-CHF2 or C-CF3. In some cases, W 2 is C-CH3 or C-CH2CH3. In some cases, W 2 CC 2~3 Alkenyl or CC 2~3 and alkynyl, wherein each of the alkenyl and alkynyl is unsubstituted or substituted with one or more substituents. In some cases, each of the alkenyl and alkynyl is unsubstituted. In some cases, each of the alkenyl and alkynyl is substituted with 1 to 3 substituents, and each substituent is independently selected from halo, C 1~3 Haloalkyl, C 0~3 Alkylene OH or C 0~3 Alkylene C 1~4 In some cases, W 2 is C-CH=CH2, CC(OH)=CH2, C-CH=CH(OH) or C-CCH. In some cases, W 2 CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 In some cases, W 2 is C—OH, C—CH2OH, C—CH2CH2OH, C—OCH3, C—CH2OCH3, or C—CH2CH2OCH3. In some cases, W 2 is C-OH, C-CH2OH, C-OCH3 or C-CH2OCH3. In some cases, W 2is CH, CF, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, C-CH2F, C-OH, C-CH2OH, C-CH2CH2OH, C-OCH3, C-CH2OCH3 or C-CH2CH2OCH3. In some cases, W 2 is CH, CF, C—Cl, C—CN, C—CH3, C—CH2CH3, C—OH, C—CH2OH, C—OCH3, or C—CH2OCH3. In some cases, W 2 is CF, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2F, C-CHF2, C-CF3, C-CH=CH2, CC(OH)=CH2, C-CH=CH(OH), C-CCH, C-OH, C-CH2OH, C-OCH3 or C-CH2OCH3. In some cases, W 1 and W 2 Each of W is independently N, CH, or C—CH. 1 is CH and W 2 is N, CH, or C-CH3. In some cases, W 2 is N and W 1 is N, CH, or C-CH3. In some cases, W 1 is CH and W 2 is N. In some cases, [ka] In some cases, [ka] In some cases, [ka] In some cases, [ka] is.

[0041] In some cases, R 5 is a halo. In some cases, R5 is Br, Cl, or F. In some cases, R 5 is C 1~3 In some cases, R 5 is CF3, CF2H, CFH2, or CF2CH3. In some cases, R 5 is CF3 or CF2H. In some cases, R 5 is CF3. In some cases, R 5 is CF2H. In some cases, R 5 is CHF2. In some cases, R 5 is C 1~3 Alkoxy or C 1~3 In some cases, R 5 is OCH3, OCH2CH3, SCH3 or SCH2CH3. In some cases, R 5 is OCH3 or SCH3. In some cases, R 5 is C 1~6 Alkyl, C 2~4 Alkenyl or C 2~4 alkynyl, each of which is unsubstituted or substituted with one or more substituents. 1~6 Alkyl is CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, each of the foregoing being unsubstituted or substituted with one or more substituents. In some cases, C 2~4 Alkenyl is CH=CH2 or CH=CHCH3, each of the above being unsubstituted or substituted with one or more substituents. In some cases, C 2~4 Alkynyl is [ka] wherein each of the above is unsubstituted or substituted with one or more substituents. In some cases, C 1~6 Alkyl, C 2~4 Alkenyl and C 2~4 The alkynyl is unsubstituted. In some cases, R 5 is CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2. In some cases, C1~6 Alkyl, C 2~4 Alkenyl and C 2~4 The alkynyl is substituted with 1 to 3 substituents. In some cases, each of the 1 to 3 substituents is independently selected from C 1~3 Haloalkyl, C 0~6 Alkylene (OH), C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 Cycloalkyl, C 5~7 The heterocycloalkyl group may be a cycloalkenyl, a heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, a heterocycloalkenyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or phenyl. In some cases, each of the 1 to 3 substituents is independently CH, CF, CFH, CFH, OH, OCH, OCF, CHOH, CHOCH, cyclopropyl, cyclobutyl, or phenyl. In some cases, R 5 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, [ka] In some cases, R 5 is C 3~7 Cycloalkyl, C 5~7 cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, each of the foregoing being unsubstituted or selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~6 Alkylene (OH) or C 0~6 Alkylene-C 1~3 In some cases, C is substituted with 1 to 3 substituents independently selected from alkoxy. 3~7 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is unsubstituted or substituted with 1 to 3 substituents.5~7 Cycloalkenyl is cyclopentenyl or cyclohexenyl, each of which is unsubstituted or substituted with 1 to 3 substituents. In some cases, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S is aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, oxathiolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydropyranyl, dithianyl, morpholinyl, or thiomorpholinyl, each of which is unsubstituted or substituted with 1 to 3 substituents. In some cases, heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S is dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothiopyranyl, each of the foregoing being unsubstituted or substituted with 1 to 3 substituents. 5 is cyclopropyl, cyclobutyl, cyclopentenyl, oxetanyl, or tetrahydrofuranyl. 5 are CH3, CF3, CF2H, CFH2, CH2CH3, CH2CH2CH3, CH(CH3)2, [ka] In some cases, R 5 are Br, Cl, F, OCH3, SCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, [ka] is.

[0042] In some cases, W 1 is CH and W 2 is N and R5 is CF3, CF2H, or CFH2. In some cases, [ka] [ka] In some cases, [ka] [ka] In some cases, [ka] is.

[0043] In some cases, X is [ka] and Y is N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 alkoxy, o is 0, 1, 2, 3, or 4, and each R 6 are independently halo, CN, C 1~3 Alkyl, C 2~3 Alkenyl, C 1~3 Haloalkyl, C 0~3 Alkylene-OH, C 0~3 Alkylene-C 1~3 Alkoxy, deuterated C 0~3 Alkylene-C 1~3 Alkoxy or C 1~4 Alkylene-N(R N1 )2, and two geminal R 6 together with the atoms to which they are attached, form oxo, =CH2, spiro-C 3~7 Cycloalkyl, spiro-C 4~7a cycloalkenyl, a spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a spiro-heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, and two adjacent R 6 together with the atoms to which they are attached to form a fused C 3~7 Cycloalkyl, fused C 4~7 a fused heterocycloalkyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or two non-adjacent R 6 are joined together to form C 1~3 Alkylene bridge, C 2~3 Alkenylene bridge, C 1~3 Ether bridge or C 1~3 Form a thioether bridge or connect Y and the adjacent R 6 together with the atoms to which they are attached to form a fused C 3~7 Cycloalkyl, fused C 4~7 a cycloalkenyl, a fused heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, wherein any of the cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is unsubstituted or substituted with one or more substituents, and each R N1 are independently H or C 1~4 In some cases, o is 0. In some cases, o is 1. In some cases, o is 2. In some cases, o is 3. In some cases, o is 4. In some cases, at least one R 6 is halo or CN. In some cases, at least one R 6 is Br, Cl, F, or CN. In some cases, at least one R 6is F. In some cases, o is 1 or 2, and each R 6 are independently F. In some cases, at least one R 6 is C 1~3 Alkyl or C 1~3 In some cases, at least one R 6 is CH3, CH2F, CHF2, or CF3. In some cases, o is 1 or 2, and each R 6 are independently CH3. In some cases, at least one R 6 is C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 Alkoxy, deuterated C 0~3 Alkylene-C 1~3 Alkoxy or C 1~4 Alkylene-N(R N1 )2, and each R N1 is independently H or CH. In some cases, each R N1 are independently H. In some cases, at least one R 6 is OH, CH2OH, CH2CH2OH, OCH3, OCD3, CH2OCH3, or CH2CH2OCH3. In some cases, at least one R 6 is CHN(CH), CHNH(CH), or CHNH. In some cases, at least one R 6 is OH, CH2OH, OCH3, OCD3, CH2OCH3, or CH2N(CH3)2. In some cases, o is 1 and R 6 is OH, CH2OH, OCH3, or CH2OCH3. In some cases, two geminal R 6 forms oxo (=O) or =CH2. In some cases, two geminal R 6 together with the atoms to which they are attached form spiro-C having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S. 3~7 Cycloalkyl, spiro-C 4~7Form a cycloalkenyl, spiro-heterocycloalkyl, or spiro-heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, any of which are unsubstituted or substituted with one or more substituents. In some cases, two geminal R 6 together with the atoms to which they are attached form spiro-C 3~7 Forms a cycloalkyl or a spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, any of which is unsubstituted or substituted with one or more substituents. In some cases, two geminal R 6 together with the atoms to which they are attached form spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl, any of the foregoing being unsubstituted or substituted with one or more substituents. In some cases, two geminal R 6 together with the atoms to which they are attached form a spirocyclopropyl which is unsubstituted or substituted with one or more substituents. In some cases, two adjacent R 6 together with the atoms to which they are attached to form a fused C 3~7 Cycloalkyl, fused C 4~7 Cycloalkenyl, fused heterocycloalkyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or Y and adjacent R 6 together with the atoms to which they are attached to form a fused C 3~7 Cycloalkyl, fused C having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S 4~7 cycloalkenyl, forming a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, any of which may be unsubstituted or substituted with one or more substituents. In some cases, two adjacent R6 together with the atoms to which they are attached to form a fused C 3~7 or Y and the adjacent R 6 together with the atoms to which they are attached to form a fused C 3~7 In some cases, the fused C 3~7Cycloalkyl is fused cyclopropyl, fused cyclobutyl, or fused cyclopentyl, any of which is unsubstituted or substituted with one or more substituents. In some cases, any of the above spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused cycloalkyl, fused cycloalkenyl, fused heterocycloalkyl, and fused heterocycloalkenyl are unsubstituted. In some cases, any of the above spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused cycloalkyl, fused cycloalkenyl, fused heterocycloalkyl, and fused heterocycloalkenyl are substituted with one or more substituents. In some cases, any of the above spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused cycloalkyl, fused cycloalkenyl, fused heterocycloalkyl, and fused heterocycloalkenyl are unsubstituted. In some cases, any of the above spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused cycloalkyl, fused cycloalkenyl, fused heterocycloalkyl, and fused heterocycloalkenyl are substituted with 1 to 4 substituents. In some cases, any of the above spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused cycloalkyl, fused cycloalkenyl, fused heterocycloalkyl, and fused heterocycloalkenyl are substituted with 1 or 2 substituents. In some cases, each substituent of the spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused cycloalkyl, fused cycloalkenyl, fused heterocycloalkyl, and fused heterocycloalkenyl is independently selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~2 Alkylene OH, C 0~2 Alkylene C 1~3 Alkoxy or C 0~2alkyleneCN. In some cases, each substituent is independently halo, OH, C 1~3 In some cases, each substituent is independently F, Cl, OH, OCH, OCHCH, or CN. In some cases, two non-adjacent R 6 are joined together to form C 1~3 Alkylene bridge, C 2~3 Alkenylene bridge, C 1~3 Ether bridge or C 1~3 Forms a thioether bridge. In some cases, two non-adjacent R 6 are joined together to form C 1~3 Alkylene bridge, C 2~3 Alkenylene bridge or C 1~3 Forms an ether bridge. In some cases, two non-adjacent R 6 are joined together to form C 1~3 Alkylene bridge or C 2~3 Forms an alkenylene bridge. In some cases, two non-adjacent R 6 are joined together to form C 1~3 Alkylene bridge or C 2~3 Forms an alkenylene bridge. In some cases, two non-adjacent R 6 are joined together to form C 1~3 Ether bridge or C 1~3 Forms a thioether bridge. In some cases, two non-adjacent R 6 are joined together by a C1 alkylene bridge (e.g., [ka] ). In some cases, two non-adjacent R 6 are joined together by a C2 alkylene bridge (e.g., [ka] ). In some cases, two non-adjacent R 6 are joined together by a C3 alkylene bridge (e.g., [ka] ). In some cases, two non-adjacent R 6 are joined together to form a C2 alkenylene bridge (e.g., [ka] ). In some cases, two non-adjacent R 6 are linked together to form a C3 alkenylene bridge (e.g., [ka] ). In some cases, two non-adjacent R 6 are joined together to form C 1~3 Ether bridges (e.g., [ka] ). In some cases, two non-adjacent R 6 are joined together to form C 1~3 Thioether crosslinks (e.g., [ka] ). In some cases, two non-adjacent R 6 are bonded together to form -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2-CH=CH-, or -CH2OCH2-. In some cases, Y is N. In some cases, Y is CH. In some cases, Y is C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 In some cases, Y is alkoxy, or in some cases, Y is CF, C—Cl, or C—CN. In some cases, Y is CC 1~3 Alkyl or CC 1~3 In some cases, Y is C-CH3, C-CH2CH3, C-CH2F, C-CHF2, or C-CF3. In some cases, Y is CC0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 In some cases, Y is C—OH, C—CH2OH, C—OCH3, or C—CH2OCH3. In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] [ka] [ka] In some cases, X is [ka] In some cases, X is [ka] is.

[0044] In some cases, Z is unsubstituted phenyl or phenyl substituted with one or more substituents. In some cases, Z is unsubstituted phenyl. In some cases, Z is phenyl substituted with 1 to 4 substituents. In some cases, each of the phenyl substituents is independently selected from halo, C 0~3 Alkylene CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~4 Alkoxy, C 0~3 Alkylene-C 1~4 thioalkyl, or [ka] In some cases, each R N1 are independently H or C 1~3 In some cases, each R N1 is independently H or CH. In some cases, each R N1 is H. In some cases, each of the phenyl substituents is independently F, Cl, CN, OCH3, SCH3, CH2OH, or [ka] In some cases, Z is [ka] In some cases, Z is [ka] is.

[0045] In some cases, Z is heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, and the heteroaryl is unsubstituted or substituted with one or more substituents. In some cases, the heteroaryl contains 5 total ring atoms. In some cases, the heteroaryl contains 6 total ring atoms. In some cases, the heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl. In some cases, the heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, or triazolyl. In some cases, heteroaryl is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, or triazolyl. In some cases, heteroaryl is pyrazolyl, imidazolyl, thiazolyl, or isothiazolyl. In some cases, heteroaryl is pyrazolyl. In some cases, heteroaryl is imidazolyl. In some cases, heteroaryl is thiazolyl. In some cases, heteroaryl is isothiazolyl. In some cases, heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In some cases, heteroaryl is pyridyl. In some cases, heteroaryl is pyrazolyl, thiazolyl, pyridyl, or pyridazinyl. In some cases, heteroaryl is pyrazolyl or pyridyl.

[0046] In some cases, the heteroaryl is unsubstituted. In some cases, the heteroaryl is substituted with 1 to 4 substituents. In some cases, the heteroaryl is substituted with 1 or 2 substituents. In some cases, the heteroaryl is substituted with 3 or 4 substituents. In some cases, the heteroaryl is substituted with 1 substituent. In some cases, the heteroaryl is substituted with 2 substituents. In some cases, the heteroaryl is substituted with 3 substituents. In some cases, the heteroaryl is substituted with 4 substituents. In some cases, each of the heteroaryl substituents is independently selected from halo, CN, C, CI ... 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 0~6 Alkylene-N(R N1 )2C 0~2 Alkylene-C 3~6 Cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0~2 Alkylene-heterocycloalkyl or C 0~2 alkylene-phenyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 Each of the cycloalkyl, heterocycloalkyl, and phenyl substituents is independently optionally substituted with one or more further substituents, and each R N1 are independently H or C 1~3 In some cases, the C of heteroaryl 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 The cycloalkyl, heterocycloalkyl, and phenyl substituents are not further substituted. In some cases, the C of heteroaryl 1~6Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 The cycloalkyl, heterocycloalkyl, and phenyl substituents are substituted with one or more further substituents. In some cases, the C 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 The cycloalkyl, heterocycloalkyl, and phenyl substituents are substituted with 1 to 3 further substituents. In some cases, the C 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 The cycloalkyl, heterocycloalkyl and phenyl substituents are substituted with one or two further substituents. In some cases, the C of heteroaryl 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 The cycloalkyl, heterocycloalkyl and phenyl substituents are substituted with one further substituent.

[0047] In some cases, each additional substituent is independently selected from D, halo, OH, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~2 Alkylene OH, C 1~2 Alkylene-C 1~3 Alkoxy, C 1~3 Deuterated alkoxy, N(R N1 )2, (C=O)C 1~3 Alkyl, C 3~5 cycloalkyl or heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, form a spiro-C 3~5or two adjacent further substituents together with the atoms to which they are attached form a fused C 3~5 Form a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, wherein each of the cycloalkyl and heterocycloalkyl groups is independently unsubstituted or selected from halo, C 1~3 and each R is substituted with alkyl or a combination thereof. N1 are independently H or C 1~3 In some cases, each additional substituent is independently D, Br, Cl, F, OH, CH3, OCH3, OCD3, N(CH3)2, (C=O)C 1~3 alkyl, oxetanyl, or azetidinyl, or two geminal additional substituents, together with the atoms to which they are attached, form a spiro-oxetanyl or spiroazetidinyl, wherein each of said oxetanyl, azetidinyl, spiro-oxetanyl, and spiroazetidinyl is independently unsubstituted or substituted with F, CH, or a combination thereof. In some cases, each additional substituent is independently D, Br, Cl, F, OH, CH, CF, CFH, CFH, OCH, OCD, CHOCH, N(CH), (C=O)CH, oxetanyl, or azetidinyl. The oxetanyl or azetidinyl or each of the two geminal further substituents, together with the atom to which they are attached, form a spiro-oxetanyl or spiro-azetidinyl, and each of the oxetanyl, azetidinyl, spiro-oxetanyl, and spiro-azetidinyl is unsubstituted or substituted with F, CH, or a combination thereof. In some cases, each further substituent is independently D, Br, Cl, F, OH, CH, CF, CFH, CFH, OCH, OCD, N(CH), (C=O)CH, [ka] or two geminal further substituents, together with the atoms to which they are attached, [ka] In some cases, each additional substituent is independently D, CH3, OCH3, OCD3, N(CH3)2, [ka] or two geminal further substituents, together with the atoms to which they are attached, [ka] Form.

[0048] In some cases, heteroaryl is substituted with Br, Cl, F, or a combination thereof. In some cases, heteroaryl is substituted with F. In some cases, heteroaryl is substituted with CN. In some cases, heteroaryl is substituted with C 1~6 In some cases, heteroaryl is substituted with CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, each of which is independently optionally substituted with one or more further substituents. In some cases, heteroaryl is substituted with CH3, which is optionally substituted with one or more further substituents. In some cases, C 1~6 The alkyl is unsubstituted. In some cases, C 1~6 Alkyl is CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2. In some cases, heteroaryl is C 1~6 In some cases, C 1~6 The alkyl is substituted with 1 to 3 substituents, each of which is independently deuterium and halo. In some cases, the substituted C 1~6 Alkyl is C D . In some cases, heteroaryl is C1~6 In some cases, C 1~6 Haloalkyl is CF, CHF, CHF, CHCHF, CHCHF, CH(CHF), CH(CH)CHF, or CH(CH)CHF. In some cases, heteroaryl is C 2~6 In some cases, C is substituted with alkenyl, which is optionally substituted with one or more further substituents. 2~6 Alkenyl is CH=CH2, CH2CH=CH2, or CH=CHCH3, each of which is independently optionally substituted with one or more further substituents. 2~6 The alkenyl is unsubstituted. In some cases, C 2~6 Alkenyl is CH=CH2, CH2CH=CH2 or CH=CHCH3. In some cases, C 2~6 The alkenyl is substituted with 1 to 3 substituents, each of which is independently deuterium, halo, OH, OCH3, and OCD3. In some cases, the heteroaryl is C 2~6 In some cases, C is substituted with haloalkenyl. 2~6 Haloalkenyl is C(=CH2)CH2F. In some cases, heteroaryl is C 0~6 In some cases, C is substituted with alkylene-OH. 0~6 Alkylene -OH is OH, CH2OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, or CH2C(CH3)2OH. In some cases, C 0~6 Alkylene -OH is OH, CHOH, CHCHOH, or C(CH)CHOH. In some cases, heteroaryl is C 0~6 Alkylene-C 1~3 In some cases, C is substituted with an alkoxy, which is optionally substituted with one or more further substituents. 0~6 Alkylene-C 1~3Alkoxy is OCH3, CHOCH3, CHCH2OCH3, CHCH2OCH2CH3, CHCH2CH2OCH3, CH(CH3)OCH3, CH(CH3)CHOCH3, CH(OCH3)CHOCH3, CH(CH3)(OCH3)CHOCH3, C(CH3)2OCH3, C(CH3)2CH2OCH3, CHCH(CH3)OCH3, CH2(CH3)(OCH3)OCH3, CH2C(CH3)2OCH3, or CH2C(CH3)2OCH3, each of the foregoing independently optionally substituted with one or more further substituents. In some cases, C 0~6 Alkylene-C 1~3 Alkoxy is OCH, CH2OCH3, CH2CH2OCH3, or CH2CH2CH2OCH3, each of the foregoing independently optionally substituted with one or more further substituents. 0~6 Alkylene-C 1~3 Alkoxy is CH(CH3)OCH3 or CH2CHOCH3, each of the foregoing being independently optionally substituted with one or more additional substituents. In some cases, heteroaryl is substituted with OCH3, OCD3, CHOCH3, CH2OCD3, CH2CHOCH3, CH2CHOCH3, CH2CHOCH3, CH2CHOCH3, CHFCHOCH3, CF2CHOCH3CH2CH2CH2CH2OCH3, CH2CH2CH2OCD3, CH(CH3)CHOCH3, C(CH3)2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2CH2OCD3, CH(CH3)CH2OCD3, C(CH3)2CH2OCD3, CH2CH(CH3)OCD3, CH2C(CH3)2OCD3, or combinations thereof. In some cases, heteroaryl is substituted with C 0~6 Alkylene-N(R N1 )2. In some cases, C 0~6 Alkylene-N(R N1 )2 is NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, or CH2CH2N(CH3)2. In some cases, heteroaryl is C 0~2 Alkylene-C 3~6In some cases, C is substituted with cycloalkyl, which is optionally substituted with one or more further substituents. 0~2 Alkylene-C 3~6 The cycloalkyl of cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is independently optionally substituted or substituted with one or more further substituents. 0~2 Alkylene-C 3~6 The cycloalkyl of cycloalkyl is cyclopropyl or cyclobutyl, each of which is independently optionally substituted with one or more additional substituents. In some cases, each substituent is independently halo, OH, CH, OCH, or OCD. In some cases, C 0~2 The alkylene-cycloalkyl is substituted with 1 to 3 substituents, and each substituent is independently Br, Cl, F, OH, CH3, OCH3, or OCD3. In some cases, the optionally substituted C 0~2 Alkylene-cycloalkyl is [ka] In some cases, heteroaryl is a C aryl having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S. 0~2 In some cases, C is substituted with alkylene-heterocycloalkyl. 0~2 The heterocycloalkyl of alkylene-heterocycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, isoxazolidinyl, or morpholinyl, each of which is independently optionally substituted with one or more further substituents. 0~2 The heterocycloalkyl of alkylene-heterocycloalkyl is azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, each of which is optionally substituted with one or more further substituents. In some cases, optionally substituted C 0~2The heterocycloalkyl of the alkylene-heterocycloalkyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or piperidinyl. 0~2 The heterocycloalkyl of the alkylene-heterocycloalkyl is azetidinyl or oxetanyl, each of which is independently optionally substituted with one or more further substituents. 0~2 The heterocycloalkyl of the alkylene-heterocycloalkyl is azetidinyl, which is optionally substituted with one or more further substituents. 0~2 The heterocycloalkyl of the alkylene-heterocycloalkyl is oxetanyl, which is optionally substituted with one or more further substituents. 0~2 The alkylene-heterocycloalkyl is unsubstituted. In some cases, C 0~2 The alkylene-heterocycloalkyl is substituted with 1 to 3 further substituents. In some cases, C 0~2 The alkylene-heterocycloalkyl is substituted with one or two further substituents. In some cases, C 0~2 The alkylene-heterocycloalkyl is substituted with two further substituents. In some cases, C 0~2 The alkylene-heterocycloalkyl is substituted with one additional substituent. In some cases, each additional substituent is independently halo, OH, CH, OCH, or OCD. In some cases, each additional substituent is independently Br, Cl, F, OH, CH, CF, CFH, CHF, OCH, OCD, or C(=O)CH. In some cases, each additional substituent is independently D, Br, Cl, F, OH, CH, CH(CH), CF, CFH, CFH, OCH, OCD, N(CH), (C=O)CH, [ka] or two geminal further substituents, together with the atoms to which they are attached, [ka] In some cases, C 0~2 Alkylene-heterocycloalkyl is [ka] [ka] In some cases, C 0~2 Alkylene-phenyl is phenyl or CH2-phenyl, each of which is independently optionally substituted with one or more further substituents. In some cases, each substituent of the heteroaryl of Z is independently selected from Br, Cl, F, CN, CF3, CHF2, CH2F, CH2CHF2, CH2CH2F, CH(CH2F)2, CH(CH3)CH2F, CH(CH3)CHF2, C(=CH2)CH2F, OH, CH2OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, CH2C(CH3)2OH, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2. 1~6 C selected from alkyl, CH=CH2, CH2CH=CH2 and CH=CHCH3 2~6 Alkenyl, OCH3, CH2OCH3, CH2CH2OCH3, CH2CH2OCH2CH3, CH2CH2CH2OCH3, CH(CH3)OCH3, CH(CH3)CH2OCH3, CH(OCH3)CH2OCH3, CH(CH3)(O C selected from CH3)CH2OCH3, C(CH3)2OCH3, C(CH3)2CH2OCH3, CH2CH(CH3)OCH3, CH2(CH3)(OCH3)OCH3, CH2C(CH3)2OCH3 and CH2C(CH3)2OCH3 0~6 Alkylene-C 1~3is a cycloalkyl selected from alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, or a heterocycloalkyl selected from azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, isoxazolidinyl, and morpholinyl; 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Each of the alkoxy, cycloalkyl, and heterocycloalkyl substituents is independently substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~2 Alkylene OH, C 1~2 Alkylene-C 1~3 Alkoxy, C 1~3 Deuterated alkoxy, N(R N1 )2, (C=O)C 1~3 Alkyl, C 3~5 cycloalkyl, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, form spiro-C 3~5 or two adjacent further substituents together with the atoms to which they are attached form a fused C 3~5Forms a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, each additional substituent is independently D, Br, Cl, F, OH, CH, CF, CFH, CFH, OCH, OCD, CHOCH, N(CH), (C=O)CH, oxetanyl, azetidinyl, or two geminal additional substituents that, together with the atoms to which they are attached, form a spiro-oxetanyl or spiroazetidinyl, each of said oxetanyl, azetidinyl, spiro-oxetanyl, and spiro-azetidinyl, independently, unsubstituted or substituted with F, CH, or a combination thereof. In some cases, each additional substituent is independently D, Br, Cl, F, OH, CH3, CF3, CF2H, CFH2, OCH3, CH2OCH3, OCD3, N(CH3)2, (C=O)CH3, [ka] or two geminal substituents which, together with the atoms to which they are attached, are [ka] In some cases, each substituent of the heteroaryl of Z is independently Cl, F, CN, CH3, CD3, CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH2CHF2, CH2CH2F, CH(CH2F)2, CH(CH3)CH2F, CH(CH3)CHF2, C(=CH2)CH2F, OH, CH2OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, CH2C(CH3)2OH, OCH3, OCD3, CH2OCH3, CH2OCD3, CH2CH2OCH3, CHFCH2OCH3, CF2CH 2OCH3, CH2CH2OCD3, CH2CH2OCH2CH3, CH2CH2CH2OCH3, CH2CH2CH2OCD3, CH(CH3)OCH3, CH(CH3)CH2OCH3, CH(CH3)CH2OCD3, C(CH3)2CH2OCH3, C(CH3)2CH2OCD 3, CH2CH(CH3)OCH3, CH2CH(CH3)OCD3, CH2C(CH3)2OCH3, CH2C(CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] [ka] In some cases, each heteroaryl substituent of Z is independently CH3, C(CH3)2CH2OH, CH2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, [ka] In some cases, each heteroaryl substituent of Z is independently CH3, C(CH3)2CH2OH, CH2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, [ka] In some cases, each substituent of the heteroaryl of Z is independently CH3, CH2CH2OCH3, [ka] In some cases, Z is CH3 and CH2CH2OCH3, [ka] In some cases, the heteroaryl group is a heteroaryl substituted with CH3, CH2CH2OCH3, [ka] and has two substituents selected from:

