Compounds, compositions, and methods

Abstract

The present disclosure relates generally to small molecule inhibitors of the 1 (SARM1) protein containing sterile alpha and TIR motif, or pharmaceutically acceptable salts thereof, isotopically enriched analogs, stereoisomers, mixtures or prodrugs of stereoisomers, methods and intermediates for their preparation, and methods of their use.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Publication Number (43) Publication Date (21) Application Number 202480068924.7 (22) Application Date 2024.09.05 (30) Priority Data 63 / 580,981 2023.09.06 US (85) PCT International Application Entering National Phase Date 2026.04.27 (86) PCT International Application Application Data PCT / US2024 / 045443 2024.09.05 (87) PCT International Application Publication Data WO2025 / 054368 EN 2025.03.13 (71) Applicant: Tengwei Therapeutics Company Address: California, USA (72) Inventors: A.L. Baghdad Salian, C. Buch, J. De Vincent Fedalgo, A.A. Estrada, B.M. Fox, B.J. Huffman, Naoshi Miyamoto, M. Osipov, A. Tottumkala (74) Patent Agency: Beijing Kunrui Law Firm, 11494 Patent Attorney: Feng Xinqin (51) Int.Cl. A61K 31 / 167 (2006.01) A61K 31 / 4155 (2006.01) A61K 31 / 4178 (2006.01) A61K 31 / 4192 (2006.01) A61K 31 / 4196 (2006.01) A61K 31 / 4245 (2006.01) A61K 31 / 439(2006.01) C07D 211 / 10(2006.01) C07D 231 / 12(2006.01) C07D 233 / 64(2006.01) C07D 249 / 06(2006.01) C07D 249 / 08(2006.01) C07D 271 / 10(2006.01) (54) Invention Name Compounds, Compositions and Methods (57) Abstract This disclosure generally relates to small molecule inhibitors of the 1 (SARM1) protein containing sterile α and TIR motifs, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers or prodrugs thereof, methods of their preparation and intermediates, and methods of their use. Claims (22 pages), Description (262 pages), Serial Number (electronic publication) CN 122138828 A 2026.06.02 CN 1 22 13 88 28 A 1. A compound of formula I: I or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X1 is N, NR8a, O, S, or CR6a; X2 is N, NR8b, O, S, or CR6b;X3 is N, NR8c, or CR6c; X4 is N or CR6d; the condition is that at least one of X1, X2, X3, and X4 is N, and the ring containing X1, X2, X3, and X4 is aromatic; R is -NR2R3, -OR7, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups; R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; R3 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; or R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups; R4 represents hydrogen, halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R 11)2、-OC(O)N(R 11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted with one to five Z1 groups; R5 is hydrogen, halogroup, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2、-OR 11、-SR11、-C(O)R11、-C(O)OR11、-S(O)R11、-S(O)2R 11、-C(O)N(R11)2、-NR 11C(O)R11、-NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted with one to five Z1 groups; R6a, R6b, R6c and R6d are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R 11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted with one to five Z1 substituted groups; R7 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted with one to five Z1 substituted groups; R8a, R8b, and R8c are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl are independently and optionally substituted with one to five Z1 groups; or R8a and R6b, or R8b and R6c, or R6b and R6c, or R8c and R6d, or R6c and R6d together form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further be independently and optionally substituted with one to five Z1 groups; Each Z1 is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12. ‑SR12, ‑C(O)R12, ‑C(O)OR12, ‑S(O)R12, ‑S(O) 2R 12. ‑C(O)N(R12)2, ‑NR 12C(O)R12, ‑NR12S(O)R12, ‑NR12S(O)2R 12. ‑S(O)N(R12)2, ‑S(O)2N(R 12)2, ‑NR12C(O)N(R12)2, ‑NR 12S(O)N(R12)2, ‑NR 12S(O)2N(R 12)2, ‑OC(O)N(R 12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1a; each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; Each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; each R12 group is independently hydrogen, a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each Z1a group is independently a halogroup, cyanogroup, -NO2, a C1-6 alkyl, a C2-6 alkenyl, a C2-6 ynyl, a C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, or -OR. 13. ‑SR13, ‑C(O)R13, ​​‑C(O)OR13, ‑S(O)R13, ​​‑S(O)2R 13. ‑C(O)N (R13)2, ‑NR 13C(O)R13, ​​‑NR13S(O)R13, ​​‑NR13S(O)2R 13. ‑S(O)N(R13)2, ‑S(O)2N(R 13)2, ‑NR 13C(O)N (R13)2, ‑NR 13S(O)N(R13)2, ‑NR 13S(O)2N(R 13)2, ‑OC(O)N(R 13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1b groups;Each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1b is independently halogroup, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 Haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C (O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl claims 2 / 22 page 3 CN 122138828 A and heteroaryl is further independently and optionally substituted by one to five independently selected substituents: halogroup, cyanogroup, - OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl; The condition is that at least one of A, B, C, D, or E is present: A. X1 is N and X2 is NR8b; and a. When R is C1-6 alkyl; the C1-6 alkyl is substituted with a halogroup or a C3-10 cycloalkyl and optionally one to four Z1 groups; and / or b. R8b is not hydrogen; and / or c. When R is -OR7; then R7 is not methyl, ethyl, isopropyl, tert-butyl, 2-bromoethyl, 2-methoxyethyl, or 2-cyanoethyl.The compound is not: B. X2 is N or NR8b; and R is -NR2R3; and a. R2 and R3 are not simultaneously methyl; and / or b. when X1 is O, at least one of R8b, R8c, R6c or R6d is not hydrogen; and the compound is not: C. X1 is N or CR6a, X2 is O, X3 is N or CR6c, and X4 is N; and a. when R is C1-6 alkyl, the C1-6 alkyl is substituted with one to five Z1; and / or b. R6c is not 4-amino-2-[(3,4-methyl)-2-[(3,4-methyl)-2-methyl]-2-methyl ... [,5-trimethoxyphenyl)amino]-5-thiazolyl, [[4-(1-pyrrolidinylmethyl)phenyl]amino]-5-thiazolyl, or [[6-(4-methyl-1-hexahydropyrazinyl)-3-pyridinyl]amino]-5-thiazolyl; and / or c. when R is -OR7, then R7 is not isobutyl or tert-butyl; and the compound is not: D. X1 is O, X2 is N or CR6b, X3 is CR6c, X4 is N, and R6c is not hydrogen; and R is -NR2R3, wherein R2 and R3 together form a heterocyclic group, which may be further independently optionally substituted by one to five Z1; and at least one of the following a. to d. appears: a. X2 is N; b. R1 is not methyl; c. R2 and R3 form an optionally substituted bridging heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; d. R2 and R3 form an optionally substituted monocyclic 7-membered heterocyclic group, optionally fused to an aryl or heteroaryl ring; and the compound is not: Claim 4 / 22 page 5 CN 122138828 A Claim 5 / 22 page 6 CN 122138828 A E. R is, where q is 0, 1, 2, 3, 4 or 5; and p is 0, 1, 2 or 3. 2. A compound of formula II: II or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X3 is N or CR6c; X4 is N or CR6d; R is -NR2R3, -OR7, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl; wherein the C1-6 alkyl is substituted with a halogroup or C3-10 cycloalkyl and optionally one to four Z1 substitutions; and wherein the C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 substitutions; R1 is a halogroup, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, or C3-6 alkenyl is substituted with a halogroup, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, or C3-6 alkenyl is substituted with a halogroup, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl;R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkenyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkenyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; R3 is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkenyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkenyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; or R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups. R4 represents hydrogen, halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R 11)2, -OC(O)N(R 11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted with one to five Z1 groups; R5 is hydrogen, halogroup, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R 11, -C(O)N(R11)2, -NR 11C(O)R11, -NR11S(O)R11, -NR11S(O)2R 11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted with one to five Z1 groups;R6c and R6d are each independently hydrogen, halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR 11S(O)2N(R 11)2, -OC(O)N(R 11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted with one to five Z1 groups; Claims 6 / 22, page 7, CN 122138828, A, R7 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; R8b is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; or R8b and R6c, or R6c and R6d together form a 5-membered heterocyclic group, which may further be independently and optionally substituted with one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR 12. ‑SR12, ‑C(O)R12, ‑C(O)OR12, ‑S(O)R12, ‑S(O) 2R 12. ‑C(O)N(R12)2, ‑NR 12C(O)R12, ‑NR12S(O)R12, ‑NR12S(O)2R 12.