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 containing said 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 present disclosure provides compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein the substituents are as described: TIFF2025535045001277.tif45170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 413,397, filed October 5, 2022, the entirety of which is incorporated herein by reference 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 GTP-bound, active state and dysregulated cell proliferation. See Simanshu et al., Cell 2017, 170, 17-33.

[0004] Attempts to develop inhibitors of mutant KRAS proteins have historically been hampered by the picomolar affinity with which KRAS binds GDP and GTP, and the lack of a druggable pocket on the surface of the protein. See Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-851. The G12C mutant of KRAS ("KRAS") G12C Covalent inhibitors of GDP-KRAS have been identified. G12C KRAS inhibitors can bind to a previously unrecognized allosteric pocket on the cytoskeleton and prevent its subsequent activation. See O'Bryan, JP Pharmacol. Res. 2019, 139, 503-511 and Ostrem et al., Nature 2013, 503, 548-551. This discovery led to significant new efforts in KRAS inhibitor research, leading to the entry of KRAS inhibitors into human clinical trials in recent years. 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] In one aspect, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof (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, CC 1-3 Alkyl, CC 1-3 Haloalkyl, CC 0-3 Alkylene OH or CC 0-3 Alkylene-C 1-4 is 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 optionally substituted with 1 to 3 substituents, each substituent independently being selected from halo, C 1-3 Haloalkyl, C 0-3 Alkylene OH or C 0-3 Alkylene C 1-4 is 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 optionally substituted with 1 to 3 substituents, each of which 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 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 ring, heteroaryl ring, and bicyclic ring is optionally substituted with 1 to 4 substituents, each substituent 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 with 3 to 6 total ring atoms 0-2 Alkylene-cycloalkyl, C having 3-6 total ring atoms and 1-3 heteroatoms selected from N, O and S 0-2 Alkylene-heterocycloalkyl, or C 0-2 alkylene-phenyl; where 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 optionally substituted with 1 to 3 additional substituents, each of which 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 1-3alkyl, cycloalkyl having 3 to 5 total ring atoms, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, spiro-cycloalkyl having 3 to 5 total ring atoms, or spiro-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 cycloalkyl having 3 to 5 total ring atoms 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 aforementioned further substituents of cycloalkyl and heterocycloalkyl is optionally substituted with 1 or 2 substituents, each of which is independently halo or C 1-3 is alkyl; 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 3 to 6 total ring atoms selected from 2, N, O and S and 1 or 2 heteroatoms 1-2 alkylene-heterocycloalkyl, or 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, C 0-3 Alkylene-C 1-3 alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-cycloalkenyl having 4 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, 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 are, together with the atoms to which they are attached, a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl ring 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, 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 5 is C 1-3 Haloalkyl, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 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 being independently optionally substituted with 1 to 3 substituents, each of which is independently selected from C 1-3 Haloalkyl, C 0-6 Alkylene-OH, C 0-6 Alkylene-C 1-3 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 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 cycloalkyl having 3 to 5 total ring atoms; and Each R N1 are independently H or C 1-4 alkyl) to provide.

[0007] In some cases, R 1a , R 1b , and R 2 At least one of R is H or D. In some cases, 1a , R 1b , and R 2 Each of R is H or D. In some cases, 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, C0-2 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 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. [ka] teeth, [ka] is.

[0008] In some cases, m is 0. In some cases, m is 1. In some cases, m is 2. In some cases, each R 3 are independently CH3, CH2 C H3, CF3, CHF2, CH2F, [ka] , CN, CHCN, OH, CHOH, CHCHOH, OCH, CHOCH, CHCHOCH, oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R 3together with the atom to which it is attached form a fused cyclopropyl ring or a fused cyclobutyl ring. In some cases, m is 0; or m is 1 and R 3 is CH3, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl. [ka] teeth, [ka] In some cases, [ka] teeth, [ka] is.

[0009] 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, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl. [ka] teeth, [ka] In some cases, [ka] teeth, [ka] is.

[0010] 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—CH, C—CHCH, C—CHF, C—CHF, C—CF, C—CH═CH, CC(OH)═CH, C—CH═CH(OH), C—CCH, C—OH, C—CHOH, C—OCH, or C—CHOCH. 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—CH, C—CHCH, C—CHF, C—CHF, C—CF, C—CH═CH, CC(OH)═CH, C—CH═CH(OH), C—CCH, C—OH, C—CHOH, C—OCH, or C—CHOCH. 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, CF2H, CFH2. In some cases, R 5 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CH=CH2, CH=CHCH3, [ka] wherein each of the foregoing is optionally substituted with 1 to 3 substituents, each substituent independently being selected from the group consisting of: C 1-3 Haloalkyl C 0-6 Alkylene-OH, C 0-6 Alkylene-C 1-3alkoxy, 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 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or phenyl. In some cases, each substituent is independently CH3, CF3, CF2H, CFH2, OH, OCH3, OCF3, CH2OH, CHOCH3, cyclopropyl, cyclobutyl, or phenyl. In some cases, R 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] teeth, [ka] is.

[0011] 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; each R 6 are independently halo, CN, C 1-3 Alkyl, C 2-3 Alkenyl, 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, oxo, =CH2, spiro-cycloalkyl having 3 to 7 total atoms, spiro-cycloalkenyl having 4 to 7 total atoms, spiro-heterocycloalkyl having 4 to 7 total ring atoms and one or two heteroatoms selected from N, O and S, or spiro-heterocycloalkenyl having 4 to 7 total ring atoms and one or two 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, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl ring 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 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, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl ring having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; wherein any of the foregoing cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionally substituted with 1 to 4 substituents, each of which is independently selected from halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C0-2 Alkylene OH, C 0-2 Alkylene C 1-3 Alkoxy or C 0-2 alkyleneCN; 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, 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 6 are independently Br, Cl, F, CN, CH3, CH2F, CHF2, CF3, OH, CH2OH, OCH3, OCD3, CHOCH3, CH2N(CH3)2, oxo, =CH2, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R 6 taken together with the atom to which they are attached form a fused cyclopropyl, fused cyclobutyl, or fused cyclopentyl, wherein any of said spiro and fused rings are optionally substituted with one or two substituents, each of which 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 on the spiro and fused rings is independently F, Cl, OH, OCH, OCHCH, or CN. In some cases, two non-adjacent R 6 are bonded to each other, C 1-3 Alkylene bridge, C 2-3 Alkenylene bridge, C 1-3 Ether bridge, or C 1-3 Forming 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] In some cases, X is [ka] is.

[0012] In some instances, Z is phenyl optionally substituted with 1 to 4 substituents, each substituent independently being 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 on the phenyl is independently F, Cl, CN, OCH, SCH, CHOH, or [ka] In some cases, Z is [ka] is.

[0013] 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, where the heteroaryl is optionally substituted with 1 to 4 substituents, each substituent 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 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 or C 0-2 alkylene-phenyl; 1-6 Alkyl, C 2-6 Alkenyl, C 0-6 Alkylene-C 1-3 Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is optionally substituted with 1 to 3 additional substituents, each of which 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 1-3alkyl, cycloalkyl having 3 to 5 total ring atoms, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, spiro-cycloalkyl having 3 to 5 total ring atoms, or spiro-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 cycloalkyl having 3 to 5 total ring atoms 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 aforesaid cycloalkyl and heterocycloalkyl is halo or C 1-3 optionally substituted with alkyl; each R N1 are independently H or C 1-3 In some cases, Z is optionally substituted with pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl. In some cases, Z is optionally substituted with pyrazolyl or pyridyl.

[0014] 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, 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, CHCHCH. 1-6 alkyl, and C selected from CH(CH3)2, CH=CH2, CH2CH=CH2, and CH=CHCH32-6 Alkenyl, OCH3, CH2OCH3, CH2CH2OCH3, CH2CH2OCH2CH3, CH2CH2CH2OCH3, CH(CH3)OCH3, CH(CH3)CH2OCH3, CH(OCH3)CH2OCH3, CH(CH3)(OC C selected from H3)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 cycloalkyl selected from alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, or 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, each of which 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 1-3alkyl, cycloalkyl having 3 to 5 total ring atoms, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, spiro-cycloalkyl having 3 to 5 total ring atoms, spiro-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 cycloalkyl having 3 to 5 total ring atoms 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, spiro-oxetanyl, or spiro-azetidinyl; each of the oxetanyl, azetidinyl, spiro-oxetanyl, and spiro-azetidinyl may be 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, CHOCH, OCD, N(CH), (C=O)CH, [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)2CH 2OCD3, 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, each heteroaryl substituent of Z is independently CH3, CH(CH3)2, C(CH3)2OH, CH2OCD3, C(CH3)2CH2OH, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] is.

[0015] In some cases, Z is [ka] [ka] [ka] [ka] [ka] [ka] [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] is.

[0016] In some instances, Z is a bicyclic ring comprising a heteroaryl ring having 5 or 6 total ring atoms and 1-3 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 the bicyclic ring is optionally substituted with 1-4 substituents, each substituent 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.

[0017] In some cases, [ka] teeth [ka] and; [ka] teeth [ka] and; [ka] teeth [ka] In some cases, [ka] teeth [ka] In some cases, X is [ka] In some cases, Z is [ka] [ka] [ka] is.

[0018] In some cases, the compound of formula (I) has formula (I'): [ka] Formula (IA): [ka] (In the formula, R aは ,H,Halo,CN,C 1-3 Alkyl, C 1-3 Haloalkyl, C 0-3 Alkylene OH or C 0-3 Alkylene-C 1-4 alkoxy); Formula (IB): [ka] ;Formula (IC): [ka] (In the formula, R Y H, halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 0-3 Alkylene OH or C 0-3 Alkylene-C 1-4 alkoxy); Formula (ID): [ka] ;Expression (IE): [ka] or the formula (IF): [ka] 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 E or a pharmaceutically acceptable salt thereof.

[0019] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of formula (I), a compound of formula (I'), a compound of formula (IA), a compound of formula (IB), a compound of formula (IC), a compound of formula (ID), a compound of formula (IE), a compound of formula (IF), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, a compound listed in Table D, or a compound listed in Table E) or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient.

[0020] A further aspect of the present disclosure provides a compound of the present disclosure (e.g., a compound of formula (I), a compound of formula (I'), a compound of formula (IA), a compound of formula (IB), a compound of formula (IC), a compound of formula (ID), a compound of formula (IE), a compound of formula (IF), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, a compound listed in Table D, or a compound listed in Table E), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of the present disclosure, for use as a medicament.

[0021] Yet another aspect of the present disclosure provides a compound of the present disclosure (e.g., a compound of formula (I), a compound of formula (I'), a compound of formula (IA), a compound of formula (IB), a compound of formula (IC), a compound of formula (ID), a compound of formula (IE), a compound of formula (IF), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, a compound listed in Table D, or a compound listed in Table E), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of the present disclosure, for use in treating cancer. In some cases, the cancer is caused by a KRAS G12C 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, or a solid tumor.

[0022] Still other aspects of the present disclosure provide for the use of a compound of the present disclosure (e.g., a compound of formula (I), a compound of formula (I'), a compound of formula (IA), a compound of formula (IB), a compound of formula (IC), a compound of formula (ID), a compound of formula (IE), a compound of formula (IF), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, a compound listed in Table D, or a compound listed in Table E), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of the present disclosure, in the preparation of a medicament for the treatment of cancer. In some cases, the cancer is a KRAS G12C 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, or a solid tumor.

[0023] Another aspect of the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of formula (I), a compound of formula (I'), a compound of formula (IA), a compound of formula (IB), a compound of formula (IC), a compound of formula (ID), a compound of formula (IE), a compound of formula (IF), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, a compound listed in Table D, or a compound listed in Table E), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of the present disclosure. In some cases, the cancer is caused by a KRAS G12C The subject is characterized by one or more cells expressing a 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, or a solid tumor. In some cases, the subject is diagnosed with KRAS prior to administration of the compound, salt, or pharmaceutical composition. G12CThe patient has a cancer determined to have one or more cells expressing a mutant protein. In some cases, the method further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound. 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, a SOC1 inhibitor, a Src kinase inhibitor, or one or more chemotherapeutic agents.

[0024] 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

[0025] 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.

[0026] Compounds of the Disclosure As used herein, compounds of formula (I): [ka] and pharmaceutically acceptable salts thereof (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, CC 1-3 Alkyl, CC1-3 Haloalkyl, CC 0-3 Alkylene OH or CC 0-3 Alkylene-C 1-4 is 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 optionally 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 optionally substituted with one or more substituents; Z is phenyl, heteroaryl containing 5 or 6 total ring atoms and 1-3 heteroatoms selected from N, O, and S, or a bicyclic ring containing a heteroaryl ring having 5 or 6 total ring atoms and 1-3 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 ring, heteroaryl ring, and bicyclic ring is optionally 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, C0-2 Alkylene-CN, C 0-2 Alkylene-N(R N1 ) C having 3 to 6 total ring atoms selected from 2, N, O and S and 1 or 2 heteroatoms 1-2 alkylene-heterocycloalkyl, or 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, C 0-3 Alkylene-C 1-3 alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-cycloalkenyl having 4 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, 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 are, together with the atoms to which they are attached, a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl ring 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, C1-3 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 5 is C 1-3 Haloalkyl, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 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 one or more substituents; R A1 and R A2 each independently represents H, C 1-3 Alkyl, C 1-3 haloalkyl, or cycloalkyl having 3 to 5 total ring atoms; and Each R N1 are independently H or C 1-4 alkyl) is provided.

[0027] 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 independently H or D. 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 independently H or D. 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 are each independently H or D. In some cases, R 1a , R 1b , and R 2 are each independently H. In some cases, R 1a , R 1b , and R 2 are each independently D. In some cases, 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 ) C having 2, or 3-6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S 1-2In some cases, R is an alkylene-heterocycloalkyl. 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 are each 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 or Cl, and R 1b and R 2 are each 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 2is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2F, CHF2, or CF3. In some cases, R 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 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 2is CHOH, OCH, CHOCH, OCF, CHOCF, CN, CHCN, NH, N(CH), CHNH, or CHN(CH). In some cases, R 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 1-2 Alkylene-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, isoxythiodinyl, 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 2is 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 R 2 together with the carbon atoms to which they are attached, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] is.

[0028] In some cases, m is 0; [ka] teeth, [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] teeth, [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 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, at least one R 3 is CH3. In some cases, m is 1 or 2, and each R 3is 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 cycloalkyl having 3 to 5 total ring atoms. 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] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some embodiments, at least one R 3 teeth, [ka] In some embodiments, 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, 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 3is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl. In some cases, m is 1 and R 3 is spiro-cyclopropyl or spiro-oxetanyl. In some cases, at least one R 3 is a spiro-cycloalkenyl having 4 to 7 total ring atoms or a spiro-heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, two adjacent R 3 are taken together with the atoms to which they are attached to form a fused cycloalkyl ring having 3 to 7 total ring atoms or a fused heterocycloalkyl ring having 3 to 7 total atoms and 1 or 2 heteroatoms selected from N, O, and S. 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, two adjacent R 3 are taken together with the atoms to which they are attached to form a fused cycloalkenyl ring having 4 to 7 total ring atoms, or a fused heterocycloalkenyl ring having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, each R 3 are independently CH3, CH2CH3, CF3, CHF2, CH2F, CN, CH2CN, OH, CH2OH, CH2CH2OH, OCH3, CHOCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, fused cyclopropyl, or fused cyclobutyl. In some cases, each R 3are independently CH3, CH2CH3, CF3, CHF2, CH2F, [ka] , CN, CHCN, OH, CHOH, CHCHOH, OCH, CHOCH, CHCHOCH, 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 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 H, CF, CHF, CHF, CN, CHCN, CHOH, CHOCH, or spiro-oxetanyl. [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] is.

[0029] 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 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 4is CH3. In some cases, one R 4 is 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, at least one R 4 is oxo. In some cases, at least one R 4 is a spiro-cycloalkyl having 3 to 7 total ring atoms. In some cases, at least one R 4 is spiro-cyclopropyl, spiro-cyclobutyl, or spiro-cyclopentyl. In some cases, n is 1 and R 4 is spiro-cyclopropyl or spiro-cyclobutyl. In some cases, at least one 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, at least one R 4 is spiro-oxetanyl or spiro-tetrahydrofuranyl; in some cases, n is 1 and R 4 is 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, oxo, spiro-cyclopropyl, spiro-cyclobutyl, or spiro-cyclopentyl. 4 is independently CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, 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, spiro-cyclopropyl, or spiro-oxetanyl. [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] is.

[0030] 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 1is C—Br, C—Cl, or CF. In some cases, W 1 is CF, C—Cl, or C—CN. In some cases, R 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 is CC 2-3 Alkenyl or CC 2-3 and alkynyl, each of the alkenyl and alkynyl is optionally 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, each of which 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 is an alkoxy group. 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 1is 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—CH, C—CHCH, C—OH, C—CHOH, C—OCH, or C—CHOCH. In some cases, W 1 is CF, C—Cl, C—CN, C—CH, C—CHCH, C—CHF, C—CHF, C—CF, C—CH═CH, CC(OH)═CH, C—CH═CH(OH), C—CCH, C—OH, C—CHOH, C—OCH, or C—CHOCH. In some cases, W 2 is N. In some cases, W 2 is CH. In some cases, W 2 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 C-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 2-3and alkynyl, each of the alkenyl and alkynyl is optionally 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, each of which 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 is an alkoxy group. 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 is an alkoxy group. 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 2 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 2 is CH, CF, C—Cl, C—CN, C—CH, C—CHCH, C—OH, C—CHOH, C—OCH, or C—CHOCH. In some cases, W 2 is CF, C—Cl, C—CN, C—CH, C—CHCH, C—CHF, C—CHF, C—CF, C—CH═CH, CC(OH)═CH, C—CH═CH(OH), C—CCH, C—OH, C—CHOH, C—OCH, or C—CHOCH. In some cases, W 1 and W 2Each 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] teeth [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] is.

[0031] In some cases, R 5 is C 1-3 In some cases, R 5 is CF3, CF2H, CFH2, or CF2CH3. In some cases, R 5is CF3, CF2H, or CFH2. 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 a halo. In some cases, R 5 is Br, Cl, or F. 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 and alkynyl, where each of the alkyl, alkenyl, and alkynyl is optionally substituted with 1, 2, or 3 substituents. 1-6 Alkyl is CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, each of the foregoing being optionally substituted with one or more substituents. In some cases, C 2-4 Alkenyl is CH=CH2 or CH=CHCH3, each of the above optionally substituted with one or more substituents. In some cases, C 2-4 Alkynyl is [ka] and each of the above is optionally substituted with one or more substituents. In some cases, C 1-6 Alkyl, C 2-4 Alkenyl, and C 2-4 Alkynyl is unsubstituted. In some cases, R 5 is CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2. In some cases, C 1-6Alkyl, 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, 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, or phenyl. In some cases, each of the one, two, or three substituents is independently selected from CH3, CF3, CF2H, CFH2, OH, OCH3, OCF3, CH2OH, CHOCH3, cyclopropyl, cyclobutyl, or phenyl. In some cases, R 5 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, [ka] In some cases, R 5 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 the foregoing optionally substituted with 1, 2, or 3 substituents, each of which is independently selected from halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 0-6 Alkylene (OH) or C 0-6 Alkylene-C 1-3In some cases, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1 to 3 substituents. In some cases, the cycloalkenyl is cyclopentenyl or cyclohexenyl, each of which is optionally substituted with 1 to 3 substituents. In some cases, the heterocycloalkyl 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 optionally substituted with 1 to 3 substituents. In some cases, heterocycloalkenyl is dihydropyrrolyl, dihydrofuranyl, dihydrothiopheneyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydropyranyl, each of the foregoing optionally substituted with 1 to 3 substituents. 5 CH3, CF3, CF2H, CFH2, CH2CH3, CH2CH2CH3, CH(CH3)2, [ka] In some cases, R 5 is cyclopropyl, cyclobutyl, cyclopentenyl, oxetanyl, or tetrahydrofuranyl. In some cases, R 5 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, [ka] In some cases, R 5 is CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2. In some cases, R 5is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CH=CH2, CH=CHCH3, [ka] wherein each of the foregoing is optionally substituted with 1 to 3 substituents, each substituent independently being selected from the group consisting of: C 1-3 Haloalkyl C 0-6 Alkylene-OH, C 0-6 Alkylene-C 1-3 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 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or phenyl. In some cases, R 5 Each of the above substituents 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] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] is.