[0049] In some cases, Z is heteroaryl and has the structure [ka] and R ZA and R ZB are as defined herein for substituents of the heteroaryl group of Z. In some cases, Z is heteroaryl and has the structure [ka] and R ZA and R ZB are as defined herein for substituents of the heteroaryl group of Z. In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, R ZA and R ZB each independently represents a halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 0~6 Alkylene-N(R N1 )2, C 0~2 Alkylene-C 3~6 Cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0~2 Alkylene-heterocycloalkyl or C 0~2 alkylene-phenyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 Each of the cycloalkyl, heterocycloalkyl, and phenyl substituents is independently optionally substituted with one or more further substituents, and each R N1 are independently H or C 1~3 In some cases, C 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is independently unsubstituted or substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~2 Alkylene OH, C1~2 Alkylene-C 1~3 Alkoxy, C 1~3 Deuterated alkoxy, N(R N1 )2, (C=O)C 1~3 Alkyl, C 3~5 cycloalkyl, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, form spiro-C 3~5 or two adjacent further substituents together with the atoms to which they are attached form a fused C 3~5 forming a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, wherein each of the further substituents of the cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently halo or C 1~3 In some cases, R ZA and R ZBEach of is independently Cl, F, CN, CH3, CD3, CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH2CHF2, CH2CH2F, CH(CH2F)2, CH(CH3)CH2F, CH(CH3)CHF2, C(=CH2)CH2F, OH, CH2 OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, CH2C(CH3)2OH, OCH3, OCD3, CH2OCH3, CH2OCD3, CH2CH2OCH3, CHFCH2OCH3, CF2CH2OCH3, CH2C H2OCD3, CH2CH2OCH2CH3, CH2CH2CH2OCH3, CH2CH2CH2OCD3, CH(CH3)OCH3, CH(CH3)CH2OCH3, CH(CH3)CH2OCD3, C(CH3)2CH2OCH3, C(CH3)2CH2OCD3, CH2 CH(CH3)OCH3, CH2CH(CH3)OCD3, CH2C(CH3)2OCH3, CH2C(CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] [ka] In some cases, R ZA is Cl, F, CH3, CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH2CHF2 or CH2CH2F, and R ZB are CH3, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] In some cases, R ZAは、C H3 and R ZB are CH3, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] In some cases, R ZAは、C H3 and R ZB are CH3, C(CH3)2CH2OH, CH2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, [ka] In some cases, R ZA is CH3 and R ZB is CH3, CH2CH2OCH3, [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] is.

[0050] In some cases, Z is C 5~6Bicyclic rings comprising a heteroaryl ring having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S fused to a cycloalkyl or heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, wherein the bicyclic ring is unsubstituted or substituted with 1 to 4 substituents. In some cases, the heteroaryl ring of the bicyclic ring is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. The cycloalkyl ring of the bicyclic ring is cyclopentyl or cyclohexyl, and the heterocycloalkyl ring of the bicyclic ring is pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or tetrahydrothiophenyl. In some cases, the heteroaryl group is pyridyl and the heterocycloalkyl group is furanyl. In some cases, Z is a bicyclic ring comprising a heteroaryl having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, fused to a ring having 5 or 6 total ring atoms and 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the bicyclic ring is unsubstituted or substituted with one or more substituents, such as 1 to 4 substituents, or 1 to 3 substituents, or 1 to 2 substituents, or 1 substituent. In some cases, the heteroaryl of the bicyclic ring is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and the fused ring has a total of 5 atoms and 1 oxygen atom in the fused ring, a total of 5 atoms and 1 nitrogen atom in the fused ring, a total of 6 atoms and 1 nitrogen or oxygen atom in the ring, or a total of 6 atoms, 1 oxygen atom, and 1 nitrogen atom in the fused ring. In some cases, the heteroaryl group is pyridyl, and the fused ring has a total of 5 atoms and 1 oxygen atom in the fused ring. In some cases, the heteroaryl group is imidazolyl or pyrazolyl, and the fused ring has 5 total atoms and 1 nitrogen atom in the fused ring, 6 total atoms and 1 nitrogen or oxygen atom in the ring, or 6 total atoms, 1 oxygen atom, and 1 nitrogen atom in the fused ring. In some cases, the bicyclic ring is unsubstituted. In some cases, the bicyclic ring is substituted with 1 to 4 substituents, and each substituent is independently selected from halo, CN, C ... 1~6 Alkyl, C1~6 Haloalkyl, C 0~6 Alkylene-OH or C 0~6 Alkylene-C 1~3 In some cases, each substituent on the bicyclic ring is independently Br, Cl, F, CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH2CHF2, CH2CH2F, CH(CH2F)2, CH(CH3)CH2F, CH(CH3)CHF2), OH, CH2OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, CH2C(CH3)2OH, OCH3, CHOCH3, CH2CH2OCH3, CH2CH2CH2OCH3, CH(CH3)CHOCH3, C(CH3)2CH2OCH3, CH2CH(CH3)OCH3, or CH2C(CH3)2OCH3. In some cases, each substituent on the bicyclic ring is independently Cl, Br, F, CH, OH, CHOH, OCH, or CHOCH. [ka] is.

[0051] In some cases, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3 or 4; n is 0, 1 or 2; A is N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy; W 1 and W 2 each independently represents N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 2~3 Alkenyl, CC2~3 Alkynyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 alkoxy, wherein each of the alkenyl and alkynyl is unsubstituted or substituted with 1 to 3 substituents, and each substituent is independently selected from halo, C 1~3 Haloalkyl, C 0~3 Alkylene OH or C 0~3 Alkylene C 1~4 is an alkoxy; X is a heterocycloalkyl or heterocycloalkenyl, each having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, wherein each of the heterocycloalkyl and heterocycloalkenyl is unsubstituted or substituted with 1 to 3 substituents, and each substituent is independently selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~2 Alkylene OH, C 0~2 Alkylene C 1~3 Alkoxy or C 0~2 is alkylene CN, Z is phenyl, heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or a bicyclic ring; C 5~6 a bicyclic ring containing a heteroaryl having 5 or 6 total ring atoms and 1-3 heteroatoms selected from N, O, and S fused to a cycloalkyl or heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; Each of the phenyl, heteroaryl, and bicyclic ring is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C0~6 Alkylene-N(R N1 )2, C 0~2 Alkylene-C 3~6 Cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0~2 Alkylene-heterocycloalkyl or C 0~2 alkylene-phenyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is independently unsubstituted or substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~2 Alkylene OH, C 1~2 Alkylene-C 1~3 Alkoxy, C 1~3 Deuterated alkoxy, N(R N1 )2, (C=O)C 1~3 Alkyl, C 3~5 cycloalkyl or heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, form a spiro-C 3~5 or two adjacent further substituents together with the atoms to which they are attached form a fused C 3~5 forming a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; Each of the above further substituents of cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently halo or C 1~3 is alkyl, [ka] is C 2~6 Alkylene, C 3~6 alkenylene, heteroalkylene having 2 to 6 total atoms and 1 to 3 heteroatoms selected from N, O, and S, or heteroalkenylene having 3 to 6 total atoms and 1 or 2 heteroatoms selected from N, O, and S; [ka] is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from C 1~3 Alkyl, C 1~3 Haloalkyl, C 2~3 Alkenyl, Halo, CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 4~5 cycloalkenyl, heterocycloalkyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl; or two geminal substituents, together with the atoms to which they are attached, may be oxo, =CH2, spiro-C 3~5 Cycloalkyl, spiro-C 4~5 or two adjacent substituents, taken together with the atoms to which they are attached, form a fused C ring; a spiro-heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or a spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or two adjacent substituents, taken together with the atoms to which they are attached, form a fused C ring; 3~5 Cycloalkyl, fused C 4~5forming a cycloalkenyl, a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R 1a , R 1b and R 2 each independently selected from H, D, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~2 Alkylene-OH, C 0~2 Alkylene-C 1~4 Alkoxy, C 0~2 Alkylene-C 1~4 Haloalkoxy, C 0~2 Alkylene-CN, C 0~2 Alkylene-N(R N1 ) C having 2, 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S 1~2 alkylene-heterocycloalkyl, and R 1b and R 2 together with the carbon atoms to which they are attached, [ka] Forming Each R 3 independently, C 1~3 Alkyl, C 1~3 haloalkyl, [ka] , C 0~3 Alkylene CN, C 0~3 Alkylene OH or C 0~3 Alkylene-C 1~3 Alkoxy and two geminal R 3 together with the atom to which they are attached, form oxo, spiro-C 3~7 Cycloalkyl, spiro-C 4~7a cycloalkenyl, a spiro-heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a spiro-heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or two adjacent R 3 together with the atoms to which they are attached to form a fused C 3~7 Cycloalkyl, fused C 4~7 form a cycloalkenyl, a fused heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or [ka] is deuterated, Each R 4 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene CN, C 1~3 Alkylene OH or C 1~3 Alkylene-C 1~3 Alkoxy or two geminal R 4 together with the atom to which they are attached, form oxo, spiro-C 3~7 forming a cycloalkyl or a spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R 5 Ha, Halo, C 1~3 Haloalkyl, C 1~6 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~3 Alkoxy, C 1~3 Thioalkyl, C 3~7 Cycloalkyl, C 5~7cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, each of the foregoing being independently unsubstituted or substituted with 1 to 3 substituents, and each substituent being independently selected from C 1~3 Haloalkyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 Cycloalkyl, C 5~7 cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl; R A1 and R A2 each independently represents H, C 1~3 Alkyl, C 1~3 Haloalkyl or C 3~5 is cycloalkyl, Each R N1 are independently H or C 1~4 It is alkyl.

[0052] In some cases, m is 0 or 1, n is 0, o is 0 or 1, A is N, and W 1 is CH and W 2 is N and X is [ka] wherein Y is CH or N, Z is heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, the heteroaryl being substituted with one or more substituents, and R 1a , R 1b and R 2 is H and R 3 is CH3 and R 5is CHF, CHF, or CF. In some cases, [ka] and R 5 is CHF2 or CF3, and X is [ka] where o is 0 or 1, and R 6 is CH3, Y is CH or N, Z is pyrazolyl or pyridyl each substituted with 1 or 2 substituents, and each substituent is independently Cl, F, CN, CH3, CD3, CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH2CHF2, CH2CH2F, CH(CH2F)2, CH(CH3)CH2F, CH(CH3)CHF2, C(=CH2)CH2F, OH, CH2OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, CH2C(CH3)2OH, OCH3, OCD3, CH2OCH3, CH2OCD3, CH2CH2OCH3, CHFCH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2 OCH2CH3, CH2CH2CH2OCH3, CH2CH2CH2OCD3, CH(CH3)OCH3, CH(CH3)CH2OCH3, CH(OCH3)CH2OCH3, CH (CH3)(OCH3)CH2OCH3, CH(CH2F)(CH3)CH2OCD3, CH(CH3)CH2OCD3, C(CH3)2OCH3, C(CH3)2CH2OCH3 , C(CH3)2CH2OCD3, CH2CH(CH3)OCH3, CH2(CH3)(OCH3)OCH3, CH2CH(CH3)OCD3, CH2C(CH3)2OCH3, C H2C(CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, [ka] In some cases, [ka] In some cases, the heteroaryl of Z is pyrazolyl, thiazolyl, pyridyl, or pyridazinyl, each of which is substituted with 1 or 2 substituents. In some cases, the heteroaryl of Z is pyrazolyl or pyridyl, each of which is substituted with 2 substituents. In some cases, each substituent is independently selected from C 1~6 Alkyl, C 0~2 Alkylene-C 3~6 Cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0~2 alkylene-heterocycloalkyl or combinations thereof, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or two further substituents, and each further substituent is independently selected from D, CH3, OCH3, OCD3, N(CH3)2, [ka] or two geminal further substituents, together with the atoms to which they are attached, [ka] In some cases, Z forms [ka] [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] is.

[0053] In some cases, the compound of formula (II) [ka] teeth, [ka] In some cases, formula (II) has the structure of formula (IIA): [ka] or a pharmaceutically acceptable salt thereof. In some cases, Formula (II) has Formula (IIB), or Formula (IIC), or Formula (IID), or Formula (IIE), or Formula (IIF): [ka] or a pharmaceutically acceptable salt of any of the above.

[0054] In some cases, [ka] is the stereochemical configuration: [ka] In some cases, [ka] In some cases, [ka] has the following stereochemical configuration: [ka] In some cases, [ka] has the following stereochemical configuration: [ka] In some cases, formula (II) has the stereochemical configuration shown in formula (II'): [ka] Shows.

[0055] In some cases, the compound of formula (II) is a compound as listed in Table A or a pharmaceutically acceptable salt thereof.

[0056] [Table 1]

[0057] [Table 2]

[0058] [Table 3]

[0059] [Table 4]

[0060] [Table 5]

[0061] [Table 6]

[0062] [Table 7]

[0063] [Table 8]

[0064] [Table 9]

[0065]

Table 10

[0066]

Table 11

[0067]

Table 12

[0068]

Table 13

[0069]

Table 14

[0070]

Table 15

[0071] Table 16

[0072] Table 17

[0073] Table 18

[0074] Table 19

[0075] [Table 20]

[0076] In some cases, formula (II) has the structure of formula (IIB): Possible compounds of formula (IIB) include, for example: [ka] and pharmaceutically acceptable salts thereof.

[0077] In some cases, formula (II) has the structure of formula (IID): Contemplated compounds of formula (IID) where Y is CH include, for example: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof. Contemplated compounds of formula (IID) where Y is CH and Z is substituted pyrazolyl include, for example: [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof. Contemplated compounds of formula (IID) where Y is CH and Z is substituted thiazolyl include, for example: [ka] and pharmaceutically acceptable salts thereof. Contemplated compounds of formula (IID) where Y is CH and Z is substituted pyridyl include, for example: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. Contemplated compounds of formula (IID) where Y is CH and Z is substituted pyridazinyl include, for example: [ka] and pharmaceutically acceptable salts thereof. Contemplated compounds of formula (IID) where Y is N include, for example: [ka] and pharmaceutically acceptable salts thereof.

[0078] In some cases, formula (II) has the structure of formula (IIE): Possible compounds of formula (IIE) include, for example: [ka] and pharmaceutically acceptable salts thereof.

[0079] In some cases, the compound of formula (II) is a compound listed in Table B or a pharmaceutically acceptable salt thereof.

[0080] [Table 21]

[0081] [Table 22]

[0082] [Table 23]

[0083] [Table 24]

[0084] In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof.

[0085] In some cases, the compound of formula (II) is a compound listed in Table A' below. When the stereochemistry of a structure or portion of a structure in Table A' is not explicitly shown (e.g., using a dashed or bold line, etc.), the structure or portion of the structure is understood to be achiral or any of the possible stereoisomers of the structure or portion of the structure. When the stereochemistry of a structure or portion of a structure in Table A' is explicitly shown, a single stereoisomer of the structure or portion of the structure is represented.

[0086] [Table 25]

[0087] [Table 26]

[0088] [Table 27]

[0089] [Table 28]

[0090] [Table 29]

[0091] [Table 30]

[0092] Table 31

[0093] Table 32

[0094] Table 33

[0095] Table 34

[0096] Table 35

[0097] Table 36

[0098] Table 37

[0099] Table 38

[0100] Table 39

[0101] Table 40

[0102] [Table 41]

[0103] [Table 42]

[0104] [Table 43]

[0105] [Table 44]

[0106] [Table 45]

[0107] [Table 46]

[0108] In some cases, the compound of formula (II) is Compound 1-001 to Compound 1-109, or a pharmaceutically acceptable salt thereof, as shown in Table A'.

[0109] In some cases, X is [ka] and contemplated compounds of formula (II) include, for example, compounds 1-089 and 1-105, and pharmaceutically acceptable salts thereof.

[0110] In some cases, X is [ka] and contemplated compounds of formula (II) include, for example, compounds 1-001 to 1-034, 1-036 to 1-070, 1-072 to 1-088, 1-090 to 1-104, and 1-106 to 1-109, and pharmaceutically acceptable salts thereof.

[0111] In some cases, Y is CH and Z is substituted pyrazolyl, and contemplated compounds of formula (II) include, for example, compounds 1-002, 1-003, 1-006 through 1-010, 1-013 through 1-016, 1-018 through 1-021, 1-024 through 1-026, 1-028 through 1-030, 1-032 through 1-034, 1-035 through 1-036, 1-037 through 1-038, 1-039 through 1-040, 1-041 through 1-042, 1-043 through 1-044, 1-045 through 1-046, 1-047 through 1-048, 1-049 through 1-050, 1-051 through 1-052, 1-053 through 1-054, 1-055 through 1-056, 1-057 through 1-058, 1-059 through 1-060, 1-061 through 1-062, 1-063 through 1-064, 1-065 through 1-066, 1-067 through 1-068, 1-069 through 1-070, 1-071 through 1-072, 1-073 through 1-074, 1-075 through 1-076, 1-077 through 1-078, 1-079 through 1-080, 1-081 through 1-082, 1-083 through 1-084, 1-085 through 1-086, 1-087 through 1-088, 1 7 to 1-041, 1-044 to 1-047, 1-049 to 1-052, 1-055, 1-056, 1-058 to 1-060, 1-065, 1-072, 1-088, 1-091, 1-092, 1-094, 1-095, 1-097 to 1-104 and 1-106 to 1-109 and pharmaceutically acceptable salts thereof.

[0112] In some instances, Y is CH and Z is substituted thiazolyl; contemplated compounds of formula (II) include, for example, compound 1-066 and pharmaceutically acceptable salts thereof.

[0113] In some cases, Y is CH and Z is substituted pyridyl, and contemplated compounds of Formula (II) include, for example, 1-001, 1-004, 1-005, 1-011, 1-012, 1-017, 1-027, 1-031, 1-036, 1-042, 1-043, 1-048, 1-053, 1-054, 1-057, 1-061 through 1-064, 1-067 through 1-070, 1-073 through 1-082, 1-084, 1-086, 1-090, and pharmaceutically acceptable salts thereof.

[0114] In some instances, Y is CH and Z is substituted pyridazinyl, and contemplated compounds of formula (II) include, for example, compounds 1-022, 1-023, 1-083, 1-085, and 1-087, and pharmaceutically acceptable salts thereof.

[0115] In some cases, Y is N, and contemplated compounds of formula (II) include, for example, compounds 1-093 and 1-096, and pharmaceutically acceptable salts thereof.

[0116] In some cases, X is [ka] and contemplated compounds of formula (II) include, for example, compound 1-035 and pharmaceutically acceptable salts thereof.

[0117] In some cases, the compound of formula (II) is a compound listed in Table B' below. When the stereochemistry of a structure or portion of a structure in Table B' is not explicitly shown (e.g., using a dashed or bold line, etc.), the structure or portion of the structure is understood to be achiral or any of the possible stereoisomers of the structure or portion of the structure. When the stereochemistry of a structure or portion of a structure in Table B' is explicitly shown, a single stereoisomer of the structure or portion of the structure is represented.

[0118] [Table 47]

[0119] [Table 48]

[0120] [Table 49]

[0121] [Table 50]

[0122] In some cases, the compound of Formula (II) is Compound 1-001 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-002 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-003 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-009 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-017 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-018 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-019 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-020 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-021 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-067 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-075 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-076 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-077 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-107 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) is Compound 1-108 or a pharmaceutically acceptable salt thereof.

[0123] Compounds of formula (I) In other embodiments, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3 or 4; n is 1 or 2, o is 0, 1, 2, 3 or 4; A is N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy; W is CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy; X is [ka] and Y is N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy; Z is phenyl, heteroaryl having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a bicyclic ring containing a heteroaryl ring having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S fused to a cycloalkyl ring having 5 or 6 total ring atoms or a heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, wherein each of the phenyl, heteroaryl, and bicyclic ring is optionally substituted with 1 to 4 substituents; R 1a , R 1b and R 2 each independently selected from H, D, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~2 Alkylene-OH, C 0~2 Alkylene-C 1~4 Alkoxy, C 0~2 Alkylene-C 1~4 Haloalkoxy, C 0~2 Alkylene-CN, C 0~2 Alkylene-N(RN1 ) C having 2, 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S 1~2 alkylene-heterocycloalkyl, and R 1b and R 2 together with the carbon atoms to which they are attached, [ka] Forming a base, Each R 3 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two adjacent R 3 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms; 1 R 4 and R 5a together with the atoms to which they are attached form an optionally substituted ring having 6 to 10 total ring atoms and 0, 1 or 2 heteroatoms selected from N, O and S, which ring is saturated or unsaturated; When n is 2, the other R 4 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene CN, C 1~3 Alkylene OH, C 1~3 Alkylene-C 1~3 alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, or spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R 5b is C 1~3 Haloalkyl, C 1~4Alkyl, C 2~3 Alkenyl, C 2~3 Alkynyl, Halo, C 1~3 Alkoxy, C 1~3 thioalkoxy, cycloalkyl having 3 to 7 total ring atoms, cycloalkenyl having 5 to 7 total ring atoms, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, each of the foregoing independently optionally substituted with 1 to 3 substituents, or R 5a and R 5b taken together with the atoms to which they are attached form a cycloalkyl ring having 3 to 7 total ring atoms. Each R 6 are independently halo, CN, oxo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 Alkoxy, deuterated C 0~3 Alkylene-C 1~3 Alkoxy, C 1~4 Alkylene-N(R N1 ) 2, spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two adjacent R 6 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms, or Y and an adjacent R 6 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms, any of the above fused cycloalkyl rings being optionally substituted with 1 or 2 substituents; or Two non-adjacent R 6 are joined together to form C 1~3 Alkylene bridge or C 1~3 Forming an ether bridge, Each R N1 are independently H or C1~4 It is alkyl.

[0124] In some cases, R 1a is H or D. In some cases, R 1a is H. In some cases, R 1a is D. In some cases, R 1b is H or D. In some cases, R 1b is H. In some cases, R 1b is D. In some cases, R 2 is H or D. In some cases, R 2 is H. In some cases, R 2 is D. In some cases, R 1a , R 1b and R 2 At least one of R is H or D. In some cases, R 1a , R 1b and R 2 At least one of R is H. In some cases, 1a , R 1b and R 2 At least one of is D. In some cases, R 1a , R 1b and R 2 At least two of R are H. In some cases, 1a , R 1b and R 2 At least two of R are H. In some cases, 1a , R 1b and R 2 At least two of the are D. In some cases, R 1a , R 1b and R 2 Each of R is independently H or D. 1a , R 1b and R 2 Each of R is independently H. 1a , R 1b and R 2 Each of R is independently D. 1a , R 1b and R 2At least one of R is halo (e.g., Br, Cl, or F). 1a , R 1b and R 2 One of the is a halo. In some cases, R 1a is the halo and R 1b and R 2 Each of R is H. In some cases, R 1a , R 1b and R 2 At least one of R is Br, Cl, or F. In some cases, R 1a , R 1b and R 2 One of R is Br, Cl, or F. In some cases, R 1a is Br, Cl or F, and R 1b and R 2 Each of R is H. In some cases, R 1a , R 1b and R 2 At least one of R is Br or Cl. 1a , R 1b and R 2 One of R is Br or Cl. 1a is Br or Cl, and R 1b and R 2 Each of R is H. In some cases, R 1a , R 1b and R 2 At least one of 1~4 Alkyl or C 1~4 In some cases, R 1a , R 1b and R 2 One of them is C 1~4 Alkyl or C 1~4 In some cases, R 1a , R 1b and R 2 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2F, CHF2, or CF3. 1a , R 1b and R 2is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2F, CHF2, or CF3. In some cases, R 1a , R 1b and R 2 At least one of R is CH or CF. 1a , R 1b and R 2 One of R is CH3 or CF3. In some cases, R 1a , R 1b and R 2 At least one of 1~2 Alkylene-OH, C 0~2 Alkylene-C 1~4 Alkoxy, C 0~2 Alkylene-C 1~4 Haloalkoxy, C 0~2 Alkylene-CN or C 0~2 Alkylene-N(R N1 )2, and each R N1 are independently H or C 1~4 In some cases, each R N1 is independently H or CH. In some cases, each R N1 are independently H. In some cases, R 1a , R 1b and R 2 is CHOH, OCH, CHOCH, OCF, CHOCF, CN, CHCN, NH, N(CH), CHNH, or CHN(CH). 1a , R 1b and R 2 is CH2OH, OCH3, CH2OCH3, OCF3, CH2OCF3, CN, CH2CN, NH2, N(CH3)2, CH2NH2, or CH2N(CH3)2. In some cases, R 1a , R 1b and R 2 At least one of 1~2Alkylene-heterocycloalkyl, where the heterocycloalkyl group contains 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, the heterocycloalkyl is aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxathiolidinyl, isoxathiodinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, diazinyl, or morpholinyl. In some cases, the heterocycloalkyl is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In some cases, R 1a , R 1b and R 2 At least one of R is aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidin-1-yl-methyl, piperidin-1-yl-methyl, or morpholin-1-yl-methyl. 1a , R 1b and R 2 is aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidin-1-yl-methyl, piperidin-1-yl-methyl, or morpholin-1-yl-methyl. 1b and R 2 along with the carbon atoms to which they are attached [ka] In some cases, R 1a is H. In some cases, R 1b and R 2 together with the carbon atoms to which they are attached, [ka] In some cases, [ka] In some cases, [ka] In some cases, [ka] is.