‑S(O)N(R12)2,‑S(O)2N(R 12)2,‑NR12C(O)N(R12)2,‑NR 12S(O)N(R12)2,‑NR 12S(O)2N(R 12)2,‑OC(O)N(R 12)2 or‑NR12C(O)OR12; whereEach C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; each R11 is independently hydrogen, a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; Each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; each R12 group is independently hydrogen, a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each Z1a group is independently a halogroup, cyanogroup, -NO2, a C1-6 alkyl, a C2-6 alkenyl, a C2-6 ynyl, a C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, or -OR. 13. ‑SR13, ‑C(O)R13, ​​‑C(O)OR13, ‑S(O)R13, ​​‑S(O)2R 13. ‑C(O)N (R13)2, ‑NR 13C(O)R13, ​​‑NR13S(O)R13, ​​‑NR13S(O)2R 13. ‑S(O)N(R13)2, ‑S(O)2N(R 13)2, ‑NR 13C(O)N (R13)2, ‑NR 13S(O)N(R13)2, ‑NR 13S(O)2N(R 13)2, ‑OC(O)N(R 13) 2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each R13 group is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each Z1b group is independently halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 halogroup, or C2-6 alkenyl.Alkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C (O)-、-C(O)O-、-C(O)NH-、-C(O)N(C1-6 alkyl)-、-C(O)N(C2-6 alkenyl)-、-C(O)N(C2-6 alkynyl)-、-C(O)N(C1-6 haloalkyl)-、-C(O)N(C3-10 cycloalkyl)-、-C(O)N(heterocyclic)-、-C(O)N(aryl)-、-C(O)N(heteroaryl)-、-NHC(O)O-、-NHC(O)NH-、-NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, and aryl groups in Z1b and L is claimed on page 7 / 22 of 8 CN. 122138828 A and the heteroaryl group are further independently and optionally substituted by one to five independently selected substituents from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl; provided that: when R is -OR7; then R7 is not methyl, ethyl, isopropyl, tert-butyl, 2-bromoethyl, 2-methoxyethyl, 2-cyanoethyl, 2-phenylethyl, benzyl, or 9H-fluorene-9-ylmethyl; and the compound is not: . 3. A compound of formula III: III or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X1 is N, NR8a, O, S, or CR6a; X2 is N or NR8b; X3 is N, NR8c, or CR6c; X4 is N or CR6d; provided that the ring containing X1, X2, X3, and X4 is aromatic; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynylyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynylyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups;R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; R3 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; or R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups; R4 represents hydrogen, halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R 11)2, -OC(O)N(R 11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted with one to five Z1 groups; R5 is hydrogen, halogroup, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R 11, -C(O)N(R11)2, -NR 11C(O)R11, -NR11S(O)R11, -NR11S(O)2R 11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted with one to five Z1 groups;R6a, R6b, R6c, and R6d are each independently hydrogen, halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR 11S(O)N(R11)2, -NR 11S(O)2N(R 11)2, -OC(O)N(R 11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1 substituted groups; R8a, R8b and R8c are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1 substituted groups; R6a and R8b, R8b and R6c, or R8c and R6d, or R6c and R6d together form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may be further independently and optionally substituted by one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R 12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; whereinEach C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; Each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each Z1a is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R 13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2, -OC(O)N(R13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted by one to five Z1b; each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; Each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each Z1b group is independently a halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; andEach L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C (O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups in Z1b and L is further independently and optionally substituted by one to five independently selected substituents from: halogroup, cyanogroup, - OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl; The conditions are: R2 and R3 are not simultaneously methyl; when X1 is O, at least one of R8b, R8c, R6c, or R6d is not hydrogen; and the compound is not: . Claims 10 / 22, page 11, CN 122138828 A 4. A compound of formula IV: IV or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X1 is N or CR6a; X3 is N or CR6c; R is -NR2R3, -OR7, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl or C3-10 cycloalkyl; wherein the C1-6 alkyl is substituted with one to five Z1s; and wherein the C2-6 alkenyl, C2-6 ynyl or C3-10 cycloalkyl is optionally substituted with one to five Z1s; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups; R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted with one to five Z1 groups;R3 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; or R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups; R4 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR 11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted with one to five Z1 groups; R5 represents hydrogen, halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R) 11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted with one to five Z1 groups; R6a and R6c are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR 11C(O)N(R11)2, -NR 11S(O)N(R11)2, -NR 11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted with one to five Z1 groups; R7 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O) Claims 11 / 22 pages 12 CN 122138828 A 2R 12, -C(O)N(R12)2, -NR 12C(O)R12, -NR12S(O)R12, -NR12S(O)2R 12, -S(O)N(R12)2, -S(O)2N(R 12)2, -NR12C(O)N(R12)2, -NR 12S(O)N(R12)2, -NR 12S(O)2N(R 12)2, -OC(O)N(R 12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1a. Each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; each R11 is independently hydrogen, a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups;Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1a is independently a halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR 13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR 13C(O)N(R13)2, -NR 13S(O)N(R13)2, -NR 13S(O)2N(R13)2, -OC(O)N(R13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted by one to five Z1b; each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; Each of the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups is independently and optionally substituted with one to five Z1b groups; each Z1b group is independently a halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 Haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups in Z1b and L is further independently and optionally substituted by one to five independently selected substituents from: halogroup, cyanogroup, - OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl; The condition is that R6c is not 4-amino-2-[(3,4,5-trimethoxyphenyl)amino]-5-thiazolyl, [[4-(1-pyrrolidinylmethyl)phenyl]amino]-5-thiazolyl, or [[6-(4-methyl-1-hexahydropyrazinyl)-3-pyridyl]amino]-5-thiazolyl; and when R is -OR7, R7 is not isobutyl or tert-butyl; and the compound is not: Claims 12 / 22, page 13, CN 122138828 A. 5. A compound of formula V: V or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X2 is N or CR6b; R1 is a halogroup, cyanogroup, C1-3 alkyl group, C2-3 alkenyl group, C2-3 ynyl group, or C3-6 cycloalkyl group; wherein the C1-6 alkyl group, C2-6 alkenyl group, C2-6 ynyl group, or C3-10 cycloalkyl group is optionally substituted with one to five Z1 groups; R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups; R4 is hydrogen, halogroup, cyanogroup, C1-6 alkyl group, C2-6 alkenyl group, C2-6 ynyl group, C3-10 cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -N(R11)2, -OR group. 11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6The alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; R5 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR 11S(O)N(R11)2, -NR 11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one to five Z1 groups; R6b is hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR 11C (O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1 groups; R6c represents halogenated, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R)11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; or R6b and R6c together form a 5-membered heterocyclic group, which may be further independently and optionally substituted with one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R 12、-C(O)N(R12)2、-NR 12C(O)R12、-NR12S(O)R12、-NR12S(O)2R 12、-S(O)N(R12)2、-S(O)2N(R 12)2、- Claims 13 / 22 Page 14 CN 122138828 A NR12C(O)N(R12)2、-NR 12S(O)N(R12)2、-NR 12S(O)2N(R 12)2、-OC(O)N(R 12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1a; each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; Each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; each R12 group is independently hydrogen, a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each Z1a group is independently a halogroup, cyanogroup, -NO2, a C1-6 alkyl, a C2-6 alkenyl, a C2-6 ynyl, a C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, or -OR.13. ‑SR13, ‑C(O)R13, ​​‑C(O)OR13, ‑S(O)R13, ​​‑S(O)2R 13. ‑C(O)N (R13)2, ‑NR 13C(O)R13, ​​‑NR13S(O)R13, ​​‑NR13S(O)2R 13. ‑S(O)N(R13)2, ‑S(O)2N(R 13)2, ‑NR 13C(O)N (R13)2, ‑NR 13S(O)N(R13)2, ‑NR 13S(O)2N(R 13)2, ‑OC(O)N(R 13) 2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b; each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b; Each Z1b is independently a halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Each of the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl groups in Z1b and L is further independently and optionally substituted by one to five independently selected substituents from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl; provided that at least one of the following is present: X2 is N; or R1 is not methyl; or R2 and R3 form an optionally substituted bridging heterocyclic group, optionally fused to an aryl or heteroaryl ring; or R2 and R3 form an optionally substituted monocyclic 7-membered heterocyclic group, optionally fused to an aryl or heteroaryl ring; and the compound is not: Claims 14 / 22 pages 15 CN 122138828 A Claims 15 / 22 pages 16 CN 122138828 A. 6. The compound according to any one of claims 1-5, wherein R or the portion is optionally fused to a C6 aryl group; wherein: q is 0, 1, 2 or 3; r is 0 or 1; s is 0, 1 or 2; t is 1 or 2; X is CH2, CHZ1, C(Z1)2, NR9, O or S; and R9 is H or Z1. 