[0032] 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; 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 d C 0-3 Alkylene-C 1-3 Alkoxy, C 1-4 Alkylene-N(R N1)2, oxo, =CH2, spiro-cycloalkyl having 3 to 7 total atoms, spiro-cycloalkenyl having 4 to 7 total atoms, spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or 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 form a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl ring 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 the adjacent R 6 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl ring having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; wherein any of the foregoing cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionally substituted by one or more substituents, 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, 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 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 1-4 In 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 or =CH2. In some cases, at least one R 6 is oxo. In some cases, o is 1 or 2, and each R6 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-NR 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, at least one R 6 is CHN(CH), CHNH(CH), or CHNH. In some cases, at least one R 6 is OH, CHOH, OCH, OCD, CHOCH, or CHN(CH). In some cases, o is 1 and R 6 is OH, CHOH, OCH, or CHOCH. In some cases, at least one R 6 is a spiro-cycloalkyl having 3 to 7 total atoms, a spiro-cycloalkenyl having 4 to 7 total atoms, 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, any of the foregoing optionally substituted with one or more substituents. 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, where the cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents. In some cases, at least one R 6 is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl, any of the foregoing optionally substituted with one or more substituents. In some cases, o is 1 and R 6 is a spiro-cyclopropyl, where the cyclopropyl is optionally substituted with one or more substituents. 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, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring 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 Y and an adjacent R 6 are taken together with the atoms to which they are attached to form a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl ring 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 optionally substituted with one or more substituents. 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, where the fused cycloalkyl ring is optionally substituted with one or more substituents. In some cases, Y and an adjacent R 6together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms, wherein the fused cycloalkyl ring is optionally substituted with one or more substituents. In some cases, any of the above fused cycloalkyl rings is a fused cyclopropyl, fused cyclobutyl, or fused cyclopentyl, any of the above being optionally 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 one or two substituents. In some cases, 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 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 bonded to each other, C 1-3 Alkylene bridge, C 2-3 Alkenylene bridge, C 1-3 Ether bridge, or C 1-3 Forming a thioether bridge. In some cases, two non-adjacent R 6are bonded to each other, C 1-3 Alkylene bridge, C 2-3 Alkenylene bridge, or C 1-3 Forming an ether bridge. In some cases, two non-adjacent R 6 are bonded to each other, C 1-3 Alkylene bridge or C 2-3 Forms an alkenylene bridge. In some cases, two non-adjacent R 6 are bonded to each other, C 1-3 Ether bridge or C 1-3 Forming a thioether bridge. In some cases, two non-adjacent R 6 are bonded to each other, C 1-2 Alkylene bridge or C 1-3 Forming an ether bridge. In some cases, two non-adjacent R 6 are linked together by a C1 alkylene bridge (e.g., [ka] ). In some cases, two non-adjacent R 6 are linked together by a C2 alkylene bridge (e.g., [ka] ). In some cases, two non-adjacent R 6 are linked together by a C3 alkylene bridge (e.g., [ka] ). In some cases, two non-adjacent R 6 are linked together by a C2 alkenylene bridge (e.g., [ka] ). In some cases, two non-adjacent R 6 are linked together by a C3 alkenylene bridge (e.g., [ka] ). In some cases, two non-adjacent R 6are bonded to each other to form C 1-3 Ether bridges (e.g., [ka] ). In some cases, two non-adjacent R 6 are bonded to each other to form C 1-3 Thioether crosslinks (e.g., [ka] ). In some cases, two non-adjacent R 6 are linked together to form -CH-, -CHCH-, -CHCHCH-, -CH-CH=CH-, or -CHOCH. In some cases, two non-adjacent R 6 are combined with each other [ka] In some cases, X forms [ka] [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] 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.

[0033] In some cases, Z is phenyl optionally substituted with 1 to 4 substituents. In some cases, 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] In some cases, each R N1 is independently H or CH. In some cases, each R N1 is independently H. In some cases, each of the 1 to 4 substituents is independently F, Cl, CN, OCH3, SCH3, CH2OH, or [ka] In some cases, Z is [ka] In some cases, Z is [ka] is.

[0034] In some cases, Z is heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, where the heteroaryl is optionally 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, each of the foregoing optionally substituted with one or more substituents. In some cases, heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, or triazolyl, each of which is optionally substituted with one or more substituents. In some cases, heteroaryl is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, or triazolyl, each of which is optionally substituted with one or more substituents. In some cases, heteroaryl is pyrazolyl, imidazolyl, thiazolyl, or isothiazolyl, each of which is optionally substituted with one or more substituents. In some cases, heteroaryl is pyrazolyl, and the pyrazolyl is optionally substituted with one or more substituents. In some cases, heteroaryl is imidazolyl, and the imidazolyl is optionally substituted with one or more substituents. In some cases, the heteroaryl is thiazolyl, which is optionally substituted with one or more substituents. In some cases, the heteroaryl is isothiazolyl, which is optionally substituted with one or more substituents. In some cases, the heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of the above optionally substituted with one or more substituents. In some cases, the heteroaryl is pyridyl, which is optionally substituted with one or more substituents.In some cases, heteroaryl is pyrazolyl, thiazolyl, pyridyl, or pyridazinyl. In some cases, heteroaryl is pyrazolyl or pyridyl, each of the foregoing optionally substituted with one or more substituents.

[0035] 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 selected from halo, CN, C, C, C-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, where each R N1 are independently H or C 1-3 Alkyl, C with 3-6 total ring atoms 0-2 Alkylene-cycloalkyl, C having 3-6 total ring atoms and 1-3 heteroatoms selected from N, O, and S 0-2 Alkylene-heterocycloalkyl, or C 0-2 alkylene-phenyl, where alkyl, alkenyl, C 0-6 Alkylene-C 1-3 The alkoxy, cycloalkyl, cycloalkyl, cycloalkyl, and phenyl substituents are each independently substituted with one or more additional substituents. In some cases, alkyl, alkenyl, C 0-6 Alkylene-C 1-3The alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents are each independently substituted with 1 to 3 additional substituents. In some cases, alkyl, alkenyl, C 0-6 Alkylene-C 1-3 The alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents are each independently substituted with one or two additional substituents. In some cases, alkyl, alkenyl, C 0-6 Alkylene-C 1-3 The alkoxy, cycloalkyl, heterocycloalkyl and phenyl substituents are each independently substituted with one further substituent.

[0036] In some cases, 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, cycloalkyl having 3 to 5 total ring atoms, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, spiro-cycloalkyl having 3 to 5 total ring atoms or spiro-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 cycloalkyl having 3 to 5 total ring atoms 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 cycloalkyl and heterocycloalkyl groups independently optionally substituted with 1 or 2 substituents, each substituent independently selected from halo or C 1-3 alkyl, and each R N1 are independently H or C 1-3In some cases, each additional substituent is independently D, halo, OH, CH, OCH, or OCD. In some cases, each additional substituent is independently D, Br, Cl, F, OH, CH, OCH, or OCD. 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, spiro-oxetanyl, or spiro-azetidinyl; each of the foregoing oxetanyl, azetidinyl, spiro-oxetanyl, and spiro-azetidinyl is optionally substituted with F, CH, or a combination thereof. In some cases, each additional substituent is independently D, Br, Cl, F, OH, CH, CH(CH), CF, CFH, CFH, OCH, OCD, CHOCH, N(CH), (C=O)CH, [ka] In some cases, each additional substituent is independently D, CH3, OCH3, OCD3, N(CH3)2, [ka] is.

[0037] In some cases, heteroaryl is substituted with CN. In some cases, heteroaryl is substituted with halo. In some cases, heteroaryl is substituted with Br, Cl, F, or CN. In some cases, heteroaryl is 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 additional substituents. In some cases, heteroaryl is substituted with CH3, which is optionally substituted with one or more additional substituents. In some cases, C1-6 The alkyl is unsubstituted. In some cases, C 1-6 Alkyl is H, CH, CH, CH, or CH(CH). 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 3 . In some cases, heteroaryl is C 1-6 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 an alkenyl, which is optionally substituted with one or more further substituents. 2-6 Alkenyl is CH=CH2, CH2CH=CH2, or CH=CHCH3, each of the foregoing independently optionally substituted with one or more further substituents. C2-6 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, OCH, and OCD. 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, CHOH, or CHCHOH. In some cases, C 0-6Alkylene -OH is OH, CH2OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, or CH2C(CH3)2OH. 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 1-3 Alkoxy 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 CH(CH3)OCH3 or CH2CHOCH3, each of which is 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, CF2CHOCH3CH2CH2CH2CHOCH3, CH2CH2CH2OCD3, CH(CH3)CHOCH3, C(CH3)2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2CHOCH3, 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 3-6 In some cases, C is substituted with cycloalkyl, which is optionally substituted with one or more further substituents. 0-2 The cycloalkyl of alkylene-cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is independently optionally substituted with one or more further substituents. 0-2 The cycloalkyl of the alkylene-cycloalkyl atom is cyclopropyl or cyclobutyl, each of the foregoing independently optionally substituted with one or more further substituents. 0-2 The alkylene-cycloalkyl is unsubstituted. In some cases, C 0-2 The alkylene-cycloalkyl is substituted with 1 to 3 substituents. In some cases, each substituent is independently selected from halo, OH, CH3, OCH3, or OCD3. In some cases, C 0-2 The alkylene-cycloalkyl is substituted with 1 to 3 substituents, each of which is independently Br, Cl, F, OH, CH3, OCH3, or OCD3. In some cases, an optionally substituted C 0-2 Alkylene-cycloalkyl [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, which is optionally substituted with one or more further substituents. 0-2The heterocycloalkyl of alkylene-heterocycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, isoxazolidinyl, or morpholinyl, each of which may be independently 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. 0-2 The heterocycloalkyl of the alkylene-heterocycloalkyl is azetidinyl or oxetanyl, each of which is optionally substituted with one or more further substituents. 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 heterocycloalkyl of the alkylene-heterocycloalkyl is azetidinyl, which is optionally substituted with one or more further substituents. In some cases, C 0-2 The heterocycloalkyl of the alkylene-heterocycloalkyl is oxetanyl, which is optionally substituted with one or more further substituents. 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, C 0-2 The alkylene-heterocycloalkyl is unsubstituted. In some cases, C 0-2 The alkylene-heterocycloalkyl is substituted with 1 to 3 substituents. In some cases, C 0-2 The alkylene-heterocycloalkyl is substituted with one or two substituents. In some cases, C 0-2The alkylene-heterocycloalkyl is substituted with two substituents. In some cases, C 0-2 The alkylene-heterocycloalkyl is substituted with one substituent. In some cases, each substituent is independently halo, OH, CH, OCH, or OCD. In some cases, each substituent is independently Br, Cl, F, OH, CH, CF, CFH, CHF, OCH, OCD, or C(=O)CHD, Br, Cl, F, OH, CH, CH(CH), CF, CFH, CFH, OCH, OCD, CHOCH, N(CH), (C=O)CH, [ka] In some cases, C 0-2 Alkylene-heterocycloalkyl [ka] is.

[0038] In some cases, each substituent of the heteroaryl 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, CHCHCH 1-6 alkyl, and C selected from CH(CH3)2, CH=CH2, CH2CH=CH2, and CH=CHCH3 2-6Alkenyl OCH3, CH2OCH3, CH2CH2OCH3, CH2CH2OCH2CH3, CH2CH2CH2OCH3, CH(CH3)OCH3, CH(CH3)CH2OCH3, CH(OCH3)CH2OCH3, CH(CH3)(OC C selected from H3)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 cycloalkyl selected from alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, or 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, each of which 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 1-3alkyl, cycloalkyl having 3 to 5 total ring atoms, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S, spiro-cycloalkyl having 3 to 5 total ring atoms, or spiro-cycloalkyl 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 cycloalkyl having 3 to 5 total ring atoms 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, the additional substituents are each independently D, Br, Cl, F, OH, CH, CF, CFH, CFH, OCH, OCD, CHOCH, N(CH), (C=O)CH, oxetanyl, azetidinyl, spiro-oxetanyl, or spiro-azetidinyl; each of the oxetanyl, azetidinyl, spiro-oxetanyl, and spiro-azetidinyl may be substituted with F, CH, or a combination thereof. In some cases, the additional substituents are each independently D, Br, Cl, F, OH, CH, CF, CFH, CFH, OCH, CHOCH, OCD, N(CH), (C=O)CH, [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, C2OCH3, CHOCD3, 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)2CH 2OCD3, 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 substituent of the heteroaryl is independently CH3, CH(CH3)2, C(CH3)2OH, CH2OCD3, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] In some cases, each substituent of the heteroaryl is independently CH3, CH(CH3)2, C(CH3)2OH, CH2OCD3, C(CH3)2CH2OH, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] In some cases, each substituent of the heteroaryl is independently CH3, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] In some cases, each substituent of the heteroaryl is independently CH3, C(CH3)2CH2OH, CH2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, [ka] or any combination of the foregoing. In some cases, Z is CH3, CH2CH2OCH3, [ka] or heteroaryl substituted with any combination of the foregoing. In some cases, the heteroaryl of Z is selected from CH3 and C(CH3)2CH2OH, CH2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, [ka] In some cases, each substituent of the heteroaryl is independently substituted with CH3, CH2CH2OCH3, [ka] or any combination of the above. In some cases, the heteroaryl group is CH3, CH2CH2OCH3, [ka] In some cases, Z has two substituents selected from CH3, CH2CH2OCH3, [ka] In some cases, Z is heteroaryl substituted with the structure [ka] and R ZA and R ZB are as defined herein for the substituents of the heteroaryl group of Z. 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 heteroaryl and the structure [ka] and R ZA and R ZB are as defined herein for the 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 of the independently 2OH, C(CH3)2OH, C(CH3)2CH2OH, CH2C(CH3)2OH, OCH3, OCD3, CH2OCH3, CH2OCD3, CH2CH2OCH3, CHFCH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2OCH2CH3,CH2CH2CH2OCH3, CH2CH2CH2 OCD3, 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, CH2C(CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] In some cases, R ZAis Cl, F, CH3, CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH2CHF2 or CH2CH2F; R ZB are CH3, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] In some cases, R ZA is CH3; R ZB are CH3, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3, CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] In some cases, R ZA is CH3; R ZB are CH3, C(CH3)2CH2OH, CH2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, [ka] In some cases, R ZA is CH3; R ZB is CH3, CH2CH2OCH3, [ka] is.

[0039] In some cases, Z is [ka] [ka] [ka] [ka] [ka] [ka] In some cases, Z is [ka] [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] 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] 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] [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] In some cases, Z is [ka] is.

[0040] 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 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 ring having 5 or 6 total ring atoms and 1-3 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; the bicyclic ring is optionally substituted with 1-4 substituents. In some cases, the heteroaryl ring is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl; 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 bicyclic ring is unsubstituted. In some cases, the bicyclic ring is selected from halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene-OH or C 0-6 Alkylene-C 1-3alkoxy, or any combination of the foregoing. 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, the bicyclic ring is substituted with Cl, Br, F, CH, OH, CHOH, OCH, or CHOCH. [ka] is.

[0041] In some cases, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (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, CC 1-3 Alkyl, CC 1-3 Haloalkyl, CC 0-3 Alkylene OH or CC 0-3 Alkylene-C 1-4 is 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 0-3Alkylene OH or CC 0-3 Alkylene-C 1-4 alkoxy, wherein each of the alkenyl and alkynyl is optionally substituted with 1 to 3 substituents, each substituent independently being selected from halo, C 1-3 Haloalkyl, C 0-3 Alkylene OH or C 0-3 Alkylene C 1-4 is 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 optionally substituted with 1 to 3 substituents, each of which 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 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 ring, heteroaryl ring, and bicyclic ring is optionally substituted with 1 to 4 substituents, each substituent 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 with 3 to 6 total ring atoms 0-2Alkylene-cycloalkyl, C having 3-6 total ring atoms and 1-3 heteroatoms selected from N, O and S 0-2 Alkylene-heterocycloalkyl, or C 0-2 alkylene-phenyl; where 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 optionally substituted with 1 to 3 additional substituents, each of which 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, cycloalkyl having 3 to 5 total ring atoms, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, spiro-cycloalkyl having 3 to 5 total ring atoms or spiro-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 cycloalkyl having 3 to 5 total ring atoms 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 aforementioned further substituents of cycloalkyl and heterocycloalkyl is optionally substituted with 1 or 2 substituents, each of which is independently halo or C 1-3 is alkyl; 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 0-2Alkylene-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 3 to 6 total ring atoms selected from 2, N, O and S and 1 or 2 heteroatoms 1-2 alkylene-heterocycloalkyl, or 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, C 0-3 Alkylene-C 1-3 alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-cycloalkenyl having 4 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, 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 are, together with the atoms to which they are attached, a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl ring 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, 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 5 is C 1-3 Haloalkyl, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 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 of which is independently selected from C 1-3 Haloalkyl, C 0-6 Alkylene-OH, C 0-6 Alkylene-C 1-3 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 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 cycloalkyl having 3 to 5 total ring atoms; and Each RN1 are independently H or C 1-4 is alkyl; The substituents are as defined herein.

[0042] In some cases, the compound of formula (I) [ka] teeth, [ka] and; [ka] teeth, [ka] and; [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, [ka] teeth, [ka] In some cases, X is [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] [ka] In some cases, Z is [ka] In some cases, Z is [ka] is.

[0043] In some cases, the compound of formula (I) [ka] teeth, [ka] In some cases, [ka] has the following stereochemical configuration: [ka] 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] Shows.

[0044] In some cases, the present disclosure provides a compound of formula (I'): [ka] and pharmaceutically acceptable salts thereof, wherein the substituents are as previously described herein.

[0045] It is understood that selection of values ​​for each variable is one that results in the formation of stable or chemically feasible compounds.

[0046] Specific compounds contemplated include those in the table below.

[0047] The compound of formula (I) can be a compound listed in Table A or a pharmaceutically acceptable salt thereof. [ka] [ka] [ka] [ka]

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[0048] In some cases, the compound of formula (I) is selected from the list of compounds in Table A or a pharmaceutically acceptable salt thereof.

[0049] 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 X is an alkoxy group; [ka] and the present disclosure relates to a compound 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 defined herein above. Contemplated compounds of formula (IA) include: [ka] [ka] and pharmaceutically acceptable salts thereof.

[0050] 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. Contemplated compounds of formula (IB) include, but are not limited to, those listed in Table B below, and pharmaceutically acceptable salts thereof.

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[0051] In some cases, the compound of formula (I) is selected from the list of compounds in Table B or a pharmaceutically acceptable salt thereof.

[0052] In some cases, A is N; X is [ka] and Y 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 and the present disclosure provides compounds of formula (IC): [ka] and pharmaceutically acceptable salts thereof (wherein R Y H, halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 0-3 Alkylene OH or C 0-3 Alkylene-C 1-4 alkoxy; the remaining substituents are as previously defined herein). Contemplated compounds of formula (IC) include, but are not limited to, those listed in Table C below, and pharmaceutically acceptable salts thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0053] In some cases, the compound of formula (I) is selected from the list of compounds in Table C of its pharmaceutically acceptable salts.

[0054] In some cases, A is N; X is [ka] and Y is N, the present disclosure provides compounds of formula (ID): [ka] and pharmaceutically acceptable salts thereof, wherein the substituents are as defined hereinabove. Contemplated compounds of formula (ID) include, but are not limited to, those listed in Table D below, and pharmaceutically acceptable salts thereof. [ka] [ka]

[0055] In some embodiments, the compound of formula (I) is selected from the list of compounds in Table D.