[0125] In some cases, m is 0; [ka] In some cases, m is 1. In some cases, m is 2. In some cases, m is 3. In some cases, m is 4. In some cases, at least one R 3 is C 1~3 Alkyl or C 1~3 In some cases, at least one R 3 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, at least one R 3 is CH3, CH2CH3, CF3, CHF2, or CH2F. In some cases, m is 1 or 2, and each R 3 is CH3. In some cases, m is 1 and R 3 is CF, CHF, or CHF. In some cases, at least one R 3 is C 0~3 alkyleneCN. In some cases, at least one R 3 is CN or CHCN. In some cases, m is 1 and R 3 is CN or CHCN. In some cases, at least one R 3 is C 0~3 Alkylene OH or C 0~3 Alkylene-C 1~3 In some cases, at least one R 3 is OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3. In some cases, m is 1 and R 3is OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3. In some cases, at least one R 3 is oxo. In some cases, at least one R 3 is a spiro-cycloalkyl having 3 to 7 total ring atoms or a spiro-heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, at least one R 3 is spiro-cyclopropyl, spiro-cyclobutyl, spiro-cyclopentyl, spiro-azetidinyl, spiro-oxetanyl, spiro-pyrrolidinyl, spiro-imidazolidinyl, spiro-pyrazolidinyl, or spiro-tetrahydrofuranyl. In some cases, at least one R 3 is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl. In some cases, m is 1 and R 3 is spirocyclopropyl or spiro-oxetanyl. In some cases, two adjacent R 3 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms. In some cases, two adjacent R 3 together with the atoms to which they are attached form a fused cyclopropyl ring, a fused cyclobutyl ring, a fused cyclopentyl ring, or a fused cyclohexyl ring. In some cases, two adjacent R 3 together with the atoms to which they are attached form a fused cyclopropyl ring or a fused cyclobutyl ring. In some cases, each R 3 is independently CH3, CH2CH3, CF3, CHF2, CH2F, CN, CH2CN, OH, CH2OH, CH2CH2OH, OCH3, CHOCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl. In some cases, m is 1 and R 3 is CH3, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl. [ka] In some cases, [ka] is.

[0126] In some cases, A is N. In some cases, A is CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 In some cases, A is alkoxy. In some cases, A is CH. In some cases, A is C-halo or C-CN. In some cases, A is CF or C-Cl. In some cases, A is CF. In some cases, A is C-CN. In some cases, A is CC 1~3 Alkyl or CC 1~3 In some cases, A is C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, or C-CH2F. In some cases, A is C-CH3, C-CH2F, C-CHF2, or C-CF3. In some cases, A is CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4In some cases, A is C—OH, C—CH2OH, C—CH2CH2OH, C—OCH3, C—CH2OCH3, or C—CH2CH2OCH3. In some cases, A is C—OH, C—CH2OH, C—OCH3, or C—CH2OCH3. In some cases, A is N, CH, CF, C—Cl, C—CN, C—CH3, C—CH2CH3, C—CH2CH2CH3, C—CH(CH3)2, C—CF3, C—CHF2, C—CH2F, C—OH, C—CH2OH, C—CH2CH2OH, C—OCH3, C—CH2OCH3, or C—CH2CH2OCH3. In some cases, A is N, CH, CF, C—Cl, C—CN, C—CH, C—CF, C—CHF, C—CHF, C—OH, C—CHOH, C—OCH, or C—CHOCH.

[0127] 1 R 4 and R 5a taken together with the atoms to which they are attached form an optionally substituted ring having 6 to 10 total ring atoms and 0, 1, or 2 heteroatoms selected from N, O, and S. In some cases, the optionally substituted ring is saturated. In some cases, the optionally substituted ring is unsaturated. In some cases, the optionally substituted ring has a total of 6 ring atoms. In some cases, the optionally substituted ring has a total of 7 ring atoms. In some cases, the optionally substituted ring has a total of 8 ring atoms. In some cases, the optionally substituted ring has 9 or 10 total ring atoms. In some cases, the optionally substituted ring has 0 heteroatoms. In some cases, the optionally substituted ring has 1 or 2 heteroatoms selected from N, O, and S. In some cases, the optionally substituted ring has 1 or 2 oxygen atoms. In some cases, the optionally substituted ring is an ether. In some cases, the optionally substituted ring is a polyether. In some cases, the optionally substituted ring has one or two nitrogen atoms. In some cases, the ring is a cyclic amide (e.g., a lactam) or a cyclic amine. In some cases, the ring is unsubstituted. In some cases, the ring is C1~3 Alkyl, C 1~3 Haloalkyl, oxo, halo, CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 and phenyl. In some cases, n is 1. In some cases, n is 2. In some cases, n is 3. In some cases, n is 4. In some cases, n is 5. In some cases, n is 6. In some cases, n is 7. In some cases, n is 8. In some cases, n is 9. In some cases, n is 10. In some cases, n is 11. In some cases, n is 12. In some cases, n is 13. In some cases, n is 14. In some cases, n is 15. In some cases, n is 16. In some cases, n is 17. In some cases, n is 18. In some cases, n is 19. In some cases, n is 20. In some cases, n is 19. In some cases, n is 21. In some cases, n is 18. In some cases, n is 19. In some cases, n is 22. In some cases, n is 19. In some cases, n is 22. In some cases, n is 19. In some cases, n is 22. In some cases, n is 14. In some cases, n is 15. In some cases, n is 22. In some cases, n is 16. In some cases, n is 17. In some cases, n is 18. In some cases, n is 22. In some cases, n is 19. In some cases, n is 19. In some cases, n is 2 ...19. In some cases, n is 22. In some cases, n is 4 is C 1~3 Alkyl or C 1~3 In some cases, the other R 4 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, the other R 4 is CH3. In some cases, the other R 4 is C 0~3 alkyleneCN. In some cases, the other R 4 is CN or CHCN. In some cases, the other R 4 is C 1~3 Alkylene OH or C 1~3 Alkylene-C 1~3 In some cases, the other R 4 is CH2OH, CH2CH2OH, OCH3, CH2OCH3 or CH2CH2OCH3. In some cases, the other R 4 is oxo. In some cases, the other R 4 is a spiro-cycloalkyl having 3 to 7 total ring atoms. In some cases, the other R 4 is spiro-cyclopropyl, spiro-cyclobutyl, or spiro-cyclopentyl. In some cases, the other R 4 is spiro-cyclopropyl or spiro-cyclobutyl. In some cases, the other R 4is a spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, the other R 4 is spiro-oxetanyl or spiro-tetrahydrofuranyl. In some cases, the other R 4 is spiro-oxetanyl. In some cases, the other R 4 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2CH2OH, OCH3, CH2OCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl or spiro-cyclopentyl. In some cases, the other R 4 is CH3, CH2CH3, CH2CH2CH3, CH2F, CN, CH2CN, CH2OH, CH2CH2OH, CH2OCH3, spirocyclopropyl or spiro-oxetanyl. [ka] is.

[0128] In some cases, W is CH. In some cases, W is C-halo (e.g., CF, C-Cl, or C-Br) or C-CN. In some cases, W is CF, C-Cl, or C-CN. In some cases, W is CC 1~3 Alkyl or CC 1~3 In some cases, W is C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, or C-CH2F. In some cases, W is C-CH3 or C-CH2CH3. In some cases, W is CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4In some cases, W is C—OH, C—CH2OH, C—CH2CH2OH, C—OCH3, C—CH2OCH3, or C—CH2CH2OCH3. In some cases, W is C—OH, C—CH2OH, C—OCH3, or C—CH2OCH3. In some cases, W is CH, CF, C—Cl, C—CN, C—CH3, C—CH2CH3, C—CH2CH2CH3, C—CH(CH3)2, C—CF3, C—CHF2, C—CH2F, C—OH, C—CH2OH, C—CH2CH2OH, C—OCH3, C—CH2OCH3, or C—CH2CH2OCH3. In some cases, W is CH, CF, C—Cl, C—CN, C—CH, C—CHCH, C—OH, C—CHOH, C—OCH, or C—CHOCH. 5b is C 1~3 In some cases, R 5b is CF3, CF2H, CFH2, or CF2CH3. In some cases, R 5b is CF3, CF2H, or CFH2. In some cases, R 5b is CF3. In some cases, R 5b is CF2H. In some cases, R 5b is CHF2. In some cases, R 5b is a halo. In some cases, R 5b is Br, Cl, or F. In some cases, R 5b is C 1~3 Alkoxy or C 1~3 In some cases, R 5b is OCH3, OCH2CH3, SCH3 or SCH2CH3. In some cases, R 5b is C 1~4 Alkyl, C 2~3 Alkenyl or C 2~3 and alkynyl, wherein each of alkyl, alkenyl and alkynyl is C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~6 Alkylene (OH), C 0~6 Alkylene-C 1~3and optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy, cycloalkyl having 3 to 7 total ring atoms, cycloalkenyl having 5 to 7 total ring atoms, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, heterocycloalkenyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, and phenyl. 1~4 Alkyl, C 2~3 Alkenyl and C 2~3 The alkynyl is unsubstituted. In some cases, C 1~4 Alkyl, C 2~3 Alkenyl and C 2~3 The alkynyl is substituted with 1, 2, or 3 substituents. In some cases, each of the 1, 2, or 3 substituents is independently selected from CH, CF, CFH, CFH, OH, OCH, OCF, CHOH, CHOCH, cyclopropyl, cyclobutyl, and phenyl. In some cases, R 5b is a cycloalkyl having 3 to 7 total ring atoms, a cycloalkenyl having 5 to 7 total ring atoms, a heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or a heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, each of which may be selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~6 Alkylene (OH) or C 0~6 Alkylene-C 1~3 In some cases, R is optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy. 5 is cyclopropyl, cyclobutyl, cyclopentenyl, oxetanyl, or tetrahydrofuranyl. 5b is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, [ka] In some cases, R 5bis CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2.

[0129] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, Y is N. In some cases, Y is CH. In some cases, Y is C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 In some cases, Y is alkoxy, or in some cases, Y is CF, C—Cl, or C—CN. In some cases, Y is CC 1~3 Alkyl, CC 1~3 In some cases, Y is C-CH3, C-CH2CH3, C-CH2F, C-CHF2, or C-CF3. In some cases, Y is CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4In some cases, Y is C—OH, C—CH2OH, C—OCH3, or C—CH2OCH3. In some cases, o is 0. In some cases, o is 1. In some cases, o is 2. In some cases, o is 3. In some cases, o is 4. In some cases, at least one R 6 is halo or CN. In some cases, at least one R 6 is Br, Cl, F, or CN. In some cases, at least one R 6 is oxo. In some cases, o is 1 or 2, and each R 6 are independently F. In some cases, at least one R 6 is C 1~3 Alkyl or C 1~3 In some cases, at least one R 6 is CH3, CH2F, CHF2, or CF3. In some cases, o is 1 or 2, and each R 6 are independently CH3. In some cases, at least one R 6 is C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 Alkoxy, deuterated C 0~3 Alkylene-C 1~3 Alkoxy or C 1~4 Alkylene-N(R N1 )2, and each R N1 is independently H or CH. In some cases, each R N1 are independently H. In some cases, at least one R 6 is OH, CH2OH, CH2CH2OH, OCH3, OCD3, or CH2OCH3 or CH2CH2OCH3. In some cases, o is 1 and R 6 is OH, CHOH, OCH, or CHOCH. In some cases, at least one R 6is a spiro-cycloalkyl having 3 to 7 total ring atoms or a spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, at least one R 6 is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl. In some cases, o is 1 and R 6 is spirocyclopropyl. In some cases, two adjacent R 6 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms. In some cases, Y and an adjacent R 6 may, together with the atoms to which they are attached, form a fused cycloalkyl ring having 3 to 7 total ring atoms, and any of the above fused cycloalkyl rings may be selected from the group consisting of halo, OH, C 1~3 Optionally, the fused cycloalkyl ring is substituted with one or two substituents selected from alkoxy and CN. In some cases, any of the above fused cycloalkyl rings is fused cyclopropyl, fused cyclobutyl, or fused cyclopentyl. In some cases, two non-adjacent R 6 are joined together to form C 1~2 Alkylene bridge or C 1~3 Forms an ether bridge. In some cases, two non-adjacent R 6 are linked together to form a C alkylene bridge. In some cases, two non-adjacent R 6 are linked together to form a C2 alkylene bridge. In some cases, two non-adjacent R 6 are linked together to form a C alkylene bridge. In some cases, two non-adjacent R 6 are joined together to form C 1~3 Forming ether bridges (e.g., [ka] ). In some cases, X is [ka] [ka] [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] In some cases, X is [ka] is.

[0130] In some cases, Z is a halo, C 0~3 Alkylene CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~4 Alkoxy, C 0~3 Alkylene-C 1~4 thioalkoxy, and [ka] In some cases, each R is phenyl optionally substituted with 1 to 4 substituents selected from N1 is independently H or CH. In some cases, each R N1 are independently H. In some cases, the 1 to 4 substituents are selected from F, Cl, CN, OCH, SCH, CHOH, and [ka] In some cases, Z is selected from [ka] In some cases, Z is [ka] is.

[0131] In some cases, Z is heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S. In some cases, the heteroaryl contains 5 total ring atoms. In some cases, the heteroaryl contains a total of 6 ring atoms. In some cases, the heteroaryl is optionally substituted with 1 to 4 substituents. In some cases, the heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl. In some cases, the heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, or triazolyl. In some cases, heteroaryl is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, or triazolyl. In some cases, heteroaryl is pyrazolyl, imidazolyl, thiazolyl, or isothiazolyl. In some cases, heteroaryl is pyrazolyl. In some cases, heteroaryl is imidazolyl. In some cases, heteroaryl is thiazolyl. In some cases, heteroaryl is isothiazolyl. In some cases, heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In some cases, heteroaryl is pyridyl.

[0132] In some cases, the heteroaryl is unsubstituted. In some cases, the heteroaryl is substituted with 1 to 4 substituents. In some cases, the heteroaryl is substituted with 1 or 2 substituents. In some cases, the heteroaryl is substituted with 3 or 4 substituents. In some cases, the heteroaryl is substituted with 1 substituent. In some cases, the heteroaryl is substituted with 2 substituents. In some cases, the heteroaryl is substituted with 3 substituents. In some cases, the heteroaryl is substituted with 4 substituents. In some cases, each of the 1 to 4 substituents is independently halo (e.g., Br, Cl, or F), CN, C, or CI. 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 0~6 Alkylene-N(R N1 )2, wherein each R N1 are independently H or C 1~3 alkyl, C 0~2 Alkylene-cycloalkyl has 3 to 6 total ring atoms and is C 0~2 Alkylene-heterocycloalkyl has 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, and C 0~2 In some cases, heteroaryl is a C alkylene-phenyl having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S. 0~2 Alkylene-heterocycloalkyl substituted. Alkyl, alkenyl, C 0~6 Alkylene-C 1~3 The alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents are each independently optionally substituted with 1 to 3 substituents selected from deuterium, halo (e.g., Br, Cl, or F), OH, CH3, OCH3, and OCD3. 1~6 The alkyl is unsubstituted. In some cases, C 1~6Alkyl is CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2. In some cases, C 1~6 The alkyl is substituted with 1 to 3 substituents selected from deuterium, halo, OH, OCH3, and OCD3. In some cases, the substituted C 1~6 Alkyl is CD3, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, CH2C(CH3)2OH, CH(CH3)CH2OCH3, C(CH3)2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, CH(CH3)CH2OCD3, C(CH3)2CH2OCD3, CH2CH(CH3)OCD3 or CH2C(CH3)2OCD3. In some cases, C 1~6 Haloalkyl is CF, CHF, CHF, CHCHF, CHCHF, CH(CHF), CH(CH)CHF, or CH(CH)CHF. In some cases, C 2~6 The alkenyl is unsubstituted. In some cases, C 2~6 Alkyl is CH=CH2, CH2CH=CH2 or CH=CHCH3. In some cases, C 2~6 The alkyl is substituted with 1 to 3 substituents selected from deuterium, halo, OH, OCH3, and OCD3. 2~6 Haloalkenyl is C(=CH2)CH2F. In some cases, C 0~6 Alkylene -OH is OH, CHOH, or CHCHOH. In some cases, optionally substituted C 0~6 Alkylene-C 1~3 Alkoxy is OCH3, OCD3, CH2OCH3, CH2OCD3, CH2CH2OCH3, CH2CH2OCD3, CHFCH2OCH3, CF2CH2OCH3 or CH2CH2CH2OCH3 or CH2CH2CH2OCD3. In some cases, C 0~6 Alkylene-N(R N1 )2 is NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3 or CH2CH2N(CH3)2. In some cases, optionally substituted C 0~2The cycloalkyl of alkylene-cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 0~2 The alkylene-cycloalkyl is unsubstituted. In some cases, C 0~2 The alkylene-cycloalkyl is substituted with 1 to 3 substituents each independently selected from halo (e.g., Br, Cl, or F), OH, CH3, OCH3, and OCD3. In some cases, the optionally substituted C 0~2 Alkylene-cycloalkyl is [ka] In some cases, optionally substituted C 0~2 The heterocycloalkyl of the alkylene-heterocycloalkyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or piperidinyl. 0~2 The alkylene-heterocycloalkyl is unsubstituted. In some cases, C 0~2 The alkylene-heterocycloalkyl is substituted with 1 to 3 substituents each independently selected from halo (e.g., Br, Cl, or F), OH, CH3, OCH3, and OCD3. 0~2 Alkylene-heterocycloalkyl is [ka] is.

[0133] In some cases, Z is a heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, and each of the 1 to 4 substituents of the heteroaryl is independently Cl, F, CN, CH3, CD3, CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH2CHF2, CH2CH2F, CH(CH2F)2, CH(CH3)CH2F, CH(CH3)CHF2, C(=CH2)CH2F, OH, CH2OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, CH2C(CH3)2OH, OCH3, OCD3, CHOCH3, CH2OCD3, CH2CH2OCH3, CHFCH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2OCH2CH3, CH2CH2CH2OCH3, CH2CH2CH2OCD3, CH(CH3)CH2OCH3, CH(CH3)CH2OCD3, C(CH3)2CH2OCH3, C (CH3)2CH2OCD3, CH2CH(CH3)OCH3, CH2CH(CH3)OCD3, CH2C(CH3)2OCH3, CH2C(CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] In some cases, Z is a heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, and each of the 1 to 4 substituents of the heteroaryl is independently CH3, CH(CH3)2, C(CH3)2OH, CHOCD3, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] In some cases, Z is a heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, and each of the 1 to 4 substituents of the heteroaryl is independently CH3, CH2CHOCH3, CF2CHOCH3, CH2CH2OCD3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] In some cases, the heteroaryl group is CH3, CH2CH2OCH3, [ka] and has two substituents selected from:

[0134] In some cases, Z is [ka] and R ZA and R ZB are the same as defined above for the 1 to 4 substituents of the heteroaryl group of Z. In some cases, Z is [ka] is.

[0135] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, R ZA and R ZBEach of is Cl, F, CN, CH3, CD3, CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH2CHF2, CH2CH2F, CH(CH2F)2, CH(CH3)CH2F, CH(CH3)CHF2, C(=CH2)CH2F, OH, CH2 OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, CH2C(CH3)2OH, OCH3, OCD3, CH2OCH3, CH2OCD3, CH2CH2OCH3, CHFCH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2OCH2CH3, CH2CH2CH2OCH3, CH2CH2CH2OCD3, CH(CH3)CH2OCH3, CH(CH3)CH2OCD3, C(CH3)2CH2OCD3, C(CH3)2CH2OCD3, CH2CH(C H3)OCH3, CH2CH(CH3)OCD3, CH2C(CH3)2OCH3, CH2C(CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] In some cases, R ZA is Cl, F, CH3, CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH2CHF2 or CH2CH2F, and R ZB are CH3, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] In some cases, R ZAは、C H3 and R ZB are CH3, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] is.

[0136] In some cases, Z is [ka] [ka] [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] In some cases, Z is [ka] is.

[0137] In some cases, Z is a bicyclic ring containing a heteroaryl ring having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, fused to a cycloalkyl ring having 5 or 6 total ring atoms or a heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. The bicyclic ring is optionally substituted with 1 to 4 substituents. In some cases, the heteroaryl ring of the bicyclic ring is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. The heterocycloalkyl ring of the bicyclic ring is pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or tetrahydrothiophenyl. In some cases, the heteroaryl group is pyridyl and the heterocycloalkyl group is furanyl. In some cases, the bicyclic ring is unsubstituted. In some cases, the bicyclic ring is fused to a halo, CN, C, or C-substituted heterocyclic ring.1~6 Alkyl, C 1~6 Haloalkyl, C 0~6 Alkylene -OH and C 0~6 Alkylene-C 1~3 In some cases, Z is substituted with 1 to 4 substituents selected from: [ka] is.

[0138] In some cases, the compound of formula (I) [ka] teeth, [ka] In some cases, [ka] has the following stereochemical configuration: [ka] In some cases, [ka] has the following stereochemical configuration: [ka] In some cases, the present disclosure provides a compound represented by formula (I'): [ka] and pharmaceutically acceptable salts thereof, wherein the substituents are as previously described herein.

[0139] In some cases, A is CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC0~3 Alkylene-C 1~4 alkoxy, and X is [ka] and the present disclosure provides compounds of formula (IA): [ka] and pharmaceutically acceptable salts thereof, wherein R A H, halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene OH or C 0~3 Alkylene-C 1~4 and the remaining substituents are as previously defined herein.

[0140] In some cases, A is N and X is [ka] and the present disclosure provides a compound of formula (IB): [ka] and pharmaceutically acceptable salts thereof, wherein the substituents are as defined hereinabove.

[0141] In some cases, A is N and X is [ka] and R 5a and R 4 taken together with the atoms to which they are attached form an optionally substituted ring having 6 to 10 total ring atoms and 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the ring is saturated or unsaturated, and the remainder of the substituents are as defined herein. Contemplated compounds include, but are not limited to, the following: [ka]

[0142] In some cases, X is [ka] and the present disclosure provides compounds of formula (IE): [ka] and pharmaceutically acceptable salts thereof.

[0143] In some cases, X is [ka] and the present disclosure provides a compound of formula (IF): [ka] and pharmaceutically acceptable salts thereof.

[0144] In some cases, X is [ka] and the present disclosure provides a compound of formula (IG): [ka] and pharmaceutically acceptable salts thereof.

[0145] In some cases, the present disclosure provides compounds of formula (I) where A is N and X is [ka] and Z is optionally substituted phenyl or pyridyl.

[0146] In some cases, the present disclosure provides compounds listed in Table E below. When the stereochemistry of a structure or portion of a structure in Table E is not explicitly shown (e.g., using a dashed or bold line, etc.), the structure or portion of the structure is understood to be achiral or any of the possible stereoisomers of the structure or portion of the structure. When the stereochemistry of a structure or portion of a structure in Table E is explicitly shown, a single stereoisomer of the structure or portion of the structure is represented.

[0147] [Table 51]

[0148] [Table 52]

[0149] In some cases, A is N and X is [ka] In some cases, the compound of Formula (I) or Formula (IB) is selected from compounds 1-119 to 1-123 and 1-152, or a pharmaceutically acceptable salt of any of the foregoing. In some cases, A is N and X is [ka] and R 5a and R 4 together with the atoms to which they are attached form an optionally substituted ring having 6 to 10 total ring atoms and 0, 1, or 2 heteroatoms selected from N, O, and S, which ring is saturated or unsaturated. In some cases, the compound of Formula (I) or Formula (IB) is selected from compounds 1-119 to 1-123 and 1-152, or a pharmaceutically acceptable salt of any of the above.

[0150] Examples of Formula (I) For example, Formula (I), wherein the substituents are as defined in this "Examples of Formula (I)" section: [ka] or a pharmaceutically acceptable salt thereof.

[0151] In some cases, [ka] is.

[0152] In some cases, [ka] is.

[0153] In some cases, A is N.

[0154] In some cases, n is 1. In some cases, n is 2. In some cases, the other R 4 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, W is CH.

[0155] In some cases, one R 4 and R 5a are taken together with the atoms to which they are attached to form a saturated, optionally substituted ring. In some cases, one R 4 and R 5a taken together with the atoms to which they are attached form an unsaturated, optionally substituted ring. In some cases, one R 4 and R 5a are taken together with the atoms to which they are attached to form an optionally substituted ring having a total of 6 ring atoms. In some cases, one R 4 and R 5a are taken together with the atoms to which they are attached to form an optionally substituted ring having a total of 7 ring atoms. In some cases, one R 4 and R 5aare taken together with the atoms to which they are attached to form an optionally substituted ring having a total of 8 ring atoms. In some cases, one R 4 and R 5a taken together with the atoms to which they are attached form an optionally substituted ring having 9 or 10 total ring atoms. In some cases, one R 4 and R 5a are taken together with the atoms to which they are attached to form an optionally substituted ring having 0 heteroatoms. In some cases, one R 4 and R 5a are taken together with the atoms to which they are attached to form an optionally substituted ring having one or two heteroatoms selected from N, O, and S. In some cases, the one or two heteroatoms are each O. In some cases, one R 4 and R 5a are taken together with the atoms to which they are attached to form an optionally substituted ring that is an ether. In some cases, the one or two heteroatoms are each N. In some cases, one R 4 and R 5a taken together with the atoms to which they are attached form an optionally substituted ring that is a lactam or a cyclic amine. In some cases, one R 4 and R 5a are taken together with the atoms to which they are attached to form an unsubstituted ring. In some cases, one R 4 and R 5a together with the atoms to which they are attached, C 1~3 Alkyl, C 1~3 Haloalkyl, oxo, halo, CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3and forming a ring substituted with one or two substituents selected from the group consisting of alkoxy, cycloalkyl having 3 to 7 total ring atoms, cycloalkenyl having 5 to 7 total ring atoms, heterocycloalkyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, and phenyl. In some cases, [ka] is.