7. A compound of formula VI: VI or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: Claims 16 / 22 pages 17 CN 122138828 A X1 is N, NR8a, O, S, or CR6a; X2 is N, NR8b, O, S, or CR6b; X3 is N, NR8c, or CR6c; X4 is N or CR6d; The condition is that at least one of X1, X2, X3, and X4 is N, and the ring containing X1, X2, X3, and X4 is aromatic; q is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is independently and optionally substituted by one to five Z1 groups; R4 is hydrogen, halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R 11. ‑S(O)N(R11)2, ‑S(O)2N(R 11)2, ‑NR 11C(O)N(R11)2, ‑NR 11S(O)N (R11)2, ‑NR 11S(O)2N(R11)2, -OC(O)N(R 11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are independently and optionally substituted with one to five Z1 groups; R5 is hydrogen, halogroup, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R 11, -C(O)N(R11)2, -NR 11C(O)R11, -NR11S(O)R11, -NR11S(O)2R 11. -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are independently and optionally substituted with one to five Z1 groups; R6a, R6b, R6c and R6d are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 10. ‑SR10, ‑C(O)R11, ‑C(O)OR11, ‑S(O)R11, ‑S(O) 2R 11. ‑C(O)N(R11)2, ‑NR 11C(O)R11, ‑NR11S(O)R11, ‑NR11S(O)2R 11. ‑S(O)N(R11)2, ‑S(O)2N(R 11)2, ‑NR11C(O)N(R11)2, ‑NR 11S(O)N(R11)2, ‑NR 11S(O)2N(R 11)2, ‑OC(O)N(R 11) 2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; R8a, R8b, and R8c are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; or R8a and R6b, or R8b and R6c, or R6b and R6c, or R8c and R6d, or R6c and R6d together form a 5-membered cycloalkyl or a 5-membered heterocycle.The group may be further independently and optionally substituted by one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR 12S(O)N(R12)2, -NR 12S(O)2N(R12)2, -OC(O)N(R12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1a; Claims 17 / 22 pages 18 CN 122138828 A Each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1a; each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; Each Z1a is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR 13S(O)N(R13)2, -NR 13S(O)2N(R 13)2, -OC(O)N(R 13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1b; each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1b; Each Z1b is independently a halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl group of Z1b and L is further optionally and independently substituted by one to five substituents independently selected from: haloyl, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl. 8. The compound according to any one of claims 1-5 or 7, wherein R, the portion or the portion is; wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3;Ring B is a C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1b groups; and L1 is a bond, C1-4 alkylene, C2-4 alkenyl, or C2-4 ynylene. 9. The compound of claim 7 or 8, wherein p is 1. 10. The compound of claim 6, 7, or 8, wherein q is 1 or 2. 11. The compound of any preceding claim, wherein R1 is a halogroup, cyano, C1-3 alkyl, C1-3 haloalkyl, or C3-6 cycloalkyl, optionally substituted with a cyano or methyl group. 12. The compound of any preceding claim, wherein R1 is fluorine, chlorine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclobutyl, or cyclopropyl, optionally substituted with a cyano or methyl group. 13. The compound of any preceding claim, wherein R1 is chloro, cyano, or trifluoromethyl. 14. The compound of any preceding claim, wherein R4 is hydrogen or a C1-6 alkyl group. 15. The compound of any preceding claim, wherein R4 is hydrogen or methyl. 16. The compound of any preceding claim, wherein R5 is hydrogen or a halogroup. 17. The compound of any preceding claim, wherein R5 is hydrogen or fluorine. 18. The compound of claim 1 or 7, wherein the moiety is , ... 21. A pharmaceutical composition comprising any of the compounds of any preceding claim or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers, and a pharmaceutically acceptable carrier. 22. A method for inhibiting SARM1 activity, the method comprising contacting cells with an effective amount of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers, or the pharmaceutical composition of claim 21. 23. The method of claim 22, wherein the contact is in vivo. Claims 19 / 22 pages 20 CN 122138828 A 24. A method for treating a disease or ailment at least partially mediated by SARM1, the method comprising administering to a subject in need an effective amount of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers, or the pharmaceutical composition of claim 21.25. A method for inhibiting axonal degeneration, the method comprising administering to a subject in need an effective amount of the compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21. 26. A method for treating neurodegeneration or a neurological disease or condition, the method comprising administering to a subject in need an effective amount of the compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21. 27. The method of claim 26, wherein the neurodegeneration or neurological disease or condition is associated with axonal degeneration, axonal damage, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI), leukodystrophy, or leukodystrophy. 28. The method of claim 24, wherein the disease or disorder is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Peyreke-Merck disease, periventricular leukomalacia, spherical leukodystrophy (Clapey's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS). Lew-Jarrig disease, Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty-Sachs disease, Gaucher's disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, retinitis pigmentosa, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphotropic virus 1 Type 1 (HTLV-1) related myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalitis,29. A method for treating chemotherapy-induced peripheral neuropathy (CIPN), comprising administering to a subject in need an effective amount of any one of the compounds of claims 1-20 or a pharmaceutically acceptable salt thereof, an isotopically enriched analogue, a stereoisomer, a tautomerism, or a mixture of stereoisomers or the pharmaceutical composition of claim 21. 30. The use of any compound of claims 1-20 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21, for the treatment of diseases or ailments at least in part mediated by SARM1. (Pages 21, CN 122138828 A) 31. The use as described in claim 29, wherein the disease or ailment is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Peyreke-Merck disease, periventricular leukomalacia, spherical leukodystrophy (Clapey's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS), The following are listed as potential complications of chemotherapy: Lew-Jaliger disease, Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty-Sachs disease, Gaucher's disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, and human T-lymphotropic virus type 1 (HTLV-1)-related spinal cord injury.Myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Shamadoosan disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axononeuropathy (AMAN). 32. The compound of any one of claims 1-20 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21, used in therapy. 33. The compounds of any one of claims 1-20, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, tautomers, or mixtures of stereoisomers thereof, or the pharmaceutical composition of claim 21, for the treatment of spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukodystrophy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Peyreke-Merck disease, periventricular leukomalacia, spherical leukodystrophy (Clapey's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Luke Jariger's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tai-Sachs disease, Gaucher disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Basen- Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paresis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Shamadudine disease, motor neuron diseaseDiseases, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear paralysis (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome or severe acute motor axononeuropathy (AMAN). Claims 21 / 22 pages 22 CN 122138828 A 34. The use of any compound of claims 1-20 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21, for the manufacture of an agent for the treatment of: spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Peyre-Merck disease, periventricular leukomalacia, spherical leukodystrophy (Clapey's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Luke Jariger's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tey-Sachs disease, Gaucher disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma. Ocular, tropical spastic paralysis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Shamadoocin disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy,HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome or severe acute motor axonal neuropathy (AMAN). Claims 22 / 22 pages 23 CN 122138828 A Cross-reference to related applications of compounds, compositions and methods