[0056] In some cases, A is N and X is [ka] and the present disclosure provides compounds of formula (IE): [ka] and pharmaceutically acceptable salts thereof, wherein the substituents are as defined hereinabove. Contemplated compounds of formula (IE) include: [ka] and pharmaceutically acceptable salts thereof.

[0057] In some cases, A is N and X is [ka] and the present disclosure provides a compound of formula (IF): [ka] and pharmaceutically acceptable salts thereof, wherein the substituents are as defined hereinabove. Contemplated compounds of formula (IF) are: [ka] is.

[0058] In some cases, the present disclosure provides that A is N; [ka] and Z is optionally substituted pyrazolyl. Examples of such compounds include: [ka] [ka]

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[0059] In some cases, the present disclosure provides compounds wherein A is N; and X is [ka] and Z is thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, or triazolyl, each of the above being optionally substituted. Examples of such compounds include: [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof.

[0060] In some cases, the present disclosure provides that A is N; [ka] and Z is optionally substituted pyridyl. Examples of such compounds include: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof.

[0061] In some cases, the present disclosure provides that A is N; [ka] and Z is optionally substituted pyrazinyl. Examples of such compounds include: [ka] [ka] and pharmaceutically acceptable salts thereof.

[0062] In some cases, the present disclosure provides that A is N; [ka] and Z is an optionally substituted bicyclic ring comprising a heteroaryl ring having 6 total ring atoms and 1-3 heteroatoms selected from N, O, and S fused to a heterocycloalkyl ring having 5 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. Examples of such compounds include the following: [ka] and pharmaceutically acceptable salts thereof, but are not limited to these.

[0063] 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 depicted (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 depicted, a single stereoisomer of the structure or portion of the structure is represented.

[0064] [Table 1]

[0065] [Table 2]

[0066] [Table 3]

[0067] [Table 4]

[0068] [Table 5]

[0069] [Table 6]

[0070] [Table 7]

[0071]

Table 8

[0072]

Table 9

[0073]

Table 10

[0074]

Table 11

[0075]

Table 12

[0076]

Table 13

[0077]

Table 14

[0078]

Table 15

[0079] Table 16

[0080] Table 17

[0081]

Table 18

[0082] Table 19

[0083] Table 20

[0084] Table 21

[0085] Table 22

[0086] Table 23

[0087] Table 24

[0088] Table 25

[0089] Table 26

[0090] Table 27

[0091] Table 28

[0092] Table 29

[0093]

Table 30

[0094] Table 31

[0095] Table 32

[0096] Table 33

[0097] Table 34

[0098] Table 35

[0099] Table 36

[0100] Table 37

[0101] Table 38

[0102] Table 39

[0103] Table 40

[0104] Table 41

[0105] Table 42

[0106] Table 43

[0107] Table 44

[0108] Table 45

[0109] Table 46

[0110] Table 47

[0111] Table 48

[0112] Table 49

[0113]

Table 50

[0114] Table 51

[0115] Table 52

[0116] Table 53

[0117] Table 54

[0118] Table 55

[0119] Table 56

[0120] Table 57

[0121] Table 58

[0122] Table 59

[0123] Table 60

[0124] Table 61

[0125] Table 62

[0126] Table 63

[0127] Table 64

[0128] Table 65

[0129] Table 66

[0130] Table 67

[0131] Table 68

[0132] Table 69

[0133] Table 70

[0134] Table 71

[0135] Table 72

[0136] Table 73

[0137] Table 74

[0138] Table 75

[0139] Table 76

[0140] Table 77

[0141] Table 78

[0142] Table 79

[0143] Table 80

[0144] Table 81

[0145] Table 82

[0146] Table 83

[0147] Table 84

[0148] Table 85

[0149] Table 86

[0150] Table 87

[0151] Table 88

[0152] Table 89

[0153] Table 90

[0154]

Table 91

[0155] Table 92

[0156]

Table 93

[0157] Table 94

[0158] Table 95

[0159] Table 96

[0160] Table 97

[0161] Table 98

[0162]

Table 99

[0163]

Table 100

[0164] Table 101

[0165] Table 102

[0166] Table 103

[0167] Table 104

[0168] Table 105

[0169] Table 106

[0170] Table 107

[0171] Table 108

[0172] Table 109

[0173] Table 110

[0174] Table 111

[0175] Table 112

[0176] Table 113

[0177] Table 114

[0178] Table 115

[0179] Table 116

[0180] Table 117

[0181] Table 118

[0182] Table 119

[0183] Table 120

[0184] Table 121

[0185] [Table 122]

[0186] In some cases, the compound of formula (I) is selected from the list of compounds in Table E or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (I) is a compound selected from Compound 2-001 to Compound 2-647.

[0187] 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 X is an alkoxy group; [ka] In some cases, the compounds of formula (I) and / or (IA) are compounds 2-137, 2-138, 2-306 to 2-309, 2-335, 2-337, 2-350, 2-357, 2-367, 2-392, 2-392-1, 2-429, 2-457, 2-457-1, 2-462, 2-462-1, 2-477, 2- 2-477-1, 2-478, 2-478-1, 2-479, 2-479-1, 2-480, 2-481, 2-486, 2-488, 2-514, 2-514-1, 2-526, 2-620, 2-621, 2-622, 2-629, 2-630 and 2-631 or a pharmaceutically acceptable salt of any of the foregoing.

[0188] In some cases, A is N and X is [ka] In some cases, the compounds of formula (I) and / or formula (IB) are compounds 2-001 to 2-136 and 2-139 to 2-305, 2-310 to 2-334, 2-336, 2-338 to 2-349, 2-351 to 2-355, 2-358 to 2-366, 2-368 to 2-370, 2-371 to 2-380, 2-382 to 2-391-1, 2-393 to 2-428-2, 2-430 to 2- 2-453, 2-455, 2-456, 2-458 to 2-461, 2-463 to 2-476, 2-482 to 2-485, 2-487, 2-489 to 2-513, 2-515 to 2-525, 2-527 to 2-586, 2-588 to 2-619, 2-623 to 2-628, 2-632 to 2-642, and 2-644 to 2-647, or a pharmaceutically acceptable salt of any of the foregoing.

[0189] In some cases, A is N; X is [ka] and Y 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 1-4In some cases, the compounds of Formula (I) and / or Formula (IC) are selected from the group consisting of compounds 2-001 to 2-007, 2-015, 2-022, 2-026 to 2-063, 2-067 to 2-133, 2-135 to 2-157, 2-159 to 2-165, 2-168 to 2-175, 2-177 to 2-180, 2-182 to 2-190, 2-193 to 2-204, 2-207 to 2-243, 2-245 to 2-282, 2-284 to 2-292, 2-294 to 2-305, 2-310, 2-312 to 2-334, 2-336, 2-339 to 2-349, 2-351 to 2-3 2-489 to 2-513, 2-515 to 2-525, 2-527 to 2-586, 2-588 to 2-619, 2-623 to 2-628, 2-632 to 2-642, and 2-644 to 2-647, or a pharmaceutically acceptable salt of any of the foregoing.

[0190] In some cases, A is N; X is [ka] and Y is N. In some cases, the compound of Formula (I) and / or Formula (ID) is selected from compounds 2-008 to 2-014, 2-017 to 2-021, 2-023 to 2-025, 2-065, 2-066, 2-134, 2-158, 2-167, 2-176, 2-181, 2-244, 2-283, 2-293, 2-306, 2-484, and 2-487, or a pharmaceutically acceptable salt of any of the foregoing.

[0191] In some cases, A is N and X is [ka] In some cases, the compound of Formula (I) and / or Formula (IE) is selected from compounds 2-144, 2-191, 2-192, 2-205, 2-206, 2-311, and 2-454, or a pharmaceutically acceptable salt of any of the foregoing.

[0192] In some cases, A is N; X is [ka] and Y is N. In some cases, the compound of Formula (I) and / or Formula (IF) is Compound 2-338 or a pharmaceutically acceptable salt thereof.

[0193] In some cases, the present disclosure provides that A is N; [ka] and Z is optionally substituted pyrazolyl. In some cases, the compound of formula (I) may be selected from the group consisting of compounds: 2-001 to 2-014, 2-017 to 2-021, 2-023 to 2-025, 2-027, 2-029 to 2-031, 2-033, 2-035, 2-036, 2-039, 2-042, 2-044 to 2-048, 2-050 to 2-054, 2-057, 2-061 to 2-063, 2-067, 2-069 to 2-081, 2-084 to 2-088, 2-094 to 2-097, 2-099, 2-100, 2-103 to 2-130, 2-132, 2-133, 2-135 to 2-141, 2-142, 2-143, 2-144, 2-145, 2-146, 2-147, 2-148, 2-149, 2-150, 2-151, 2-152, 2-153, 2-154, 2-155, 2-156, 2-157, 2-158, 2-159, 2-160, 2-161, 2-162, 2-163, 2-164, 2-165, 2-166, 2-167, 2-168, 2-169, 2-170, 2-171, 2-172, 2-173, 2-174, 2-175, -143, 2-145~2-148, 2-151~2-155, 2-157, 2-159, 2-161, 2-162, 2-164, 2-168, 2-170, 2-171, 2-173, 2-176, 2-178~2-180, 2-182, 2-186~2-188, 2-190~2-194, 2-196, 2-198~2-202, 2-208~2-212, 2-216, 2-218, 2-219, 2-221~2-227, 2-229~2-232, 2-234~2-237, 2-242, 2-245~2-50, 2-253~2-2 56, 2-259, 2-261~2-269, 2-272~2-274, 2-276~2-278, 2-282~2-285, 2-290~2-295, 2-299, 2-303~2-313, 2-318~2-323, 2-329, 2-330, 2-333~2-342, 2-344, 2-345, 2-347~2-352, 2-354~2-357, 2-362, 2-363, 2-365~2-369, 2-371, 2-391, 2-391-1, 2-394~2-398, 2-400~2-404, 2-406, 2-408, 2- 414, 2-418~2-422, 2-428, 2-428-1, 2-428-2, 2-430, 2-439, 2-439-1, 2-441, 2-442, 2-44, 2-446~2-449, 2-452, 2-453, 2-456, 2-458, 2-460, 2-461, 2-465~2-471, 2-484, 2-485, 2-487, 2-489~2-492-1, 2-495~2-497, 2-499, 2-501~2-506, 2-508, 2-509, 2-511, 2-516, 2-516-1, 2-518, 2-520,2-520-1, 2-520-2, 2-528, 2-536 to 2-551, 2-588 to 2-595, 2-619, 2-625 to 2-628, 2-633 to 2-635, and 2-642, or a pharmaceutically acceptable salt of any of the foregoing.

[0194] In some cases, the present disclosure provides that A is N; [ka] and Z is thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, or triazolyl. In some cases, the compound of formula (I) is selected from the group consisting of compounds 2-026, 2-028, 2-032, 2-034, 2-037, 2-038, 2-040, 2-041, 2-043, 2-049, 2-055, 2-058, 2-059, 2-065 to 2-066, 2-068, 2-082, 2-083, 2-089 to 2-093, 2-101, 2-102, 2-131, 2-134, 2-142, 2-149, 2-150, 2-156, 2-158, 2-160, 2-163, 2-165, 2-167, 2-169, 2-172, 2-174, 2-175, 2-181, 2-184, 2-185, 2-195, 2-203, 2-204, 2-207, 2 -213, 2-214, 2-217, 2-220, 2-228, 2-233, 2-239, 2-240, 2-244, 2-270, 2-271, 2-286~2-289, 2-296, 2-297, 2-298, 2-314, 2-315, 2-324, 2-331, 2-332, 2-343, 2-364, 2-370, 2- 390, 2-407, 2-409, 2-409-1, 2-409-2, 2-411, 2-412, 2-415 to 2-417, 2-423 to 2-427, 2-507, 2-507-1, 2-507-2, 2-512, 2-532 to 2-534-1 and 2-552, or a pharmaceutically acceptable salt of any of the foregoing.

[0195] In some cases, the present disclosure provides that A is N; [ka] and Z is optionally substituted pyridyl. In some cases, the compound of formula (I) is selected from the group consisting of the compounds: 2-056, 2-060, 2-098, 2-177, 2-189, 2-197, 2-205, 2-206, 2-215, 2-238, 2-241, 2-251, 2-252, 2-257, 2-258, 2-260, 2-275, 2-279 to 2-2 81, 2-300~2-302, 2-317, 2-325~2-327, 2-346, 2-353, 2-360, 2-361, 2-372~2-387-2, 2-384, 2-387, 2-389, 2-393, 2-399, 2-405, 2-410, 2-413, 2-431~2-433, 2-435 ~2-438, 2-440, 2-445, 2-450, 2-451, 2-455, 2-459, 2-464, 2-472~2-476, 2-493~2-494-1, 2-498, 2-500, 2-510, 2-510-1, 2-510-2, 2-513, 2-515, 2-517, 2-519, 2-5 2-618, 2-623, 2-624, 2-632, 2-636 to 2-641, and 2-644 to 2-646, or a pharmaceutically acceptable salt of any of the foregoing.

[0196] In some cases, the present disclosure provides that A is N; [ka] and Z is optionally substituted pyrazinyl. In some cases, the compound of Formula (I) is selected from the compounds 2-379, 2-379, 2-383, 2-383, 2-385, 2-386, 2-388, 2-434, 2-443, 2-463, 2-527, 2-599, and 2-647, or a pharmaceutically acceptable salt of any of the foregoing.

[0197] In some cases, the present disclosure provides compounds wherein A is N; and X is [ka] and Z is an optionally substituted bicyclic ring comprising a heteroaryl ring having 5 or 6 total ring atoms and 1-3 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. In some cases, the compound of Formula (I) is selected from: 2-015, 2-022, 2-243, 2-316, 2-328, 2-358, 2-359, 2-482, and 2-483, or a pharmaceutically acceptable salt of any of the foregoing.

[0198] In some cases, the compound of Formula (I) is selected from the group consisting of 2-002, 2-003, 2-004, 2-067, 2-114, 2-115, 2-226, 2-227, 2-238, 2-249, 2-255, 2-258, 2-263, 2-299, 2-329, 2-336, 2-347, and 2-353, or a pharmaceutically acceptable salt of any of the foregoing. In some cases, the compound of Formula (I) is 2-002 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-003 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-004 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-067 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-114 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-115 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-226 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-227 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-238 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-249 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-255 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-258 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-263 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-299 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-329 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-336 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-347 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is 2-353 or a pharmaceutically acceptable salt thereof.

[0199] biological activity In some cases, a compound disclosed herein (e.g., a compound of Formula (I), a compound of Formula (I'), a compound of Formula (IA), a compound of Formula (IB), a compound of Formula (IC), a compound of Formula (ID), a compound of Formula (IE), a compound of Formula (IF), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, a compound listed in Table D, or a compound listed in Table E) or a pharmaceutically acceptable salt thereof, exhibits a binding exchange assay as described in the "Biological Evaluation" section. IC of less than 5 μM, or 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, or pharmaceutically acceptable salts thereof, have an IC value of less than 1 μM. 50 In some cases, the compounds disclosed herein and pharmaceutically acceptable salts thereof have an IC value of less than 0.5 μM. 50 In some cases, the compounds disclosed herein and pharmaceutically acceptable salts thereof have an IC value of less than 0.3 μM. 50 In some cases, the compounds disclosed herein and pharmaceutically acceptable salts thereof have an IC value of less than 0.1 μM. 50 Provided herein are compounds having an IC value of less than 5 μM in the 2-hour binding exchange assay described herein. 50 or a pharmaceutically acceptable salt thereof. Also provided herein are compounds of the present disclosure having an IC of less than 3 μM in the 2-hour binding exchange assay described herein. 50 or a pharmaceutically acceptable salt thereof. Still further provided herein are compounds of the present disclosure having an IC of less than 1 μM in the 2-hour binding exchange assay described herein. 50or a pharmaceutically acceptable salt thereof. Further provided herein are compounds of the present disclosure having an IC of less than 0.5 μM in the 2-hour binding exchange assay described herein. 50 or a pharmaceutically acceptable salt thereof. Also provided herein are compounds of the present disclosure having an IC of less than 0.1 μM in the 2-hour binding exchange assay described herein. 50 or a pharmaceutically acceptable salt thereof. Also provided herein are compounds of the present disclosure having an IC of less than 0.05 μM in the 2-hour binding exchange assay described herein. 50 or a pharmaceutically acceptable salt thereof. Also provided herein are compounds of the present disclosure having an IC of less than 0.04 μM in the 2-hour binding exchange assay described herein. 50 or a pharmaceutically acceptable salt thereof. Also provided herein are compounds of the present disclosure having an IC of less than 0.03 μM in the 2-hour binding exchange assay described herein. 50 or a pharmaceutically acceptable salt thereof. Also provided herein are compounds of the present disclosure having an IC of less than 0.02 μM in the 2-hour binding exchange assay described herein. 50 or a pharmaceutically acceptable salt thereof. Also provided herein are compounds of the present disclosure having an IC of less than 0.01 μM in the 2-hour binding exchange assay described herein. 50 or a pharmaceutically acceptable salt thereof.

[0200] 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.

[0201] Formulation and route 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, further provided herein is a pharmaceutical composition comprising the compound disclosed herein (e.g., the compound of formula (I), the compound of formula (I'), the compound of formula (IA), the compound of formula (IB), the compound of formula (IC), the compound of formula (ID), the compound of formula (IE), the compound of formula (IF), the compound listed in table A, the compound listed in table B, the compound listed in table C, the compound listed in table D, or the compound listed in table E) or any of the pharmaceutically acceptable salts described above, in combination with one or more pharmaceutically acceptable excipients and optionally 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.

[0202] 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 in dosage unit formulations containing conventional pharmaceutically acceptable excipients, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by infusion techniques.

[0203] 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, drop, 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.

[0204] Thus, a further aspect of the present disclosure is a pharmaceutical composition comprising one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Also provided herein are compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use as a medicament.

[0205] How to use The compounds described herein inhibit the G12C mutant KRAS protein ("KRAS G12C In some cases, the compounds described herein can inhibit KRAS by, for example, permanently inactivating the protein. G12C 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"), a key downstream effector of KRAS, leading to tumor regression.

[0206] In addition to being useful for human treatment, the compounds provided herein may be useful for the veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. For example, animals including horses, dogs, and cats may be treated with the compounds provided herein.

[0207] Monotherapy Another aspect of the present disclosure is the use of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present disclosure, to treat, but not limit, KRAS G12C Methods for treating disease states, including conditions caused by mutations (e.g., cancer), are provided. See, e.g., U.S. Patent No. 10,519,146 B2, issued December 31, 2019, specifically the section from column 198, line 1 to column 201, line 36, which is incorporated herein by reference.

[0208] Without wishing to be bound by any particular theory, it is noted that sotorasib, like the compounds disclosed herein, inhibits KRAS G12C Sotorasib is a small molecule that specifically and irreversibly inhibits KRAS (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" (ibid.; 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).

[0209] Sotorasib was shown to inhibit histologically confirmed KRAS markers 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. G12C It was evaluated in a Phase 1 dose-escalation and expansion study in 129 subjects with locally advanced or metastatic cancer, including the mutation (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, p. 1212 (Figure A), and appendix (p. 59 (Figure S5) and p. 63 (Figure S6))).

[0210] KRAS G12C Mutations occur 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.

[0211] [Table 123]

[0212] Another aspect of the present disclosure provides a compound disclosed herein (e.g., a compound of Formula (I), a compound of Formula (I'), a compound of Formula (IA), a compound of Formula (IB), a compound of Formula (IC), a compound of Formula (ID), a compound of Formula (IE), a compound of Formula (IF), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, a compound listed in Table D, or a compound listed in Table E), or a pharmaceutically acceptable salt of any of the foregoing, 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.