[0156] In some cases, R 5b is CF3, CF2H, CFH2, or CF2CH3. In some cases, R 5b is CF3. In some cases, R 5b is CF2H. In some cases, R 5b is CFH2. In some cases, R 5b is CF2CH3.

[0157] In some cases, X is [ka] In some cases, Y is CH. In some cases, o is 0. In some cases, o is 1. In some cases, R 6 is CH3, CH2F, CHF2, or CF3. In some cases, [ka] In some cases, [ka] In some cases, [ka] is.

[0158] In some cases, Z is heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, and the heteroaryl is optionally substituted with 1 to 4 substituents. In some cases, the heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl. In some cases, the heteroaryl is pyrazolyl or pyridyl. In some cases, the heteroaryl is halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 0~6 Alkylene-N(R N1 )2(in the formula, each R N1 are independently H or C 1~3 alkyl), C with 3 to 6 total ring atoms 0~2 Alkylene-cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0~2 Alkylene-heterocycloalkyl and C 0~2 alkylene-phenyl, and is substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, alkenyl, C 0~6 Alkylene-C 1~3Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is optionally substituted with 1 to 3 substituents independently selected from deuterium, halo, OH, CH, OCH, and OCD. In some cases, each of the 1 to 4 substituents is independently selected from Cl, F, CN, CH, CD, CHCH, CH(CH), CF, CHF, CHF, CHCHF, CHCHF, CH(CHF), CH(CH)CHF, CH(CH)CHF, C(=CH)CHF, OH, CHOH, CHCHOH, CH(CH)CHOH, C(CH)OH, C(CH)CHOH, CHC(CH)OH, OCH, OCD, CHOCH, CHOCD, CHCHOCH, CHFCHOCH, C(CH)CHF, C(=CH)CHF, C(=CH)CHF, OH, CHOH, CHCHOH, CH(CH)CHOH, C(CH)OH, C(CH)CHOH, CHC(CH)OH, OCH, OCD, CHOCH, CHOCD, CHCHOCH, CHFCHOCH, C(=CH)CH, C(=CH)CHF, C(=CH)CHF, C(=CH)CHF, C(=CH)CHF, C(=CH)CHF, C(=CH)CHF, C(=CH)CHF, C(=CH)CHF, C(=CH)CHF, C(=CH)CHOH ... F2CH2OCH3, CH2CH2OCD3, CH2CH2OCH2CH3, CH2CH2CH2OCH3, CH2CH2CH2OCD3, CH(CH3)CH2OCH3, CH(CH3)CH2OCD3, C(CH3)2CH2OCH3, C(CH3)2CH2OCD3, CH 2CH(CH3)OCH3, CH2CH(CH3)OCD3, CH2C(CH3)2OCH3, CH2C(CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] In some cases, each of the 1 to 4 substituents is independently selected from CH3, CH2CH2OCH3, CH2CH2OCD3, [ka] In some cases, Z is [ka] [ka] [ka] In some cases, Z is [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] is.

[0159] Further provided herein are compounds of formula (I) or a pharmaceutically acceptable salt thereof: [ka] and Z is pyrazolyl or pyridyl, each optionally substituted with 1 to 4 substituents. In some cases, each of the 1 to 4 substituents on Z is independently CH3, CH2CH2OCH3, CH2CH2OCD3, [ka] In some cases, Z is substituted with two substituents. In some cases, at least one substituent is CH3. In some cases, each substituent is CH3. In some cases, Z is substituted with CH3 and CH2CH2OCH3. In some cases, Z is substituted with CH3 and [ka] In some cases, Z is substituted with CH3 and [ka] In some cases, Z is substituted with CH3 and [ka] In some cases, Z is substituted with [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] In some cases, Z is [ka] is.

[0160] It is understood that selection of values ​​for each variable is one that results in the formation of stable or chemically feasible compounds.

[0161] biological activity In some cases, the compounds disclosed herein (e.g., compounds of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), and Formula (IIF) and compounds listed in Table A, Table A', Table B, Table B', and Table E) and pharmaceutically acceptable salts thereof have a cytotoxicity of less than 5 μM in the coupling exchange assay described in the "Biological Evaluation" section, or IC of less than 4 μM, or less than 3 μM, or less than 2 μM, or less than 1 μM, or less than 0.9 μM, or less than 0.7 μM, or less than 0.6 μM, or less than 0.5 μM, or less than 0.4 μM, or less than 0.3 μM, or less than 0.2 μM, or less than 0.1 μM, or less than 0.09 μM, or less than 0.08 μM, or less than 0.07 μM, or less than 0.06 μM, or less than 0.05 μM, or less than 0.04 μM, or less than 0.03 μM, or less than 0.02 μM, or less than 0.01 μM 50 In some cases, the compounds disclosed herein and the pharmaceutically acceptable salts thereof have an IC value of less than 1 μM. 50 In some cases, the compounds disclosed herein and the pharmaceutically acceptable salts thereof have an IC value of less than 0.5 μM. 50 In some cases, the compounds disclosed herein and the pharmaceutically acceptable salts thereof have an IC value of less than 0.3 μM. 50 In some cases, the compounds disclosed herein and the pharmaceutically acceptable salts thereof have an IC value of less than 0.1 μM. 50 has an IC value of less than 5 μM in the 2-hour coupling exchange assay described herein 50Also provided herein are compounds of the present disclosure having an IC of less than 3 μM in the 2-hour coupling exchange assay described herein, and pharmaceutically acceptable salts thereof. 50 Further provided herein are compounds of the present disclosure and pharmaceutically acceptable salts thereof, having an IC of less than 1 μM in the 2-hour coupled exchange assay described herein. 50 Further provided herein are compounds of the present disclosure having an IC of less than 0.5 μM in the 2-hour coupling exchange assay described herein, or a pharmaceutically acceptable salt thereof. 50 Further provided herein are compounds of the present disclosure having an IC of less than 0.1 μM in the 2-hour coupling exchange assay described herein, or a pharmaceutically acceptable salt thereof. 50 Also provided herein are compounds of the present disclosure having an IC of less than 0.05 μM in the 2-hour coupling exchange assay described herein, or a pharmaceutically acceptable salt thereof. 50 Also provided herein are compounds of the present disclosure having an IC of less than 0.04 μM in the 2-hour coupling exchange assay described herein, or a pharmaceutically acceptable salt thereof. 50 Also provided herein are compounds of the present disclosure having an IC of less than 0.03 μM in the 2-hour coupling exchange assay described herein, or a pharmaceutically acceptable salt thereof. 50 Also provided herein are compounds of the present disclosure having an IC of less than 0.02 μM in the 2-hour coupling exchange assay described herein, or a pharmaceutically acceptable salt thereof. 50 Also provided herein are compounds of the present disclosure having an IC of less than 0.01 μM in the 2-hour coupling exchange assay described herein, or a pharmaceutically acceptable salt thereof. 50 Also provided herein are compounds of the present disclosure having the formula: or a pharmaceutically acceptable salt thereof.

[0162] The foregoing merely outlines certain aspects of the disclosure and is not intended, nor should it be construed, to limit the disclosure in any way.

[0163] Formulations and Routes of Administration In the described use, although it may be possible to administer the compound disclosed herein alone, the compound administered is usually present as an active ingredient in a pharmaceutical composition.Therefore, the present invention further provides pharmaceutical compositions comprising the compounds disclosed herein (for example, the compounds of formula (I), formula (I'), formula (IA), formula (IB), formula (IE), formula (IF), formula (IG), formula (II), formula (II'), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) and formula (IIF) and the compounds listed in Table A, Table A', Table B, Table B' and Table E) and the pharmaceutically acceptable salts thereof, in combination with one or more pharmaceutically acceptable excipients and, if desired, other active ingredients. See, for example, Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by G. D. Tovey, Royal Society of Chemistry, 2018. In some cases, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0164] The compounds disclosed herein can be administered by any suitable route in the form of a pharmaceutical composition adapted to such route and in a dose effective for the intended treatment. The compounds and compositions presented herein can be administered, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally in dosage unit formulations containing conventional pharmaceutically acceptable excipients, or by infusion techniques.

[0165] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, mini-tablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drops, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension or oily suspension. In some cases, the pharmaceutical composition is made in the form of a dosage unit containing a specific amount of the active ingredient.

[0166] Thus, a further aspect of the present disclosure is a pharmaceutical composition comprising one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient. Further provided herein is a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use as a medicament.

[0167] How to use The compounds described herein inhibit the G12C mutant KRAS protein ("KRAS G12C In some cases, the compounds described herein inhibit KRAS by, for example, permanently inactivating the protein. G12C) can act as potent inhibitors of KRAS. Without intending to be bound by any particular theory, compounds of the present disclosure can, in some cases, inhibit phosphorylation of extracellular signal-regulated kinase ("ERK"), an important downstream effector of KRAS, resulting in tumor regression. In addition to being useful for human treatment, compounds provided herein can be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, and the like. For example, animals including horses, dogs, and cats can be treated with compounds provided herein.

[0168] Monotherapy Another aspect of the present disclosure provides methods for treating disease states, including but not limited to, conditions associated with KRAS G12C mutations (e.g., cancer), using compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present disclosure. See, e.g., U.S. Patent No. 10,519,146 B2, issued December 31, 2019, specifically the passages at column 198, line 1 to column 201, line 36, which are incorporated herein by reference.

[0169] Without wishing to be bound by any particular theory, it is noted that sotorasib, like the compounds disclosed herein, inhibits KRAS G12C (Hong et al., N. Engl. J. Med. 2020, 383, 1207, at 1208). Hong et al. report that "[p]re-clinical studies demonstrated that [sotorasib] inhibited nearly all detectable phosphorylation of extracellular signal-regulated kinase (ERK), a key downstream effector of KRAS, and resulted in durable complete tumor regression in mice bearing KRAS p.G12C tumors" (id. See also the section entitled "BIOLOGICAL EVALUATION" below, Canon et al., Nature 2019, 575(7781), 217; and Lanman et al., J. Med. Chem. 2020, 63, 52).

[0170] Sotorasib was evaluated in a Phase 1 dose-escalation and expansion study in 129 subjects with locally advanced or metastatic cancer containing a histologically confirmed KRAS G12C mutation identified by local molecular testing on tumor tissue, including 59 subjects with non-small cell lung cancer, 42 subjects with colorectal cancer, and 28 subjects with other tumor types (Hong et al., 2020, pp. 1208-1209). Hong et al. reported disease control rates (95% CI) of 88.1% for non-small cell lung cancer, 73.8% for colorectal cancer, and 75.0% for other tumor types (Hong et al., 2020, p. 1213, Table 3). The cancer types showing either stable disease (SD) or partial regression (PR) reported by Hong et al. were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, cholangiocarcinoma, or melanoma (Hong et al., 2020, page 1212 (Figure A) and appendix (page 59 (Figure S5) and page 63 (Figure S6))).

[0171] The KRAS G12C mutation occurs at the alteration frequencies shown in the table below (Cerami et al., Cancer Discov. 2012, 2(5), 401; Gao et al., Science Signaling 2013, 6(269), p11). For example, the table shows that 11.6% of subjects with non-small cell lung cancer have cancer in which one or more cells express the KRAS G12C mutant protein. Therefore, KRAS G12C Compounds provided herein that specifically and irreversibly bind to (see the section below entitled "Biological Evaluation") are useful for treating subjects with cancer, including, but not limited to, those listed in the table below.

[0172] [Table 53]

[0173] [Table 54]

[0174] Another aspect of the present disclosure provides a compound disclosed herein (e.g., a compound of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), and Formula (IIF) or a compound listed in Table A, Table A', Table B, Table B', or Table E) and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating cancer. Yet another aspect of the present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating cancer in which one or more cells express a KRAS G12C mutant protein.

[0175] Another aspect of the present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, in the preparation of a medicament for treating cancer. Yet another aspect of the present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the preparation of a medicament for treating cancer in which one or more cells express a KRAS G12C mutant protein.

[0176] A further aspect provided by the present disclosure is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. Another aspect of the present disclosure is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, wherein one or more cells express a KRAS G12C mutant protein. In some cases, the subject has cancer that has been determined to have one or more cells expressing a KRAS G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[0177] In some cases, the cancer is metastatic. In some cases, the cancer is non-metastatic. In some cases, the cancer disclosed herein is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer type, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, or a solid tumor. In some cases, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, melanoma, or a solid tumor. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is colorectal cancer. In some cases, the cancer is prostate cancer. In some cases, the cancer is a solid tumor.

[0178] Combination therapy The present disclosure provides methods of combination therapy in which agents known to regulate other pathways or other components of the same pathway or even overlapping sets of target enzymes are used in combination with a compound of the present disclosure (e.g., a compound of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), or Formula (IIF) or a compound listed in Table A, Table A', Table B, Table B', or Table E) or a pharmaceutically acceptable salt thereof. In one aspect, such therapy includes, but is not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and / or radiation treatment to provide a synergistic or additive therapeutic effect. See, for example, U.S. Patent No. 10,519,146 B2, issued December 31, 2019, which is incorporated herein by reference (specifically, sections from columns 201 (line 37) to 212 (line 46) and from columns 219 (line 64) to 220 (line 39)).

[0179] A compound of the present disclosure may be administered simultaneously, separately, or sequentially with an effective amount of a second compound in any of the methods described herein. In some cases, the second compound is an ATR inhibitor, an Aurora kinase A inhibitor, an AKT inhibitor, an arginase inhibitor, a CDK2 inhibitor, a CDK4 / 6 inhibitor, an ErbB family inhibitor, an ERK inhibitor, a FAK inhibitor, an FGFR inhibitor, a glutaminase inhibitor, an IGF-1R inhibitor, a KIF18A inhibitor, a MAT2A inhibitor, an MCL-1 inhibitor, a MEK inhibitor, an mTOR inhibitor, a PARP inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PI3K inhibitor, a PRMT5 inhibitor, a Raf kinase inhibitor, a SHP2 inhibitor, an SOS1 inhibitor, a Src kinase inhibitor, or one or more chemotherapeutic agents. In some cases, the second compound is administered as a pharmaceutically acceptable salt. In some cases, the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0180] In some cases, the compounds of the present disclosure may be administered simultaneously, separately, or sequentially with an effective amount of an ATR inhibitor in any of the methods described herein, and the ATR inhibitor is a compound that targets ataxia-telangiectasia mutated and Rad3-related kinase. Exemplary ATR inhibitors for use in the methods provided herein include dactolisib, VE-821 (3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide, 3-amino-6-[4-(methylsulfonyl)phenyl]-N-phenyl-2-pyrazinecarboxamide), Torin 2 (9-(6-amino-3-pyridinyl)-1-[3-(trifluoromethyl)phenyl]-benzo[h]-1,6-naphthyridin-2(1H)-one), ETP-46464 (α,α-dimethyl-4-[2-oxo-9-(3-quinolinyl)-2H-[1,3]oxazino[5,4μzetidinlin-1(4H)-yl]-benzeneacetonitrile). , CGK733 (α-phenyl-N-[2,2,2-trichloro-1-[[[(4-fluoro-3-nitrophenyl)amino]thioxomethyl]amino]ethyl]benzeneacetamide), AZ20 (4-[4-[(3R)-3-methyl-4-morpholinyl]-6-[1-(methylsulfonyl)cyclopropyl]-2-pyrimidinyl]-1H-indole), SKLB-197 ((R)-4-(2-(1H-indol-4-yl)-6-(1-methyl-1H-pyrazol-5-yl)quinazolin-4-yl)-3-methylmorpholine), elimsertib, galtisertib, elimsertib hydrochloride, serasertib, and schisandrin B.

[0181] Aurora Kinase A Inhibitors In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an Aurora Kinase A inhibitor in any of the methods described herein.Exemplary Aurora kinase A inhibitors for use in the methods provided herein include, but are not limited to, alisertib (alisertinib), senisertib (senisertib), danusertib (danusertib), tozasertib (tozasertib), LY3295668 ((2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2-methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4-methylpiperazine)-2-ylmethyl) ... (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide), TT-00420 (4-[9-(2-chlorophenyl)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3,6,8,10,12-hexaen-13-yl]morpholine), AMG 900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine), MLN 8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undec-2(7),3,5-trimethyl-2-pyrimidin-2-yl]amino) [1-(3-chlorophenyl)-3-[5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)ethyl]-1,3-thiazol-2-yl]urea), CYC116 (4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine), TAS-119, BI 811283, and TTP607.

[0182] AKT inhibitors. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an AKT inhibitor in any of the methods described herein. Exemplary AKT inhibitors for use in the methods provided herein include, but are not limited to, afarestib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ092 (3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4- f][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-, 2,10-diethyl ester), ONC201 (11-benzyl-7-[2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ751 (N-(3-aminopropyl)-N-[(1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3-chloro-2-fluorobenzamide), RX-0201, and LY2780301.

[0183] Arginase inhibitor. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an arginase inhibitor in any of the methods described herein. Exemplary arginase inhibitors used in the methods provided herein include, but are not limited to, numidarthistat and CB 280.

[0184] CDK2 inhibitors. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a CDK2 inhibitor in any of the methods described herein. As used herein, the term "CDK2" refers to cyclin-dependent kinase ("CDK") 2, a member of the mammalian serine / threonine protein kinases. As used herein, the term "CDK2 inhibitors" refers to compounds that can negatively regulate or inhibit all or part of the enzymatic activity of CDK2. Exemplary CDK2 inhibitors for use in the methods provided herein include, but are not limited to, flavopiridol, roscovitine, dinaciclib, milciclib, meriolin, variolin, AZD5438 (4-[2-methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine), roniciclib, SNS-032 (N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide).

[0185] CDK4 / 6 inhibitor. In some cases, the compounds of the present disclosure may be administered simultaneously, separately, or sequentially with an effective amount of a CDK4 / 6 inhibitor in any of the methods described herein. The term "CDK4 / 6," as used herein, refers to cyclin-dependent kinases ("CDKs") 4 and 6, which are members of the mammalian serine / threonine protein kinases. The term "CDK4 / 6 inhibitor," as used herein, refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of CDK4 and / or 6. Exemplary CDK4 / 6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl)-4-piperidinyl]amino]). In some cases, the CDK4 / 6 inhibitor is palbociclib.

[0186] ErbB family inhibitors. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an ErbB family inhibitor in any of the methods described herein. The term "ErbB family" as used herein refers to members of the mammalian transmembrane protein tyrosine kinase family, including ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). The term "ErbB family inhibitor" as used herein refers to an agent (e.g., a compound or antibody) capable of negatively regulating or inhibiting all or part of the activity of at least one member of the ErbB family. The modulation or inhibition of one or more ErbB tyrosine kinases can occur by modulating or inhibiting the kinase enzymatic activity of one or more ErbB family members, or by blocking the homodimerization or heterodimerization of ErbB family members. In some cases, the ErbB family inhibitor is an EGFR inhibitor, such as an anti-EGFR antibody. Exemplary anti-EGFR antibodies used in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab, and cetuximab. In some cases, the anti-EGFR antibody is cetuximab. In some cases, the anti-EGFR antibody is panitumumab. In some cases, the ErbB family inhibitor is a HER2 inhibitor, such as an anti-HER2 antibody. Exemplary anti-HER-2 antibodies used in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine. In some cases, the ErbB family inhibitor is a HER3 inhibitor, such as an anti-HER3 antibody, such as HMBD-001 (Hummingbird Bioscience). In some cases, the ErbB family inhibitor is a combination of an anti-EGFR antibody and an anti-HER2 antibody. In some cases, the ErbB family inhibitor is an irreversible inhibitor.Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-propenamide)), PF 6274484 (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide). In some cases, the irreversible ErbB family inhibitor is afatinib. In some cases, the irreversible ErbB family inhibitor is dacomitinib. In some cases, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, erlotinib, gefitinib, sapitinib, varlitinib, talloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine), BMS 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate) and GW 583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine). In some cases, the reversible ErbB family inhibitor is sapitinib.In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.

[0187] ERK inhibitors. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an ERK inhibitor in any of the methods described herein. Exemplary ERK inhibitors for use in the methods provided herein include, but are not limited to, ulixertinib, lavoxertinib, CC-90003 (N-[2-[[2-[(2-methoxy-5-methylpyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide), LY3214996 (6,6 -dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one), KO-947 (1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462 and JSI-1187.

[0188] FAK inhibitors. In some cases, the compounds of the present disclosure may be administered simultaneously, separately, or sequentially with an effective amount of a FAK inhibitor in any of the methods described herein. Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-N-methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]methanesulfonamide), VS-4718 (2-[[2-(2-methoxy-4-morpholin-4-ylanilino)-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide), and APG-2449.

[0189] FGFR inhibitors. In some cases, the compounds of the present disclosure may be administered simultaneously, separately, or sequentially with an effective amount of an FGFR inhibitor in any of the methods described herein. Exemplary FGFR inhibitors for use in the methods provided herein include futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5-dimethoxyphenyl)methoxy]pyrimidin-2-yl]amino]pyrazol-1-yl]ethanol), AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide), Debio 1347 ([5-amino

[0037] Examples of compounds that may be used include, but are not limited to, N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl-methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide), ICP-105, CPL304110, HMPL-453, and HGS1036.

[0190] Glutaminase inhibitor. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a glutaminase inhibitor in any of the methods described herein. Exemplary glutaminase inhibitors used in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.

[0191] IGF-1R inhibitors. In some cases, the compounds of the present disclosure may be administered simultaneously, separately, or sequentially with an effective amount of an IGF-1R inhibitor in any of the methods described herein. Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, lobatumumab, BMS-754807 ((2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.

[0192] KIF18A inhibitor. In some cases, the compound of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a KIF18A inhibitor in any of the methods described herein. Exemplary KIF18A inhibitors used in the methods provided herein include, but are not limited to, the inhibitors disclosed in U.S. Patent Application Publication No. 2020 / 0239441, International Publication No. 2020 / 132649, International Publication No. 2020 / 132651, and International Publication No. 2020 / 132653 (each of which is incorporated herein by reference in its entirety). In some cases, the KIF18A inhibitor is sovirnesib (AMG650).

[0193] MAT2A inhibitor. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a MAT2A inhibitor in any of the methods described herein. A MAT2A inhibitor is a compound that inhibits methionine adenosyltransferase II alpha. An exemplary MAT2A inhibitor for use in the methods provided herein is AG270 (3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-μ-zetidin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one).

[0194] MCL-1 inhibitors. In some cases, compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an MCL-1 inhibitor in any of the methods described herein. Exemplary MCL-1 inhibitors for use in the methods provided herein include, but are not limited to, murizatoclax, topotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29-hexahydro-2,3,24,33-tetramethyl-22H-9,4,8-(metheniminomethino)-14,20:26,23-dimetheno-10H,20H-pyrazolo[4,3-1][2,15,22,18,19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), MIK 665 ((αR)-α-[[(5S)-5-[3-chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4-pyrimidinyl]methoxy]benzenepropanoic acid) and ABBV-467. In some cases, the MCL-1 inhibitor is murizatoclax. In some cases, the MCL-1 inhibitor is tapotoclax.

[0195] MEK inhibitors. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a MEK inhibitor in any of the methods described herein. Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl- 6-oxopyridine-3-carboxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]- 6-Fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2, 3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide), PD98059 (2-(2-amino-3-methoxyphenyl)-4H-chromen-4-one), PD334581 (N-[5-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-1,3,4-oxadiazol-2-yl]-4-morpholineethanamine), FCN-159, CS3006, HL-085, SHR 7390, and WX-554. In some cases, the MEK inhibitor is trametinib.

[0196] mTOR inhibitors. In some cases, compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an mTOR inhibitor in any of the methods described herein. Exemplary mTOR inhibitors for use in the methods provided herein include, but are not limited to, everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, bistosertib, dactolisib, torin-1(1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h] [1,6]naphthyridin-2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea), and VS-5584 (SB2343, (5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine). In some cases, the mTOR inhibitor is everolimus.

[0197] PARP inhibitor. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a PARP inhibitor in any of the methods described herein. A PARP inhibitor is a compound that targets poly(adenosine diphosphate)-ribose polymerase. The term PARP inhibitor encompasses PARP1, PARP2, and PARP3 inhibitors. Exemplary PARP inhibitors for use in the methods provided herein include, but are not limited to, tuzetidirib, rucaparib, laczavalib, niraparib, niraparib tosylate, talazoparib, AG-1461, A-966492, PJ34 HCl, niraparib, UPF 1069, ME0328, benadalib, AZD5305, DR2313, BYK204165, pamiparib, NMS-P118, and NU 1025.

[0198] PD-1 inhibitors. In some cases, the compounds of the present disclosure may be administered simultaneously, separately, or sequentially with an effective amount of a PD-1 inhibitor in any of the methods described herein. Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and anti-PD-1 antibodies such as those described in U.S. Pat. No. 10,640,504 B2 ("Anti-PD-1 Antibody A," column 66, lines 56-67, line 24 and column 67, lines 54-57), which are incorporated herein by reference. In some cases, the PD-1 inhibitor is pembrolizumab. In some cases, the PD-1 inhibitor is anti-PD-1 antibody A.

[0199] PD-L1 inhibitor. In some cases, a compound of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a PD-L1 inhibitor in any of the methods described herein. Exemplary PD-L1 inhibitors for use in the methods provided herein include, but are not limited to, atezolizumab, avelumab, durvalumab, ZKAB001, TG-1501, SHR-1316, MSB2311, MDX-1105, KN035, IMC-001, HLX20, FAZ053, CS1001, CK-301, CBT-502, BGB-A333, BCD-135, and A167. In some cases, the PD-L1 inhibitor is atezolizumab.