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 580,981, filed September 6, 2023, pursuant to 35 USC § 119(e), the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0002] This disclosure generally relates to small molecule regulators of the 1 (SARM1) protein containing sterile α and TIR motifs and their use as therapeutic agents. Background Art

[0003] Neurodegenerative diseases are a class of progressive neurological disorders in which nerve cells malfunction and eventually die. Neuronal degeneration in patients with neurodegenerative diseases can manifest as a variety of symptoms, including changes in mood and behavior, irritability, sensory disturbances, motor and cognitive difficulties, and memory loss. These symptoms may progress to immobility or speech impairment, dementia, and ultimately death.

[0004] Axonal degeneration has been identified as an important pathology in most neurodegenerative diseases. Axons are susceptible to both mechanical damage (Wallerian degeneration) and disease (Wallerian-like degeneration).

[0005] In healthy axons, the N-terminus of SARM1 interacts with the TIR domain, preventing TIR dimerization and subsequent enzymatic cleavage of NAD+. However, under conditions of neuronal damage or disease, the N-terminal-TIR domain interaction of SARM1 is disrupted, leading to TIR multimerization, followed by rapid loss of NAD+ and associated axonal degeneration.

[0006] This invention provides compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, that can be used to treat and / or prevent diseases at least partially mediated by SARM1.

[0007] In some embodiments, compounds that inhibit SARM1 are provided.

[0008] In another embodiment, a pharmaceutical composition is provided comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0009] In another embodiment, a method for treating a disease or ailment at least partially mediated by SARM1 is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0010] This disclosure also provides compositions, including pharmaceutical compositions; kits, which comprise said compounds or pharmaceutically acceptable salts thereof.The present disclosure further provides methods for using (or administering) and preparing said compound or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers or prodrugs thereof; and intermediates thereof.

[0011] The present disclosure further provides methods for using said compound or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers or prodrugs thereof, or compositions thereof, for treating diseases, symptoms or disorders at least partially mediated by SARM1. Specification 1 / 262 pages 24 CN 122138828 A

[0012] In addition, the present disclosure provides the use of said compound or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers or prodrugs thereof, or compositions thereof, in manufacturing medicaments for treating diseases, symptoms or disorders at least partially mediated by SARM1.

[0013] The summary of this invention describes exemplary embodiments of the present technology. However, it should be understood that such summary is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0014] 1. Definition: A dash (“-”) not between two letters or symbols is used to indicate the connection point of a substituent. For example, -C(O)NH2 is connected by carbon atoms. A dash at the beginning or end of a chemical group is for convenience; a chemical group may be depicted with or without one or more dashes without losing its ordinary meaning. A wavy or dashed line drawn through a line in a structure indicates the designated connection point of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0015] The prefix “Cu-v” indicates that the following group has u to v carbon atoms. For example, “C1-6 alkyl” indicates that an alkyl group has 1 to 6 carbon atoms.

[0016] References herein to “about” a value or parameter include (and describe) embodiments relating to said value or parameter itself. In some embodiments, the term “about” includes an indicated amount ± 10%. In other embodiments, the term “about” includes an indicated amount ± 5%. In some other embodiments, the term “about” includes an indicated amount ± 1%. Furthermore, the term “about X” includes a description of “X”. Unless the context clearly specifies otherwise, the singular forms “a” and “said” also include plural indicators. Thus, for example, a reference to “compound” includes a variety of such compounds, and a reference to “test” includes a reference to one or more tests and their equivalents known to those skilled in the art.

[0017] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e.Alkyl groups consist of 1 to 12 carbon atoms (i.e., C1 to 12 alkyl groups), 1 to 8 carbon atoms (i.e., C1 to 8 alkyl groups), 1 to 6 carbon atoms (i.e., C1 to 6 alkyl groups), or 1 to 4 carbon atoms (i.e., C1 to 4 alkyl groups). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by a chemical name or identified by a molecular formula, it can cover all positional isomers having that number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0018] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl", divalent "aryl", and divalent heteroaryl can also be referred to as "alkylene" or "alkylenyl" (e.g., methylene, ethylene, and propylene), "arylene" or "arylenyl" (e.g., phenylene or naphthylene, or quinolinyl for heteroaryl). Furthermore, unless otherwise explicitly indicated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last mentioned group contains the atoms used by which said moiety is attached to the remainder of the molecule.

[0019] "Alkenyl" refers to an alkyl group containing at least one (e.g., 1-3 or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 12 carbon atoms (i.e., C2-12 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include, for example, vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0020] "Alkynyl" refers to an alkyl group containing at least one (e.g., 1-3 or 1) carbon-carbon linkage and having 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 12 carbon atoms (i.e., C2-12 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl) or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term "alkynyl" also includes those groups having one linkage and one double bond.

[0021] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include (e.g.) methoxy, ethoxy, and propoxy.The groups are: alkyl, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0022] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl".

[0023] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O)2-". "Alkylsulfonylalkyl" refers to -alkyl-S(O)2-alkyl.

[0024] "Acyl" refers to the group -C(O)Ry, wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. Examples of acyl groups include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0025] “Amide group” means both “C-amide group” (which refers to the group -C(O)NRyRz) and “N-amide group” (which refers to the group -NRyC(O)Rz), wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each may optionally be substituted as defined herein, or Ry and Rz together form a cycloalkyl or heterocyclic group; each may optionally be substituted as defined herein.

[0026] “Amino group” means the group -NRyRz, wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each may optionally be substituted as defined herein.

[0027] “Formamidinyl” refers to -C(NRy)(NRz2), wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein.

[0028] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbocyclic atoms (i.e., C6-12 aryl), or 6 to 10 carbocyclic atoms (i.e., C6-10 aryl). Examples of aryl include, for example, phenyl, naphthyl, fluorenyl, and anthracene. However, aryl never in any way encompasses or overlaps with heteroaryl as defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl, regardless of the junction point. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic group, regardless of the bonding point. If one or more aryl groups are fused with a cycloalkyl group, the resulting ring system is a cycloalkyl group, regardless of the bonding point.

[0029] "Arylalkyl" or "arylalkyl" refers to the group "aryl-alkyl-".

[0030] "Carbamoyl" refers to "O-carbamoyl" (which refers to the group -O-C(O)NRyRz) and "N-carbamoyl".(It refers to the group -NRyC(O)ORz) both, wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each may optionally be substituted as defined herein.

[0031] “Carboxyl ester” or “ester” refers to both -OC(O)Rx and -C(O)ORx, wherein Rx is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each may optionally be substituted as defined herein.

[0032] “Cyanoalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 or 2) hydrogen atoms are substituted with a cyano (-CN) group.

[0033] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings (including fused, bridged and spirocyclic systems). The term "cycloalkyl" includes cycloalkenyl (i.e., a cyclic group having at least one double bond) and a carbocyclic fused ring system having at least one sp3 carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Multiple specification 3 / 262 pages 26 CN 122138828 A Cyclic groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Furthermore, the term cycloalkyl is intended to cover any non-aromatic ring that can fused to an aryl ring, regardless of its connection to the rest of the molecule. Additionally, cycloalkyl also includes "spirocycloalkyl" when two substitution positions are present on the same carbon atom, such as spiro[2.5]octyl, spiro[4.5]dodecyl, or spiro[5.5]undecyl.

[0034] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0035] “Imine” means the group -C(NRy)Rz, wherein Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein.

[0036] “Imidyl” means the group -C(O)NRyC(O)Rz, wherein Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein.

[0037] “Halogen” or “halogenated” means an atom occupying Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0038] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are halogenated. For example, if a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may be (but are not necessarily) the same halogen. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0039] "Haloalkoxy" refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are halogenated.

[0040] "Haloalkoxyalkyl" refers to an alkoxyalkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are halogenated.

[0041] "Hydroxyalkyl" refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are hydroxylated.