[0213] 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.

[0214] A further aspect provided by the present disclosure is a method for 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 for 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.

[0215] In some cases, the subject has a cancer that is determined to have one or more cells expressing a KRAS G12C mutant protein before administration of the compound or a pharmaceutically acceptable salt thereof. 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 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, or 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 site, ampullary cancer, gastric cancer, small intestine cancer, 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 pancreatic cancer. In some cases, the cancer is a solid tumor.

[0216] Combination therapy The present disclosure also provides methods for combination therapy in which a compound of the present disclosure (e.g., a compound of formula (I), a compound of formula (I'), a compound of formula (IA), a compound of formula (IB), a compound of formula (IC), a compound of formula (ID), a compound of formula (IE), a compound of formula (IF), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, a compound listed in Table D, or a compound listed in Table E) or a pharmaceutically acceptable salt of any of the foregoing, is used in combination with agents known to modulate other pathways or other components of the same pathway, or even overlapping sets of target enzymes. 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 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)).

[0217] In any of the methods described herein, the compound of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound. 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, a SOC1 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.

[0218] ATR inhibitors. In some cases, the compounds of the present disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an ATR inhibitor in any of the methods described herein. ATR inhibitors are compounds that target ATR (Ataxia telangiectasia 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[5,4-c]quinolin-1(4H)-yl]-benzeneacetonitrile), CGK 733 (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, gartisertib, elimsertib hydrochloride, selasertib, and schisandrin B.

[0219] 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, cenisertib, danusertib, 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- (methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (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.

[0220] 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), ARQ 092 (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.

[0221] 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, numidardistat and CB 280.

[0222] CDK2 inhibitor. 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 "CDK 2" refers to cyclin-dependent kinase ("CDK") 2, a member of the mammalian serine / threonine protein kinases. As used herein, the term "CDK 2 inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the enzymatic activity of CDK 2. Exemplary CDK 2 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).

[0223] CDK4 / 6 inhibitor. In some cases, the compounds of the present disclosure can 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.

[0224] ErbB family inhibitor. 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.

[0225] 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.

[0226] FAK inhibitors. In some cases, the compounds of the present disclosure can 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.

[0227] 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.

[0228] 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.

[0229] IGF-1R inhibitors. In some cases, the compounds of the present disclosure can 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.

[0230] KIF18A inhibitor. In some cases, the compounds 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, inhibitors disclosed in U.S. Patent Application Publication No. 2020 / 0239441, WO 2020 / 132649, WO 2020 / 132651, and WO 2020 / 132653 (each of which is incorporated herein by reference in its entirety). In some cases, the KIF18A inhibitor is sovirnesib (AMG 650).

[0231] 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 AG 270 (3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one).

[0232] MCL-1 inhibitors. In some cases, the 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.

[0233] 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.

[0234] mTOR inhibitors. In some cases, the 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.

[0235] PARP inhibitor. In some cases, the compound 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, olaparib, 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.

[0236] 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.

[0237] PD-L1 inhibitor. In some cases, the compounds 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.

[0238] 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-1-oxo-2 ... morpholin-4-ylthieno[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]methox- [Ci]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).

[0239] 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 are 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]-N-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-deazaadenosine; 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), PRT 811, 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).

[0240] 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 mammalian serine / threonine kinases 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 kinases, 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.

[0241] 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 Medicine; bosiprotafib (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 (bosiprotafib, Revolution Medicine). In some cases, 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 10144-10-1). 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]decan-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, but are not limited to, 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(2,3-dichlorophenyl)thio]-6-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5 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 (CAS 2238840-60-1), (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-[(2,3-dichlorophenyl)thio]-2--3-pyridinol (CAS 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-S,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--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-azaspiro4.5-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(2,3-dichlorophenyl)-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)thio]-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]-6-methyl-3-pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S)-4-amino-3-methyl-oxa-8-azaspiro[4.5]-yl]-5-(2,3-dichlorophenyl)-6-methyl-3-pyridinemethanol (CAS 2238840-74-7), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-75-8), and 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 for use 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 A1, each of which is incorporated by reference in its entirety.

[0242] SOS1 inhibitor. 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, BI 3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxalan-3-yl]oxyquinazolin-4-amine), BI 1701963, 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.

[0243] 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.

[0244] 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.

[0245] Definitions and General Terms The following definitions are provided to facilitate understanding of the scope of the present disclosure.

[0246] 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 appended claims are approximations that may vary depending on the standard deviation found in their respective testing measurements.

[0247] 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. In the case of conflicts between the chemical structure and the chemical name, the chemical structure is determinative of the compound's identity.

[0248] 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 thus 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 foregoing) of any chemical structure (in whole or in part) disclosed herein, unless the stereochemistry is specifically specified.

[0249] 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 of the structure. 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] Represents. 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.

[0250] 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 the 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.

[0251] The present disclosure also encompasses pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compound disclosed herein. Furthermore, 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).

[0252] 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.

[0253] Therefore, the scope of the present disclosure should be understood to encompass all tautomeric forms of the compounds disclosed herein.

[0254] 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 normally 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 isotope-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 methods similar to those described in the accompanying General Synthetic Procedures and Examples sections, substituting the appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0255] definition This section defines additional terms used to describe the compounds, compositions, and scope of uses disclosed herein.

[0256] 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.

[0257] 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.

[0258] Unless otherwise indicated, depictions of substructures do not imply any particular orientation of the substructures. For example, [ka] of [ka] The compound of formula (I) has the formula [ka] or [ka] The present invention includes compounds of formula (I) shown below:

[0259] As described herein, the compounds described herein may be 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 0-2Alkylene-cycloalkenyl, C having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S 0-2 Alkylene-heterocycloalkenyl, and C 0-2 Alkylene-C 6-10 aryl.

[0260] 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 for at least one week in the absence of moisture or other chemically reactive conditions. Only choices and combinations of substituents that result in stable structures are contemplated. Such choices and combinations will be apparent to one of ordinary skill in the art and can be determined without undue experimentation.

[0261] The term "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I).

[0262] The term "oxo" refers to =O.

[0263] 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 ( [ka] ) is, for example, [ka] It can be shown as:

[0264] 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 ( [ka] ) is, for example, [ka] It can be shown as:

[0265] 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 1-6 Alkyl 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 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.

[0266] 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.

[0267] 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 the entire range (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.

[0268] 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), as well as 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.

[0269] 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] and the C2 alkylene bridge ( [ka] ) is, for example, [ka] and the C3 alkylene bridge ( [ka] ) is, for example, [ka] It can be shown as C 1-2 Further examples of rings with alkylene bridges are: [ka] is.

[0270] 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 any number of carbon atoms, including 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).

[0271] 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:

[0272] 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.

[0273] 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. The halogen is independently selected at each occurrence. This term includes perfluoroalkyl 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).

[0274] 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.

[0275] The term "thioalkoxy" refers to an alkyl group, as defined hereinabove, attached to the molecule via a sulfur atom (eg, --S-alkyl).

[0276] 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).

[0277] 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 cycloalkyl groups having any number of carbon atoms, including the entire range (e.g., 3, 4, 5, 6, and 7 carbon atoms in the ring) and 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 is: [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: [ka] It can be expressed as:

[0278] 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.

[0279] 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), as well as 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, 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 via one common atom. For example, a methylpiperidine ring having a spiro-oxetanyl group as a substituent is: [ka] The term "fused-heterocycloalkyl" refers to a heterocycloalkyl group, as defined hereinabove, which 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: [ka] It can be expressed as:

[0280] The term "heterocycloalkenyl" is defined similarly to "heterocycloalkyl," except that the ring contains one or more carbon-carbon double bonds.

[0281] 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).

[0282] The term "heteroaryl" refers to an aromatic ring containing carbon and 1, 2, or 3 heteroatoms, 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 the number of total ring atoms in the indicated range (e.g., 5, 6, or 7 total atoms), as well as 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, 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 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, benzothiazolyl, benzothiazolyl, benzotriazolyl, and benzothiazolyl. These include, but are not limited to, thiazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, thiazolinyl, thiadiazolopyrimidyl, and thienopyridyl.

[0283] The term "bicyclic ring" refers to a functional group containing two linked rings. Unless otherwise indicated, a bicyclic ring can 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.

[0284] 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) selectively attaches to a functional group in good yield; (b) provides a protecting group that is stable against reactions occurring at one or more of the other reactive sites; and (c) is selectively removable 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 does 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 polyfunctional compound. In some cases, the nitrogen protecting group also has the characteristics exemplified for the protecting group above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 of Greene, TW, Wuts, PG in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are incorporated herein by reference.

[0285] The term "bond" indicates the absence of a particular functional group.

[0286] 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.

[0287] 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 can be 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).

[0288] The term "adjacent" refers 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:

[0289] The term "non-adjacent" refers to substituents that are attached to atoms along a chain or within a ring that are not attached to adjacent atoms and are not geminal. Non-adjacent R groups along a chain and within a ring are, respectively: [ka] It can be shown as:

[0290] 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.

[0291] 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 can be 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).

[0292] 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.

[0293] 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.

[0294] 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 that is desired by a researcher, veterinarian, physician, or other clinician.

[0295] 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.

[0296] The term "binding exchange assay" or "2h binding exchange assay" as used herein refers to the assay described in the section entitled "Biological Evaluation."

[0297] 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 would be understood by one of ordinary skill 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.

[0298] In general, compounds of Formula I can be synthesized according to the following schemes. The variables used in the following schemes are those defined for Formula I unless otherwise noted. 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 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 herein and in general terms. In the following schemes, each PG can be the same as or different from another PG in the compound, as long as each protecting group can be selectively removed.

[0299] Generally, compounds of formula I can be synthesized according to Scheme 1 below. Scheme 1 [ka]

[0300] Nitrogen-protected linker moieties of formula (I): [ka] can be synthesized by reacting the desired 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. The resulting linker can be coupled to the desired halogenated core, e.g., a pyrimidine core: [ka] is coupled to the azetidine nitrogen by deprotection and then nucleophilic aromatic substitution in the presence of a suitable base to give the compound of formula (I): [ka] can form the intermediate portion of the compound.

[0301] The variable Z can be synthesized, for example, by starting with the 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 attachment 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 portion of formula (I) 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 attachment reaction to form the ZX(N-PG) tail portion of formula (I). When Y in formula (I) is other than N, the double bond resulting from the attachment reaction can be reduced to a single bond, if necessary.

[0302] The ZX(N-PG) tail of formula (I) can be prepared by deprotecting the nitrogen atom of variable X in ZX(N-PG) to form ZX(NH), followed by nucleophilic aromatic substitution with the central moiety of formula (I) and a suitable base in a nucleophilic aromatic substitution reaction; [ka] In some cases, the tail of formula (I) can be installed via a palladium-catalyzed amination reaction, such as the Buchwald reaction. A Michael acceptor can be installed on the 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 the compound of formula (I).

[0303] As will be readily appreciated by one of ordinary skill in the art, Scheme 1 illustrates the feasibility of preparing W by using the appropriate core starting material.2 is not N.

[0304] Accordingly, a further aspect of the disclosure provides a method for preparing a compound of Formula (I) (e.g., (e.g., a compound of Formula (I), a compound of Formula (I'), a compound of Formula (IA), a compound of Formula (IB), a compound of Formula (IC), a compound of Formula (ID), a compound of Formula (IE), a compound of Formula (IF), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, a compound listed in Table D, or a compound listed in Table E) or a pharmaceutically acceptable salt of any of the foregoing, the method comprising converting an intermediate described herein to a compound of Formula (I).

[0305] 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.

[0306] 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.

[0307] 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. In some cases, the present disclosure provides an intermediate selected from intermediates A-1 through A-53 or a pharmaceutically acceptable salt of any of the foregoing, the structure of which can be found in the Examples section below. In some cases, the present disclosure provides an intermediate selected from intermediates B-1 through B-110 or a pharmaceutically acceptable salt of any of the foregoing, the structure of which can be found in the Examples section below. In some cases, the present disclosure provides an intermediate selected from intermediates C-1 through C-17 or a pharmaceutically acceptable salt of any of the foregoing, the structure of which can be found in the Examples section below. In some cases, the present disclosure provides an intermediate selected from intermediates D-1 through D-15 or a pharmaceutically acceptable salt of any of the foregoing, the structure of which can be found in the Examples section below. In some cases, the present disclosure provides an intermediate selected from intermediates E-1 to E-20 or a pharmaceutically acceptable salt of any of the foregoing, the structure of which can be found in the Examples section below. In some cases, the present disclosure provides an intermediate selected from intermediates F-1 to F-7 or a pharmaceutically acceptable salt of any of the foregoing, the structure of which can be found in the Examples section below. In some cases, the present disclosure provides an intermediate selected from intermediates G-1 to G-2 or a pharmaceutically acceptable salt of any of the foregoing, the structure of which can be found in the Examples section below.In some cases, the present disclosure provides intermediates H-1-1, H-2-2, H-3-1, H-3-2, H-4-1, H-4-2, H-5-1, H-5-2, H-6-1, H-6-2, H-7-1, H-7-2, H-8-1, H-8-2, H-9-1, H-9-2, H-10-1, H-10-2, H-11-1, H-11-2, H-12- 1, H-13-1, H-14-1, H-15-1, H-16-1, H-16-2, H-17-1, H-17-2, H-17-3, H-18-1, H-18-2, H -19-1, H-19-2, H-20-1, H-21-1, H-21-2, H-22-1, H-22-2, H-23-3, H-24-2, H-25-4, H-26 -1, H-26-2, H-27-3, H-28-1, H-29-1, H-29-2, H-30-1, H-31-1, H-31-2, H-32-2, H-33-1 , H-33-2, H-34-1, H-34-2, H-35-1, H-35-2, H-36-1, H-36-2, H-37-1, H-37-2, H-38-1, H- 39-1, H-40-1, H-40-2, H-41-1, H-42-1, H-43-1, H-43-2, H-44-1, H-45-1, H-46-1, H-46-2 and H-47-1, or a pharmaceutically acceptable salt of any of the foregoing, the structures of which can be found in the Examples section below.

[0308] Other embodiments Provided herein as embodiment 1 is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (In the formula: 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 1-4is 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 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 alkoxy; Z is phenyl, heteroaryl containing 5 or 6 total ring atoms and 1-3 heteroatoms selected from N, O, and S, or a bicyclic ring containing a heteroaryl ring having 5 or 6 total ring atoms and 1-3 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 ring, heteroaryl ring, and bicyclic ring is optionally substituted with 1-4 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 3 to 6 total ring atoms selected from 2, N, O and S and 1 or 2 heteroatoms 1-2alkylene-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 1-3 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; 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 5 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 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 ) spiro-cycloalkyl having 2, 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 taken together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms; or Y and adjacent R 6 together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms; wherein any of said fused cycloalkyl rings is optionally substituted with 1 or 2 substituents; or Two non-adjacent R 6 are bonded to each other, C 1-3 Alkylene bridge or C 1-3 Forming ether bridges; Each R N1 are independently H or C 1-4 alkyl).

[0309] Provided herein as embodiment 2 is a compound comprising R 1a , R 1b and R 2is H or D.

[0310] Provided herein as embodiment 3 is a compound comprising R 1a , R 1b and R 2 is independently H or D.

[0311] Provided herein as embodiment 4 is a compound comprising R 1a , R 1b and R 2 is independently H.

[0312] Provided herein as embodiment 5 is a compound comprising R 1a , R 1b and R 2 is independently D.

[0313] Provided herein as embodiment 6 is a compound comprising R 1a , R 1b and R 2 is halo.

[0314] Provided herein as embodiment 7 is a compound comprising R 1a is the halo, and R 1b and R 2 and each of is H.

[0315] Provided herein as embodiment 8 is a compound or salt according to embodiment 6 or 7, wherein each halo is independently Br, Cl, or F.

[0316] Provided herein as embodiment 9 is a compound comprising R 1a , R 1b and R 2 At least one of C1-4 Alkyl or C 1-4The compound or salt according to embodiment 1 or 2, wherein R is haloalkyl.

[0317] Provided herein as embodiment 10 is a compound comprising R 1a , R 1b and R 2 is CH3 or CF3.

[0318] Provided herein as embodiment 11 is a compound comprising 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.

[0319] Provided herein as embodiment 12 is a compound in which each R N1 is independently H or CH.sub.3.

[0320] Provided herein as embodiment 13 is a compound in which each R N1 is independently H.

[0321] Provided herein as embodiment 14 is a compound comprising R 1a , R 1b and R 2 is CH2OH, OCH3, CH2OCH3, OCF3, CH2OCF3, CN, CH2CN, NH2, N(CH3)2, CH2NH2, or CH2N(CH3)2.

[0322] Provided herein as embodiment 15 is a compound comprising R 1a , R1b and R 2 at 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 The compound or salt of embodiment 1 or 2, wherein the alkylene-heterocycloalkyl.

[0323] Provided herein as embodiment 16 is a compound or salt according to embodiment 15, wherein heterocycloalkyl is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl.

[0324] Provided herein as embodiment 17 is a compound comprising R 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.

[0325] Provided herein as embodiment 18 is a compound comprising R 1b and R 2 together with the carbon atoms to which they are attached, [ka] The compound or salt according to embodiment 1 forms a group.

[0326] Provided herein as embodiment 19 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis recurrence inhibitor (RAR) to a patient having a pulmonary arthritis recurrence syndrome (RAR) syndrome. [ka] but [ka] The compound or salt of embodiment 1, wherein

[0327] Provided herein as embodiment 20 is a method for treating a pulmonary arthritis (PTA) comprising: [ka] but [ka] 20. The compound or salt of embodiment 19, wherein:

[0328] Provided herein as embodiment 21 is a compound or salt according to any one of embodiments 1 to 20, wherein m is 0.

[0329] Provided herein as embodiment 22 is a compound or salt of any one of embodiments 1 to 20, wherein m is 1.

[0330] Provided herein as embodiment 23 is a compound or salt of any one of embodiments 1 to 20, wherein m is 2.

[0331] Provided herein as embodiment 24 is a compound or salt of any one of embodiments 1 to 20, wherein m is 3.

[0332] Provided herein as embodiment 25 is a compound or salt according to any one of embodiments 1 to 20, wherein m is 4.

[0333] Provided herein as embodiment 26 is a compound comprising at least one R 3 C 1-3 Alkyl or C 1-3 26. A compound or salt according to any one of embodiments 22 to 25, wherein the alkyl group is haloalkyl.

[0334] Provided herein as embodiment 27 is a compound comprising at least one R 3 is CH3, CH2CH3, CF3, CHF2, or CH2F.

[0335] Provided herein as embodiment 28 is a compound comprising at least one R 3 C0-3 26. A compound or salt according to any one of embodiments 22 to 25, wherein alkylene is CN.

[0336] Provided herein as embodiment 29 is a compound comprising at least one R 3 is CN or CHCN.

[0337] Provided herein as embodiment 30 is a compound comprising at least one R 3 C 0-3 Alkylene OH or C 0-3 Alkylene-C 1-3 26. A compound or salt according to any one of embodiments 22 to 25, wherein R is alkoxy.

[0338] Provided herein as embodiment 31 is a compound comprising at least one R 3 is OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3.

[0339] Provided herein as embodiment 32 is a compound comprising at least one R 3 26. A compound or salt according to any one of embodiments 22 to 25, wherein is oxo.

[0340] Provided herein as embodiment 33 is a compound comprising 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.

[0341] Provided herein as embodiment 34 is a compound comprising at least one R 3 34. A compound or salt according to embodiment 33, wherein is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl.

[0342] Provided herein as embodiment 35 is a compound comprising two adjacent R 3 and together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms.

[0343] Provided herein as embodiment 36 is a compound comprising two adjacent R 3 and R are, together with the atoms to which they are attached, form a fused cyclopropyl ring or a fused cyclobutyl ring.

[0344] Provided herein as embodiment 37 is a compound in which 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.