[0200] PI3K inhibitors. In some cases, the compounds of the present disclosure may be administered simultaneously, separately, or sequentially with an effective amount of a PI3K inhibitor in any of the methods described herein. Exemplary PI3K inhibitors for use in the methods provided herein include, but are not limited to, idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, dactolisib, voxtalisib, sonolisib, tenalisib, selavelsib, acalisib, CUDC-907 (N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-methyl-2-oxo-2-methyl-4-oxo ... methyl-4-methylthieno[3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide), ME-401 (N-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2-amine), IPI-549 (2-amino-N-[(1S)-1-[8- [2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), SF1126 (((2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]meth [oxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate), XL147 (N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4-methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3-thiazolidine-2,4-dione), and AMG 319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine).

[0201] PRMT5 inhibitors. In some cases, the compounds of the present disclosure may be administered simultaneously, separately, or sequentially with an effective amount of a PRMT5 inhibitor in any of the methods described herein. PRMT5 inhibitors in compounds that inhibit protein arginine methyltransferase 5. The term "PRMT5 inhibitor" includes PRMT5 inhibitors that are cooperative with MTA. Exemplary PRMT5 inhibitors for use in the methods provided herein include pemuramettostat (6-[(1-acetylpiperidin-4-yl)amino]-N-[(2S)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]pyrimidine-4-carboxamide), GSK3203591 (2-(cyclobutylamino)-N-[(2S)-3-(3,4-dihydro-2(1H)-isoquinolinyl)-2-hydropropyl]-4-pyridinecarboxamide dihydrochloride)), LLY-283 ((R)-5'-phenyl-7-deazaadenosyl) 6-amino-9-[(R)-5'-phenyl(ribofuranosyl)]-7-deazapurine, (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-hydroxy(phenyl)methyl)tetrahydrofuran-3,4-diol), PRT811, and MRTX1719 (2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile).

[0202] Raf kinase inhibitor. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a Raf kinase inhibitor in any of the methods described herein. The term "RAF kinase" as used herein refers to a member of the mammalian serine / threonine kinase family, which is composed of three isoforms (C-Raf, B-Raf, and A-Raf), including homodimers of each isoform and heterodimers between isoforms (e.g., C-Raf / B-Raf heterodimers). The term "Raf kinase inhibitor" as used herein refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of one or more members of the Raf family kinase, or a compound capable of disrupting Raf homodimer or heterodimer formation to inhibit activity.In some cases, Raf kinase inhibitors include, but are not limited to, encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide), Raf-709 (N-(2-methyl-5- Morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino) )pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP-32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole -3-yl)urea), CCT196969 (1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea), and RO5126766 (N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide). In some cases, the Raf kinase inhibitor is encorafenib. In some cases, the Raf kinase inhibitor is sorafenib. In some cases, the Raf kinase inhibitor is lifirafenib.

[0203] SHP2 inhibitors. In some cases, the compounds of the present disclosure may be administered simultaneously, separately, or sequentially with an effective amount of an SHP2 inhibitor in any of the methods described herein. Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol), TNO155, (3S,4S)-8-[6-amino-5-(2-amino-3-chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine), and RMC-4630 (Revolution Revolution Medicine; vociprotafib (RMC-4630; 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol). In some cases, the SHP inhibitor for use in the methods provided herein is RMC-4630 (vociprotafib, Revolution Medicine). In some instances, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy-1-azetidinyl)-4-pyridinyl]thio]-5-methyl-2-pyrazinemethanol (CAS 2172652~38-7) and 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol (CAS 2172652~48-9). In some cases, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-57-2), 4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-7-(2,3-dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6), 7-[(2-amino-3-chloro-4-pyridinyl)thio]-4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2) and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (CAS 2240982-77-6). In some cases, the SHP inhibitor used in the methods provided herein is (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4). In some cases, exemplary SHP2 inhibitors for use in the methods provided herein include 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl) Thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decan-1-amine (CAS 2238840-62-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyridinemethanol (CAS 2238840- 63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decan-1-amine (CAS 2238840-64-5), 5-(4-amino-4-methyl-1-piperidinyl)-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy 2-pyridinemethanol (CAS 2238840-68-9), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-69-0), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2- Pyridinemethanol (CAS 2238840-70-3), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinemethanol (CAS 2238840-72-5), 5-[(2-amino-3-chloro-4-pyridinyl)thio]-2-[(3S ,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-3-pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-(2,3-dichlorophenyl)-6-methyl-3-pyridinemethanol (CAS 2238840-74-7), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.Examples of SHP inhibitors include, but are not limited to, 2-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(hydroxymethyl)pyridin-3-ol. In some cases, the SHP inhibitor used in the methods provided herein is 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5). In some cases, an SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in U.S. Pat. No. 10,590,090 B2, U.S. Patent Application Publication No. 2020 / 017517 A1, U.S. Patent Application Publication No. 2020 / 017511 A1, WO 2019 / 075265 A1, or WO 2021 / 142026, each of which is incorporated by reference in its entirety.

[0204] SOS1 inhibitors. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an SOS1 inhibitor in any of the methods described herein. Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine), BI1701963, AST-NS2102, MRTX-0902 ((R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile), ERAS-9, RMC-5845, HM-99462, and GH-52.

[0205] Src kinase inhibitor. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an Src kinase inhibitor in any of the methods described herein. The term "Src kinase" as used herein refers to members of the mammalian non-receptor tyrosine kinase family, including Src, Yes, Fyn, and Fgr (SrcA subfamily); Lck, Hck, Blk, and Lyn (SrcB subfamily) and the Frk subfamily. The term "Src kinase inhibitor" as used herein refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of one or more members of the Src kinase family. Exemplary Src kinase inhibitors for use in the methods provided herein include, but are not limited to, dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7-tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6-dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate), and KX-01 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide). In some cases, the Src kinase inhibitor is dasatinib. In some cases, the Src kinase inhibitor is saracatinib. In some cases, the Src kinase inhibitor is ponatinib. In some cases, the Src kinase inhibitor is vandetanib. In some cases, the Src kinase inhibitor is KX-01.

[0206] Chemotherapeutic agents. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of one or more chemotherapeutic agents in any of the methods described herein. Exemplary chemotherapeutic agents used in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate.

[0207] Definitions and General Terms The following definitions are provided to facilitate understanding of the scope of the present disclosure.

[0208] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification or claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending on the standard deviation found in their respective testing measurements.

[0209] As used herein, when any variable occurs more than once in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. When the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0210] stereoisomer The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with rotational hindrance, and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropisomers. Accordingly, it should be understood that the scope of the present disclosure encompasses all possible stereoisomers of the exemplified compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, diastereomerically pure, and atropisomerically pure) as well as mixtures of stereoisomers (e.g., mixtures of geometric isomers, enantiomers, diastereomers, and atropisomers, or mixtures of any of the above) of any chemical structure (in whole or in part) disclosed herein, unless the stereochemistry is specifically specified.

[0211] If the stereochemistry of a structure or portion of a structure is not shown, for example, with bold or dashed lines, then the structure or portion of the structure should be interpreted as encompassing all stereoisomers thereof. If the stereochemistry of a structure or portion of a structure is shown, for example, with bold or dashed lines, then the structure or portion of the structure should be interpreted as encompassing only the designated stereoisomer unless otherwise stated. For example, [ka] teeth, [ka] Similarly, for example, the chemical name (4R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole represents (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole and (4R,5S)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole. A dashed bond is sometimes used to indicate that both stereoisomers are encompassed. This should not be confused with the wavy line drawn perpendicular to a bond indicating the point of attachment of a group to the rest of the molecule.

[0212] The term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer (e.g., geometric isomer, enantiomer, diastereomer, and atropisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror-image enantiomer of that compound, and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomers and diastereomers of that compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, or greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound.

[0213] The present disclosure also encompasses pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compound disclosed herein. Additionally, the present disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compound disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized according to methods known in the art and disclosed herein. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0214] tautomers As known to those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because a chemical structure may be used to represent only one tautomeric form, for convenience, reference to a compound of a given structural formula will be understood to include other tautomeric forms of that structural formula. For example, [ka] teeth, [ka] Similarly, for example, the chemical name (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-1H-indazole represents (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-1H-indazole and (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-indazole. Accordingly, it should be understood that the scope of the present disclosure encompasses all tautomeric forms of the compounds disclosed herein.

[0215] isotope labeled compounds Additionally, the scope of the present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of the compounds disclosed herein, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon such as C, 36 chlorine such as Cl, 18 fluorine such as F, 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen such as O 32 Phosphorus such as P and 35 Certain isotopically labeled compounds of Formula I (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose given their ease of incorporation and ready means of detection. 2Substitution with isotopes such as H or D may be preferable in some situations because they may offer certain therapeutic advantages resulting from increased metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Thus, the term "deuteration" refers to the replacement of one or more hydrogen atoms with one or more deuterium atoms on a particular structure or functional group. 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes, such as N, can be useful, for example, in positron emission tomography (PET) studies to determine target occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those of skill in the art or by processes analogous to those described in the accompanying General Synthetic Procedures and Examples sections, in which suitable isotopically labeled reagents are substituted for conventionally used non-labeled reagents.

[0216] definition The following definitions are provided to facilitate understanding of the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0217] For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements (CAS version), Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0218] Unless otherwise indicated, depictions of substructures do not imply any particular orientation of the substructures. For example, [ka] as [ka] Compounds of formula (II) having the formula [ka] or [ka] Also includes compounds of formula (II): [ka] of [ka] The compound of formula (II) has the formula [ka] It includes a structure in which:

[0219] As described herein, the compounds described herein are optionally substituted with one or more substituents, as exemplified generally below or by the specific classes, subclasses, and species described herein. It will be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally," refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. When the term "optionally substituted" precedes a list, the term refers to all subsequent substitutable groups in that list. If a substituent group or structure is not identified or defined as "optionally substituted," the substituent group or structure is unsubstituted. Unless otherwise indicated, substituents include deuterium, halo, oxo, carboxyl, CHO, NH2, amide, NO2, ester, thioester, C 0~3 Alkylene CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 0~6 Alkylene-OH, C 0~3 Alkylene-C 1~4 Alkoxy, C 0~3 Alkylene-C 1~4 Haloalkoxy, C 0~3 Alkylene-C 1~4 Thioalkoxy, C 0~6 Alkylene-C 1~3 Alkoxy, deuterated C 0~6 Alkylene-OC 1~3 Alkoxy, amide, C with 3-7 total ring atoms 0~2 Alkylene-cycloalkyl, C with 5-7 total ring atoms 0~2 Alkylene-cycloalkyl, C having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0~2C having 3 to 7 total ring atoms selected from alkylene-cycloalkenyl and 1 to 3 heteroatoms selected from N, O and S 0~2 Alkylene-heterocycloalkenyl and C 0~2 Alkylene-C 6~10 aryl.

[0220] The selection of substituents and combinations of substituents contemplated herein are those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that do not change substantially when subjected to conditions that allow for their production, detection, and, specifically, their recovery, purification, and use for one or more purposes disclosed herein. In some cases, a stable compound or a chemically feasible compound is one that does not change substantially when maintained at a temperature of 40°C or less in the absence of moisture or other chemically reactive conditions for at least one week. Only selections and combinations of substituents that result in stable structures are contemplated. Such selections and combinations will be apparent to one of ordinary skill in the art and can be determined without undue experimentation.

[0221] The term "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br) or iodo (-I).

[0222] The term "oxo" refers to =0. For example, an oxo substituent on a cyclopentyl ring can be depicted as follows: [ka] Compounds with multiple occurrences of the same R group on the core structure (e.g., [ka] ), the phrase "two geminal R groups together with the atoms to which they are attached form an oxo group" refers to =O groups attached to a single atom (e.g., [ka] ) refers to

[0223] The term "ether" refers to an oxygen atom bonded to two alkyl or aryl groups (ROR). The term "ether bridge" refers to an ether group that forms a bridge on a ring, the bridge having the indicated number of carbon atoms. For example, a C1 ether bridge on a cyclohexylene ring ( [ka] ) is, for example, [ka] It can be shown as:

[0224] The term "thioether" refers to a sulfur atom bonded to two alkyl or aryl groups (RSR). The term "thioether bridge" refers to a thioether group that forms a bridge on a ring, the bridge having the indicated number of carbon atoms. For example, a C1 thioether bridge on a cyclohexylene ring ( [ka] ) is, for example, [ka] It can be shown as:

[0225] The term "alkyl" refers to a saturated straight or branched chain hydrocarbon containing the specified number of carbon atoms. For example, C3 alkyl means that the alkyl group has 3 carbon atoms. C 1~6Alkyl refers to alkyl groups having any number of carbon atoms, including the entire range (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms) and including all subgroups (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0226] The term "alkenyl" refers to a straight or branched chain hydrocarbon containing the indicated number of carbon atoms and one or more double bonds. For example, C3 alkenyl means that the alkenyl group has 3 carbon atoms. 2~6 Alkenyl refers to alkenyl groups having any number of carbon atoms, including the entire range (e.g., 2, 3, 4, 5, or 6 carbon atoms) and all subgroups (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms). Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, and butenyl.

[0227] The term "alkynyl" refers to a straight or branched chain hydrocarbon containing the indicated number of carbon atoms and one or more triple bonds. For example, C3 alkynyl means that the alkynyl group has 3 carbon atoms. C 2~6 Alkynyl refers to alkynyl groups having any number of carbon atoms, including all ranges (e.g., 2, 3, 4, 5, and 6 carbon atoms) and all subgroups (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms). Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, and butynyl.

[0228] The term "alkylene" refers to a divalent saturated aliphatic radical containing the specified number of carbon atoms. For example, C alkylene means that the alkylene group has 3 carbon atoms.1~6 Alkylene refers to alkylene groups having a number of carbon atoms, including the entire range (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms) and including all subgroups (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms). When the number of carbon atoms in an alkylene group is indicated as "C0," the alkylene group is absent and the recited substituent is directly attached to the remainder of the compound. For example, C 0~6 The term alkylene-OH refers to the OH group attached directly to the compound or to the C 1~6 It indicates that the bond can be established via an alkylene linker.

[0229] The term "alkylene bridge" refers to an alkylene group that forms a bridge on a ring, the bridge having the indicated number of carbon atoms. For example, a C alkylene bridge ( [ka] ) is, for example, [ka] The C2 alkylene bridge on the cyclohexylene ring ( [ka] ) is, for example, [ka] The C3 alkylene bridge on the cyclohexylene ring ( [ka] ) is, for example, [ka] It can be shown as C 1~2 Further examples of rings with alkylene bridges are: [ka] is.

[0230] The term "alkenylene" refers to a divalent straight or branched hydrocarbon chain containing the indicated number of carbon atoms and one or more double bonds. For example, C3 alkenylene means that the alkenylene group has 3 carbon atoms. C 1~6 Alkenylene refers to alkenylene groups having a number of carbon atoms inclusive of all ranges (e.g., 1, 2, 3, 4, 5 or 6 carbon atoms) and all subgroups (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6 and 5-6 carbon atoms).

[0231] The term "alkenylene bridge" refers to an alkenylene group that forms a bridge on a ring, the bridge having the indicated number of carbon atoms. [ka] ) is, for example, [ka] The C3 alkenylene bridge on the cyclohexylene ring ( [ka] ) is, for example, [ka] It can be shown as:

[0232] The term "heteroatom," unless otherwise specified herein, refers to an atom that is not carbon or hydrogen. Examples of heteroatoms include oxygen, sulfur, nitrogen, or phosphorus.

[0233] The term "haloalkyl" refers to an alkyl group as previously defined herein in which one or more hydrogen atoms have been replaced with a halogen. Each occurrence of halogen is independently selected. This term includes perfluorinated alkyl groups such as CF3 and CF2CF3. For example, "C 1~4 The term "haloalkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with halogen. 1~4 Refers to alkyl. C 1~4 Representative examples of haloalkyl include, but are not limited to, CH2F, CHF2, CF3, CHFCl, CH2CF3, CFHCF3, CF2CF3, CH(CF3)2, CF(CHF2)2, and CH(CH2F)(CF3).

[0234] The term "heteroalkylene" refers to an alkylene group or combination thereof that includes one or more heteroatoms (e.g., one or more of N, O, and S) at one or more of the points of attachment of the heteroalkylene (e.g., -OCH2CHO- or -OCH2CH2-) or between two carbon atoms (e.g., ether). The heteroalkylene includes the specified number of total atoms (i.e., the total of carbon atoms and heteroatoms in the chain). When a range is given, all members of that range and all subgroups within that range are contemplated. For example, a heteroalkylene having 2 to 6 total atoms and 1, 2, or 3 heteroatoms independently selected from O and S includes heteroalkylene groups having 2, 3, 4, 5, or 6 total atoms in the heteroalkylene chain (or any combination of the above) as well as all subgroups of all atoms in the stated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 total atoms or any combination of the above ranges), where 1, 2, or 3 (or any combination of the above) of all atoms in the chain are heteroatoms as well as all subgroups in the stated range (e.g., 1-2, 1-3, or 2-3 heteroatoms or any combination of the above). Thus, a heteroalkylene having 5 to 7 total atoms and 1 to 3 heteroatoms independently selected from N, O, and S includes, for example, moieties containing 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom is independently selected from N, O, and S. Non-limiting examples of heteroalkylene groups include -O(CH2)2O-.

[0235] The term "heteroalkenylene" refers to an alkenylene group containing one or more heteroatoms (e.g., one or more of N, O, and S) at one or more of the points of attachment of the heteroalkenylene, between two carbon atoms, or combinations thereof. The heteroalkenylene includes the specified number of total atoms (i.e., the total of carbon atoms and heteroatoms in the chain). When a range is given, all members of that range and all subgroups within that range are contemplated. For example, a heteroalkenylene having 4 to 6 total atoms and one or two heteroatoms independently selected from O and S includes heteroalkenylene groups having 4, 5, or 6 total atoms in the heteroalkenylene chain (or any combination of the above), as well as all subgroups of total atoms within the specified range (e.g., 4-5, 4-6, or 5-6 total atoms, or any combination of the above ranges), where one or two of the total atoms in the chain are heteroatoms. Thus, a heteroalkenylene having 5 to 7 total atoms and 1 to 3 heteroatoms independently selected from N, O, and S includes, for example, moieties containing 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, each of which is independently selected from N, O, and S.

[0236] The term "alkoxy" refers to an alkyl group, as defined hereinabove, attached to the molecule via an oxygen atom (e.g., -O-alkyl). Non-limiting examples of alkyl groups include methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0237] The terms "thioalkyl" and "thioalkoxy" are interchangeable and refer to an alkyl group, as defined hereinabove, attached to the molecule via a sulfur atom (eg, --S-alkyl).

[0238] The term "haloalkoxy" refers to an alkoxyl group, as previously defined herein, in which one or more of the hydrogen atoms has been replaced with a halogen. This term includes perfluorinated alkyl groups such as OCF3 and OCF2CF3. 1~4 Representative examples of haloalkoxy include, but are not limited to, OCH2F, OCHF2, OCF3, OCHFCl, OCH2CF3, OCFHCF3, OCF2CF3, OCH(CF3)2, OCF(CHF2)2, and OCH(CH2F)(CF3).

[0239] The term "cycloalkyl" refers to an aliphatic cyclic hydrocarbon group containing the indicated number of carbon atoms in its ring. For example, C5 cycloalkyl refers to a cycloalkyl group having 5 carbon atoms in the ring. C 3~7 Cycloalkyl refers to a cycloalkyl group having any number of carbon atoms, including the entire range (e.g., 3, 4, 5, 6, and 7 carbon atoms in the ring) and including all subgroups (e.g., 3-4, 3-5, 3-6, 3-7, 4-5, 4-6, 4-7, 5-6, 5-7, and 6-7 carbon atoms in the ring). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "spiro-cycloalkyl" refers to a cycloalkyl group as previously defined herein that is attached to a compound through one common atom. For example, a methylpiperidine ring having a spiro-cyclopropyl group as a substituent can be represented as follows: [ka] The terms "fused cycloalkyl ring" or "fused cycloalkyl" can be used interchangeably and refer to a cycloalkyl group, as defined hereinabove, that shares two adjacent atoms (i.e., one covalent bond) with the compound to which it is attached. For example, a methylpiperidine ring having a fused cyclopropyl group as a substituent can be represented as follows: [ka]

[0240] The term "cycloalkenyl" refers to a cyclic hydrocarbon group containing the indicated number of carbon atoms in the ring and one or more double bonds. For example, C5 cycloalkenyl refers to a cycloalkenyl group having 5 carbon atoms in the ring. C 5~7 Cycloalkenyl refers to cycloalkenyl groups having any number of carbon atoms, including all ranges (e.g., 5, 6, and 7 carbon atoms in the ring) and all subgroups (e.g., 5-6, 5-7, and 6-7 carbon atoms in the ring). Non-limiting examples of cycloalkyl groups include cyclopentenyl and cyclohexenyl.

[0241] The term "heterocycloalkyl" refers to a saturated ring containing carbon and 1, 2, or 3 heteroatoms and having the indicated number of total ring atoms (the sum of the carbon atoms and heteroatoms in the ring). For example, a heterocycloalkyl having 5 total atoms and 2 heteroatoms selected from N and S refers to a ring having 3 carbon atoms and 2 heteroatoms, where each heteroatom in the ring is independently N or S. As another example, a heterocycloalkyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S refers to a ring having a total number of ring atoms in the indicated range (e.g., 5, 6, or 7 total atoms), and includes all subgroups (e.g., 5 to 6 or 6 to 7 total ring atoms) where 1, 2, or 3 of the atoms in the ring are heteroatoms, where each heteroatom is independently selected from N, O, and S. Thus, a heterocycloalkyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S includes, for example, rings containing 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, each of which is independently selected from N, O, and S. Non-limiting examples of heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, azepanyl, diazepanyl, triazepanyl, oxazepanyl, azocanyl, diazocanyl, triazocanyl, oxazocanyl, thiazepanyl and thiazocanyl. The term "spiro-heterocycloalkyl" refers to a heterocycloalkyl group as defined herein before, which is bonded to a compound through one common atom. For example, a methylpiperidine ring having a spiro-oxetanyl group as a substituent can be represented as follows: [ka]

[0242] The term "fused heterocycloalkyl" refers to a heterocycloalkyl group, as previously defined herein, that shares two adjacent atoms (i.e., one covalent bond) with the compound to which it is attached. For example, a methylpiperidine ring having a fused azetidinyl group as a substituent can be represented as follows: [ka]

[0243] The term "heterocycloalkenyl" is defined similarly to "heterocycloalkyl," except that the ring contains one or more carbon-carbon double bonds.

[0244] The term "aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon ring atoms. For example, C6 aryl refers to an aryl group having 6 carbon atoms in the ring (e.g., phenyl). The aryl group can be isolated (e.g., phenyl) or fused to another aryl group (e.g., naphthyl or anthracenyl).

[0245] The term "heteroaryl" refers to an aromatic ring containing carbon and 1, 2, or 3 heteroatoms and having the indicated number of total ring atoms (the sum of the carbon atoms and heteroatoms in the ring). For example, a heteroaryl group having 5 total atoms and 2 heteroatoms selected from N and S refers to an aromatic ring having 3 carbon atoms and 2 heteroatoms, where each heteroatom in the ring is independently N or S. As another example, a heteroaryl group having 5-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S refers to an aromatic ring having a total number of ring atoms in the indicated range (e.g., 5, 6, or 7 total atoms), and includes all subgroups (e.g., 5-6 or 6-7 total ring atoms), where 1, 2, or 3 of the atoms in the ring are heteroatoms, where each heteroatom is independently selected from N, O, and S. Thus, a heteroaryl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S includes, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms, 2 carbon atoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom is independently selected from N, O, and S.Non-limiting examples of heteroaryl groups include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, thiazolyl, thiophenyl, tetrazolyl, triazinyl, triazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, and benzotriazolyl. These include, but are not limited to, azolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindoleyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolepyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, ciazolinyl, thiadiazolepyrimidyl, and thienopyridyl.

[0246] The term "bicyclic ring" refers to a functional group containing two linked rings. Unless otherwise indicated, a bicyclic ring may be spirocyclic, where the two rings share a single atom (e.g., a quaternary carbon atom), fused, where the two rings share two adjacent atoms (i.e., one covalent bond), or bridged, where the rings share three or more atoms and include a bridge having at least one atom.

[0247] As used herein, the terms "protecting group" and "protecting group" are interchangeable and refer to agents used to temporarily block one or more desired functional groups in a compound having multiple reactive sites. In some cases, a protecting group has one or more, or specifically all, of the following characteristics: (a) it can be selectively added to a functional group in good yield, (b) it provides a protecting group that is stable against reactions occurring at one or more of the other reactive sites; and (c) it can be selectively removed in good yield by a reagent that does not attack the regenerated, deprotected functional group. As will be understood by those skilled in the art, in some cases, the reagent will not attack other reactive groups in the compound. In other cases, the reagent may also react with other reactive groups in the compound. Examples of protecting groups are detailed in Greene, TW, Wuts, PG in "Protective Groups in Organic Synthesis," Third Edition, John Wiley & Sons, New York: 1999 (and other editions of this book), the entire contents of which are incorporated herein by reference. As used herein, the term "nitrogen protecting group" refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. In some cases, the nitrogen protecting group will also have the characteristics exemplified for the protecting groups above; certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P.G. in "Protective Groups in Organic Synthesis," Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are incorporated herein by reference.

[0248] The term "bond" indicates the absence of a particular functional group.

[0249] The term "geminal" refers to substituents that are attached to the same atom. Geminal R groups on chains and rings can be depicted as follows, respectively: [ka]

[0250] The terms "adjacent" and "adjacent" are interchangeable and refer to substituents that are attached to adjacent atoms along a chain or within a ring. Adjacent R groups along a chain and within a ring are [ka] It can be shown as:

[0251] The terms "non-adjacent" and "non-adjacent" are interchangeable and refer to substituents that are attached to atoms along a chain or atoms within a ring that are not attached to adjacent atoms and are not geminal. Non-adjacent R groups along a chain and non-adjacent R groups within a ring are, respectively [ka] It can be shown as:

[0252] As used herein, the term "pharmaceutically acceptable" refers to a composition or component of a composition that is generally safe, non-toxic, and not biologically or otherwise undesirable.