[0042] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently substituted with the same or different heteroatom groups, provided that the connection point with the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, 1, 2, or 3 carbon atoms may be independently substituted with the same or different heteroatom groups. Heteroatomic groups include (but are not limited to) -NRy-, -O-, -S-, -S(O)-, -S(O)2-, etc., wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each may optionally be substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.), and amines (e.g., -CH2NR yCH3, -CH(CH3)NR yCH3, -CH2CH2NR yCH3, -CH2CH2NR yCH2CH2NR yCH3, etc.), wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heterocyclic.Aryl groups; each of which may optionally be substituted as defined herein). As used herein, heteroalkyl groups comprise 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0043] "Heteroaryl" means an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 cyclic carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl), and 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatom, independently selected from nitrogen, oxygen, and sulfur. In some cases, heteroaryl groups include 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently described in the specification 4 / 262 page 27 CN 122138828 A, having 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzooxazolyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazolyl, indazole, indolyl, indazole, isoindolyl, isoquinolinyl, isoxazolyl, acetyl, oxadiazolyl, oxazolyl, 1-pyridyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide. 1-Opyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include (but are not limited to) benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazole, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group can be linked through any ring of the fused system. Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of the connection of the rest of the molecule (i.e., linked through any of the fused rings). Heteroaryl does not encompass or overlap with aryl groups as defined above.

[0044] “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.

[0045] “Heterocyclic group” refers to a saturated or partially unsaturated cyclic alkyl group, wherein one or more cyclic heteroatoms are independently selected from…Nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. Heterocyclic groups can be a single ring or multiple rings, wherein multiple rings can be fused, bridged, or spirocoupled, and can contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O-) moieties. Non-aromatic rings containing at least one heteroatom are considered heterocyclic groups, regardless of linkage (i.e., bonding via carbon atoms or heteroatoms). Furthermore, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom, which can be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of the linkage of the rest of the molecule. As used herein, a heterocyclic group has 2 to 20 cyclic carbon atoms (i.e., C2-20 heterocyclic group), 2 to 12 cyclic carbon atoms (i.e., C2-12 heterocyclic group), 2 to 10 cyclic carbon atoms (i.e., C2-10 heterocyclic group), 2 to 8 cyclic carbon atoms (i.e., C2-8 heterocyclic group), 3 to 12 cyclic carbon atoms (i.e., C3-12 heterocyclic group), 3 to 8 cyclic carbon atoms (i.e., C3-8 heterocyclic group), or 3 to 6 cyclic carbon atoms (i.e., C3-6 heterocyclic group); and has 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomium, independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include, for example, aziridine, aziridine, benzo[b][1,4]dioxane, 1,4-benzodioxane, benzopyranyl, benzodioxane-hexenyl, benzopyranone, benzofuranone, dioxane, dihydropyranyl, hydrogenpyranyl, thiophene[1] [3] Dithiazinyl, decahydroisoquinolinyl, furanoneyl, imidazolinyl, imidazoalkyl, indololinyl, inazinyl, isoindololinyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxohexahydropyrazinyl, 2-oxohexahydropyridyl, 2-oxopyrrolidinyl, oxazolyl, epoxyethyl, oxacyclobutyl, phenthiazinyl, phenoxazinyl, hexahydropyridyl, hexahydropyrazinyl, 4-hexahydropyridinoneyl, pyrrolidinyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, tetrahydropyranyl, trithiazinyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. When two substitution sites are present on the same carbon atom, the term "heterocyclic group" also includes "spiroheterocyclic group." Examples of spiroheterocyclic rings include, for example, bicyclic and tricyclic ring systems such as oxabicyclo[2.2.2]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include (but are not limited to)...1,2,3,4-Tetrahydroisoquinolinyl, 4,5,6,7-Tetrahydrothieno[2,3-c]pyridyl, indololinyl, and isoindololinyl, wherein the heterocyclic group can be linked to any ring of the fused system.

[0046] "Heterocyclic alkyl" means "heterocyclic-alkyl-". Specification 5 / 262 page 28 CN 122138828 A

[0047] "Oxime" means "-CRy (=NOH)" where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein.

[0048] "Sulfoyl" means "-S(O)2Ry" where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0049] “Sulfinyl” refers to the group -S(O)Ry, wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0050] “Sulfanamide” refers to the groups -SO2NR yRz and -NRySO2R z, wherein Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein.

[0051] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both the case where the event or situation occurs and the case where the event or situation does not occur. Similarly, the term “optionally substituted” means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the specified atom or group may be partially substituted with hydrogen atoms or may not be partially substituted with hydrogen atoms.

[0052] As used herein, the term “substituted” means any of the above-mentioned groups (i.e., alkyl, alkenyl, alkynylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl and / or heteroalkyl), wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is substituted with a non-hydrogen atom, such as (but not limited to) alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, formamidinyl, aryl, aralkyl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidinyl, haloalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, -NHNH2, =NNH2, imino, imide, hydroxy, oxo,Oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thionyl, N-oxide or -Si(Ry)3, wherein each Ry is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclic.

[0053] In some embodiments, “substituted” includes any of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently substituted with: deuterium, haloyl, cyano, nitro, azide, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NRgRh, -NRgC(O)Rh, -NRgC(O)NRgRh, -NRgC(O)ORh, -NRgS(O)1-2Rh, -C(O)Rg, -C(O)ORg, -OC(O)ORg, -OC(O)Rg, -C(O)NRgRh, -OC(O)NRgRh, -ORg, -SRg, -S(O)Rg, -S(O)2R g, -OS(O)1-2R g, -S(O)1-2OR g, -NRgS(O)1-2NR gRh, =NSO2R g, =NORg, -S(O)1-2NR gRh, -SF5, -SCF3, or -OCF3. In some embodiments, "substituted" also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are substituted with -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -CH2SO2R g, or -CH2SO2NR gRh. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, heterocyclic alkyl, heteroaryl, and / or heteroarylalkyl. In some embodiments, "substituted" also means any of the above groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are substituted with an amino, cyano, hydroxyl, imino, nitro, oxo, thionyl, haloyl, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, and / or heteroarylalkyl; or both of Rg and Rh and Ri together with the atoms to which they are attached form a heterocyclic ring, said heterocyclic ring optionally substituted with an oxo, haloyl, or optionally an alkyl group substituted with an oxo, haloyl, amino, hydroxyl, or alkoxy group. Specification 6 / 262 page 29 CN 122138828 A

[0054] This document is not intended to include polymers or similar indeterminate structures (e.g., substituted aryl groups having substituted alkyl groups, said substituted alkyl groups being substituted by themselves, said substituted aryl groups being further substituted by substituted heteroalkyl groups, etc.) obtained by defining substituents by an unlimited number of other substituents. Unless otherwise noted, the maximum number of successive substitutions in the compounds described herein is three. For example, successive substitution of a substituted aryl group with two other substituted aryl groups is limited to an aryl group substituted by ((substituted aryl)-substituted)-aryl. Similarly, the above definition is not intended to include unpermitted substitution patterns (e.g., methyl groups substituted with five fluorine atoms or heteroaryl groups having two adjacent oxygen ring atoms). Such unpermitted substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term “substituted” may describe other chemical groups as defined herein.

[0055] In some embodiments, as used herein, the phrase “one or more” means one to five. In some embodiments, as used herein, the phrase “one or more” refers to one to three species.

[0056] Any compound or structure given herein is also intended to represent both unlabeled and isotopically labeled forms of the compound. These compound forms may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have the structures illustrated herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Various isotopically labeled compounds of this disclosure, such as those containing radioactive isotopes (e.g., 3H and 14C), are also included. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques (e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays) or radiotherapy of patients.

[0057] The term “isotopically enriched analog” includes “deuterated analogs” of the compounds described herein, wherein one or more hydrogen atoms are replaced by deuterium (e.g., hydrogen on a carbon atom). Such compounds exhibit increased resistance to metabolism when administered to mammals (humans in particular) and can therefore be used to prolong the half-life of any compound. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527.(1984). Such compounds are synthesized by means well known in the art, for example by using one or more hydrogen-substituted deuterium starting materials.

[0058] The deuterated or substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (e.g., deuterium) can provide certain therapeutic advantages due to greater metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, and / or improved therapeutic index. Compounds labeled with 18F, 3H, or 11C can be used for PET or SPECT or other imaging studies. The isotope-labeled compounds of this disclosure and their prodrugs can generally be prepared by replacing unlabeled reagents with readily available isotope-labeled reagents by performing the procedures disclosed in the protocols or in the examples and preparations described below. It should be understood that deuterium is considered a substituent in the compounds described herein in this context.