[0345] Provided herein as embodiment 38 is a compound wherein m is 0; or m is 1 and R 3 is CH3, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl.

[0346] Provided herein as embodiment 39 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a compound comprising: [ka] but [ka] 21. The compound or salt of any one of embodiments 1 to 20, wherein:

[0347] Provided herein as embodiment 40 is a method for treating a pulmonary arthritis (PAS) comprising: [ka] but [ka] 40. The compound or salt of embodiment 39, wherein:

[0348] Provided herein as embodiment 41 is a compound or salt according to any one of embodiments 1 to 40, wherein A is N.

[0349] Provided herein as embodiment 42 is a compound wherein 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 41. A compound or salt according to any one of embodiments 1 to 40, wherein R is alkoxy.

[0350] Provided herein as embodiment 43 is a compound or salt according to embodiment 42, wherein A is CH.

[0351] Provided herein as embodiment 44 is a compound or salt according to embodiment 42, wherein A is CF, C—Cl, or C—CN.

[0352] Provided herein as embodiment 45 is a compound in which A is CC 1-3 Alkyl or CC 1-3 43. A compound or salt according to embodiment 42, wherein R is 1 or 2;

[0353] Provided herein as embodiment 46 is a compound or salt according to embodiment 45, wherein A is C-CH3, C-CH2F, C-CHF2, or C-CF3.

[0354] Provided herein as embodiment 47 is a compound in which A is CC0-3 Alkylene OH or CC 0-3 Alkylene-C 1-4 43. A compound or salt according to embodiment 42, wherein R is alkoxy.

[0355] Provided herein as embodiment 48 is a compound in which A is C—OH, C—CH O H, C—OCH 3 , or C—CH 2 OCH 3 .

[0356] Provided herein as embodiment 49 is a compound or salt according to any one of embodiments 1 to 48, wherein n is 0.

[0357] Provided herein as embodiment 50 is a compound or salt according to any one of embodiments 1 to 48, wherein n is 1.

[0358] Provided herein as embodiment 51 is a compound or salt according to any one of embodiments 1 to 48, wherein n is 2.

[0359] Provided herein as embodiment 52 is a compound comprising at least one R 4 C 1-3 Alkyl or C 1-3 52. A compound or salt according to embodiment 50 or 51, wherein R is haloalkyl.

[0360] Provided herein as embodiment 53 is a compound comprising at least one R 4 53. A compound or salt of embodiment 52, wherein is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F.

[0361] Provided herein as embodiment 54 is a compound comprising at least one R 4 C 0-3 52. A compound or salt according to embodiment 50 or 51, wherein R is alkylene CN.

[0362] Provided herein as embodiment 55 is a compound comprising at least one R 4 is CN or CHCN.

[0363] Provided herein as embodiment 56 is a compound comprising at least one R 4 C 1-3 Alkylene OH or C 1-3 Alkylene-C 1-3 52. A compound or salt according to embodiment 50 or 51, wherein R is alkoxy.

[0364] Provided herein as embodiment 57 is a compound comprising at least one R 4 is CH2OH, CH2CH2OH, CH2OCH3, or CH2CH2OCH3.

[0365] Provided herein as embodiment 58 is a compound comprising at least one R 4 52. A compound or salt according to embodiment 50 or 51, wherein is oxo.

[0366] Provided herein as embodiment 59 is a compound comprising at least one R 4 is 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.

[0367] Provided herein as embodiment 60 is a compound comprising at least one R 4 is spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl.

[0368] Provided herein as embodiment 61 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 42. The compound or salt of embodiment 41, wherein:

[0369] Provided herein as embodiment 62 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 62. The compound or salt of embodiment 61, wherein:

[0370] Provided herein as embodiment 63 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 63. The compound or salt of embodiment 62, wherein

[0371] Provided herein as embodiment 64 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 43. The compound or salt of embodiment 42, wherein:

[0372] Provided herein as embodiment 65 is a compound or salt of any one of embodiments 1 to 64, wherein W is CH.

[0373] Provided herein as embodiment 66 is a compound or salt according to any one of embodiments 1 to 64, wherein W is CF, C—Cl, or C—CN.

[0374] Provided herein as embodiment 67 is a compound in which W is CC 1-3 Alkyl or CC 1-3 65. A compound or salt according to any one of embodiments 1 to 64, wherein the compound or salt is haloalkyl.

[0375] Embodiment 68 is a compound or salt according to embodiment 67, wherein W is C-CH3 or C-CH2CH3.

[0376] Provided herein as embodiment 69 is a compound in which W is CC 0-3 Alkylene OH or CC 0-3 Alkylene-C 1-4 65. A compound or salt according to any one of embodiments 1 to 64, wherein R is alkoxy.

[0377] Provided herein as embodiment 70 is a compound in which W is C—OH, C—CH O H, C—OCH 3 , or C—CH 2 OCH 3 .

[0378] Provided herein as embodiment 71 is a compound comprising R 5 C 1-3 A compound or salt according to any one of embodiments 1 to 70, wherein the alkyl is haloalkyl.

[0379] Provided herein as embodiment 72 is a compound comprising R 5 is CF3, CF2H, CFH2, or CF2CH3.

[0380] Provided herein as embodiment 73 is a compound comprising R 5 is Br, Cl, or F.

[0381] Provided herein as embodiment 74 is a compound comprising R 5 C 1-3 Alkoxy or C 1-3The compound or salt of any one of embodiments 1 to 70, wherein the alkoxy group is thioalkoxy.

[0382] Provided herein as embodiment 75 is a compound comprising R 5 is OCH3 or SCH3.

[0383] Provided herein as embodiment 76 is a compound comprising R 5 C 1-4 Alkyl, C 2-3 Alkenyl, or C 2-3 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is optionally C 1-3 Alkyl, C 1-3 Haloalkyl, C 0-6 Alkylene (OH), C 0-6 Alkylene-C 1-3 71. A compound or salt according to any one of embodiments 1 to 70, wherein the compound or salt is independently substituted with 1, 2, or 3 substituents 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.

[0384] Provided herein as embodiment 77 is a compound or salt according to embodiment 76, wherein each of the one, two, or three substituents is independently selected from CH, CF, CFH, CFH, OH, OCH, OCF, CHOH, CHOCH, cyclopropyl, cyclobutyl, and phenyl.

[0385] Provided herein as embodiment 78 is a compound comprising R 5 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, [ka] 78. A compound or salt according to embodiment 77, wherein

[0386] Provided herein as embodiment 79 is a compound wherein W is CH and R 5 is CF3, CF2H, or CFH2.

[0387] Provided herein as embodiment 80 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 65. The compound or salt of any one of embodiments 1 to 64, wherein:

[0388] Provided herein as embodiment 81 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 81. The compound or salt of embodiment 80, wherein

[0389] Provided herein as embodiment 82 is a method for treating a cancer, wherein X is [ka] 82. The compound or salt of any one of embodiments 1 to 81, wherein:

[0390] Provided herein as embodiment 83 is a method for treating a cancer, wherein X is [ka] 82. The compound or salt of any one of embodiments 1 to 81, wherein:

[0391] Provided herein as embodiment 84 is a method for treating a cancer, wherein X is [ka] 82. The compound or salt of any one of embodiments 1 to 81, wherein:

[0392] Provided herein as embodiment 85 is a method for treating a cancer, wherein X is [ka] 82. The compound or salt of any one of embodiments 1 to 81, wherein:

[0393] Provided herein as embodiment 86 is a compound or salt according to any one of embodiments 1 to 84, wherein Y is N.

[0394] Provided herein as embodiment 87 is a compound or salt according to any one of embodiments 1 to 84, wherein Y is CH.

[0395] Provided herein as embodiment 88 is a compound wherein 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 85. A compound or salt according to any one of embodiments 1 to 84, wherein R is alkoxy.

[0396] Provided herein as embodiment 89 is a compound or salt according to embodiment 88, wherein Y is CF, C—Cl, C—CH, C—CH, C—CHF, C—CHF, C—CF, C—OH, C—CHOH, C—OCH, or C—CHOCH.

[0397] Provided herein as embodiment 90 is a compound or salt according to any one of embodiments 1 to 89, wherein o is 0.

[0398] Provided herein as embodiment 91 is a compound or salt of any one of embodiments 1 to 89, wherein o is 1.

[0399] Provided herein as embodiment 92 is a compound or salt of any one of embodiments 1 to 89, wherein o is 2.

[0400] Provided herein as embodiment 93 is a compound or salt according to any one of embodiments 1 to 89, wherein o is 3.

[0401] Provided herein as embodiment 94 is a compound or salt according to any one of embodiments 1 to 89, wherein o is 4.

[0402] Provided herein as embodiment 95 is a compound comprising at least one R 6 95. A compound or salt according to any one of embodiments 91 to 94, wherein is Br, Cl, F, CN, or oxo.

[0403] Provided herein as embodiment 96 is a compound comprising at least one R 6 is F.

[0404] Provided herein as embodiment 97 is a compound comprising at least one R 6 C 1-3 Alkyl or C 1-3 95. A compound or salt according to any one of embodiments 91 to 94, wherein the alkyl group is haloalkyl.

[0405] Provided herein as embodiment 98 is a compound comprising at least one R 6 is CH3, CH2F, CHF2, or CF3.

[0406] Provided herein as embodiment 99 is a compound comprising at least one R 6 C 0-3 Alkylene OH, C 0-3Alkylene-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 CH3.

[0407] Provided herein as embodiment 100 is a compound comprising at least one R 6 is OH, CH2OH, OCH3, OCD3, or CH2OCH3.

[0408] Provided herein as embodiment 101 is a compound comprising at least one R 6 is 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.

[0409] Provided herein as embodiment 102 is a compound comprising at least one R 6 102. A compound or salt according to embodiment 101, wherein is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl.

[0410] Provided herein as embodiment 103 is a compound comprising R 6 is spiro-cyclopropyl.

[0411] Provided herein as embodiment 104 is a compound comprising 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 6together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms; any of the foregoing fused cycloalkyl rings may be selected from the group consisting of halo, OH, C 1-3 A compound or salt according to any one of embodiments 91 to 94, optionally substituted with one or two substituents selected from alkoxy or CN.

[0412] Provided herein as embodiment 105 is a compound or salt according to embodiment 104, wherein the fused cycloalkyl ring is a fused cyclopropyl, a fused cyclobutyl, or a fused cyclopentyl.

[0413] Provided herein as embodiment 106 is a method for preparing a compound having two non-adjacent R 6 are bonded to each other to form C 1-3 Alkylene bridge or C 1-3 The compound or salt according to any one of embodiments 91 to 94, which forms an ether bridge.

[0414] Provided herein as embodiment 107 is a method for treating a cancer, wherein X is [ka] 83. The compound or salt of any one of embodiments 1 to 82, wherein:

[0415] Provided herein as embodiment 108 is a method for treating a cancer, wherein X is [ka] 84. The compound or salt of any one of embodiments 1 to 81 and 83, wherein

[0416] Provided herein as embodiment 109 is a method for treating a cancer, wherein X is [ka] [ka] 85. The compound or salt of any one of embodiments 1 to 84, wherein

[0417] Provided herein as embodiment 110 is a method for treating a cancer, wherein X is [ka] 85. The compound or salt of any one of embodiments 1 to 84, wherein

[0418] Provided herein as embodiment 111 is a compound in which X is [ka] 86. A compound or salt according to any one of embodiments 1 to 81 and 85, wherein

[0419] Provided herein as embodiment 112 is a compound wherein Z is 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] wherein each R N1 is independently H or CH3.

[0420] Provided herein as embodiment 113 is an alkyl group wherein each of the 1 to 4 substituents is independently F, Cl, CN, OCH, SCH, CHOH, and [ka] 113. A compound or salt according to embodiment 112, selected from:

[0421] Provided herein as embodiment 114 is a method for treating a liver comprising administering to a subject therapies ... [ka] 114. A compound or salt according to embodiment 113, wherein:

[0422] Provided herein as embodiment 115 is a compound or salt of any one of embodiments 1 to 111, wherein Z is heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, wherein heteroaryl is optionally substituted with 1 to 4 substituents.

[0423] Provided herein as embodiment 116 is a compound or salt according to embodiment 115, wherein heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

[0424] Provided herein as embodiment 117 is a compound or salt according to embodiment 116, wherein heteroaryl is imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, or triazolyl.

[0425] Provided herein as embodiment 118 is a compound or salt according to embodiment 116, wherein heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0426] Provided herein as embodiment 119 is a heteroaryl substituted with 1 to 4 substituents, each of which 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 1-3Alkoxy, C 0-6 Alkylene-N(R N1 ) 2 wherein each R N1 are independently H or C 1-3 Alkyl, C with 3-6 total ring atoms 0-2 Alkylene-cycloalkyl, C having 5 or 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, alkyl, alkenyl, C 0-6 Alkylene-C 1-3 The compound or salt of any one of embodiments 115-118, wherein each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is optionally substituted with 1 to 3 substituents independently selected from deuterium, halo, OH, CH3, OCH3, and OCD3.

[0427] Provided herein as embodiment 120 is a compound in which each of the 1 to 4 substituents 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, CH2CH2CH2 OCD3, CH(CH3)CH2OCH3, CH(CH3)CH2OCD3, C(CH3)2CH2OCH3, C(CH3)2CH2OCD3, CH2CH(CH3)OCH3, CH2CH(CH3)OCD3, CH2C(CH3)2OCH 3、 CH2C(CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] 120. The compound or salt according to embodiment 119, selected from the group consisting of:

[0428] Provided herein as embodiment 121 is a compound wherein each of the 1 to 4 substituents is independently CH3, CH(CH3)2, C(CH3)2OH, CH2OCD3, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3,CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] 121. A compound or salt according to embodiment 120, wherein:

[0429] Provided herein as embodiment 122 is a method for treating a liver comprising administering to a subject therapies ... [ka] [ka] [ka] 118. The compound or salt of any one of embodiments 115 to 117, wherein

[0430] Provided herein as embodiment 123 is a method for treating a liver comprising administering to a subject therapies ... [ka] [ka] 123. A compound or salt according to embodiment 122, wherein

[0431] Provided herein as embodiment 124 is a method for treating a liver comprising administering to a subject therapies ... [ka] 124. A compound or salt according to embodiment 123, wherein:

[0432] Provided herein as embodiment 125 is a method for treating a liver comprising administering to a subject therapies ... [ka] [ka] 118. The compound or salt of any one of embodiments 115 to 117, wherein

[0433] Provided herein as embodiment 126 is a method for treating a liver comprising administering to a subject therapies ... [ka] 126. A compound or salt according to embodiment 125, wherein:

[0434] Provided herein as embodiment 127 is a method for treating a liver comprising administering to a subject therapies ... [ka] [ka] 119. A compound or salt according to embodiment 118, wherein

[0435] Provided herein as embodiment 128 is a method for treating a liver comprising administering to a subject therapies ... [ka] 128. A compound or salt according to embodiment 127, wherein:

[0436] Provided herein as embodiment 129 is a compound or salt according to any one of embodiments 1 to 111, wherein Z is a bicyclic ring comprising a heteroaryl ring having 5 or 6 total ring atoms and 1-3 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 1-3 heteroatoms selected from N, O, and S, wherein the bicyclic ring is optionally substituted with 1-4 substituents.

[0437] Provided herein as embodiment 130 is a compound or salt of embodiment 129, wherein the heteroaryl ring is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl; the cycloalkyl ring is cyclopentyl or cyclohexyl; and the heterocycloalkyl ring is pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or tetrahydrothiophenyl.

[0438] Provided herein as embodiment 131 is a method wherein the bicyclic ring is selected from the group consisting of halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkylene -OH and C 0-6 Alkylene-C 1-3 131. The compound or salt of embodiment 129 or 130, substituted with 1 to 4 substituents selected from alkoxy.

[0439] Provided herein as embodiment 132 is a method for treating a liver comprising administering to a subject therapies ... [ka] 132. The compound or salt of any one of embodiments 129 to 131, wherein

[0440] Provided herein as embodiment 133 are: [ka] but [ka] and [ka] but [ka] and [ka] but [ka] The compound or salt of embodiment 1, wherein

[0441] Provided herein as embodiment 134 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 134. A compound or salt according to embodiment 133, wherein:

[0442] Provided herein as embodiment 135 is a method for treating a cancer, wherein X is [ka] 135. A compound or salt according to embodiment 133 or 134, wherein

[0443] Provided herein as embodiment 136 is a method for treating a liver comprising administering to a subject therapies ... [ka] 136. The compound or salt of any one of embodiments 133 to 135, wherein

[0444] Provided herein as embodiment 137 is a compound having Formula (I'): [ka] Formula (IA): [ka] (In the formula, R aは ,H,Halo,CN,C 1-3 Alkyl, C 1-3 Haloalkyl, C 0-3 Alkylene OH or C 0-3 Alkylene-C 1-4 alkoxy); Formula (IB): [ka] ;Formula (IC): [ka] (In the formula, R Y H, halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 0-3 Alkylene OH or C 0-3 Alkylene-C 1-4 alkoxy); Formula (ID): [ka] ;Expression (IE): [ka] or the formula (IF): [ka] or a pharmaceutically acceptable salt of any of the foregoing.

[0445] Provided herein as embodiment 138 is a compound of embodiment 1, wherein the compound is a compound listed in Table A or a pharmaceutically acceptable salt thereof.

[0446] Provided herein as embodiment 139 is a compound according to embodiment 1, wherein the compound is a compound listed in Table E or a pharmaceutically acceptable salt thereof.

[0447] Provided herein as embodiment 140 is a pharmaceutical composition comprising a compound or salt according to any one of embodiments 1 to 139 and a pharmaceutically acceptable excipient.

[0448] Provided herein as embodiment 141 is a compound according to any one of embodiments 1 to 139 or a pharmaceutical composition according to embodiment 140 for use as a medicament.

[0449] Provided herein as embodiment 142 is a compound according to any one of embodiments 1 to 139 or a pharmaceutical composition according to embodiment 140 for use in treating cancer.

[0450] Provided herein as embodiment 143 is a compound or salt of any one of embodiments 1 to 139 or a pharmaceutical composition of embodiment 140 for use in treating a cancer in which one or more cells express a KRAS G12C mutant protein.

[0451] Provided herein as embodiment 144 is a compound, salt, or pharmaceutical composition for use in embodiment 142 or 143, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer of unknown primary, 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, or a solid tumor.

[0452] Provided as embodiment 145 is the use of a compound or salt according to any one of embodiments 1 to 139 or a pharmaceutical composition according to embodiment 140 in the preparation of a medicament for treating cancer.

[0453] Provided herein as embodiment 146 is the use of a compound or salt according to any one of embodiments 1 to 139, or a pharmaceutical composition according to embodiment 140, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G12C mutant protein.

[0454] Provided herein as embodiment 147 is the use of embodiment 145 or 146, wherein 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 carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, or a solid tumor.

[0455] Provided herein as embodiment 148 is 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 embodiments 1 to 139, or a pharmaceutical composition of embodiment 140.

[0456] Provided herein as embodiment 149 is the method of embodiment 148, wherein the one or more cells express a KRAS G12C mutant protein.

[0457] Provided herein as embodiment 150 is the method of embodiment 148 or 149, wherein 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 carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, or a solid tumor.

[0458] Provided herein as embodiment 151 is the method of embodiment 150, wherein 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, sinus cancer, bile duct cancer, melanoma, or a solid tumor.

[0459] Provided herein as embodiment 152 is the method of embodiment 151, wherein the cancer is non-small cell lung cancer.

[0460] Provided herein as embodiment 153 is the method of embodiment 151, wherein the cancer is colorectal cancer.

[0461] Provided herein as embodiment 154 is the method of embodiment 151, wherein the cancer is pancreatic cancer.

[0462] Provided herein as embodiment 155 is the method of embodiment 151, wherein the cancer is a solid tumor.