[0253] The term "pharmaceutically acceptable salt," as used herein, refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, and methanesulfonic acid; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or salts formed when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and dicyclohexylamine. Additional examples of such salts are found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). Stahl et al., Pharmaceutical Salts: Properties, Selection and Use, 2 nd See also Revised Edition (2011).

[0254] The term "pharmaceutically acceptable excipient," as used herein, refers to a wide variety of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0255] As used herein, the terms "subject" and "patient" are used interchangeably and refer to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In some cases, the subject is a human.

[0256] The term "therapeutically effective amount," as used herein, refers to an amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, system, or subject desired by a researcher, veterinarian, physician, or other clinician.

[0257] The term "metastatic" refers to cancer that has spread from where it first formed to another part of the body. The term non-metastatic refers to cancer that has not spread from where it first formed to another part of the body.

[0258] As used herein, the term "binding exchange assay" or "2-hour binding exchange assay" refers to the assay described in the section entitled "Biological Evaluation."

[0259] General synthesis procedure The compounds provided herein can be synthesized according to the procedures described in this section and in the following sections. The synthetic methods described herein are exemplary only, and the compounds disclosed herein can also be synthesized by alternative routes using alternative synthetic strategies, as will be appreciated by those skilled in the art. It should be understood that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any way.

[0260] In general, compounds of formula (II) can be synthesized according to the following schemes. The variables used in the following schemes are those defined for formula (II) unless otherwise specified. All starting materials are either commercially available from, for example, Merck Sigma-Aldrich Inc., Fluorochem Ltd., and Enamine Ltd., or known in the art, and can be synthesized by using known procedures using conventional techniques. The starting materials can also be synthesized by the procedures disclosed herein. Suitable reaction conditions (e.g., solvents, reaction temperatures, and reagents) for the schemes discussed in this section can be found in the examples provided herein. The abbreviation PG refers to a protecting group as defined in the Definitions and General Terms section of this specification. In the following schemes, each PG can be the same as or different from another PG in the compound, so long as each protecting group can be selectively removed.

[0261] Generally, compounds of formula (II) can be synthesized according to Scheme 1 below. Scheme 1. Scheme 1 [ka]

[0262] A nitrogen-protected piperazine linker moiety of formula (II): [ka] can be synthesized by reacting the desired alkene-substituted nitrogen-protected 3-azetidinone with the desired nitrogen-protected piperazine in the presence of a suitable reducing reagent, such as a borohydride reagent, in a reductive amination reaction to form the desired alkene-substituted aryl / heteroaryl halide core: [ka] teeth, [ka] wherein each of halo1 and halo2 is a halogen. and the desired arylboronic acid compound: [ka] The nitrogen-protected linker moiety of formula (II) can be synthesized by a palladium-catalyzed cross-coupling reaction with: [ka] Alkene-substituted, halogenated, aryl / heteroaryl core: [ka] The azetidine nitrogen is deprotected and subjected to a nucleophilic aromatic substitution reaction in the presence of a suitable base to give the di-alkenyl moiety of the compound of formula (II): [ka] The resulting compound can undergo an olefin metathesis reaction using, for example, Grubb's catalyst, to form a central moiety of formula (II) bearing an alkene tether. [ka]

[0263] The variable Z can be synthesized, for example, by starting with a desired optionally substituted phenyl, heteroaryl, or bicyclic ring and optionally attaching additional desired substituents to the ring by common techniques known to those skilled in the art. Z-halo can be prepared for coupling by halogenating the phenyl, heteroaryl, or bicyclic ring of Z using, for example, an appropriate iodination reagent (e.g., N-iodosuccinimide), bromination reagent (e.g., CBr), or chlorination reagent (e.g., (CCl)), optionally in the presence of a suitable base. The tail moiety of formula (II) can be synthesized by reacting the desired halogenated variable Z ("Z-halo") with the desired organoboron-functionalized variable X ("BX(N-PG)") containing a protected nitrogen atom in a palladium-catalyzed coupling reaction to form the ZX(N-PG) tail moiety of formula (II). When Y in formula (II) is other than N, the double bond resulting from the coupling reaction can be reduced to a single bond, if necessary.

[0264] The ZX(N-PG) tail of formula (II) can be linked to the central moiety of formula (II) by deprotecting the nitrogen atom of variable X in ZX(N-PG) to form ZX(NH) and performing nucleophilic aromatic substitution with the central moiety of formula (II) and a suitable base in a nucleophilic aromatic substitution reaction: [ka] In some cases, the tail of formula (II) can be installed via a palladium-catalyzed amination reaction, such as a Buchwald reaction.

[0265] The double bond of the tether can be functionalized to form a compound of formula (II). For example, the double bond of the tether can be reduced to a saturated hydrocarbon using a reducing agent such as Pd / C. Alternatively, the double bond of the tether can be reacted with an allylic oxidizing agent such as SeO to give an allylic alcohol. The allylic alcohol can be further oxidized to form an α,β-unsaturated carbonyl (e.g., under Dess-Martin oxidation conditions). The carbon of the α,β-unsaturated carbonyl can undergo difluorination to form an allylic geminal difluoride. The double bond of either the α,β-unsaturated carbonyl or the allylic geminal difluoride can be reduced via an appropriate reducing agent to form a ketone- or geminal difluoride-substituted tether, respectively. Alcohol-substituted tethers can be formed by subjecting the double bond of the tether to a halogenating agent and an alcohol (e.g., N-bromosuccinimide and AcOH, etc.) to form a vicinal alkoxy halide, which can then be epoxidized with a suitable base (e.g., NaOMe) and then reduced (e.g., using Pd / C) to form the alcohol. Alcohol-substituted tethers can be oxidized to a ketone (e.g., using Dess-Martin oxidation conditions) and then difluorinated using an organosulfur fluorinating agent such as diethylaminosulfur trifluoride (DAST).

[0266] A Michael acceptor can be installed in a compound by deprotecting the nitrogen atom of the piperazine ring in the presence of an acid, such as TFA, and reacting the deprotected piperazine ring with the desired halogenated α,β-unsaturated ketone, such as acryloyl chloride, to form a compound of formula (II) bearing an alkene tether.

[0267] Compounds of formula (II) having a tether substituted with a methylene group (=CH2) can be synthesized similarly to the general procedures described herein for compounds having an alkene tether, except that the nitrogen-protected linker moiety of formula (II): [ka] of the halogenated aryl / heteroaryl core: [ka] The tether can be formed via palladium-catalyzed cross-coupling with, as shown in Scheme 2 below. Scheme 2 [ka]

[0268] Compounds of formula (II) bearing ether tethers can be synthesized similarly to the general procedures described herein for compounds bearing alkene tethers, except that the tether can be formed by introducing an alkylene-OMe group to the azetidine of the nitrogen-protected linker moiety of formula (II) and coupling the resulting intermediate to the desired core. [ka] The alkylene can then be demethylated, coupled to chloroacetic acid, and cyclized to the core to form the ether linker, as shown in Scheme 3. Scheme 3 [ka]

[0269] Compounds of formula (I) can be synthesized analogously to the general procedures described herein for formula (II).

[0270] As will be appreciated by those of skill in the art, the synthetic schemes and representative examples described above are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Additional methods will be apparent to those of skill in the art. Additionally, the various synthetic steps described above can be performed in an alternate sequence or order to give the desired compounds.

[0271] Methods for purification of the compounds described herein are known in the art and include, for example, crystallization, chromatography (eg, liquid, gas phase, and supercritical fluid), extraction, distillation, trituration, and reverse phase HPLC.

[0272] Intermediates The present disclosure further encompasses "intermediate" compounds, including structures produced by the described synthetic procedures prior to obtaining the final desired compound, whether isolated or produced in situ and not isolated. These intermediates are included within the scope of the present disclosure.

[0273] Formula (Int-AA): [ka] , formula (Int-AB): [ka] , formula (Int-AC): [ka] , formula (Int-AD): [ka] , formula (Int-AE): [ka] , Formula (Int-AF): [ka] , formula (Int-AG): [ka] , Formula (Int-AH): [ka] , formula (Int-AI): [ka] and formula (Int-AJ): [ka] Provided herein are intermediates of the formula: ZA and R ZB are each independently as defined herein for the heteroaryl group of Z in the compound of formula (II). In some cases, the compound of formula (Int-AA): [ka] , formula (Int-AI): [ka] and formula (Int-AJ): [ka] Provided herein are intermediates of the formula (Int-AA): [ka] Provided herein is an intermediate of the formula (Int-AF): or a pharmaceutically acceptable salt thereof. [ka] Provided herein is an intermediate of formula (Int-AI): or a pharmaceutically acceptable salt thereof. [ka] Provided herein is an intermediate of formula (Int-AJ): or a pharmaceutically acceptable salt thereof. [ka] or a pharmaceutically acceptable salt thereof.ZA and R ZB each independently represents a halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 0~6 Alkylene-N(R N1 )2, C 0~2 Alkylene-C 3~6 Cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0~2 Alkylene-heterocycloalkyl or C 0~2 alkylene-phenyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 0~6 Alkylene-C 1~3 Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is independently unsubstituted or substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~2 Alkylene OH, C 1~2 Alkylene-C 1~3 Alkoxy, C 1~3 Deuterated alkoxy, N(R N1 )2, (C=O)C 1~3 Alkyl, C 3~5 cycloalkyl, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, form spiro-C 3~5 or two adjacent further substituents together with the atoms to which they are attached form a fused C 3~5forming a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, wherein each of the further substituents of the cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently halo or C 1~3 In some cases, R ZAは、C H3 and R ZB are CH3, C(CH3)2CH2OH, CH2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, [ka] In some cases, R ZAは、C H3 and R ZB is CH3, CH2CH2OCH3, [ka] Contemplated examples of intermediates of formula Int-AA through Int-AJ are listed in Table INT-A and pharmaceutically acceptable salts thereof.

[0274] [Table 55]

[0275] [Table 56]

[0276] [Table 57]

[0277] Further contemplated examples of intermediates are listed below in Table Int-A' and pharmaceutically acceptable salts thereof.

[0278] [Table 58]

[0279] Formula (Int-B): [ka] intermediates of the formula (I), nitrogen-protected analogs thereof (e.g., [ka] Further provided herein are pharmaceutically acceptable salts of the above, wherein A is [ka] and o and R 6 are as defined in the Compounds of Formula (II) section, and each R ZA and R ZB is as defined herein in the section on compounds of formula (II) for intermediates of formula (Int-AA), formula (Int-AB), formula (Int-AC), formula (Int-AD), formula (Int-AE), formula (Int-AF), formula (Int-AG), formula (Int-AH), formula (Int-AI), and formula (Int-AJ). In some cases, o is 0, 1, 2, 3, or 4, and each R 6 are independently Br, Cl, F, CN, CH3, CH2F, CHF2, CF3, OH, CH2OH, OCH3, OCD3, CH2OCH3, or CH2N(CH3)2, or two geminal R 6 together with the atom to which they are attached form oxo, ═CH2, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R 6 taken together with the atoms to which they are attached form a fused cyclopropyl, fused cyclobutyl, or fused cyclopentyl, wherein any of the spiro and fused rings are unsubstituted or substituted with one or two substituents, each of which is selected from the group consisting of halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~2 Alkylene OH, C 0~2 Alkylene C 1~3Alkoxy or C 0~2 For example, the formula (Int-B) can be replaced by the formula (Int-BA): [ka] , Formula (Int-BB): [ka] , formula (Int-BC): [ka] , formula (Int-BD): [ka] , Formula (Int-BE): [ka] , formula (Int-BF): [ka] , formula (Int-BG): [ka] , formula (Int-BH): [ka] , Formula (Int-BI): [ka] , formula (Int-BJ): [ka] , formula (Int-BK): [ka] , formula (Int-BL): [ka] , formula (Int-BM): [ka] , formula (Int-BN): [ka] , expression (Int-BO): [ka] , formula (Int-BP): [ka] , formula (Int-BQ): [ka] , formula (Int-BR): [ka] , formula (Int-BS): [ka] and formula (Int-BT): [ka] intermediates of any of the above, nitrogen-protected analogs (e.g., [ka] and N-BOC protected analogs such as INT-BA) and pharmaceutically acceptable salts of any of the above. [ka] , formula (INT-BF): [ka] , formula (INT-BI): [ka] or the formula (INT-BJ): [ka] , any nitrogen-protected analog of the above, or any pharmaceutically acceptable salt of the above. In some cases, the present disclosure provides compounds of formula (Int-BA): [ka] In some cases, the present disclosure provides an intermediate of formula (Int-BF): [ka] In some cases, the present disclosure provides an intermediate of formula (Int-BI): [ka] In some cases, the present disclosure provides an intermediate of formula (Int-BJ): [ka] In some cases, o is 0 or 1 and R 6 is CH3 and R ZA is CH3 and R ZB are CH3, C(CH3)2CH2OH, CH2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, [ka] In some cases, R ZAは、C H3 and R ZB is CH3, CH2CH2OCH3, [ka] Contemplated examples of intermediates of formula (Int-B), such as formula Int-BA to Int-BT, are listed in Table INT-B, including pharmaceutically acceptable salts thereof.

[0280] [Table 59]

[0281] [Table 60]

[0282] [Table 61]

[0283] [Table 62]

[0284] [Table 63]

[0285] [Table 64]

[0286] [Table 65]

[0287] [Table 66]

[0288] [Table 67]

[0289] [Table 68]

[0290] Table 69

[0291] Table 70

[0292] Table 71

[0293] Table 72

[0294] Table 73

[0295] Table 74

[0296] Table 75

[0297] Table 76

[0298] Table 77

[0299] Table 78

[0300] [Table 79]

[0301] Formula (Int-C): [ka] intermediates of the formula (I), nitrogen-protected analogs thereof (e.g., [ka] and BOC-protected analogs such as 6 , R ZA and R ZB are as previously defined herein for Int-B. For example, formula (Int-C) can be represented by formula (Int-CA): [ka] , formula (Int-CB): [ka] , formula (Int-CC): [ka] , formula (Int-CD): [ka] , Formula (Int-CE): [ka] , formula (Int-CF): [ka] , formula (Int-CG): [ka] , formula (Int-CH): [ka] , Formula (Int-CI): [ka] , nitrogen-protected analogs of any of the above (e.g., [ka] and N-BOC protected analogs such as Int-B) and pharmaceutically acceptable salts of any of the above, wherein each of the substituents is as previously defined for Int-B. In some cases, the present disclosure provides compounds of formula (Int-CA): [ka] , its nitrogen-protected analogs, or pharmaceutically acceptable salts thereof. Contemplated example intermediates of formula (Int-C) are listed in Table INT-C, including pharmaceutically acceptable salts thereof.

[0302] [Table 80]

[0303] Formula (Int-D): [ka] intermediates of the formula (I), nitrogen-protected analogs thereof (e.g., [ka] and BOC-protected analogs such as 3 are each as defined herein in the Compounds of Formula (II) section, and B is C 1~3 Alkylene -CH=CH2 or C 1~3 R is alkylene OH. In some cases, m is 0 or 1. 3is CH. In some cases, B is CHCH=CH or CHCHOH. Contemplated examples of intermediates of formula (Int-D) are listed in Table INT-D and include nitrogen analogs of the compounds listed in Table INT-D and pharmaceutically acceptable salts of the compounds listed in Table INT-D.

[0304] [Table 81]

[0305] [Table 82]

[0306] [Table 83]

[0307] Formula (Int-E): [ka] Further provided herein is an intermediate of the formula: [ka] , R 3 and R 5 is as defined herein in the section on compounds of formula (II). m is 0, 1, 2, 3 or 4; [ka] is C 2~6 Alkylene, C 3~6 alkenylene, heteroalkylene having 2 to 6 total atoms and 1 to 3 heteroatoms selected from N, O, and S, or heteroalkenylene having 3 to 6 total atoms and 1 or 2 heteroatoms selected from N, O, and S; [ka] is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from C 1~3 Alkyl, C 1~3 Haloalkyl, C 2~3 Alkenyl, Halo, CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 4~5 cycloalkenyl, heterocycloalkyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl; or two geminal substituents, together with the atoms to which they are attached, may be oxo, =CH2, spiro-C 3~5 Cycloalkyl, spiro-C 4~5 or two adjacent substituents, taken together with the atoms to which they are attached, form a fused C ring; a spiro-heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or a spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or two adjacent substituents, taken together with the atoms to which they are attached, form a fused C ring; 3~5 Cycloalkyl, fused C 4~5 forming a cycloalkenyl, a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; Each R 3 independently, C 1~3 Alkyl, C 1~3 haloalkyl, [ka] , C 0~3 Alkylene CN, C 0~3 Alkylene OH or C 0~3Alkylene-C 1~3 Alkoxy or two geminal R 3 together with the atom to which they are attached, form oxo, spiro-C 3~7 Cycloalkyl, spiro-C 4~7 a cycloalkenyl, a spiro-heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a spiro-heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or two adjacent R 3 together with the atoms to which they are attached to form a fused C 3~7 Cycloalkyl, fused C 4~7 forming a cycloalkenyl, a fused heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R 5 Ha, Halo, C 1~3 Haloalkyl, C 1~6 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~3 Alkoxy, C 1~3 Thioalkyl, C 3~7 Cycloalkyl, C 5~7 cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, each of the foregoing being independently unsubstituted or substituted with 1 to 3 substituents, and each substituent being independently selected from C 1~3 Haloalkyl, C 0~6 Alkylene-OH, C 0~6 Alkylene-C 1~3 Alkoxy, C 3~7 Cycloalkyl, C 5~7cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl.

[0308] In some cases, halo is Cl, m is 0 or 1, and R 3 is CH3 and R 5 is CHF2 or CF3. In some cases, n is 0 and R 5 is CHF2. In some cases, [ka] In some cases, [ka] Contemplated examples of intermediates of formula (Int-E) are listed below in Table INT-E, including pharmaceutically acceptable salts thereof.

[0309] [Table 84]

[0310] [Table 85]

[0311] [Table 86]

[0312] [Table 87]

[0313] [Table 88]

[0314] [Table 89]

[0315] [Table 90]

[0316] [Table 91]

[0317] [Table 92]

[0318] [Table 93]

[0319] [Table 94]

[0320] [Table 95]

[0321] [Table 96]

[0322] The intermediates listed in Table INT-F and pharmaceutically acceptable salts thereof are also provided herein.

[0323] [Table 97]

[0324] The intermediates listed in Table INT and pharmaceutically acceptable salts thereof are also provided herein.

[0325] Table 98

[0326]

Table 99

[0327]

Table 100

[0328] Table 101

[0329] Table 102

[0330] Table 103

[0331] Table 104

[0332] Table 105

[0333] Table 106

[0334] Another aspect of the present disclosure is the use of an intermediate described herein, such as an intermediate of Formula (Int-AA), Formula (Int-AB), Formula (Int-AC), Formula (Int-AD), Formula (Int-AE), Formula (Int-AF), Formula (Int-AG), Formula (Int-AH), Formula (Int-AI), Formula (Int-AJ), Formula (Int-B), Formula (Int-C), Formula (Int-D), and Formula (Int-E), or an intermediate listed in Table INT-A, Table INT-A', Table INT-B, Table INT-C, Table INT-D, Table INT-E, Table INT-F, or Table INT, a nitrogen-protected analog thereof, or a pharmaceutically acceptable salt thereof, to prepare a compound or salt of the present disclosure (e.g., a compound of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), A process for preparing a compound described herein (e.g., a compound of Formula (I), Formula (I'), Formula (IA), Formula (IB), Formula (IE), Formula (IF), Formula (IG), Formula (II), Formula (II'), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE) and Formula (IIF) or a compound listed in Table A, Table A', Table B, Table B' and Table E) or a pharmaceutically acceptable salt, nitrogen-protected analog thereof, or a pharmaceutically acceptable salt thereof, comprising converting In some cases, the intermediate is a compound of Formula (Int-AA), Formula (Int-AB), Formula (Int-AC), Formula (Int-AD), Formula (Int-AE), Formula (Int-AF), Formula (Int-AG), Formula (Int-AH), Formula (Int-AI), Formula (Int-AJ), or a compound listed in Table A or Table A', a nitrogen-protected analogue of any of the above, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of Formula (Int-AA), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of Formula (Int-AB), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above.In some cases, the intermediate is a compound of formula (Int-AC), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of formula (Int-AD), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of formula (Int-AE), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of formula (Int-AF), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of formula (Int-AG), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of formula (Int-AH), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of formula (Int-AI), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of formula (Int-AJ), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound listed in Table INT-A or Table INT-A', a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of formula (Int-B), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound listed in Table INT-B, a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of formula (Int-C), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound listed in Table INT-C, a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of formula (Int-D), a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound listed in Table INT-D, a nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound of formula (Int-E), a nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the above.In some cases, the intermediate is a compound listed in Table INT-E, a nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound listed in Table INT-F, a nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the above. In some cases, the intermediate is a compound listed in Table INT, a nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the above.

[0335] Other embodiments In one embodiment, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3 or 4; n is 0, 1 or 2; o is 0, 1, 2, 3 or 4; A is N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy; W is CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy; X is [ka] and Y is N, CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC 0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 is an alkoxy; Z is phenyl, heteroaryl having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a bicyclic ring containing a heteroaryl ring having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S fused to a cycloalkyl ring having 5 or 6 total ring atoms or a heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, wherein each of the phenyl, heteroaryl, and bicyclic ring is optionally substituted with 1 to 4 substituents; R 1a , R 1b and R 2 each independently selected from H, D, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~2 Alkylene-OH, C 0~2 Alkylene-C 1~4 Alkoxy, C 0~2 Alkylene-C 1~4 Haloalkoxy, C 0~2 Alkylene-CN, C 0~2 Alkylene-N(R N1 ) C having 2, 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S 1~2 alkylene-heterocycloalkyl, and R 1b and R 2 together with the carbon atoms to which they are attached, [ka] Forming a base, Each R 3 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene CN, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two adjacent R 3 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms; Each R 4 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene CN, C 1~3 Alkylene OH, C 1~3 Alkylene-C 1~3 alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, or spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R 5a H, CN, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 alkoxy or cycloalkyl having 3 to 5 total ring atoms, or R 5a and R 4 together with the atoms to which they are attached form an optionally substituted ring having 6 to 10 total ring atoms and 0, 1 or 2 heteroatoms selected from N, O and S, which ring is saturated or unsaturated; R 5b is C 1~3 Haloalkyl, C 1~4 Alkyl, C 2~3 Alkenyl, C 2~3 Alkynyl, Halo, C 1~3 Alkoxy, C 1~3thioalkoxy, cycloalkyl having 3 to 7 total ring atoms, cycloalkenyl having 5 to 7 total ring atoms, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, each of the foregoing independently optionally substituted with 1 to 3 substituents, or R 5a and R 5b together with the atoms to which they are attached form a cycloalkyl ring having 3 to 7 total ring atoms; Each R 6 are independently halo, CN, oxo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 0~3 Alkylene OH, C 0~3 Alkylene-C 1~3 Alkoxy, deuterated C 0~3 Alkylene-C 1~3 Alkoxy, C 1~4 Alkylene-N(R N1 ) 2, spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two adjacent R 6 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms, or Y and an adjacent R 6 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms, any of the above fused cycloalkyl rings being optionally substituted with 1 or 2 substituents; or Two non-adjacent R 6 are joined together to form C 1~3 Alkylene bridge or C 1~3 forming an ether bridge, and Each R N1 are independently H or C 1~4 It is alkyl.

[0336] As a second embodiment, R 1a, R 1b and R 2 is H or D.

[0337] As a third embodiment, R 1a , R 1b and R 2 is independently H or D.

[0338] As a fourth embodiment, R 1a , R 1b and R 2 is independently H.

[0339] As a fifth embodiment, R 1a , R 1b and R 2 and each independently is D.

[0340] As a sixth embodiment, R 1a , R 1b and R 2 Provided herein is a compound or salt of embodiment 1 or 2, wherein at least one of is halo.

[0341] As a seventh embodiment, R 1a is the halo and R 1b and R 2 is H.

[0342] As an embodiment 8, provided herein is a compound or salt of embodiment 6 or 7, wherein each halo is independently Br, Cl, or F.

[0343] As a ninth embodiment, R 1a , R 1b and R 2 At least one of 1~4 Alkyl or C 1~4Provided herein are compounds or salts of embodiments 1 or 2, which are haloalkyl.

[0344] As a tenth embodiment, R 1a , R 1b and R 2 is CH3 or CF3.

[0345] As an eleventh embodiment, R 1a , R 1b and R 2 At least one of 1~2 Alkylene-OH, C 0~2 Alkylene-C 1~4 Alkoxy, C 0~2 Alkylene-C 1~4 Haloalkoxy, C 0~2 Alkylene-CN or C 0~2 Alkylene-N(R N1 Provided herein are compounds or salts of embodiments 1 or 2, wherein R 1 is 1 or 2;

[0346] As a twelfth embodiment, each R N1 is independently H or CH.sub.3.

[0347] As a thirteenth embodiment, each R N1 is independently H.

[0348] As a fourteenth embodiment, R 1a , R 1b and R 2 Provided herein are compounds or salts according to embodiments 11 or 12, wherein at least one of is CH2OH, OCH3, CH2OCH3, OCF3, CH2OCF3, CN, CH2CN, NH2, N(CH3)2, CH2NH2, or CH2N(CH3)2.

[0349] As a fifteenth embodiment, R 1a , R 1b and R 2at least one of which is a C having 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S 1~2 Provided herein are compounds or salts according to embodiments 1 or 2, which are alkylene-heterocycloalkyl.

[0350] As embodiment 16, provided herein is a compound or salt of embodiment 15, wherein heterocycloalkyl is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl.

[0351] As a seventeenth embodiment, R 1a , R 1b and R 2 17. Provided herein is a compound or salt of embodiment 16, wherein at least one of is aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidin-1-yl-methyl, piperidin-1-yl-methyl, or morpholin-1-yl-methyl.

[0352] As an eighteenth embodiment, R 1b and R 2 together with the carbon atoms to which they are attached, [ka] The compounds or salts of embodiment 1 that form the group are provided herein.

[0353] As a nineteenth embodiment, [ka] Provided herein is a compound or salt of embodiment 1, wherein:

[0354] As embodiment 20, [ka] 19. Provided herein is a compound or salt of embodiment 19, wherein:

[0355] As embodiment 21, provided herein is a compound or salt of any one of embodiments 1 to 20, wherein m is 0.