[0059] The concentration of such a heavier isotope (specifically deuterium) can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope means any stable isotope representing said atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, said position should be understood to have hydrogen in its natural abundance isotopic composition. Thus, in the compounds of this disclosure, any atom specifically designated as deuterium (D) means to represent deuterium.

[0060] In many cases, the compounds of this disclosure are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups therewith.

[0061] Pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein are also provided. “Pharmaceuticalally acceptable” or “physiologically acceptable” means compounds, salts, compositions, dosage forms, and other substances that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0062] The term "pharmaceutically acceptable salt" as used for the given compounds refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts formed with inorganic acids and salts formed with organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing the acid salt solution. Conversely, if the product is a free base, the addition salt, specifically a pharmaceutically acceptable addition salt, can be produced according to the conventional procedure for preparing acid addition salts from basic compounds by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be obtained from…Preparation from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium salts, potassium salts, lithium salts, aluminum salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include (but are not limited to) salts of primary, secondary, and tertiary amines, wherein the amines are, for example, alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trienylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N... (Substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include (by way of example only) isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, hexahydropyrazine, hexahydropyridine, morpholine, N-ethylhexahydropyridine, etc.

[0063] Some compounds exist in tautomer form. Tautomers are in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with imide acid tautomers. Regardless of which tautomer is exhibited and regardless of the equilibrium nature between the tautomers, those skilled in the art will understand that a compound comprises both amide and imide acid tautomers. Therefore, amide-containing compounds should be understood to include their imide acid tautomers. Similarly, imide acid-containing compounds should be understood to include their amide tautomers.

[0064] The compounds of this disclosure or their pharmaceutically acceptable salts comprise an asymmetric center and thereby can produce enantiomers, diastereomers and other stereoisomers, which may be defined by absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. This disclosure is intended to include all such possible isomers, as well as their derivatives.Racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using palmitic synthons or palmitic reagents, or resolved using conventional techniques (e.g., chromatography and / or fractional crystallization). Conventional techniques for the preparation / separation of individual enantiomers include palmitic synthesis from suitable optically pure precursors or resolution of racemic products (or racemic products of salts or derivatives) using, for example, palmitic high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise specified, the intended compounds include both E and Z geometric isomers.

[0065] "Stereoisomers" refers to compounds composed of identical atoms bonded by the same bonds but with different (non-interchangeable) three-dimensional structures. This disclosure considers various stereoisomers or mixtures thereof, and includes “enantiomers”, as defined in this specification (page 8 / 262, 31 CN 122138828 A). An enantiomer is defined as two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0066] A “diastereomer” is a stereoisomer having at least two asymmetric atoms but not being mirror images of each other.

[0067] The relative centers of compounds as illustrated herein are graphically indicated using a “thick bond” pattern (thick lines or parallel lines), and absolute stereochemistry is illustrated using wedge bonds (thick lines or parallel lines).

[0068] A “prodrug” means any compound that releases an active parent drug substance according to the structure described herein in vivo when the prodrug is administered to a mammalian subject. Prodrugs of compounds described herein are prepared by modifying functional groups present in the compounds described herein in a manner that allows the modification to cleave in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in compounds in a manner that allows the modification to cleave into the parent compound under normal operation or in vivo. Prodrugs include compounds described herein, wherein the hydroxyl, amino, carboxyl, or thiol groups in the compounds described herein are bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl, amino, or thiol group. Examples of prodrugs include (but are not limited to) esters (e.g., acetates, formates, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), etc., of the hydroxyl functional group in the compounds described herein. The preparation, selection, and use of prodrugs are discussed in the following literature: T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14; “Design of Prodrugs,” edited by H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug.Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated in its entirety by reference.

[0069] 2. Compounds This document provides compounds as inhibitors of SARM1. In some embodiments, a compound of formula I is provided: I or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X1 is N, NR8a, O, S, or CR6a; X2 is N, NR8b, O, S, or CR6b; X3 is N, NR8c, or CR6c; X4 is N or CR6d; provided that at least one of X1, X2, X3, and X4 is N, and the ring containing X1, X2, X3, and X4 is aromatic; R is -NR2R3, -OR7, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1s; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups; R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted with one to five Z1 groups; R3 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; or R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups; R4 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R 11. ‑C(O)N(R11)2, ‑NR 11C(O) R11, ‑NR11S(O)R11, ‑NR11S(O)2R 11. ‑S(O)N(R11)2, ‑S(O)2N(R 11)2, ‑NR 11C(O)N(R11)2, ‑NR 11S(O)N(R11)2, -NR 11S(O)2N(R 11)2, -OC(O)N(R 11)2, or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one to five Z1 groups; R5 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R 11, -C(O)N(R11)2, or -NR 11C(O). R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted with one to five Z1 groups; R6a, R6b, R6c and R6d are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O) OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; R7 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; R8a, R8b, and R8c are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, or heteroaryl group.alkyl or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally substituted with one to five Z1 groups; or R8a and R6b, or R8b and R6c, or R6b and R6c, or R8c and R6d, or R6c and R6d together form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may be further independently and optionally substituted with one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S (O)2R 12, -C(O)N(R12)2, -NR 12C(O)R12, -NR12S(O)R12, -NR12S(O)2R 12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR 12C(O)N(R12)2, -NR 12S(O)N(R12)2, -NR 12S(O)2N(R 12)2, -OC(O)N(R 12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted by one to five Z1a. Each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; each R11 is independently hydrogen, a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; Specification 10 / 262 page 33 CN 122138828 A Each Z1a is independently halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13. ‑SR13, ‑C(O)R13, ​​‑C(O)OR13, ‑S(O)R13, ​​‑S(O)2R 13. ‑C(O)N (R13)2, ‑NR 13C(O)R13, ​​‑NR13S(O)R13, ​​‑NR13S(O)2R 13. ‑S(O)N(R13)2, ‑S(O)2N(R 13)2, ‑NR 13C(O)N (R13)2, ‑NR 13S(O)N(R13)2, ‑NR 13S(O)2N(R 13)2, ‑OC(O)N(R 13) 2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each R13 group is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each Z1b group is independently halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups in Z1b and L is further independently and optionally substituted by one to five independently selected substituents: halogroup, cyanogroup, alkyl group ...-H, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl.

[0070] In some embodiments, a compound of formula I is provided: I or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X1 is N, NR8a, O, S, or CR6a; X2 is N, NR8b, O, S, or CR6b; X3 is N, NR8c, or CR6c; X4 is N or CR6d; provided that at least one of X1, X2, X3, and X4 is N, and the ring containing X1, X2, X3, and X4 is aromatic; R is -NR2R3, -OR7, C1-6 alkyl, C2-6 alkenyl, C2-6 ynylyl, or C3-10 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynylyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1s; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups; R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted with one to five Z1 groups; R3 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; or R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups; R4 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR 11C(O) R11, ‑NR11S(O)R11, ‑NR11S(O)2R 11, ‑S(O)N(R11)2, ‑S(O)2N(R 11)2, ‑NR 11C(O)N(R11)2, ‑NR 11S(O)N (R11)2, ‑NR 11S(O)2N(R 11)2、‑OC(O)N(R11)2 or -NR11C(O)OR11; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl are optionally substituted by one to five Z1 groups; R5 is hydrogen, halogroup, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R 11, -C(O)N(R11)2, -NR 11C(O) R11, -NR11S(O)R11, -NR11S(O)2R 11. -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted by one to five Z1 groups; R6a, R6b, R6c and R6d are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 10. ‑SR10, ‑C(O)R11, ‑C(O)OR11, ‑S(O)R11, ‑S (O)2R 11. ‑C(O)N(R11)2, ‑NR 11C(O)R11, ‑NR11S(O)R11, ‑NR11S(O)2R 11. ‑S(O)N(R11)2, ‑S(O)2N (R11)2, ‑NR 11C(O)N(R11)2, ‑NR 11S(O)N(R11)2, ‑NR 11S(O)2N(R 11)2, ‑OC(O)N(R 11)2 or ‑NR11C(O) OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; R7 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; R8a, R8b, and R8c are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups.Selectively substituted with one to five Z1 groups; or R8a and R6b, or R8b and R6c, or R6b and R6c, or R8c and R6d, or R6c and R6d together to form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may be further independently and optionally substituted with one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR 12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted by one to five Z1a; Each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; Each R11 is independently hydrogen, a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; Specification 12 / 262 pages 35 CN 122138828 A Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1a is independently a halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR 13C(O)N(R13)2, -NR 13S(O)N(R13)2, -NR 13S(O)2N(R13)2, -OC(O)N(R13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1b groups; Each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1b is independently halogroup, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, - L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups in Z1b and L is further independently and optionally substituted by one to five independently selected substituents from the following: halogroup, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkoxyAlkyl, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl; The condition is that at least one of A, B, C, D, or E is present: A. X1 is N and X2 is NR8b; and a. When R is C1-6 alkyl; the C1-6 alkyl is substituted with a halogroup or C3-10 cycloalkyl and optionally one to four Z1 substituted groups; and / or b. R8b is not hydrogen; and / or c. When R is -OR7; then R7 is not methyl, ethyl, isopropyl, tert-butyl, 2-bromoethyl, 2-methoxyethyl, 2-cyanoethyl, 2-phenylethyl, benzyl, or 9H-fluorene-9-ylmethyl; and the compound is not: Specification 13 / 262 page 36 CN 122138828 A