[0463] Provided herein as embodiment 156 is the method of any one of embodiments 148-155, wherein the subject has a cancer determined to have one or more cells that express a KRAS G12C mutant protein prior to administration of the compound salt or pharmaceutical composition.

[0464] Provided herein as embodiment 157 is the method of any one of embodiments 148-156, further comprising the simultaneous, separate, or sequential administration of 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.

[0465] Provided herein as embodiment 158 ​​is a compound or salt having an IC of less than 1 μM in the binding exchange assay disclosed herein in the Biological Evaluation section. 50 139. The compound or salt of any one of embodiments 1 to 139, having a value of:

[0466] Alternative Embodiments Provided herein as embodiment 1 is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (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, CC 1-3 Alkyl, CC 1-3 Haloalkyl, CC 0-3 Alkylene OH or CC 0-3 Alkylene-C 1-4 is alkoxy; W 1 and W 2 each independently represents N, CH, C-halo, C-CN, CC 1-3 Alkyl, CC 2-3Alkenyl, 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 optionally 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 optionally substituted with one or more substituents; Z is phenyl, heteroaryl having 5 or 6 total ring atoms and 1-3 heteroatoms selected from N, O, and S, or a bicyclic ring comprising a heteroaryl ring having 5 or 6 total ring atoms and 1-3 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 each of the phenyl ring, heteroaryl ring, and bicyclic ring is optionally 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 3 to 6 total ring atoms selected from 2, N, O and S and 1 or 2 heteroatoms 1-2 alkylene-heterocycloalkyl, or 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, C 0-3 Alkylene-C 1-3 alkoxy, oxo, spiro-cycloalkyl having 3 to 7 total ring atoms, spiro-cycloalkenyl having 4 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, 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 are, together with the atoms to which they are attached, a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl ring 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, 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 5 is C 1-3 Haloalkyl, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, Halo, C1-3 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 one or more substituents; R A1 and R A2 each independently represents H, C 1-3 Alkyl, C 1-3 haloalkyl, or cycloalkyl having 3 to 5 total ring atoms; and Each R N1 are independently H or C 1-4 alkyl).

[0467] Provided herein as embodiment 2 is a compound comprising R 1a , R 1b and R 2 is H or D.

[0468] Provided herein as embodiment 3 is a compound comprising R 1a , R 1b and R 2 is independently H or D.

[0469] Provided herein as embodiment 4 is a compound comprising R 1a , R 1b and R 2 is independently H.

[0470] Provided herein as embodiment 5 is a compound comprising R 1a , R 1b and R 2 is independently D.

[0471] Provided herein as embodiment 6 is a compound comprising R 1a , R 1b and R 2 is halo.

[0472] Provided herein as embodiment 7 is a compound comprising R 1a is the halo, and R 1b and R 2 and each of is H.

[0473] Provided herein as embodiment 8 is a compound or salt according to embodiment 6 or 7, wherein each halo is independently Br, Cl, or F.

[0474] Provided herein as embodiment 9 is a compound comprising R 1a , R 1b and R 2 At least one of C1-4 Alkyl or C 1-4 The compound or salt according to embodiment 1 or 2, wherein R is haloalkyl.

[0475] Provided herein as embodiment 10 is a compound comprising R 1a , R 1b and R 2 is CH3, CH2F, CHF2, or CF3.

[0476] Provided herein as embodiment 11 is a compound comprising 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.

[0477] Provided herein as embodiment 12 is a compound in which each R N1 is independently H or CH.sub.3.

[0478] Provided herein as embodiment 13 is a compound in which each R N1 is independently H.

[0479] Provided herein as embodiment 14 is a compound comprising R 1a , R 1b and R 2 is CH2OH, OCH3, CH2OCH3, OCF3, CH2OCF3, CN, CH2CN, NH2, N(CH3)2, CH2NH2, or CH2N(CH3)2.

[0480] Provided herein as embodiment 15 is a compound comprising R 1a , R 1b and R 2 at 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 The compound or salt of embodiment 1 or 2, wherein the alkylene-heterocycloalkyl.

[0481] Provided herein as embodiment 16 is a compound or salt according to embodiment 15, wherein heterocycloalkyl is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl.

[0482] Provided herein as embodiment 17 is a compound comprising R 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.

[0483] Provided herein as embodiment 18 is a compound comprising R 1b and R 2 together with the carbon atoms to which they are attached, [ka] is a compound or salt according to embodiment 1, which forms:

[0484] Provided herein as embodiment 19 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis recurrence inhibitor (RAR) to a patient having a pulmonary arthritis recurrence syndrome (RAR) syndrome. [ka] but [ka] The compound or salt of embodiment 1, wherein

[0485] Provided herein as embodiment 20 is a method for treating a pulmonary arthritis (PTA) comprising: [ka] but [ka] 20. The compound or salt of embodiment 19, wherein:

[0486] Provided herein as embodiment 21 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a compound comprising: [ka] but [ka] 21. The compound or salt of embodiment 20, wherein:

[0487] Provided herein as embodiment 22 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 22. The compound or salt of embodiment 21, wherein:

[0488] Provided herein as embodiment 23 is a compound or salt according to any one of embodiments 1 to 22, wherein m is 0.

[0489] Provided herein as embodiment 24 is a compound or salt according to any one of embodiments 1 to 22, wherein m is 1.

[0490] Provided herein as embodiment 25 is a compound or salt according to any one of embodiments 1 to 22, wherein m is 2.

[0491] Provided herein as embodiment 26 is a compound or salt according to any one of embodiments 1 to 22, wherein m is 3.

[0492] Provided herein as embodiment 27 is a compound or salt according to any one of embodiments 1 to 22, wherein m is 4.

[0493] Provided herein as embodiment 28 is a method for treating a pulmonary arthritis (PA) comprising: [ka] is deuterated.

[0494] Provided herein as embodiment 29 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a compound comprising: [ka] but [ka] 29. The compound or salt of embodiment 28, wherein

[0495] Provided herein as embodiment 30 is a compound comprising at least one R 3 C 1-3 Alkyl or C 1-3 28. A compound or salt according to any one of embodiments 24 to 27, wherein the alkyl group is haloalkyl.

[0496] Provided herein as embodiment 31 is a compound comprising at least one R 3 is CH3, CH2CH3, CF3, CHF2, or CH2F.

[0497] Provided herein as embodiment 32 is a compound comprising at least one R 3 is CH3.

[0498] Provided herein as embodiment 33 is a compound comprising at least one R 3 but [ka] 28. The compound or salt of any one of embodiments 24 to 27, wherein:

[0499] Provided herein as embodiment 34 is a compound comprising R A1 and R A2 is independently H, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, or cyclobutyl.

[0500] Provided herein as embodiment 35 is a compound comprising at least one R 3 but [ka] 35. A compound or salt according to embodiment 33 or 34, wherein

[0501] Provided herein as embodiment 36 is a compound comprising at least one R 3 C0-3 28. A compound or salt according to any one of embodiments 24 to 27, wherein alkylene is CN.

[0502] Provided herein as embodiment 37 is a compound comprising at least one R 3 is CN or CHCN.

[0503] Provided herein as embodiment 38 is a compound comprising at least one R 3 C 0-3 Alkylene OH or C 0-3 Alkylene-C 1-3 28. A compound or salt according to any one of embodiments 24 to 27, wherein R is alkoxy.

[0504] Provided herein as embodiment 39 is a compound comprising at least one R 3 is OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3.

[0505] Provided herein as embodiment 40 is a compound comprising at least one R 3 28. A compound or salt according to any one of embodiments 24 to 27, wherein is oxo.

[0506] Provided herein as embodiment 41 is a compound comprising 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.

[0507] Provided herein as embodiment 42 is a compound comprising at least one R 3 is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl.

[0508] Provided herein as embodiment 43 is a compound comprising at least one R 3 is a spiro-cycloalkenyl having 4 to 7 total ring atoms, or a spiro-heterocycloalkenyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S.

[0509] Provided herein as embodiment 44 is a compound comprising two adjacent R 3 are taken together with the atoms to which they are attached to form a fused cycloalkyl ring having 3 to 7 total ring atoms, or a fused heterocycloalkyl ring having 3 to 7 total atoms and 1 or 2 heteroatoms selected from N, O, and S.

[0510] Provided herein as embodiment 45 is a compound comprising two adjacent R 3 and R are, together with the atoms to which they are attached, form a fused cyclopropyl ring or a fused cyclobutyl ring.

[0511] Provided herein as embodiment 46 is a compound comprising two adjacent R 3 are taken together with the atoms to which they are attached to form a fused cycloalkenyl ring having 4 to 7 total ring atoms, or a fused heterocycloalkenyl ring having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S.

[0512] Provided herein as embodiment 47 is a compound in which each R 3 are independently CH3, CH2CH3, CF3, CHF2, CH2F, CN, CH2CN, OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, or two adjacent R3 and R 1 and R 2 together with the atom to which they are attached form a fused cyclopropyl or fused cyclobutyl.

[0513] Provided herein as embodiment 48 is a compound wherein m is 0; or m is 1 and R 3 is CH3, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl.

[0514] Provided herein as embodiment 49 is a compound wherein m is 0; or m is 1 and R 3 is CH3.

[0515] Provided herein as embodiment 50 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] [ka] 23. The compound or salt of any one of embodiments 1 to 22, wherein:

[0516] Provided herein as embodiment 51 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 51. The compound or salt of embodiment 50, wherein

[0517] Provided herein as embodiment 52 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 52. The compound or salt of embodiment 51, wherein:

[0518] Provided herein as embodiment 53 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 52. The compound or salt of embodiment 51, wherein:

[0519] Provided herein as embodiment 54 is a compound wherein A is N, CH, or CC 1-3 54. A compound or salt according to any one of embodiments 1 to 53, wherein R is alkyl.

[0520] Provided herein as embodiment 55 is a compound or salt according to any one of embodiments 1 to 53, wherein A is N.

[0521] Provided herein as embodiment 56 is a compound wherein 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 54. A compound or salt according to any one of embodiments 1 to 53, wherein R is alkoxy.

[0522] Provided herein as embodiment 57 is a compound or salt according to embodiment 54 or 56, wherein A is CH.

[0523] Provided herein as embodiment 58 is a compound or salt according to embodiment 56, wherein A is CF, C—Cl, or C—CN.

[0524] Provided herein as embodiment 59 is a compound in which A is CC 1-3 Alkyl or CC 1-3 57. A compound or salt according to embodiment 54 or 56, wherein R is haloalkyl.

[0525] Provided herein as embodiment 60 is a compound or salt according to embodiment 59, wherein A is C-CH3, C-CH2F, C-CHF2, or C-CF3.

[0526] Provided herein as embodiment 61 is a compound in which A is CC 0-3 Alkylene OH or CC 0-3 Alkylene-C 1-4 57. A compound or salt according to embodiment 56, wherein R is alkoxy.

[0527] Provided herein as embodiment 62 is a compound in which A is C—OH, C—CH O H, C—OCH 3 , or C—CH 2 OCH 3 .

[0528] Provided herein as embodiment 63 is a compound or salt according to any one of embodiments 1 to 62, wherein n is 0.

[0529] Provided herein as embodiment 64 is a compound or salt according to any one of embodiments 1 to 62, wherein n is 1.

[0530] Provided herein as embodiment 65 is a compound or salt according to any one of embodiments 1 to 62, wherein n is 2.

[0531] Provided herein as embodiment 66 is a compound comprising at least one R 4 C 1-3 Alkyl or C 1-3 66. A compound or salt according to embodiment 64 or 65, wherein R is haloalkyl.

[0532] Provided herein as embodiment 67 is a compound comprising at least one R 4 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F.

[0533] Provided herein as embodiment 68 is a compound comprising at least one R 4 is CH3.

[0534] Provided herein as embodiment 69 is a compound comprising at least one R 4 C 0-3 66. A compound or salt according to embodiment 64 or 65, wherein alkylene is CN.

[0535] Provided herein as embodiment 70 is a compound comprising at least one R 4 is CN or CHCN.

[0536] Provided herein as embodiment 71 is a compound comprising at least one R 4 C 1-3 Alkylene OH or C 1-3 Alkylene-C 1-3 66. A compound or salt according to embodiment 64 or 65, wherein R is alkoxy.

[0537] Provided herein as embodiment 72 is a compound comprising at least one R 4 is CH2OH, CH2CH2OH, CH2OCH3, or CH2CH2OCH3.

[0538] Provided herein as embodiment 73 is a compound comprising at least one R 4 66. A compound or salt according to embodiment 64 or 65, wherein is oxo.

[0539] Provided herein as embodiment 74 is a compound comprising at least one R 4is 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.

[0540] Provided herein as embodiment 75 is a compound comprising at least one R 4 is spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl.

[0541] Provided herein as embodiment 76 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 56. A compound or salt according to embodiment 54 or 55, wherein

[0542] Provided herein as embodiment 77 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 77. A compound or salt according to embodiment 76, wherein:

[0543] Provided herein as embodiment 78 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 78. A compound or salt according to embodiment 77, wherein

[0544] Provided herein as embodiment 79 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a compound comprising: [ka] but [ka] 58. A compound or salt according to any one of embodiments 54, 56 or 57, wherein

[0545] Provided herein as embodiment 80 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS). 1 is N.

[0546] Provided herein as embodiment 81 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 1 Embodiment 79. A compound or salt according to any one of embodiments 1 to 79, wherein is CH.

[0547] Provided herein as embodiment 82 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 1 Embodiment 79. A compound or salt according to any one of embodiments 1 to 79, wherein is CF, C—Cl, or C—CN.

[0548] Provided herein as embodiment 83 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 1 CC 1-3 Alkyl or CC 1-3 A compound or salt according to any one of embodiments 1 to 79, wherein the alkyl is haloalkyl.

[0549] Provided herein as embodiment 84 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 1 is C—CH 3 , C—CH 2 CH 3 , C—CH 2 F, C—CHF 2 , or C—CF 3 .

[0550] Provided herein as embodiment 85 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 1 is C—CH 3 or C—CH 2 CH 3 .

[0551] Provided herein as embodiment 86 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 1 CC 2-3Alkenyl or CC 2-3 Embodiment 79. A compound or salt according to any one of embodiments 1 to 79, wherein the alkenyl and alkynyl are each optionally substituted with one or more substituents.

[0552] Provided herein as embodiment 87 is a CC 2-3 Alkenyl and CC 2-3 87. A compound or salt according to embodiment 86, wherein each alkynyl is unsubstituted.

[0553] Provided herein as embodiment 88 is a CC 2-3 Alkenyl and CC 2-3 each alkynyl is substituted with 1 to 3 substituents, each substituent independently selected from halo, C 1-3 Haloalkyl, C 0-3 Alkylene OH or C 0-3 Alkylene C 1-4 87. A compound or salt according to embodiment 86, wherein R is alkoxy.

[0554] Provided herein as embodiment 89 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 1 is C—CH═CH2, CC(OH)═CH2, C—CH═CH(OH), or C—CCH.

[0555] Provided herein as embodiment 90 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 1 CC 0-3 Alkylene OH or CC 0-3 Alkylene-C 1-4 80. A compound or salt according to any one of embodiments 1 to 79, wherein R is alkoxy.

[0556] Provided herein as embodiment 91 is a compound comprising W 1 is C—OH, C—CH 2 OH, C—OCH 3 , or C—CH 2 OCH 3 .

[0557] Provided herein as embodiment 92 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a compound selected from the group consisting of: 2is N.

[0558] Provided herein as embodiment 93 is a compound comprising W 2 92. A compound or salt according to any one of embodiments 1 to 91, wherein is CH.

[0559] Provided herein as embodiment 94 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 2 92. The compound or salt of any one of embodiments 1-91, wherein is CF, C—Cl, or C—CN.

[0560] Provided herein as embodiment 95 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 2 CC 1-3 Alkyl or CC 1-3 92. A compound or salt according to any one of embodiments 1 to 91, wherein the compound or salt is haloalkyl.

[0561] Provided herein as embodiment 96 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 2 is C—CH 3 , C—CH 2 CH 3 , C—CH 2 F, C—CHF 2 , or C—CF 3 .

[0562] Provided herein as embodiment 97 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving urinary tract infection (PAS) ... 2 CC 2-3 Alkenyl or CC 2-3 alkynyl, wherein each of the alkenyl and alkynyl is optionally substituted with one or more substituents.

[0563] Provided herein as embodiment 98 is a CC 2-3 Alkenyl and CC 2-3 98. A compound or salt according to embodiment 97, wherein each alkynyl is unsubstituted.

[0564] Provided herein as embodiment 99 is a CC 2-3 Alkenyl and CC 2-3each alkynyl is substituted with 1 to 3 substituents, each substituent independently selected from halo, C 1-3 Haloalkyl, C 0-3 Alkylene OH or C 0-3 Alkylene C 1-4 98. A compound or salt according to embodiment 97, wherein R is alkoxy.

[0565] Provided herein as embodiment 100 is a W 2 is C—CH═CH2, CC(OH)═CH2, C—CH═CH(OH), or C—CCH.

[0566] Provided herein as embodiment 101 is a W 2 CC 0-3 Alkylene OH or CC 0-3 Alkylene-C 1-4 92. A compound or salt according to any one of embodiments 1 to 91, wherein R is alkoxy.

[0567] Provided herein as embodiment 102 is a W 2 is C—OH, C—CH 2 OH, C—OCH 3 , or C—CH 2 OCH 3 .

[0568] Provided herein as embodiment 103 is a method for producing a medicament for the treatment of a malaria parasite comprising: 1 and W 2 is independently N, CH, or C—CH 3 .

[0569] Provided herein as embodiment 104 is a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: 1 is CH and W 2 is N, CH, or C—CH 3 .

[0570] Provided herein as embodiment 105 is a W 2 is N and W 1is N, CH, or C—CH 3 .

[0571] Provided herein as embodiment 106 is a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: 1 is CH and W 2 is N.

[0572] Provided herein as embodiment 107 is a compound comprising R 5 C 1-3 A compound or salt according to any one of embodiments 1 to 106, wherein the alkyl group is haloalkyl.

[0573] Provided herein as embodiment 108 is a compound comprising R 5 is CF3, CF2H, CFH2, or CF2CH3.

[0574] Provided herein as embodiment 109 is a method for manufacturing a semiconductor device comprising: R 5 is CF3.

[0575] Provided herein as embodiment 110 is a method for manufacturing a semiconductor device comprising: R 5 is CF2H.

[0576] Provided herein as embodiment 111 is a compound comprising R 5 is Br, Cl, or F.

[0577] Provided herein as embodiment 112 is a compound comprising R 5 C 1-3 Alkoxy or C 1-3 107. A compound or salt according to any one of embodiments 1 to 106, wherein the compound or salt is thioalkoxy.

[0578] Provided herein as embodiment 113 is a compound comprising R5 is OCH3 or SCH3.

[0579] Provided herein as embodiment 114 is a compound comprising R 5 C 1-6 Alkyl, C 2-4 Alkenyl, or C 2-4 A compound or salt of any one of embodiments 1-106, wherein R is 1 or 2; R is 1 or 2; and ...

[0580] Provided herein as embodiment 115 is a compound wherein alkyl is H3, CH2CH3, CH2CH2CH3, or CH(CH3)2; alkenyl is CH=CH2 or CH=CHCH3; alkynyl is [ka] and each of the foregoing is optionally substituted with 1 to 3 substituents.

[0581] Provided herein as embodiment 116 is a compound comprising R 5 116. A compound or salt according to embodiment 114 or 115, wherein:

[0582] Provided herein as embodiment 117 is a compound comprising R 5 is substituted with 1 to 3 substituents, each substituent independently being selected from the group consisting of C 1-3 Haloalkyl, C 0-6 Alkylene-OH, C 0-6 Alkylene-C 1-3 116. A compound or salt according to embodiment 114 or 115, wherein the cycloalkyl is 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 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or phenyl.

[0583] Provided herein as embodiment 118 is a compound or salt according to embodiment 128, wherein each substituent is independently CH, CF, CFH, CFH, OH, OCH, OCF, CHOH, CHOCH, cyclopropyl, cyclobutyl, or phenyl.