[0356] As embodiment 22, provided herein is a compound or salt of any one of embodiments 1 to 20, wherein m is 1.

[0357] As embodiment 23, provided herein is a compound or salt of any one of embodiments 1 to 20, wherein m is 2.

[0358] As embodiment 24, provided herein is a compound or salt of any one of embodiments 1 to 20, wherein m is 3.

[0359] As embodiment 25, provided herein is a compound or salt of any one of embodiments 1 to 20, wherein m is 4.

[0360] As an embodiment 26, at least one R 3 is C 1~3 Alkyl or C 1~3 Provided herein are compounds or salts according to any one of embodiments 22-25, wherein the compound or salt is haloalkyl.

[0361] In embodiment 27, at least one R 3 27. Provided herein is a compound or salt of embodiment 26, wherein is CH3, CH2CH3, CF3, CHF2, or CH2F.

[0362] In embodiment 28, at least one R 3 is C 0~3 Provided herein are compounds or salts of any one of embodiments 22-25, wherein the alkylene is CN.

[0363] In embodiment 29, at least one R 3

[0041] Provided herein is a compound or salt of embodiment 28, wherein is CN or CH2CN.

[0364] In embodiment 30, at least one R3 is C 0~3 Alkylene OH or C 0~3 Alkylene-C 1~3 Provided herein are compounds or salts of any one of embodiments 22-25, wherein is alkoxy.

[0365] In embodiment 31, at least one R 3 is OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3.

[0366] As an embodiment 32, at least one R 3 Provided herein are compounds or salts of any one of embodiments 22-25, wherein is oxo.

[0367] As an embodiment 33, at least one R 3 Provided herein are compounds or salts of any one of embodiments 22-25, wherein is a spiro-cycloalkyl having 3 to 7 total ring atoms or a spiro-heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S.

[0368] As an embodiment 34, at least one R 3 34. Provided herein are compounds or salts of embodiment 33, wherein is spirocyclopropyl, spirocyclobutyl, spiro-oxetanyl, or spirotetrahydrofuranyl.

[0369] In embodiment 35, two adjacent R 3

[0039] Provided herein are compounds or salts of any one of Embodiments 22-25, wherein: taken together with the atoms to which they are attached, form a fused cycloalkyl ring having 3 to 7 total ring atoms.

[0370] As an embodiment 36, two adjacent R 3

[0049] Provided herein are compounds or salts of embodiment 35, wherein: taken together with the atoms to which they are attached, form a fused cyclopropyl ring or a fused cyclobutyl ring.

[0371] As a thirty-seventh embodiment, each R 3 is independently CH3, CH2CH3, CF3, CHF2, CH2F, CN, CH2CN, OH, CH2OH, CH2CH2OH, OCH3, CHOCH3, CH2CHOCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl.

[0372] In embodiment 38, m is 0 or m is 1, and R 3 Provided herein are compounds or salts of any one of embodiments 1-20, wherein is CH3, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl.

[0373] As embodiment 39, [ka] Provided herein is a compound or salt of any one of embodiments 1-20, wherein:

[0374] As embodiment 40, [ka] 39. Provided herein is a compound or salt of embodiment 39, wherein:

[0375] As embodiment 41, provided herein is a compound or salt of any one of embodiments 1 to 40, wherein A is N.

[0376] In embodiment 42, A is CH, C-halo, C-CN, CC 1~3 Alkyl, CC 1~3 Haloalkyl, CC0~3 Alkylene OH or CC 0~3 Alkylene-C 1~4 Provided herein are compounds or salts of any one of emb...

Claims

1. Formula (I): 【Chemical 1】 (In the formula, m is 0, 1, 2, 3 or 4; n is 1 or 2; o is 0, 1, 2, 3 or 4; A is N, CH, C-halo, C-CN, C-C １～３ Alkyl, C-C １～３ Haloalkyl, C-C ０～３ Alkylene OH or C-C ０～３ Alkylene-C １～４ is an alkoxy, W is CH, C-halo, C-CN, C-C １～３ Alkyl, C-C １～３ Haloalkyl, C-C ０～３ Alkylene OH or C-C ０～３ Alkylene-C １～４ is an alkoxy, X is 【Chemistry 2】 and Y is N, C—H, C-halo, C—CN, C—C １～３ Alkyl, C-C １～３ Haloalkyl, C-C ０～３ Alkylene OH or C-C ０～３ Alkylene-C １～４ is an alkoxy, Z is phenyl, heteroaryl having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or a bicyclic ring containing a heteroaryl ring having 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S fused to a cycloalkyl ring having 5 or 6 total ring atoms or a heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, each of the phenyl, heteroaryl and bicyclic ring optionally substituted with 1 to 4 substituents; R １ａ , R １ｂ and R ２ each independently selected from H, D, halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～２ Alkylene-OH, C ０～２ Alkylene-C １～４ Alkoxy, C ０～２ Alkylene-C １～４ Haloalkoxy, C ０～２ Alkylene-CN,C ０～２ Alkylene-N(R Ｎ１ ) ２ , C having 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S １～２ alkylene-heterocycloalkyl, or R １ｂ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 3】 Forming a base, Each R ３ are independently １～３ Alkyl, C １～３ Haloalkyl, C ０～３ Alkylene CN, C ０～３ Alkylene OH, C ０～３ Alkylene-C １～３ alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two adjacent R ３ together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms; 1 R ４ and R ５ａ together with the atoms to which they are attached form an optionally substituted ring having 6 to 10 total ring atoms and 0, 1 or 2 heteroatoms selected from N, O and S, said ring being saturated or unsaturated; When n is 2, the other R ４ is C １～３ Alkyl, C １～３ Haloalkyl, C ０～３ Alkylene CN, C １～３ Alkylene OH, C １～３ Alkylene-C １～３ alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, or spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R ５ｂ is C １～３ Haloalkyl, C １～４ Alkyl, C ２～３ Alkenyl, C ２～３ Alkynyl, Halo, C １～３ Alkoxy, C １～３ thioalkoxy, cycloalkyl having 3 to 7 total ring atoms, cycloalkenyl having 5 to 7 total ring atoms, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, each of the foregoing being independently optionally substituted with 1 to 3 substituents; Each R ６ are independently halo, CN, oxo, C １～３ Alkyl, C １～３ Haloalkyl, C ０～３ Alkylene OH, C ０～３ Alkylene-C １～３ Alkoxy, deuterated C ０～３ Alkylene-C １～３ Alkoxy, C １～４ Alkylene-N(R Ｎ１ ) ２ , spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two adjacent R ６ together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms, or Y and an adjacent R ６ together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms, any of said fused cycloalkyl rings above being optionally substituted with 1 or 2 substituents; or Two non-adjacent R ６ are joined together to form C １～３ Alkylene bridge or C １～３ forming an ether bridge, and Each R Ｎ１ are independently H or C １～４ alkyl) or a pharmaceutically acceptable salt thereof. 【Request 2】 【Chemical 4】 2. The compound or salt of claim 1, wherein: 【Request 3】 【Chemical 5】 3. The compound or salt according to claim 1 or 2, wherein:

4. The compound or salt according to any one of claims 1 to 3, wherein A is N.

5. The compound or salt according to any one of claims 1 to 4, wherein n is 1.

6. The compound or salt according to any one of claims 1 to 4, wherein n is 2.

7. The other R ４ is CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , CH(CH ３ ) ２ , C.F. ３ , CHF ２ or CH ２ 7. The compound or salt of claim 6, wherein:

8. 8. The compound or salt of claim 1, wherein W is CH.

9. 1 R ４ and R ５ａ are taken together with the atoms to which they are attached to form an optionally substituted ring having 6 to 10 total ring atoms and 0, 1 or 2 heteroatoms selected from N, O and S, and said ring is saturated.

10. 1 R ４ and R ５ａ are taken together with the atoms to which they are attached to form an optionally substituted ring having 6 to 10 total ring atoms and 0, 1 or 2 heteroatoms selected from N, O and S, and the ring is unsaturated.

11. 1 R ４ and R ５ａ 11. The compound or salt of any one of claims 1 to 10, wherein the optionally substituted rings formed by, together with the atoms to which they are attached, have 6 or 7 total ring atoms.

12. 1 R ４ and R ５ａ 12. The compound or salt of any one of claims 1 to 11, wherein the optionally substituted rings formed by, together with the atoms to which they are attached, have zero heteroatoms.

13. 1 R ４ and R ５ａ 12. The compound or salt of any one of claims 1 to 11, wherein the optionally substituted ring formed by, together with the atom to which it is attached, has 1 or 2 heteroatoms selected from N, O and S.

14. 14. The compound or salt of claim 13, wherein the one or two heteroatoms are each O.

15. 14. The compound or salt of claim 13, wherein the one or two heteroatoms are each N.

16. 1 R ４ and R ５ａ 16. The compound or salt of any one of claims 1 to 15, wherein the ring formed by together with the atoms to which they are attached is unsubstituted.

17. 1 R ４ and R ５ａ The ring formed by these together with the atoms to which they are attached is １～３ Alkyl, C １～３ Haloalkyl, oxo, halo, CN, C ０～３ Alkylene OH, C ０～３ Alkylene-C １～３ The compound or salt according to any one of claims 1 to 15, which is substituted by one or two substituents selected from the group consisting of alkoxy, cycloalkyl having 3 to 7 total ring atoms, cycloalkenyl having 5 to 7 total ring atoms, heterocycloalkyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, and phenyl.

18. 【Chemical 6】 2. The compound or salt of claim 1, wherein:

19. R ５ｂ is CF ３ , C.F. ２ H, C.F.H. ２ or CF ２ CH ３ The compound or salt according to any one of claims 1 to 18,

20. X is 【Chemistry 7】 The compound or salt according to any one of claims 1 to 19,

21. 21. The compound or salt of any one of claims 1 to 20, wherein Y is C-H.

22. 22. The compound or salt according to any one of claims 1 to 21, wherein o is 0.

23. 22. The compound or salt according to any one of claims 1 to 21, wherein o is 1.

24. R ６ is CH ３ , C.H. ２ F, CHF ２ or CF ３ 24. The compound or salt of claim 23, wherein:

25. [Chemical 8] 21. The compound or salt of claim 20, wherein:

26. 26. The compound or salt of any one of claims 1 to 25, wherein Z is heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, said heteroaryl being optionally substituted with 1 to 4 substituents.

27. 27. The compound or salt of claim 26, wherein the heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

28. 28. The compound or salt of claim 27, wherein the heteroaryl is pyrazolyl or pyridyl.

29. The heteroaryl may be halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ０～６ Alkylene-OH, C ０～６ Alkylene-C １～３ Alkoxy, C ０～６ Alkylene-N(R Ｎ１ ) ２ (In the formula, each R Ｎ１ are independently H or C １～３ alkyl), C having 3 to 6 total ring atoms ０～２ Alkylene-cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S ０～２ Alkylene-heterocycloalkyl and C ０～２ substituted with 1 to 4 substituents each independently selected from the group consisting of alkyl, alkenyl, C ０～６ Alkylene-C １～３ Each of the alkoxy, cycloalkyl, heterocycloalkyl and phenyl substituents independently is selected from deuterium, halo, OH, CH ３ , OCH ３ and OCD ３ 29. The compound or salt of any one of claims 26 to 28, optionally substituted with 1 to 3 substituents independently selected from:

30. Each of the 1 to 4 substituents is independently Cl, F, CN, CH ３ , CD ３ , CH ２ CH ３ , CH(CH ３ ), ２ , CF ３ , CHF ２ , CH ２ F, CH ２ CHF ２ , CH ２ CH ２ F, CH(CH ２ F), ２ , CH(CH ３ ), CH ２ F, CH(CH ３ )CHF<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​CH ２ CH ２ CH ２ OCD ３ 、CH(CH ３ )CH ２ OCH ３ 、CH(CH ３ )CH ２ OCD ３ 、C(CH ３ ) ２ CH ２ OCH ３ 、C(CH ３ ) ２ CH ２ OCD ３ CH ２ CH(CH ３ )OCH ３ CH ２ CH(CH ３ )OCD ３ CH ２ C(CH ３ ) ２ OCH ３ CH ２ C(CH ３ ) ２ OCD ３ 、NH ２ CH ２ NH ２ CH ２ NHCH ３ CH ２ N(CH ３ ) ２ CH ２ CH ２ NH ２ CH ２ CH ２ NHCH ３ CH ２ CH ２ N(CH ３ ) ２ 、 【Chemistry 9】 30. The compound or salt of claim 29, selected from the group consisting of:

31. Each of the one to four substituents is independently CH ３ , C.H. ２ CH ２ OCH ３ , C.H. ２ CH ２ OCD ３ , 【Chemistry 10】 31. The compound or salt of claim 30, wherein:

32. Z is 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 The compound or salt according to any one of claims 26 to 30,

33. Z is 【Chemistry 15】 33. The compound or salt of claim 32, wherein:

34. 【Catalog 16】 and 【Chemistry 17】 and 【Chemistry 18】 and X is 【Chemistry 19】 and 2. The compound or salt of claim 1, wherein Z is pyrazolyl or pyridyl, each optionally substituted with 1 to 4 substituents.

35. Each of said 1 to 4 substituents of Z is independently CH ３ , C.H. ２ CH ２ OCH ３ , C.H. ２ CH ２ OCD ３ , 【Chemistry 20】 35. The compound or salt of claim 34, wherein:

36. 36. The compound or salt of claim 34 or 35, wherein Z is substituted with two substituents.

37. One of the substituents is CH ３ 37. The compound or salt of claim 36, wherein:

38. The other substituent is CH ３ , C.H. ２ CH ２ OCH ３ , 【Chemical 21】 38. The compound or salt of claim 37, wherein:

39. Z is 【Chemical 22】 The compound or salt according to any one of claims 34 to 38,

40. Z is 【Chemical 23】 40. The compound or salt of claim 39, wherein:

41. structure: 【Chemistry 24】 2. The compound or salt of claim 1, wherein:

42. structure: 【Chemistry 25】 or a pharmaceutically acceptable salt thereof.

43. Formula (II): 【Chemical 26】 (In the formula, m is 0, 1, 2, 3 or 4; n is 0, 1 or 2; A is N, CH, C-halo, C-CN, C-C １～３ Alkyl, C-C １～３ Haloalkyl, C-C ０～３ Alkylene OH or C-C ０～３ Alkylene-C １～４ is an alkoxy, W １ and W ２ each independently represents N, CH, C-halo, C-CN, C-C １～３ Alkyl, C-C ２～３ Alkenyl, C-C ２～３ Alkynyl, C-C １～３ Haloalkyl, C-C ０～３ Alkylene OH or C-C ０～３ Alkylene-C １～４ alkoxy, wherein each of said alkenyl and alkynyl is unsubstituted or substituted with 1 to 3 substituents, and each substituent is independently selected from halo, C １～３ Haloalkyl, C ０～３ Alkylene OH or C ０～３ Alkylene C １～４ is an alkoxy, X is a heterocycloalkyl or heterocycloalkenyl, each having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, wherein each of said heterocycloalkyl and heterocycloalkenyl is unsubstituted or substituted with 1 to 3 substituents, and each substituent is independently selected from halo, C １～３ Alkyl, C １～３ Haloalkyl, C ０～２ Alkylene OH, C ０～２ Alkylene C １～３ Alkoxy or C ０～２ alkylene CN, Z is phenyl, heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or a bicyclic ring; ５～６ a bicyclic ring comprising a heteroaryl having 5 or 6 total ring atoms and 1-3 heteroatoms selected from N, O, and S fused to a cycloalkyl or heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; Each of the phenyl, heteroaryl, and bicyclic rings is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ０～６ Alkylene-OH, C ０～６ Alkylene-C １～３ Alkoxy, C ０～６ Alkylene-N(R Ｎ１ ) ２ , C ０～２ Alkylene-C ３～６ Cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S ０～２ Alkylene-heterocycloalkyl or C ０～２ alkylene-phenyl, Said C １～６ Alkyl, C ２～６ Alkenyl, C ０～６ Alkylene-C １～３ Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is independently unsubstituted or substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C １～３ Alkyl, C １～３ Haloalkyl, C １～２ Alkylene OH, C １～２ Alkylene-C １～３ Alkoxy, C １～３ Deuterated alkoxy, N(R Ｎ１ ) ２ , (C=O)C １～３ Alkyl, C ３～５ cycloalkyl or heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, form spiro-C ３～５ or two adjacent further substituents together with the atoms to which they are attached form a fused C ３～５ forming a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; Each of the above further substituents of cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently halo or C １～３ is alkyl, 【Chemical 27】 is C ２～６ Alkylene, C ３～６ alkenylene, heteroalkylene having 2 to 6 total atoms and 1 to 3 heteroatoms selected from N, O and S, or heteroalkenylene having 3 to 6 total atoms and 1 or 2 heteroatoms selected from N, O and S; 【Chemical Formula 28】 is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from C １～３ Alkyl, C １～３ Haloalkyl, C ２～３ Alkenyl, Halo, CN, C ０～３ Alkylene OH, C ０～３ Alkylene-C １～３ Alkoxy, C ３～５ Cycloalkyl, C ４～５ cycloalkenyl, heterocycloalkyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl; or two geminal substituents, together with the atoms to which they are attached, can be oxo, ═CH ２ , spiro-C ３～５ Cycloalkyl, spiro-C ４～５ or two adjacent substituents, together with the atoms to which they are attached, form a fused C ３～５ Cycloalkyl, fused C ４～５ forming a cycloalkenyl, a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R １ａ , R １ｂ and R ２ each independently selected from H, D, halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～２ Alkylene-OH, C ０～２ Alkylene-C １～４ Alkoxy, C ０～２ Alkylene-C １～４ Haloalkoxy, C ０～２ Alkylene-CN,C ０～２ Alkylene-N(R Ｎ１ ) ２ , C having 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S １～２ alkylene-heterocycloalkyl, or R １ｂ and R ２ together with the carbon atoms to which they are attached, 【Chemical 29】 Forming Each R ３ are independently １～３ Alkyl, C １～３ haloalkyl, 【Chemistry 30】 , C ０～３ Alkylene CN, C ０～３ Alkylene OH or C ０～３ Alkylene-C １～３ Alkoxy or two geminal R ３ together with the atom to which they are attached, form oxo, spiro-C ３～７ Cycloalkyl, spiro-C ４～７ or two adjacent R ３ together with the atoms to which they are attached to form a fused C ３～７ Cycloalkyl, fused C ４～７ form a cycloalkenyl, a fused heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; or 【Chemical 31】 is deuterated, Each R ４ are independently １～３ Alkyl, C １～３ Haloalkyl, C ０～３ Alkylene CN, C １～３ Alkylene OH or C １～３ Alkylene-C １～３ Alkoxy or two geminal R ４ together with the atom to which they are attached, form oxo, spiro-C ３～７ forming a cycloalkyl or a spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R ５ Ha, Halo, C １～３ Haloalkyl, C １～６ Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C １～３ Alkoxy, C １～３ Thioalkyl, C ３～７ Cycloalkyl, C ５～７ cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, each of the foregoing being independently unsubstituted or substituted with 1 to 3 substituents, and each substituent being independently selected from C １～３ Haloalkyl, C ０～６ Alkylene-OH, C ０～６ Alkylene-C １～３ Alkoxy, C ３～７ Cycloalkyl, C ５～７ cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl; R Ａ１ and R Ａ２ each independently represents H, C １～３ Alkyl, C １～３ Haloalkyl or C ３～５ is cycloalkyl, and Each R Ｎ１ are independently H or C １～４ alkyl) or a pharmaceutically acceptable salt thereof.

44. R １ａ , R １ｂ and R ２ 44. The compound or salt of claim 43, wherein at least one of is H or D.

45. R １ａ , R １ｂ and R ２ 45. The compound or salt of claim 43 or 44, wherein each of is independently H or D.

46. R １ａ , R １ｂ and R ２ Two of them are H and R １ａ , R １ｂ and R ２ One of them is Halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～２ Alkylene-OH, C ０～２ Alkylene-C １～４ Alkoxy, C ０～２ Alkylene-C １～４ Haloalkoxy, C ０～２ Alkylene-CN,C ０～２ Alkylene-N(R Ｎ１ ) ２ or C having 3 to 6 total ring atoms and 1 or 2 heteroatoms selected from N, O and S １～２ 45. The compound or salt of claim 43 or 44, which is alkylene-heterocycloalkyl.

47. 【Catalog 32】 44. The compound or salt of claim 43, wherein:

48. 【Catalog 33】 48. The compound or salt of claim 47, wherein:

49. 49. The compound or salt according to any one of claims 1 to 48, wherein m is 0.

50. 49. The compound or salt according to any one of claims 1 to 48, wherein m is 1.

51. 49. The compound or salt according to any one of claims 1 to 48, wherein m is 2.

52. Each R ３ are independently CH ３ , C.H. ２ CH ３ , C.H. ２ F, CHF ２ , C.F. ３ , C.N., C.H. ２ CN, OH, CH ２ OH, CH ２ CH ２ OH, OCH ３ , C.H. ２ OCH ３ or CH ２ CH ２ OCH ３ or two geminal R ３ together with the atom to which they are attached form oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R ３ The compound or salt of any one of claims 43 to 48, wherein: together with the atom to which they are attached, form a fused cyclopropyl or a fused cyclobutyl.

53. m is 0 or m is 1, and R ３ is CH ３ , C.H. ２ F, CHF ２ , C.F. ３ , C.N., C.H. ２ C.N., C.H. ２ OH or CH ２ OCH ３ or m is 2 and two geminal R ３ The compound or salt of any one of claims 43 to 48, wherein: together with the atom to which they are attached form a spiro-oxetanyl.

54. m is 0 or m is 1, and R ３ is CH ３ 54. The compound or salt of claim 53, wherein:

55. 【Catalog 34】 The compound or salt according to any one of claims 42 to 48,

56. 【Catalog 35】 56. The compound or salt of claim 55, wherein:

57. 57. The compound or salt of any one of claims 43 to 56, wherein A is N.

58. A is CH, C-F, C-Cl, C-CN, C-CH ３ , C-CH ２ F, C-CHF ２ , C-CF ３ , C-OH, C-CH ２ OH, C-OCH ３ or C-CH ２ OCH ３ 57. The compound or salt according to any one of claims 43 to 56,

59. 59. The compound or salt according to any one of claims 46 to 58, wherein n is 0.

60. 59. The compound or salt of any one of claims 46 to 58, wherein n is 1.

61. 59. The compound or salt of any one of claims 46 to 58, wherein n is 2.

62. Each R ４ are independently CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , CH(CH ３ ) ２ , C.F. ３ , CHF ２ , C.H. ２ F, CN, CH ２ C.N., C.H. ２ OH, CH ２ CH ２ OH, CH ２ OCH ３ or CH ２ CH ２ OCH ３ or two geminal R ４ 59. The compound or salt of any one of claims 46 to 58, wherein: together with the atom to which they are attached form oxo, spiro-cyclopropyl, spiro-cyclobutyl or spiro-oxetanyl. 【Request 63】 【Chemical 36】 58. The compound or salt according to any one of claims 43 to 57,

64. 【Catalog 37】 is C ２ Alkylene, C ３ Alkylene, C ３ 64. The compound or salt of any one of claims 43 to 63, which is alkenylene or heteroalkylene having 2 to 4 total atoms and 1 or 2 heteroatoms selected from N, O and S.

65.

38. The compound or salt of any one of claims 43 to 64, wherein is unsubstituted.

66.

39. is CH ３ , =CH ２ , oxo, Cl, F, OH, OCH ３ , 【Chemistry 40】 65. The compound or salt according to any one of claims 43 to 64, substituted with any of the above combinations.

67.

41. 65. The compound or salt according to any one of claims 43 to 64,

68.

42. 68. The compound or salt of claim 67, wherein:

69.

43. where p is 0, 1, 2, or 3, and each R ７ are independently CH ３ , Cl, F, OH or OCH ３ or two geminal R ７ together with the atom to which they are attached form oxo or =CH ２ or two adjacent R ７ together with the atoms to which they are attached, 【Chemical 44】 64. The compound or salt of any one of claims 43 to 63, which forms:

70. W １ The compound or salt of any one of claims 43 to 69, wherein is N.

71. W １ 70. The compound or salt of any one of claims 43 to 69, wherein is CH.

72. W １ are C-F, C-Cl, C-CN, C-CH ３ , C-CH ２ CH ３ , C-CH ２ F, C-CHF ２ , C-CF ３ , C-CH=CH ２ , CC(OH)=CH ２ , C-CH=CH(OH), C-CCH, C-OH, C-CH ２ OH, C-OCH ３ or C-CH ２ OCH ３ 70. The compound or salt according to any one of claims 43 to 69,

73. W ２ The compound or salt according to any one of claims 43 to 72, wherein is N.

74. W ２ 73. The compound or salt of any one of claims 43 to 72, wherein is CH.

75. W ２ are C-F, C-Cl, C-CN, C-CH ３ , C-CH ２ CH ３ , C-CH ２ F, C-CHF ２ , C-CF ３ , C-CH=CH ２ , CC(OH)=CH ２ , C-CH=CH(OH), C-CCH, C-OH, C-CH ２ OH, C-OCH ３ or C-CH ２ OCH ３ 73. The compound or salt according to any one of claims 43 to 72,

76. W １ is CH, and W ２ The compound or salt of any one of claims 43 to 69, wherein is N.

77. R ５ is C １～３ 77. The compound or salt of any one of claims 43 to 76, which is haloalkyl.

78. R ５ is CF ３ or CF ２ 78. The compound or salt of claim 77, wherein:

79. R ５ は、CH ３ CH ２ CH ３ CH ２ CH ２ CH ３ 、CH(CH ３ ) ２ 、CH=CH ２ 、CH=CHCH ３ 、 【Chemistry 45】 each of the foregoing is independently unsubstituted or substituted with 1 to 3 substituents, and each substituent is independently selected from the group consisting of C １～３ Haloalkyl, C ０～６ Alkylene-OH, C ０～６ Alkylene-C １～３ Alkoxy, C ３～７ Cycloalkyl, C ５～７ 77. The compound or salt of any one of claims 43 to 76, which is cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl.