[0071] B. X2 is or NR8b; and R is -NR2R3; and a. R2 and R3 are not both methyl; and / or b. when X1 is O, at least one of R8b, R8c, R6c or R6d is not hydrogen; and the compound is not:

[0072] C. X1 is N or CR6a, X2 is O, X3 is N or CR6c, and X4 is N; and a. when R is C1-6 alkyl, the C1-6 alkyl is substituted with one to five Z1; and / or b. R6c is not 4-amino-2-[(3,4,5-trimethoxyphenyl)amino]-5-thiazolyl, [[4-(1-pyrrolidinylmethyl)phenyl]amino]-5-thiazolyl or [[6-(4-methyl-1-hexahydropyrazinyl)-3-pyridyl]amino]-5-thiazolyl; and / or c. when R is -OR7, R7 is not isobutyl or tert-butyl; and the compound is not: Specification 14 / 262 Page 37 CN 122138828 A

[0073] D. X1 is O, X2 is N or CR6b, X3 is CR6c, X4 is N, R6c is not hydrogen; and R is -NR2R3, wherein R2 and R3 together form a heterocyclic group, which may be further independently optionally substituted by one to five Z1; and at least one of the following a. to d. appears: a. X2 is N; or b. R1 is not methyl; or c. R2 and R3 form an optionally substituted bridging heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; or d. R2 and R3 form an optionally substituted monocyclic 7-membered heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; and the compound is not: Specification 15 / 262 Page 38 CN 122138828 A

[0074] and / or E. R is, where q is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3.

[0075] In some embodiments, a compound of formula II is provided: II or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a stereoisomer.A mixture of structures, wherein: X3 is N or CR6c; X4 is N or CR6d; R is -NR2R3, -OR7, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl or C3-10 cycloalkyl; wherein the C1-6 alkyl is substituted with a halogroup or C3-10 cycloalkyl and optionally one to four Z1 substituted; and wherein the C2-6 alkenyl, C2-6 ynyl or C3-10 cycloalkyl is optionally substituted with one to five Z1 substituted; R1 is a halogroup, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl or C3-10 cycloalkyl is optionally substituted with one to five Z1 substituted; R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; R3 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; or R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups; R4 represents hydrogen, halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R) 11)2, -OC(O)N(R 11)2 or -NR11C(O)OR11; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted by one to five Z1 groups; R5 is hydrogen, halogroup, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R 11, -C(O)N(R11)2, -NR 11C(O) Specification 16 / 262 Page 39 CN 122138828 AR11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted with one to five Z1 groups; R6c and R6d are each independently hydrogen, halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR 11S(O)2N(R 11)2, -OC(O)N(R 11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted with one to five Z1 substituted groups; R7 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted with one to five Z1 substituted groups; R8b is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; or R8b and R6c, or R6c and R6d together form a 5-membered heterocyclic group, which may be further independently and optionally substituted with one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR 12. ‑SR12, ‑C(O)R12, ‑C(O)OR12, ‑S(O)R12, ‑S (O)2R 12. ‑C(O)N(R12)2, ‑NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted by one to five Z1a; Each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; each R11 is independently hydrogen, a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1a is independently a halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR 13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2, -OC(O)N(R13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group.Each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; Specification 17 / 262 pages 40 CN 122138828 A Each Z1b group is independently a halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, - L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl group in Z1b and L is further independently and optionally substituted by one to five independently selected substituents from the following: halogroup, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl; the conditions are: When R is -OR7; then R7 is not methyl, ethyl, isopropyl, tert-butyl, 2-bromoethyl, 2-methoxyethyl, 2-cyanoethyl, 2-phenylethyl, benzyl, or 9H-fluorene-9-ylmethyl; and the compound is not:

[0076] In some embodiments, a compound of formula III is provided: III or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: X1 is N, NR8a, O, S, or CR6a; X2 is N or NR8b; X3 is N, NR8c, or CR6c; Specification18 / 262 Page 41 CN 122138828 A X4 is N or CR6d; the condition is that the ring containing X1, X2, X3 and X4 is aromatic; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl or C3-10 cycloalkyl is optionally substituted by one to five Z1 substitutions; R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one to five Z1 substitutions; R3 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; or R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups; R4 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR 11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted with one to five Z1 groups; R5 represents hydrogen, halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R) 11)2、-OC(O)N(R)11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one to five Z1 groups; R6a, R6b, R6c, and R6d are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R 11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR 11C(O)N(R11)2, -NR 11S(O)N(R11)2, -NR 11S(O)2N(R 11)2, -OC(O)N(R 11)2 or -NR11C(O) OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1 groups; R8a, R8b, and R8c are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl are independently and optionally substituted by one to five Z1 groups; or R6a and R8b, R8b and R6c, or R8c and R6d, or R6c and R6d together form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further be independently and optionally substituted by one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR 12. ‑SR12, ‑C(O)R12, ‑C(O)OR12, ‑S(O)R12, ‑S (O)2R 12. ‑C(O)N(R12)2, ‑NR 12C(O)R12, ‑NR12S(O)R12, ‑NR12S(O)2R 12. ‑S(O)N(R12)2, ‑S(O)2N (R12)2, ‑NR 12C(O)N(R12)2, ‑NR 12S(O)N(R12)2, ‑NR 12S(O)2N(R 12)2, ‑OC(O)N(R 12)2 or ‑NR12C(O) OR12; wherein each of the following is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaromatic group.Each R10 is independently and optionally substituted with one to five Z1a groups; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; (Specification 19 / 262, page 42, CN 122138828 A) Each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1a is independently a halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR 13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR 13C(O)N(R13)2, -NR 13S(O)N(R13)2, -NR 13S(O)2N(R13)2, -OC(O)N(R13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1b groups; Each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1b is independently halogroup, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups in Z1b and L is further independently and optionally substituted by one to five independently selected substituents from the following: haloyl, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl; provided that R2 and R3 are not simultaneously methyl; When X1 is O, at least one of R8b, R8c, R6c, or R6d is not hydrogen; and the compound is not: Specification 20 / 262 page 43 CN 122138828 A