[0584] Provided herein as embodiment 119 is a compound comprising R 5 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, [ka] 115. A compound or salt according to embodiment 114, wherein:

[0585] Provided herein as embodiment 120 is a compound comprising R 5 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 the foregoing being optionally substituted with 1 to 3 substituents.

[0586] Provided herein as embodiment 121 is a compound or salt according to embodiment 120, wherein each of the cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is unsubstituted.

[0587] Provided herein as embodiment 122 are cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl groups each substituted with 1 to 3 substituents, each substituent independently selected from halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 0-6 Alkylene (OH) or C 0-6 Alkylene-C1-3 122. A compound or salt according to embodiment 121, wherein R is alkoxy.

[0588] Provided herein as embodiment 123 is a compound comprising R 5 is CH3, CF3, CF2H, CFH2, CH2CH3, CH2CH2CH3, CH(CH3)2, [ka] 107. The compound or salt of any one of embodiments 1 to 106, wherein:

[0589] Provided herein as embodiment 124 is a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: 1 is CH and W 2 is N and R 5 is CF3, CF2H, or CFH2.

[0590] Provided herein as embodiment 125 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 79. The compound or salt of any one of embodiments 1 to 79, wherein

[0591] Provided herein as embodiment 126 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 126. A compound or salt according to embodiment 125, wherein:

[0592] Provided herein as embodiment 127 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 127. A compound or salt according to embodiment 126, wherein:

[0593] Provided herein as embodiment 128 is a method for treating a pulmonary arthritis (PA) comprising: [ka] but [ka] 127. A compound or salt according to embodiment 126, wherein:

[0594] Provided herein as embodiment 129 is a compound or salt of any one of embodiments 1 to 128, wherein: 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 alkoxy; o is 0, 1, 2, 3, or 4; 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, C 1-4 Alkylene-N(R N1)2, oxo, =CH2, spiro-cycloalkyl having 3 to 7 total atoms, spiro-cycloalkenyl having 4 to 7 total atoms, spiro-heterocycloalkyl having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or 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 form a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl ring 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 bonded to each other, 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 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, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl ring having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; any of the foregoing cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl optionally substituted with one or more substituents; Each R N1 are independently H or C 1-4 It is alkyl.

[0595] Provided herein as embodiment 130 is a compound or salt according to embodiment 129, wherein o is 0.

[0596] Provided herein as embodiment 131 is a compound or salt according to embodiment 129, wherein o is 1.

[0597] Provided herein as embodiment 132 is a compound or salt according to embodiment 129, wherein o is 2.

[0598] Provided herein as embodiment 133 is a compound or salt according to embodiment 129, wherein o is 3.

[0599] Provided herein as embodiment 134 is a compound or salt according to embodiment 129, wherein o is 4.

[0600] Provided herein as embodiment 135 is a compound comprising at least one R 6 A compound or salt according to any one of embodiments 131 to 134, wherein is Br, Cl, F, or CN.

[0601] Provided herein as embodiment 136 is a compound comprising at least one R 6 is F.

[0602] Provided herein as embodiment 137 is a compound comprising at least one R 6 C 1-3 Alkyl or C 1-3 A compound or salt according to any one of embodiments 131 to 134, wherein R is haloalkyl.

[0603] Provided herein as embodiment 138 is a compound comprising at least one R 6 is CH3, CH2F, CHF2, or CF3.

[0604] Provided herein as embodiment 139 is a compound comprising at least one R 6 C 0-3 Alkylene OH, C 0-3 Alkylene-C 1-3Alkoxy, 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 CH3.

[0605] Provided herein as embodiment 140 is a compound comprising at least one R 6 is OH, CH2OH, OCH3, OCD3, CH2OCH3, or CH2N(CH3)2.

[0606] Provided herein as embodiment 141 is a compound comprising at least one R 6 A compound or salt according to any one of embodiments 131 to 134, wherein is oxo or =CH2.

[0607] Provided herein as embodiment 142 is a compound comprising at least one R 6 is a spiro-cycloalkyl having 3 to 7 total atoms, a spiro-cycloalkenyl having 4 to 7 total atoms, a spiro-heterocycloalkyl having 4 to 7 total ring atoms and one or two heteroatoms selected from N, O, and S, or a spiro-heterocycloalkenyl having 4 to 7 total ring atoms and one or two heteroatoms selected from N, O, and S, any of the foregoing optionally substituted with one or more substituents.

[0608] Provided herein as embodiment 143 is a compound comprising at least one R 6

[0113] Embodiment 143. A compound or salt according to embodiment 142, wherein is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl, any of the foregoing optionally substituted with one or more substituents.

[0609] Provided herein as embodiment 144 is a compound comprising at least one R 6 is spiro-cyclopropyl.

[0610] Provided herein as embodiment 145 is a compound comprising 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, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring 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 Y and an adjacent R 6 are taken together with the atoms to which they are attached to form a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl ring having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; any of the above cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl optionally substituted with one or more substituents.

[0611] Provided herein as embodiment 146 is a compound comprising 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 are taken together with the atoms to which they are attached to form a fused cycloalkyl ring having 3 to 7 total ring atoms, any of which cycloalkyl is optionally substituted with one or more substituents.

[0612] Provided herein as embodiment 147 is a compound or salt according to embodiment 145 or 146, wherein the fused cycloalkyl ring is a fused cyclopropyl, a fused cyclobutyl, or a fused cyclopentyl, any of the foregoing optionally substituted with one or more substituents.

[0613] Provided herein as embodiment 148 is a compound or salt according to any one of embodiments 145-147, wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is unsubstituted.

[0614] Provided herein as embodiment 149 is a compound or salt of any one of embodiments 145-147, wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is substituted with one or more substituents.

[0615] Provided herein as embodiment 150 is a compound or salt of any one of embodiments 145-147, wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is substituted with one or two substituents.

[0616] Provided herein as embodiment 151 is a compound wherein each substituent is independently halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 0-2 Alkylene OH, C 0-2 Alkylene C 1-3 Alkoxy or C 0-2 151. The compound or salt of embodiment 149 or 150, wherein alkylene is CN.

[0617] Provided herein as embodiment 152 is a compound or salt of embodiment 151, wherein each substituent is independently F, Cl, OH, OCH3, OCH2CH3, or CN.

[0618] Provided herein as embodiment 153 is a method for preparing a compound having two non-adjacent R 6are bonded together to form C 1-3 Alkylene bridge, C 2-3 Alkenylene bridge, C 1-3 Ether bridge, or C 1-3 The compound or salt according to any one of embodiments 132 to 134, which forms a thioether bridge.

[0619] Provided herein as embodiment 154 is a method for preparing a compound having two non-adjacent R 6 are joined to form -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2-CH=CH-, or -CH2OCH2-.

[0620] Provided herein as embodiment 155 is a method for preparing a compound having two non-adjacent R 6 are combined with each other [ka] 155. The compound or salt of embodiment 154, wherein

[0621] Provided herein as embodiment 156 is a compound or salt according to any one of embodiments 131 to 155, wherein Y is N.

[0622] Provided herein as embodiment 157 is a compound or salt according to any one of embodiments 131 to 155, wherein Y is CH.

[0623] Provided herein as embodiment 158 ​​is any embodiment wherein 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 1-4 156. A compound or salt according to any one of embodiments 131 to 155, wherein R is alkoxy.

[0624] Provided herein as embodiment 159 is a compound or salt according to embodiment 158, wherein Y is CF, C—Cl, C—CH, C—CH, C—CHF, C—CHF, C—CF, C—OH, C—CHOH, C—OCH, or C—CHOCH.

[0625] Provided herein as embodiment 160 is a method for treating a cancer, wherein X is [ka] 159. The compound or salt of any one of embodiments 131 to 159, wherein

[0626] Provided herein as embodiment 161 is a method for treating a cancer, wherein X is [ka] 161. A compound or salt according to embodiment 160, wherein

[0627] Provided herein as embodiment 162 is a method for treating a cancer, wherein X is [ka] 162. A compound or salt according to embodiment 161, wherein:

[0628] Provided herein as embodiment 163 is a method for treating a cancer, wherein X is [ka] 159. The compound or salt of any one of embodiments 131 to 159, wherein

[0629] Provided herein as embodiment 164 is a method for treating a cancer, wherein X is [ka] 164. A compound or salt according to embodiment 163, wherein:

[0630] Provided herein as embodiment 165 is a method for treating a cancer, wherein X is [ka] 159. The compound or salt of any one of embodiments 131 to 159, wherein

[0631] Provided herein as embodiment 166 is a method for treating a cancer, wherein X is [ka] 130. A compound or salt according to embodiment 129, wherein:

[0632] Provided herein as embodiment 167 is a method for treating a cancer, wherein X is [ka] 167. A compound or salt according to embodiment 166, wherein:

[0633] Provided herein as embodiment 168 is a method for treating a cancer, wherein X is [ka] 130. A compound or salt according to embodiment 129, wherein:

[0634] Provided herein as embodiment 169 is a method for treating a cancer, wherein X is [ka] 169. A compound or salt according to embodiment 168, wherein

[0635] Provided herein as embodiment 170 is a method for treating a cancer, wherein X is [ka] 159. The compound or salt of any one of embodiments 131 to 159, wherein

[0636] Provided herein as embodiment 171 is a method for treating a cancer, wherein X is [ka] 171. A compound or salt according to embodiment 170, wherein

[0637] Provided herein as embodiment 172 is a method for treating a cancer, wherein X is [ka] 159. The compound or salt of any one of embodiments 131 to 159, wherein

[0638] Provided herein as embodiment 173 is a method for treating a cancer, wherein X is [ka] 173. A compound or salt according to embodiment 172, wherein

[0639] Provided herein as embodiment 174 is a method for treating a cancer, wherein X is [ka] 174. A compound or salt according to embodiment 173, wherein

[0640] Provided herein as embodiment 175 is a method for treating a cancer, wherein X is [ka] [ka] 130. A compound or salt according to embodiment 129, wherein:

[0641] Provided herein as embodiment 176 is a method for treating a cancer, wherein X is [ka] 176. A compound or salt according to embodiment 175, wherein

[0642] Provided herein as embodiment 177 is a method for treating a cancer, wherein X is [ka] 177. A compound or salt according to embodiment 176, wherein:

[0643] Provided herein as embodiment 178 is a compound or salt of any one of embodiments 1 to 177, wherein Z is phenyl, and the phenyl is optionally substituted with 1 to 4 substituents.

[0644] Provided herein as embodiment 179 is a compound wherein 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 [ka] and each R N1 is independently H or CH3.

[0645] Provided herein as embodiment 180 is an alkyl group wherein each substituent is independently F, Cl, CN, OCH3, SCH3, CH2OH, or [ka] 179. A compound or salt according to embodiment 179, wherein

[0646] Provided herein as embodiment 181 is a method for treating a liver comprising administering to a subject therapies ... [ka] 181. A compound or salt according to embodiment 180, wherein

[0647] Provided herein as embodiment 182 is a compound or salt of any one of embodiments 1 to 177, wherein Z is heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, wherein heteroaryl is optionally substituted with one or more substituents.

[0648] Provided herein as embodiment 183 is a compound or salt according to embodiment 182, wherein heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

[0649] Provided herein as embodiment 184 is a compound or salt according to embodiment 183, wherein heteroaryl is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, or triazolyl.

[0650] Provided herein as embodiment 185 is a compound or salt according to embodiment 183, wherein heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0651] Provided herein as embodiment 186 is a compound or salt according to embodiment 183, wherein heteroaryl is pyrazolyl, thiazolyl, pyridyl, or pyridazinyl.

[0652] Provided herein as embodiment 187 is a compound or salt according to embodiment 186, wherein heteroaryl is pyrazolyl or pyridyl.

[0653] Provided herein as embodiment 188 is a compound or salt according to embodiment 187, wherein heteroaryl is pyrazolyl.

[0654] Provided herein as embodiment 189 is a compound or salt according to embodiment 187, wherein heteroaryl is pyridyl.

[0655] Provided herein as embodiment 190 is a compound or salt according to any one of embodiments 182 to 189, wherein heteroaryl is unsubstituted.

[0656] Provided herein as embodiment 191 is a compound or salt according to any one of embodiments 182 to 189, wherein heteroaryl is substituted with 1 to 4 substituents.

[0657] Provided herein as embodiment 192 is a compound wherein each substituent is independently 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 with 3 to 6 total ring atoms 0-2 Alkylene-cycloalkyl, C having 3-6 total ring atoms and 1-3 heteroatoms selected from N, O and S 0-2 Alkylene-heterocycloalkyl, or C 0-2 alkylene-phenyl; 1-6 Alkyl, C 2-6 Alkenyl, C 0-6 Alkylene-C 1-3 Each of the alkoxy, cycloalkyl, heterocycloalkyl, and phenyl substituents is optionally substituted with one or more further substituents, and each R N1 are independently H or C 1-3 192. A compound or salt according to embodiment 191, wherein R is alkyl.

[0658] Provided herein as embodiment 193 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving ... 1-6 Alkyl, C 2-6 Alkenyl, C0-6 Alkylene-C 1-3 Alkoxy, C 3-7 193. A compound or salt according to embodiment 192, wherein each of the cycloalkyl, heterocycloalkyl, and phenyl substituents is optionally substituted with 1 to 3 further substituents.

[0659] Provided herein as embodiment 194 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving ... 1-6 Alkyl, C 2-6 Alkenyl, C 0-6 Alkylene-C 1-3 Alkoxy, C 3-7 194. A compound or salt according to embodiment 193, wherein each of the cycloalkyl, heterocycloalkyl, and phenyl substituents is optionally substituted with one or two further substituents.

[0660] Provided herein as embodiment 195 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving ... 1-6 Alkyl, C 2-6 Alkenyl, C 0-6 Alkylene-C 1-3 Alkoxy, C 3-7 195. A compound or salt according to embodiment 194, wherein each of the cycloalkyl, heterocycloalkyl, and phenyl substituents is optionally substituted with one further substituent.

[0661] Provided herein as embodiment 196 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving ... 1-6 A compound or salt according to embodiment 192, wherein alkyl is CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, each of the foregoing optionally substituted with one or more further substituents.

[0662] Provided herein as embodiment 197 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving ... 1-6 197. A compound or salt according to embodiment 196, wherein alkyl is CH3, and CH3 is optionally substituted with one or more further substituents.

[0663] Provided herein as embodiment 198 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving ... 2-6A compound or salt according to embodiment 192, wherein alkenyl is CH=CH2, CH2CH=CH2, or CH=CHCH3, each of the foregoing independently optionally substituted with one or more further substituents.

[0664] Provided herein as embodiment 199 is a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis relieving ... 0-6 Alkylene-C 1-3 A compound or salt according to embodiment 192, wherein alkoxy 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 optionally substituted by one or more further substituents.

[0665] Provided herein as embodiment 200 is a C 0-6 Alkylene-C 1-3 199. A compound or salt according to embodiment 199, wherein alkoxy is CH(CH3)OCH3 or CH2CH2OCH3, each of the foregoing optionally substituted with one or more further substituents.

[0666] Provided herein as embodiment 201 is a compound or salt of embodiment 192, wherein cycloalkyl having 3 to 6 total ring atoms is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of the foregoing optionally substituted with one or more further substituents.

[0667] Provided herein as embodiment 202 is a compound or salt according to embodiment 201, wherein cycloalkyl having 3 to 6 total ring atoms is cyclopropyl, or cyclobutyl, each of the foregoing optionally substituted with one or more further substituents.

[0668] Provided herein as embodiment 203 are compounds or salts according to embodiment 192, wherein heterocycloalkyl having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S is azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, isoxazolidinyl, or morpholinyl, each of the foregoing optionally substituted with one or more further substituents.

[0669] Provided herein as embodiment 204 is a compound or salt of embodiment 203, wherein heterocycloalkyl having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S is azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, each of the foregoing optionally substituted with one or more further substituents.

[0670] Provided herein as embodiment 205 is a compound or salt of embodiment 204, wherein heterocycloalkyl having 3 to 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S is azetidinyl, or oxetanyl, each of the foregoing optionally substituted with one or more further substituents.

[0671] Provided herein as embodiment 206 is a compound or salt according to embodiment 192, wherein at least one substituent is Br, Cl, F, or CN.

[0672] Provided herein as embodiment 207 is a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: 1-6 A compound or salt according to embodiment 192, wherein haloalkyl is CF3, CHF2, CH2F, CH2CHF2, CH2CH2F, CH(CH2F)2, CH(CH3)CH2F, or CH(CH3)CHF2.

[0673] Provided herein as embodiment 208 is a C 1-6A compound or salt according to embodiment 192, wherein haloalkenyl is C(=CH2)CH2F.

[0674] Provided herein as embodiment 209 is a method for producing a C 0-6 A compound or salt according to embodiment 192, wherein alkylene-OH is OH, CH2OH, CH2CH2OH, CH(CH3)CH2OH, C(CH3)2OH, C(CH3)2CH2OH, or CH2C(CH3)2OH.

[0675] Provided herein as embodiment 210 is a C 0-6 Alkylene-N(R N1 )2 is NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, or CH2CH2N(CH3)2.

[0676] Provided herein as embodiment 211 is a compound wherein each further 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, cycloalkyl having 3 to 5 total ring atoms, or heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, spiro-cycloalkyl having 3 to 5 total ring atoms, or spiro-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 cycloalkyl having 3 to 5 total ring atoms 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 foregoing cycloalkyl and heterocycloalkyl groups is selected from halo or C 1-3optionally substituted with alkyl, and each R N1 are independently H or C 1-3 206. A compound or salt according to any one of embodiments 192 to 205, wherein R is alkyl.

[0677] Provided as embodiment 212 is a compound or salt according to embodiment 211, wherein each additional substituent is independently D, Br, Cl, F, OH, CH, CF, CFH, CFH, OCH, OCD, CHOCH, N(CH), (C=O)CH, oxetanyl, azetidinyl, spiro-oxetanyl, or spiro-azetidinyl; each of oxetanyl, azetidinyl, spiro-oxetanyl, and spiro-azetidinyl is optionally substituted with F, CH, or combinations thereof.