80. Each substituent is independently CH ３ , C.F. ３ , C.F. ２ H, C.F.H. ２ , OH, OCH ３ , OCF ３ , C.H. ２ OH, CH ２ OCH ３ 80. The compound or salt of claim 79, wherein R is cyclopropyl, cyclobutyl, or phenyl.

81. R ５ は、Br、Cl、F、OCH ３ 、SCH ３ ,H ３ ,H ２ CH ３ ,H ２ CH ２ CH ３ , HH(H) ３ ) ２ 、 【Chemistry 46】 77. The compound or salt according to any one of claims 43 to 76,

82. W １ is CH and W ２ is N, and R ５ is CF ３ , C.F. ２ H or CFH ２ 70. The compound or salt according to any one of claims 43 to 69,

83.

47. 【Chemistry 48】 64. The compound or salt according to any one of claims 43 to 63,

84.

49. 84. The compound of claim 83, wherein:

85. X is 【Chemistry 50】 and Y is N, C—H, C-halo, C—CN, C—C １～３ Alkyl, C-C １～３ Haloalkyl, C-C ０～３ Alkylene OH or C-C ０～３ Alkylene-C １～４ is an alkoxy, o is 0, 1, 2, 3 or 4, and Each R ６ are independently halo, CN, C １～３ Alkyl, C ２～３ Alkenyl, C １～３ Haloalkyl, C ０～３ Alkylene-OH, C ０～３ Alkylene-C １～３ Alkoxy, deuterated C ０～３ Alkylene-C １～３ Alkoxy or C １～４ Alkylene-N(R Ｎ１ ) ２ or two geminal R ６ together with the atom to which they are attached form oxo, =CH ２ , spiro-C ３～７ Cycloalkyl, spiro-C ４～７ a cycloalkenyl, a spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a spiro-heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or two adjacent R ６ together with the atoms to which they are attached to form a fused C ３～７ Cycloalkyl, fused C ４～７ a fused heterocycloalkyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or two non-adjacent R ６ are joined together to form C １～３ Alkylene bridge, C ２～３ Alkenylene bridge, C １～３ Ether bridge or C １～３ Form a thioether bridge or Y and adjacent R ６ together with the atoms to which they are attached to form a fused C ３～７ Cycloalkyl, fused C ４～７ and forming a cycloalkenyl, a fused heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, wherein any of said cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from halo, C １～３ Alkyl, C １～３ Haloalkyl, C ０～２ Alkylene OH, C ０～２ Alkylene C １～３ Alkoxy or C ０～２ alkylene CN, and Each R Ｎ１ are independently H or C １～４ 85. The compound or salt of any one of claims 43 to 84, which is alkyl.

86. X is 【Chemistry 51】 86. The compound or salt of claim 85, wherein:

87. X is 【Chemistry 52】 86. The compound or salt of claim 85, wherein:

88. X is 【Chemistry 53】 86. The compound or salt of claim 85, wherein:

89. X is 【Chemical 54】 86. The compound or salt of claim 85, wherein:

90. 89. The compound or salt of any one of claims 85 to 88, wherein Y is N.

91. 89. The compound or salt of any one of claims 85 to 88, wherein Y is CH.

92. Y is C—F, C—Cl, C—CH ３ , C-CH ２ CH ３ , C-CH ２ F, C-CHF ２ , C-CF ３ , C-OH, C-CH ２ OH, C-OCH ３ or C-CH ２ OCH ３ 89. The compound or salt according to any one of claims 85 to 88,

93. 93. The compound or salt of any one of claims 85 to 92, wherein o is 0.

94. 93. The compound or salt of any one of claims 85 to 92, wherein o is 1.

95. 93. The compound or salt of any one of claims 85 to 92, wherein o is 2.

96. Each R ６ are independently Br, Cl, F, CN, CH ３ , C.H. ２ F, CHF ２ , C.F. ３ , OH, CH ２ OH, OCH ３ , OCD ３ , C.H. ２ OCH ３ or CH ２ N (CH ３ ) ２ or two geminal R ６ together with the atom to which they are attached form oxo, =CH ２ , spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R ６ taken together with the atoms to which they are attached form a fused cyclopropyl, fused cyclobutyl, or fused cyclopentyl, and any of the above spiro and fused rings are independently unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently selected from halo, C １～３ Alkyl, C １～３ Haloalkyl, C ０～２ Alkylene OH, C ０～２ Alkylene C １～３ Alkoxy or C ０～２ 96. The compound or salt of any one of claims 85 to 92, or 94 or 95, which is alkylene CN.

97. Each substituent is independently selected from F, Cl, OH, OCH ３ , OCH ２ CH ３ or CN.

98. Two non-adjacent R ６ are joined together to form C １～３ Alkylene bridge, C ２～３ Alkenylene bridge, C １～３ Ether bridge or C １～３ 93. The compound or salt according to any one of claims 85 to 92, which forms a thioether bridge.

99. Two non-adjacent R ６ are bonded together to form -CH ２ -, -CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, -CH ２ -CH=CH- or -CH ２ OCH ２ 99. The compound or salt of claim 98, wherein the compound or salt forms:

100. X is 【Chemistry 55】 【Chemical Formula 56】 86. The compound or salt according to any one of claims 43 to 85,

101. X is 【Chemical 57】 101. The compound or salt of claim 100, wherein:

102. Z is unsubstituted phenyl or phenyl substituted with 1 to 4 substituents, and each substituent is independently halo, C ０～３ Alkylene CN, C ０～３ Alkylene OH, C ０～３ Alkylene-C １～４ Alkoxy, C ０～３ Alkylene-C １～４ thioalkoxy, or 【Chemistry 58】 and each R Ｎ１ are independently H or CH ３ The compound or salt according to any one of claims 43 to 101,

103. Each substituent is independently selected from F, Cl, CN, OCH ３ , S.C.H. ３ , C.H. ２ OH, or 【Chemical Formula 59】 103. The compound or salt of claim 102, wherein:

104. Z is 【Chemistry 60】 104. The compound or salt of claim 102 or 103, wherein:

105. Z is heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, said heteroaryl being unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ０～６ Alkylene-OH, C ０～６ Alkylene-C １～３ Alkoxy, C ０～６ Alkylene-N(R Ｎ１ ) ２ , C ０～２ Alkylene-C ３～６ Cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S ０～２ Alkylene-heterocycloalkyl or C ０～２ alkylene-phenyl, Said C １～６ Alkyl, C ２～６ Alkenyl, C ０～６ Alkylene-C １～３ Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is independently unsubstituted or substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C １～３ Alkyl, C １～３ Haloalkyl, C １～２ Alkylene OH, C １～２ Alkylene-C １～３ Alkoxy, C １～３ Deuterated alkoxy, N(R Ｎ１ ) ２ , (C=O)C １～３ Alkyl, C ３～５ cycloalkyl, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, form spiro-C ３～５ or two adjacent further substituents together with the atoms to which they are attached form a fused C ３～５ Form a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, wherein each of the further substituents of the cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently halo or C １～３ is alkyl, and Each R Ｎ１ are independently H or C １～３ 102. The compound or salt of any one of claims 43 to 101, which is alkyl.

106. 106. The compound or salt of claim 105, wherein the heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

107. 107. The compound or salt of claim 106, wherein the heteroaryl is pyrazolyl or pyridyl.

108. 108. The compound or salt of any one of claims 105 to 107, wherein the heteroaryl is substituted with one or two substituents.

109. Each substituent is independently Br, Cl, F, CN, CF ３ , CHF ２ , C.H. ２ F, CH ２ CHF ２ , C.H. ２ CH ２ F, CH (CH ２ F) ２ , CH(CH ３ ) CH ２ F, CH (CH ３ ) CHF ２ , C(=CH ２ ) CH ２ F, OH, CH ２ OH, CH ２ CH ２ OH, CH(CH ３ ) CH ２ OH, C(CH ３ ) ２ OH, C(CH ３ ) ２ CH ２ OH, CH ２ C(CH ３ ) ２ OH, NH ２ , C.H. ２ NH ２ , C.H. ２ NHCH ３ , C.H. ２ N (CH ３ ) ２ , C.H. ２ CH ２ NH ２ , C.H. ２ CH ２ NHCH ３ , C.H. ２ CH ２ N (CH ３ ) ２ , C.H. ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ and CH(CH ３ ) ２ C selected from １～６ Alkyl, CH=CH ２ , C.H. ２ CH=CH ２ and CH=CHCH ３ from ２～６ アルケニル、OCH ３ ,H ２ OCH ３ ,H ２ CH ２ OCH ３ ,H ２ CH ２ OCH ２ CH ３ ,H ２ CH ２ CH ２ OCH ３ , HH(H) ３ )OCH ３ , HH(H) ３ )CH ２ OCH ３ , CH(OCH ３ )CH ２ OCH ３ , HH(H) ３ )(OCH ３ )CH ２ OCH ３ ,C(CH ３ ) ２ OCH ３ ,C(CH ３ ) ２ CH ２ OCH ３ ,H ２ HH(H) ３ )OCH ３ ,H ２ (CH) ３ )(OCH ３ )OCH ３ ,H ２ C(CH) ３ ) ２ OCH ３ &CH ２ C(CH) ３ ) ２ OCH ３ from ０～６ アルキレン-C １～３ cycloalkyl selected from alkoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or heterocycloalkyl selected from azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, isoxazolidinyl and morpholinyl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ０～６ Alkylene-C １～３ Each of the alkoxy, cycloalkyl, and heterocycloalkyl substituents is independently unsubstituted or substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C, １～３ Alkyl, C １～３ Haloalkyl, C １～２ Alkylene OH, C １～２ Alkylene-C １～３ Alkoxy, C １～３ Deuterated alkoxy, N(R Ｎ１ ) ２ , (C=O)C １～３ Alkyl, C ３～５ cycloalkyl, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, are C ３～５ or two adjacent further substituents together with the atoms to which they are attached form a fused C ３～５ 109. The compound or salt of any one of claims 105 to 108, which forms a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S.

110. Each further substituent is independently D, Br, Cl, F, OH, CH ３ , C.F. ３ , C.F. ２ H, C.F.H. ２ , OCH ３ , OCD ３ , C.H. ２ OCH ３ , N(CH ３ ) ２ , (C=O)CH ３ , oxetanyl or azetidinyl, or two geminal further substituents together with the atoms to which they are attached form a spiro-oxetanyl or spiro-azetidinyl, each of said oxetanyl, azetidinyl, spiro-oxetanyl and spiro-azetidinyl independently being unsubstituted or selected from F, CH ３ or a combination thereof.

111. Each further substituent is independently D, Br, Cl, F, OH, CH ３ , C.F. ３ , C.F. ２ H, C.F.H. ２ , OCH ３ , OCD ３ , N(CH ３ ) ２ , (C=O)CH ３ , 【Hua 61】 or two geminal further substituents together with the atoms to which they are attached are 【Hua 62】 111. The compound or salt of claim 110, wherein

112. Each substituent of the heteroaryl of Z is independently Cl, F, CN, CH ３ , CD ３ , CH ２ CH ３ , CH(CH ３ ), ２ , CF ３ , CHF ２ , CH ２ F, CH ２ CHF ２ , CH ２ CH ２ , CH(CH ２ F) ２ , CH(CH ３ ), CH ２ , CH(CH ３ )CHF ２ , C(=CH ２ ), CH ２ F, OH, CH ２ OH, CH ２ CH ２ , CH(CH ３ ), CH ２ , C(CH ３ ), ２ , OH, C(CH ３ ), ２ CH ２ OH, CH ２ C(CH ３ ), ２ OH, OCH ３ , OCD ３ , CH ２ OCH ３ , CH ２ OCD ３ , CH ２ CH ２ OCH ３ , CHFCH ２ OCH ３ , CF ２ CH ２ OCH ３ , CH ２ CH ２ OCD ３ , CH ２ CH<​​​​​​​​​​​ ３ ,H ２ CH ２ CH ２ OOO ３ , HH(H) ３ )OCH ３ , HH(H) ３ )CH ２ OCH ３ , CH(OCH ３ )CH ２ OCH ３ , HH(H) ３ )(OCH ３ )CH ２ OCH ３ , HH(H) ２ F)(CH ３ )CH ２ OOO ３ , HH(H) ３ )CH ２ OOO ３ ,C(CH ３ ) ２ OCH ３ ,C(CH ３ ) ２ CH ２ OCH ３ ,C(CH ３ ) ２ CH ２ OOO ３ ,H ２ HH(H) ３ )OCH ３ ,H ２ (CH) ３ )(OCH ３ )OCH ３ ,H ２ HH(H) ３ )OOO ３ ,H ２ C(CH) ３ ) ２ OCH ３ ,H ２ C(CH) ３ ) ２ OOO ３ 、NH ２ ,H ２ NH ２ ,H ２ NHCH ３ ,H ２ N(CH) ３ ) ２ ,H ２ CH ２ NH ２ CH ２ CH ２ NHCH ３ CH ２ CH ２ N(CH ３ ) ２ 、 【Chemistry 63】 【Hua 64】 The compound or salt according to any one of claims 105 to 108,

113. Each substituent of said heteroaryl of Z is independently CH ３ , C(CH ３ ) ２ CH ２ OH, CH ２ CH ２ OCH ３ , C.H. ２ CH ２ OCD ３ , CH(CH ３ ) OCH ３ , 【Chemistry 65】 113. The compound or salt of claim 112, wherein:

114. Each substituent of said heteroaryl of Z is independently CH ３ , C.H. ２ CH ２ OCH ３ , 【Hua 66】 or any combination of the above.

115. Z is 【Hua 67】 【Chemistry 68】 【Chemical Formula 69】 【Chemistry 70】 【Chemical Formula 71】 【Chemical 72】 The compound or salt according to any one of claims 43 to 105,

116. Z is 【Chemical 73】 【Chemical 74】 116. The compound or salt of claim 115, wherein:

117. Z is 【Chemistry 75】 117. The compound or salt of claim 116, wherein:

118. Z is C ５～６ A bicyclic ring comprising a heteroaryl having 5 or 6 total ring atoms and 1-3 heteroatoms selected from N, O, and S fused to a cycloalkyl or heterocycloalkyl ring having 5 or 6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, said bicyclic ring being unsubstituted or substituted with 1-4 substituents, and each substituent being independently selected from halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C ０～６ Alkylene -OH or C ０～６ Alkylene-C １～３ 102. The compound or salt of any one of claims 43 to 101, which is alkoxy.

119. Z is 【Chemical 76】 119. The compound or salt of claim 118, wherein:

120. [Catalog 77] and 【Chemical 78】 and 【Chemical 79】 and R ５ is CHF ２ or CF ３ and X is 【Chemistry 80】 and o is 0 or 1; R ６ is CH ３ and Y is CH or N, and Z is pyrazolyl or pyridyl, each substituted with 1 or 2 substituents, and each substituent is independently Cl, F, CN, CH ３ , CDs ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , C.F. ３ , CHF ２ , C.H. ２ F, CH ２ CHF ２ , C.H. ２ CH ２ F, CH (CH ２ F) ２ , CH(CH ３ ) CH ２ F, CH (CH ３ ) CHF ２ , C(=CH ２ ) CH ２ F, OH, CH ２ OH, CH ２ CH ２ OH, CH(CH ３ ) CH ２ OH, C(CH ３ ) ２ OH, C(CH ３ ) ２ CH ２ OH, CH ２ C(CH ３ ) ２ OH, OCH ３ , OCD ３ , C.H. ２ OCH ３ , C.H. ２ OCD ３ , C.H. ２ CH ２ OCH ３ , CHFCH ２ OCH ３ , C.F. ２ CH ２ OCH ３ , C.H. ２ CH ２ OCD ３ , C.H. ２ CH ２ OCH ２ CH ３ , C.H. ２ CH ２ CH ２ OCH ３ ,H ２ CH ２ CH ２ OOO ３ , HH(H) ３ )OCH ３ , HH(H) ３ )CH ２ OCH ３ , CH(OCH ３ )CH ２ OCH ３ , HH(H) ３ )(OCH ３ )CH ２ OCH ３ , HH(H) ２ F)(CH ３ )CH ２ OOO ３ , HH(H) ３ )CH ２ OOO ３ ,C(CH ３ ) ２ OCH ３ ,C(CH ３ ) ２ CH ２ OCH ３ ,C(CH ３ ) ２ CH ２ OOO ３ ,H ２ HH(H) ３ )OCH ３ ,H ２ (CH) ３ )(OCH ３ )OCH ３ ,H ２ HH(H) ３ )OOO ３ ,H ２ C(CH) ３ ) ２ OCH ３ ,H ２ C(CH) ３ ) ２ OOO ３ 、NH ２ ,H ２ NH ２ ,H ２ NHCH ３ ,H ２ N(CH) ３ ) ２ CH ２ CH ２ NH ２ CH ２ CH ２ NHCH ３ CH ２ CH ２ N(CH ３ ) ２ 、 【Chemistry 81】 【Chemistry 82】 44. The compound or salt of claim 43, wherein:

121. X is 【Chemistry 83】 121. The compound or salt of claim 120, wherein:

122. [Catalog 84] 122. The compound or salt of claim 120 or 121, wherein: 【Request 123】 【Chemical 85】 123. The compound or salt of claim 122, wherein:

124. Z is 【Chemistry 86】 【Hua 87】 124. The compound or salt according to any one of claims 120 to 123,

125. Z is 【Hua 88】 125. The compound or salt of claim 124, wherein:

126. 44. The compound of claim 43, which is a compound listed in Table A or a pharmaceutically acceptable salt thereof.

127. 127. The compound of claim 126, which is a compound listed in Table B or a pharmaceutically acceptable salt thereof.

128. 44. The compound of claim 43, which is a compound listed in Table A' or a pharmaceutically acceptable salt thereof.

129. 129. The compound of claim 128, which is a compound listed in Table B' or a pharmaceutically acceptable salt thereof.

130. 130. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 129 and a pharmaceutically acceptable excipient.

131. 130. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or salt of any one of claims 1 to 129 or a composition of claim 130.

132. 132. The method of claim 131, wherein one or more cancer cells express a KRAS G12C mutant protein.

133. 133. The method of claim 131 or 132, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, solid tumor, or any combination thereof.

134. 134. The method of any one of claims 131 to 133, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer or a solid tumor.

135. 135. The method of any one of claims 131-134, wherein the subject has a cancer determined to have one or more cells that express the KRAS G12C mutant protein prior to administration of the compound, salt or pharmaceutical composition.

136. 135. The method of any one of claims 131 to 134, further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an ATR inhibitor, an Aurora kinase A inhibitor, an AKT inhibitor, an arginase inhibitor, a CDK2 inhibitor, a CDK4 / 6 inhibitor, an ErbB family inhibitor, an ERK inhibitor, a FAK inhibitor, an FGFR inhibitor, a glutaminase inhibitor, an IGF-1R inhibitor, a KIF18A inhibitor, a MAT2A inhibitor, an MCL-1 inhibitor, a MEK inhibitor, an mTOR inhibitor, a PARP inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PI3K inhibitor, a PRMT5 inhibitor, a Raf kinase inhibitor, a SHP2 inhibitor, an SOS1 inhibitor, a Src kinase inhibitor, or one or more chemotherapeutic agents.

137. A compound or salt according to any one of claims 1 to 129 or a composition according to claim 130 for use as a medicament.

138. A compound or salt according to any one of claims 1 to 129 or a composition according to claim 130 for use in the treatment of cancer.

139. 131. A compound or salt according to any one of claims 1 to 129 or a pharmaceutical composition according to claim 130 for use in the treatment of cancer, wherein one or more cancer cells express a KRAS G12C mutant protein.

140. 140. The compound or salt of claim 138 or 139, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, or a solid tumor.

141. Use of a compound or salt according to any one of claims 1 to 129 or a pharmaceutical composition according to claim 130 for the manufacture of a medicament for treating cancer.

142. 131. Use of a compound or salt according to any one of claims 1 to 129 or a pharmaceutical composition according to claim 130 in the preparation of a medicament for treating cancer, wherein one or more cancer cells express a KRAS G12C mutant protein.

143. 143. The use of claim 141 or 142, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, solid tumors, or any combination thereof.

144. (a) Formula (Int-AA): 【Chemistry 89】 , formula (Int-AB): 【Chemistry 90】 , formula (Int-AC): 【Chemistry 91】 , formula (Int-AD): 【Chemistry 92】 , formula (Int-AE): 【Chemistry 93】 , formula (Int-AF): 【Chemistry 94】 , formula (Int-AG): 【Chemistry 95】 , formula (Int-AH): 【Chemistry 96】 , formula (Int-AI): 【Chemistry 97】 Or formula (Int-AJ): 【Chemistry 98】 or a pharmaceutically acceptable salt of any of the above, or (b) Formula (Int-B): 【Hua99】 a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the foregoing; or (c) Formula (Int-C): 【Chemistry 100】 a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the foregoing; or (d) Formula (Int-D): 【Chemistry 101】 a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the foregoing; or (e) Formula (Int-E): 【Chemistry 102】 a compound of the formula (I), a nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the above. an intermediate selected from the group consisting of: A is, 【Chemistry 103】 and B is C １～３ Alkylene -CH=CH ２ or C １～３ alkylene OH, Q is F, Cl, Br, I or organoborane; m is 0, 1, 2, 3 or 4; o is 0, 1, 2, 3 or 4; halo is F, Cl, Br or I; 【Chemistry 104】 is C ２～６ Alkylene, C ３～６ alkenylene, heteroalkylene having 2 to 6 total atoms and 1 to 3 heteroatoms selected from N, O and S, or heteroalkenylene having 3 to 6 total atoms and 1 or 2 heteroatoms selected from N, O and S; 【Chemistry 105】 is unsubstituted or substituted with 1 to 4 substituents, and each substituent is independently selected from C １～３ Alkyl, C １～３ Haloalkyl, C ２～３ Alkenyl, Halo, CN, C ０～３ Alkylene OH, C ０～３ Alkylene-C １～３ Alkoxy, C ３～５ Cycloalkyl, C ４～５ cycloalkenyl, heterocycloalkyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl; or two geminal substituents, together with the atoms to which they are attached, can be oxo, ═CH ２ , spiro-C ３～５ Cycloalkyl, spiro-C ４～５ or two adjacent substituents, together with the atoms to which they are attached, form a fused C ３～５ Cycloalkyl, fused C ４～５ forming a cycloalkenyl, a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R ＺＡ and R ＺＢ each independently represents halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ０～６ Alkylene-OH, C ０～６ Alkylene-C １～３ Alkoxy, C ０～６ Alkylene-N(R Ｎ１ ) ２ , C ０～２ Alkylene-C ３～６ Cycloalkyl, C having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O and S ０～２ Alkylene-heterocycloalkyl or C ０～２ alkylene-phenyl, Said C １～６ Alkyl, C ２～６ Alkenyl, C ０～６ Alkylene-C １～３ Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is independently unsubstituted or substituted with 1 to 3 additional substituents, and each additional substituent is independently selected from D, halo, C １～３ Alkyl, C １～３ Haloalkyl, C １～２ Alkylene OH, C １～２ Alkylene-C １～３ Alkoxy, C １～３ Deuterated alkoxy, N(R Ｎ１ ) ２ , (C=O)C １～３ Alkyl, C ３～５ cycloalkyl, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or two geminal further substituents, together with the atoms to which they are attached, form spiro-C ３～５ or two adjacent further substituents together with the atoms to which they are attached form a fused C ３～５ Form a cycloalkyl or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, wherein each of the further substituents of the cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently halo or C １～３ is alkyl, and Each R Ｎ１ are independently H or C １～３ is alkyl, Each R ３ are independently １～３ Alkyl, C １～３ haloalkyl, 【Chemistry 106】 , C ０～３ Alkylene CN, C ０～３ Alkylene OH or C ０～３ Alkylene-C １～３ Alkoxy or two geminal R ３ together with the atom to which they are attached, form oxo, spiro-C ３～７ Cycloalkyl, spiro-C ４～７ or two adjacent R ３ together with the atoms to which they are attached to form a fused C ３～７ Cycloalkyl, fused C ４～７ forming a cycloalkenyl, a fused heterocycloalkyl having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; and R ５ Ha, Halo, C １～３ Haloalkyl, C １～６ Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C １～３ Alkoxy, C １～３ Thioalkyl, C ３～７ Cycloalkyl, C ５～７ cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, each of the foregoing being independently unsubstituted or substituted with 1 to 3 substituents, and each substituent being independently selected from C １～３ Haloalkyl, C ０～６ Alkylene-OH, C ０～６ Alkylene-C １～３ Alkoxy, C ３～７ Cycloalkyl, C ５～７ cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, heterocycloalkenyl having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or phenyl; and Each R ６ are independently Br, Cl, F, CN, CH ３ , C.H. ２ F, CHF ２ , C.F. ３ , OH, CH ２ OH, OCH ３ , OCD ３ , C.H. ２ OCH ３ or CH ２ N (CH ３ ) ２ or two geminal R ６ together with the atom to which they are attached form oxo, =CH ２ , spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R ６ taken together with the atoms to which they are attached form a fused cyclopropyl, fused cyclobutyl, or fused cyclopentyl, and any of said spiro and fused rings are unsubstituted or substituted with 1 or 2 substituents, and each substituent is independently selected from halo, C １～３ Alkyl, C １～３ Haloalkyl, C ０～２ Alkylene OH, C ０～２ Alkylene C １～３ Alkoxy or C ０～２ The intermediate is alkylene CN.

145. B is CH ２ CH=CH ２ or CH ２ CH ２ OH, m is 0 or 1; o is 0 or 1; Halo is Cl; 【Chemistry 107】 【Chemistry 108】 and R ３ is CH ３ and R ５ is CHF ２ or CF ３ and R ６ is CH ３ and R ＺＡ is CH ３ and R ＺＢ は、CH ３ ,C(CH ３ ) ２ CH ２ OH、CHH ２ CH ２ OCH ３ ,H ２ CH ２ OOO ３ , HH(H) ３ )OCH ３ 、 【Chemistry 109】 145. The intermediate of claim 144, wherein:

146. A compound listed in Table INT-A, Table INT-A', Table INT-B, Table INT-C, Table INT-D, Table INT-E, Table INT-F, Table INT, a nitrogen-protected analogue thereof, or a pharmaceutically acceptable salt of any of the above.

147. 130. A process for preparing a compound or salt according to any one of claims 43 to 129, said process comprising converting a compound or salt according to any one of claims 144 to 146 to a compound or salt according to any one of claims 43 to 129.

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