[0678] Provided herein as embodiment 213 is an alkyl group wherein each further substituent is independently D, Br, Cl, F, OH, CH3, CF3, CF2H, CFH2, OCH3, CH2OCH3, OCD3, N(CH3)2, (C=O)CH3, [ka] 213. A compound or salt according to embodiment 212, wherein

[0679] Provided herein as embodiment 214 is an alkyl group wherein each additional substituent is independently D, CH3, OCH3, OCD3, N(CH3)2, [ka] 214. A compound or salt according to embodiment 213, wherein:

[0680] Provided herein as embodiment 215 is a compound in which each of the 1 to 4 substituents 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, CH2CH2C H2OCH3, 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, CH2C (CH3)2OCD3, NH2, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2CH2NH2, CH2CH2NHCH3, CH2CH2N(CH3)2, [ka] [ka] 193. A compound or salt according to embodiment 191 or 192, wherein

[0681] Provided herein as embodiment 216 is a compound wherein each of the 1 to 4 substituents is independently CH3, CH(CH3)2, C(CH3)2OH, CH2OCD3, CH2CH2OCH3, CF2CH2OCH3, CH2CH2OCD3,CH2CH2CH2OCH3, CH2CH(CH3)OCH3, CH2C(CH3)2OCH3, [ka] 216. The compound or salt of embodiment 215, wherein

[0682] Provided herein as embodiment 217 is an alkyl group wherein each of the 1 to 4 substituents is independently CH3, C(CH3)2CH2OH, CH2CH2OCH3, CH2CH2OCD3, CH(CH3)OCH3, [ka] 216. A compound or salt according to embodiment 215, wherein:

[0683] Provided herein as embodiment 218 is an alkyl group wherein each of the 1 to 4 substituents is independently CH3, CH2CH2OCH3, [ka] 218. A compound or salt according to embodiment 217, wherein:

[0684] Provided herein as embodiment 219 is a method for treating a cancer, wherein Z is [ka] [ka] [ka] [ka] 178. The compound or salt of any one of embodiments 1 to 177, wherein

[0685] Provided herein as embodiment 220 is a method for treating a cancer, wherein Z is [ka] [ka] 220. The compound or salt of embodiment 219, wherein

[0686] Provided herein as embodiment 221 is a method for treating a cancer, wherein Z is [ka] 221. A compound or salt according to embodiment 220, wherein:

[0687] Provided herein as embodiment 222 is a method for treating a cancer, wherein Z is [ka] 221. A compound or salt according to embodiment 220, wherein:

[0688] Provided herein as embodiment 223 is a method for treating a cancer, wherein Z is [ka] [ka] 178. The compound or salt of any one of embodiments 1 to 177, wherein

[0689] Provided herein as embodiment 224 is a method for treating a cancer, wherein Z is [ka] 224. A compound or salt according to embodiment 223, wherein

[0690] Provided herein as embodiment 225 is a method for treating a cancer, wherein Z is [ka] [ka] [ka] 178. The compound or salt of any one of embodiments 1 to 177, wherein

[0691] Provided herein as embodiment 226 is a method for treating a cancer, wherein Z is [ka] 226. A compound or salt according to embodiment 225, wherein:

[0692] Provided herein as embodiment 227 is a method for treating a cancer, wherein Z is [ka] 226. A compound or salt according to embodiment 225, wherein:

[0693] Provided herein as embodiment 228 is a method for treating a cancer, wherein Z is [ka] [ka] 178. The compound or salt of any one of embodiments 1 to 177, wherein

[0694] Provided herein as embodiment 229 is a method for treating a cancer, wherein Z is [ka] 229. A compound or salt according to embodiment 228, wherein

[0695] Provided herein as embodiment 230 is a compound or salt according to any one of embodiments 1 to 177, wherein Z is a bicyclic ring comprising a heteroaryl ring having 5 or 6 total ring atoms and 1-3 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; said bicyclic ring is optionally substituted with 1 to 4 substituents.

[0696] Provided herein as embodiment 231 is a compound or salt according to embodiment 230, wherein the heteroaryl ring is pyridyl, pyridazinyl, pyr...

Claims

1. Compounds of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof (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 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 optionally substituted with 1 to 3 substituents, each substituent independently being selected from halo, C １－３ Haloalkyl, C ０－３ Alkylene OH or C ０－３ Alkylene C １－４ is 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 optionally substituted with 1 to 3 substituents, each of which 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 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 said phenyl ring, heteroaryl ring and bicyclic ring is optionally substituted with 1 to 4 substituents, each substituent 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 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, or C ０－２ alkylene-phenyl; Here, the 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 optionally substituted with 1 to 3 additional substituents, each of which 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, cycloalkyl having 3 to 5 total atoms, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, spiro-cycloalkyl having 3 to 5 total ring atoms or spiro-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 cycloalkyl having 3 to 5 total ring atoms 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 aforementioned cycloalkyl and heterocycloalkyl further substituents is optionally substituted with 1 or 2 substituents, each of which is independently halo or C １－３ is alkyl; 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 selected from N, O and S and 1 or 2 heteroatoms １－２ alkylene-heterocycloalkyl, or R １ｂ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 2】 Forming; Each R ３ are independently １－３ Alkyl, C １－３ haloalkyl, 【Chemistry 3】 , 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-cycloalkenyl having 4 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, 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 are, together with the atoms to which they are attached, a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 3 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, or a fused heterocycloalkenyl ring having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; or 【Chemistry 4】 is deuterated; Each R ４ are independently 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 ５ is C １－３ Haloalkyl, C １－６ Alkyl, C ２－４ Alkenyl, C ２－４ 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 substituent being independently selected from C １－３ Haloalkyl, C ０－６ Alkylene-OH, C ０－６ Alkylene-C １－３ 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 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 cycloalkyl having 3 to 5 total ring atoms; and Each R Ｎ１ are independently H or C １－４ alkyl).

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

3. R １ａ , R １ｂ and R ２ 3. The compound or salt of claim 1, wherein each of is H or D.

4. 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 3. The compound or salt of claim 1 or 2, which is alkylene-heterocycloalkyl.

5. R １ａ , R １ｂ , and R ２ One of the following is Br, Cl, F, CH ３ , C.H. ２ F, CHF ２ , C.F. ３ , C.H. ２ OH, OCH ３ , C.H. ２ OCH ３ , OCF ３ , C.H. ２ OCF ３ , C.N., C.H. ２ C.N., N.H. ２ , N(CH ３ ) ２ , C.H. ２ NH ２ , C.H. ２ N (CH ３ ) ２ , aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidin-1-yl-methyl, piperidin-1-yl-methyl, or morpholin-1-yl-methyl. 【Request 6】 【Chemical 5】 but, 【Chemistry 6】 2. The compound or salt of claim 1, wherein:

7. The compound or salt according to any one of claims 1 to 6, wherein m is 0.

8. The compound or salt according to any one of claims 1 to 6, wherein m is 1.

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

10. Each R ３ became independent and CH ３ , C.H. ２ CH ３ , C.F. ３ , CHF ２ , C.H. ２ F. 【Chemistry 7】 , C.N., C.H. ２ CN, OH, CH ２ OH, CH ２ CH ２ OH, OCH ３ , C.H. ２ OCH ３ , C.H. ２ CH ２ OCH ３ , oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R ３ 10. The compound or salt of claim 8 or 9, wherein, together with the atoms to which they are attached, form a fused cyclopropyl ring or a fused cyclobutyl ring.

11. m is 0; or m is 1, and R ３ is CH ３ , C.F. ３ , CHF ２ , C.H. ２ F, CN, CH ２ C.N., C.H. ２ OH, CH ２ OCH ３ 7. The compound or salt according to any one of claims 1 to 6, which is: or spiro-oxetanyl.

12. [Chemical 8] but, 【Chemistry 9】 2. The compound or salt of claim 1, wherein:

13. [Catalog 10] but, 【Chemistry 11】 13. The compound or salt of claim 12, wherein:

14. 14. The compound or salt of any one of claims 1 to 13, wherein A is N.

15. 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 The compound or salt according to any one of claims 1 to 13,

16. 16. The compound or salt according to any one of claims 1 to 15, wherein n is 0.

17. 16. The compound or salt according to any one of claims 1 to 15, wherein n is 1.

18. 16. The compound or salt according to any one of claims 1 to 15, wherein n is 2.

19. Each R ４ became independent and 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 , C.H. ２ CH ２ OCH ３ , oxo, spiro-cyclopropyl, spiro-cyclobutyl or spiro-oxetanyl.

20. [Catalog 12] but, 【Chemistry 13】 The compound or salt according to any one of claims 1 to 13,

21. [Catalog 14] but, 【Chemistry 15】 21. The compound or salt of claim 20, wherein:

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

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

24. W １ is 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 The compound or salt according to any one of claims 1 to 21,

25. W ２ The compound or salt according to any one of claims 1 to 24, wherein is N.

26. W ２ 25. The compound or salt of any one of claims 1 to 24, wherein is CH.

27. W ２ is 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 The compound or salt according to any one of claims 1 to 24,

28. W １ is CH and W ２ The compound or salt according to any one of claims 1 to 21, wherein is N.

29. R ５ is C １－３ 29. The compound or salt of any one of claims 1 to 28, which is haloalkyl.

30. R ５ is CF ３ , C.F. ２ H, C.F.H. ２ 30. The compound or salt of claim 29, wherein:

31. R ５ が、CH ３ CH ２ CH ３ CH ２ CH ２ CH ３ 、CH(CH ３ ) ２ 、CH=CH ２ 、CH=CHCH ３ 、 【Chemistry 16】 each of the foregoing is optionally substituted with 1 to 3 substituents, each substituent independently being selected from the group consisting of: １－３ Haloalkyl, C ０－６ Alkylene-OH, C ０－６ Alkylene-C １－３ 29. The compound or salt of any one of claims 1 to 28, which is 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 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O and S, or phenyl.

32. each substituent independently is 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 , cyclopropyl, cyclobutyl, or phenyl.

33. R ５ が、Br、Cl、F、OCH ３ 、SCH ３ ,H ３ ,H ２ CH ３ ,H ２ CH ２ CH ３ , HH(H) ３ ) ２ 、 【Chemistry 17】 The compound or salt according to any one of claims 1 to 28,

34. W １ is CH and W ２ is N and R ５ is CF ３ , C.F. ２ H or CFH ２ The compound or salt according to any one of claims 1 to 21,

35. 【Catalog 18】 but, 【Chemistry 19】 The compound or salt according to any one of claims 1 to 21,

36. X is 【Chemistry 20】 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 alkoxy; o is 0, 1, 2, 3, or 4; Each R ６ 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, C １－４ Alkylene-N(R Ｎ１ ) ２ , oxo, =CH ２ , a spiro-cycloalkyl having 3 to 7 total atoms, a spiro-cycloalkenyl having 4 to 7 total atoms, 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 are taken together with the atoms to which they are attached to form a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 4 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl ring 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 bonded together to form C １－３ Alkylene bridge, C ２－３ Alkenylene bridge, C １－３ Ether bridge, or C １－３ forming a thioether bridge; or Y and adjacent R ６ together with the atoms to which they are attached form a fused cycloalkyl ring having 3 to 7 total ring atoms, a fused cycloalkenyl ring having 4 to 7 total ring atoms, a fused heterocycloalkyl ring having 3 to 7 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, or a fused heterocycloalkenyl ring having 4 to 7 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S; wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl in any of the foregoing is optionally substituted with 1 to 4 substituents; 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; Each R Ｎ１ are independently H or C １－４ is alkyl, A compound or salt according to any one of claims 1 to 35.

37. X is, 【Chemical 21】 37. The compound or salt of claim 36, wherein:

38. X is, 【Chemical 22】 37. The compound or salt of claim 36, wherein:

39. X is, 【Chemical 23】 37. The compound or salt of claim 36, wherein:

40. X is, 【Chemistry 24】 37. The compound or salt of claim 36, wherein:

41. 40. The compound or salt of any one of claims 36 to 39, wherein Y is N.

42. 40. The compound or salt of any one of claims 36 to 39, wherein Y is CH.

43. 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 40. The compound or salt according to any one of claims 36 to 39,

44. 44. The compound or salt according to any one of claims 36 to 43, wherein o is 0.

45. 44. The compound or salt of any one of claims 36 to 43, wherein o is 1.

46. 44. The compound or salt of any one of claims 36 to 43, wherein o is 2.

47. 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 , C.H. ２ N (CH ３ ) ２ , oxo, =CH ２ , spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl or spiro-tetrahydrofuranyl, or two adjacent R ６ taken together with the atom to which they are attached form a fused cyclopropyl, fused cyclobutyl, or fused cyclopentyl, any of said spiro and fused rings being optionally substituted with one or two substituents, each of which 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 47. The compound or salt of any one of claims 36 to 43 or 45 to 46, which is alkylene CN.

48. each substituent independently selected from F, Cl, OH, OCH ３ , OCH ２ CH ３ 48. The compound or salt of claim 47, wherein:

49. Two non-adjacent R ６ are bonded to each other to form C １－３ Alkylene bridge, C ２－３ Alkenylene bridge, C １－３ Ether bridge, or C １－３ 47. A compound or salt according to any one of claims 36 to 43 or 46, which forms a thioether bridge.

50. Two non-adjacent R ６ are bonded to each other to form -CH ２ -, -CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, -CH ２ -CH=CH- or -CH ２ OCH ２ 50. The compound or salt of claim 49, wherein the compound or salt forms a

51. X is, 【Chemistry 25】 【Chemical 26】 37. The compound or salt according to any one of claims 1 to 36,

52. X is, 【Chemical 27】 52. The compound or salt of claim 51, wherein:

53. Z is phenyl optionally substituted with 1 to 4 substituents, each substituent independently being 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 【Chemical 28】 and each R Ｎ１ are independently H or CH ３ 53. The compound or salt according to any one of claims 1 to 52,

54. Each substituent is independently F, Cl, CN, OCH ３ , S.C.H. ３ , C.H. ２ OH, or 【Chemical formula 29】 54. The compound or salt of claim 53, wherein:

55. Z is 【Chemistry 30】 55. The compound or salt of claim 53 or 54, wherein:

56. Z is heteroaryl containing 5 or 6 total ring atoms and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with 1 to 4 substituents, each substituent 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 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, or C ０－２ alkylene-phenyl; Here, the 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 optionally substituted with 1 to 3 additional substituents, each of which 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, cycloalkyl having 3 to 5 total ring atoms, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, spiro-cycloalkyl having 3 to 5 total ring atoms, or spiro-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 cycloalkyl having 3 to 5 total ring atoms 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 aforementioned cycloalkyl and heterocycloalkyl further substituents is optionally substituted with 1 or 2 substituents, each of which is independently halo or C １－３ is alkyl; Each R Ｎ１ are independently H or C １－３ is alkyl, 53. A compound or salt according to any one of claims 1 to 52.

57. 57. The compound or salt of claim 56, wherein Z is optionally substituted with pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

58. 58. The compound or salt of claim 57, wherein Z is optionally substituted pyrazolyl or pyridyl.

59. 59. The compound or salt of any one of claims 56 to 58, wherein the heteroaryl is substituted with one or two substituents.

60. 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 ;CH 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 からますまするたりC 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 からますまするたりC 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; Here, the 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 optionally substituted with 1 to 3 additional substituents, each of which 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 60. The compound or salt of any one of claims 56 to 59, which is alkyl, cycloalkyl having 3 to 5 total ring atoms, heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S, spiro-cycloalkyl having 3 to 5 total ring atoms or spiro-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 cycloalkyl having 3 to 5 total ring atoms or a fused heterocycloalkyl having 3 to 5 total ring atoms and 1 or 2 heteroatoms selected from N, O and S.

61. 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, azetidinyl, spiro-oxetanyl or spiro-azetidinyl; each of the aforementioned oxetanyl, azetidinyl, spiro-oxetanyl and spiro-azetidinyl is selected from the group consisting of F, CH ３ 61. The compound or salt of any one of claims 56 to 60, optionally substituted with: or combinations thereof.

62. The further substituents are each independently selected from D, Br, Cl, F, OH, CH ３ , C.F. ３ , C.F. ２ H, C.F.H. ２ , OCH ３ , C.H. ２ OCH ３ , OCD ３ , N(CH ３ ) ２ , (C=O)CH ３ , 【Chemical 31】 62. The compound or salt of claim 61, wherein:

63. Each substituent 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 ２ , C(=CH ２ )CH ２ F, OH, CH ２ OH, CH ２ CH<从这里开始,原内容中存在格式错误,推测可能是重复的“ ２ ”,按照规则保留原样, CH(CH ３ ), CH ２ , C(CH ３ ), ２ , C(CH ３ ), ２ CH ２ , CH ２ C(CH ３ ), ２ , OCH ３ , OCD ３ , CH ２ OCH<从这里开始,原内容中存在格式错误,推测可能是重复的“ ３ ”,按照规则保留原样, CH ２ , OCD ３ , CH ２ CH ２ , OCH ３ , CHFCH [[ID=从这里开始,原内容中存在格式错误,推测可能是重复的“ ２ ”,按照规则保留原样 ２ , OCH ３ , CF ２ CH ２ , OCH ３ , CH ２ CH ２ , OCD ３ , CH ２ CH ２ , OCH ２ CH ３ , CH ２ CH ２ CH ２ , OCH ３ , CH 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 、 【Chemical Formula 32】 【Chemical 33】 63. The compound or salt according to any one of claims 56 to 62,

64. Each substituent is independently CH ３ 、CH(CH ３ ) ２ 、C(CH ３ ) ２ OH、CH ２ OCD ３ 、C(CH ３ ) ２ CH ２ OH、CH ２ CH ２ OCH ３ 、CF ２ CH ２ OCH ３ 、CH ２ CH ２ OCD ３ 、CH(CH ３ )OCH ３ 、CH ２ CH ２ CH ２ OCH ３ 、CH ２ CH(CH ３ )OCH ３ 、CH ２ C(CH ３ ) ２ OCH ３ 、 【Chemical Formula 34】 【Chemistry 35】 64. The compound or salt of claim 63, wherein:

65. Z is, 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 53. The compound or salt according to any one of claims 1 to 52,

66. Z is, 【Chemistry 42】 【Chemistry 43】 66. The compound or salt of claim 65, wherein:

67. Z is, 【Chemical Formula 44】 67. The compound or salt of claim 66, wherein:

68. Z is a bicyclic ring 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 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 the bicyclic ring is optionally substituted with 1 to 4 substituents, 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 53. The compound or salt of any one of claims 1 to 52, which is alkoxy.

69. Z is, 【Chemistry 45】 69. The compound or salt of claim 68, wherein:

70.

46. but 【Chemistry 47】 and 【Chemistry 48】 but 【Chemistry 49】 and 【Chemistry 50】 but 【Chemistry 51】 2. The compound or salt of claim 1, wherein:

71.

52. but 【Chemistry 53】 71. The compound of claim 70, wherein:

72. X is 【Chemical 54】 72. The compound or salt of claim 70 or 71, wherein:

73. Z is, 【Chemistry 55】 【Chemical Formula 56】 73. The compound or salt according to any one of claims 70 to 72,

74. The compound is Formula (I'): 【Chemical 57】 Formula (IA): 【Chemistry 58】 (In the formula, R Ａは ,H,Halo,CN,C １－３ Alkyl, C １－３ Haloalkyl, C ０－３ Alkylene OH or C ０－３ Alkylene-C １－４ alkoxy); Formula (IB): 【Chemical Formula 59】 ;Formula (IC): 【Chemistry 60】 (In the formula, R Ｙ H, halo, CN, C １－３ Alkyl, C １－３ Haloalkyl, C ０－３ Alkylene OH or C ０－３ Alkylene-C １－４ alkoxy); Formula (ID): 【Hua 61】 Formula (IE): 【Hua 62】 or formula (IF): 【Chemistry 63】 2. The compound or salt of claim 1, which is a compound of the formula: or a pharmaceutically acceptable salt of any of the foregoing.

75. 10. The compound of claim 1, which is a compound set forth in Table A or a pharmaceutically acceptable salt thereof.

76. 10. The compound of claim 1, which is a compound set forth in Table E or a pharmaceutically acceptable salt thereof.

77. 77. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 76 and a pharmaceutically acceptable excipient.

78. A compound or salt according to any one of claims 1 to 76, or a pharmaceutical composition according to claim 77, for use as a medicament.

79. A compound or salt according to any one of claims 1 to 76 or a pharmaceutical composition according to claim 77 for use in the treatment of cancer.

80. 78. A compound or salt according to any one of claims 1 to 76 or a pharmaceutical composition according to claim 77 for use in the treatment of cancer, wherein one or more of the cancer cells express a KRAS G12C mutant protein.

81. 81. The compound or salt of claim 79 or 80, 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, or a solid tumor.

82. 78. Use of a compound or salt according to any one of claims 1 to 76 or a pharmaceutical composition according to claim 77 in the preparation of a medicament for treating cancer.

83. 78. Use of a compound or salt according to any one of claims 1 to 76 or a pharmaceutical composition according to claim 77 in the preparation of a medicament for treating cancer, wherein one or more of the cancer cells express a KRAS G12C mutant protein.

84. 84. The use of claim 82 or 83, 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, or a solid tumor.

85. 78. 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 76 or a pharmaceutical composition of claim 77.

86. 86. The method of claim 85, wherein one or more of the cancer cells express a KRAS G12C mutant protein.

87. 87. The method of claim 85 or 86, 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 cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma or a solid tumor.

88. 88. The method of any one of claims 85-87, 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.

89. 89. The method of any one of claims 85-88, further comprising the simultaneous, separate, or sequential administration of 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.

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