[0077] In some embodiments, a compound of formula IV is provided: IV or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: X1 is N or CR6a; X3 is N or CR6c; R is -NR2R3, -OR7, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl or C3-10 cycloalkyl; wherein the C1-6 alkyl is substituted with one to five Z1s; and wherein the C2-6 alkenyl, C2-6 ynyl or C3-10 cycloalkyl is optionally substituted with one to five Z1s; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups; R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl group is...R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, optionally substituted with one to five Z1 groups; R3 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1 groups; or R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups; R4 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one to five Z1 groups; R5 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N (R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted with one to five Z1 groups; Specification 21 / 262 pages 44 CN 122138828 A R6a and R6c are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10. ‑SR10, ‑C(O)R11, ‑C(O)OR11, ‑S(O)R11, ‑S(O) 2R 11. ‑C(O)N(R11)2, ‑NR 11C(O)R11, ‑NR11S(O)R11, ‑NR11S(O)2R 11. ‑S(O)N(R11)2, ‑S(O)2N(R 11)2, ‑NR11C(O)N(R11)2, ‑NR 11S(O)N(R11)2, ‑NR 11S(O)2N(R 11)2, ‑OC(O)N(R 11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1 groups; R7 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted by one to five Z1 groups; each Z1 is independently a halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR 12. ‑SR12, ‑C(O)R12, ‑C(O)OR12, ‑S(O)R12, ‑S (O)2R 12. ‑C(O)N(R12)2, ‑NR 12C(O)R12, ‑NR12S(O)R12, ‑NR12S(O)2R 12. ‑S(O)N(R12)2, ‑S(O)2N (R12)2, ‑NR 12C(O)N(R12)2, ‑NR 12S(O)N(R12)2, ‑NR 12S(O)2N(R 12)2, ‑OC(O)N(R 12)2 or ‑NR12C(O) OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a; Each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted by one to five Z1a.Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1a is independently a halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR 13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR 13C(O)N(R13)2, -NR 13S(O)N(R13)2, -NR 13S(O)2N(R13)2, -OC(O)N(R13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1b groups; Each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1b is independently halogroup, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, - L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)--C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - AC(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of Z1b and L is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, The aryl and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl; provided that: R6c is not 4-amino-2-[(3,4,5-trimethoxyphenyl)amino]-5-thiazolyl, [[4-(1-pyrrolidinylmethyl)phenyl]amino]-5-thiazolyl, or [[6-(4-methyl-1-hexahydropyrazinyl)-3-pyridyl]amino]-5-thiazolyl; when R is -OR7, then R7 is not isobutyl or tert-butyl; and the compound is not:

[0078] In some embodiments, a compound of formula V is provided: V or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: X2 is N or CR6b; R1 is a halogroup, cyanogroup, C1-3 alkyl group, C2-3 alkenyl group, C2-3 ynyl group, or C3-6 cycloalkyl group; wherein the C1-6 alkyl group, C2-6 alkenyl group, C2-6 ynyl group, or C3-10 cycloalkyl group is optionally substituted with one to five Z1 groups; R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups; R4 is hydrogen, a halogroup, cyanogroup, C1-6 alkyl group, C2-6 alkenyl group, C2-6 ynyl group, C3-10 cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -N(R11)2, -OR 11. ‑SR11, ‑C(O)R11, ‑C(O)OR11, ‑S(O)R11, ‑S(O)2R 11. ‑C(O)N(R11)2, ‑NR 11C(O) R11, ‑NR11S(O)R11, ‑NR11S(O)2R 11. ‑S(O)N(R11)2, ‑S(O)2N(R 11)2, ‑NR 11C(O)N(R11)2, ‑NR 11S(O)N (R11)2, ‑NR 11S(O)2N(R 11)2, ‑OC(O)N(R11)2 or -NR11C(O)OR11; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl are optionally substituted by one to five Z1 groups; R5 is hydrogen, halogroup, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R 11, -C(O)N(R11)2, -NR 11C(O) R11, -NR11S(O)R11, -NR11S(O)2R 11. -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted by one to five Z1 groups; R6b is hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl group, C2-6 Alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally substituted with one to five Z1 groups; R6c is a halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R 11.‑S(O)N(R11)2、‑S(O)2N(R11)2、-NR 11C(O)N(R11)2、-NR11S(O)N(R11)2、-NR 11S(O)2N(R 11)2、-OC(O)N(R 11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted by one to five Z1 groups; or R6b and R6c together form a 5-membered heterocyclic group, which may be further independently and optionally substituted by one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR 12. ‑SR12, ‑C(O)R12, ‑C(O)OR12, ‑S(O)R12, ‑S (O)2R 12. ‑C(O)N(R12)2, ‑NR 12C(O)R12, ‑NR12S(O)R12, ‑NR12S(O)2R 12. ‑S(O)N(R12)2, ‑S(O)2N (R12)2, ‑NR 12C(O)N(R12)2, ‑NR 12S(O)N(R12)2, ‑NR 12S(O)2N(R 12)2, ‑OC(O)N(R 12)2 or ‑NR12C(O) OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a; Each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1a; each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; Each Z1a is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13. ‑SR13, ‑C(O)R13, ​​‑C(O)OR13, ‑S(O)R13, ​​‑S(O)2R 13. ‑C(O)N (R13)2, ‑NR 13C(O)R13, ​​‑NR13S(O)R13, ​​‑NR13S(O)2R 13. ‑S(O)N(R13)2, ‑S(O)2N(R 13)2, ‑NR 13C(O)N (R13)2, ‑NR 13S(O)N(R13)2, ‑NR 13S(O)2N(R 13)2, ‑OC(O)N(R 13) 2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each R13 group is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each Z1b group is independently halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl group of Z1b and L is further independently and optionally substituted by one to five independently selected substituents: halogroup, cyano ...122138828 A group, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl; The condition is that one or more of the following are present: X2 is N; R1 is not methyl; R2 and R3 form an optionally substituted bridging heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; or R2 and R3 form an optionally substituted monocyclic 7-membered heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; and the compound is not: Specification 25 / 262 pages 48 CN 122138828 A

[0079] In some embodiments, R or part of it is optionally fused to a C6 aryl; wherein: q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; X is CH2, CHZ1, C(Z1)2, NR9, O, or S; and R9 is H or Z1.

[0080] In some embodiments, a compound of formula VI is provided: VI or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: X1 is N, NR8a, O, S, or CR6a; X2 is N, NR8b, O, S, or CR6b; X3 is N, NR8c, or CR6c; X4 is N or CR6d; provided that at least one of X1, X2, X3, and X4 is N, and the ring containing X1, X2, X3, and X4 is aromatic; q is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups; R4 is hydrogen, halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R 11. -S(O)N(R11)2, -S(O)2N(R 11)2, -NR 11C(O)N(R11)2, -NR 11S(O)N Instruction manual 26 / 262 pages 49 CN 122138828 A (R11)2, -NR 11S(O)2N(R 11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl are optionally substituted by one to five Z1 groups; R5 is hydrogen, halogroup, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R 11, -C(O)N(R11)2, -NR 11C(O) R11, -NR11S(O)R11, -NR11S(O)2R 11. -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted by one to five Z1 groups; R6a, R6b, R6c and R6d are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 10. ‑SR10, ‑C(O)R11, ‑C(O)OR11, ‑S(O)R11, ‑S (O)2R 11. ‑C(O)N(R11)2, ‑NR 11C(O)R11, ‑NR11S(O)R11, ‑NR11S(O)2R 11. ‑S(O)N(R11)2, ‑S(O)2N (R11)2, ‑NR 11C(O)N(R11)2, ‑NR 11S(O)N(R11)2, ‑NR 11S(O)2N(R 11)2, ‑OC(O)N(R 11)2 or ‑NR11C(O) OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; R8a, R8b, and R8c are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; or R8a and R6b, or R8b and R6c, or R6b and R6c, or R8c and R6d, or R6c and R6d together form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further be independently and optionally substituted with one to five Z1 groups;Each Z1 is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR 12S(O)2N(R 12)2, -OC(O)N(R 12)2, or -NR12C(O) OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a. Each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1a; each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; Each Z1a is independently a halogenated group, cyano group, -NO2 group, C1-6 alkyl group, C2-6 alkenyl group, C2-6 ynyl group, C3-10 cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2. 13)2、-OC(O)N(R)13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b; Specification 27 / 262 pages 50 CN 122138828 A Each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1b; Each Z1b is independently halogroup, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups in Z1b and L is further independently and optionally substituted by one to five independently selected substituents from the following: haloyl, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl.

[0081] In some embodiments of the formula disclosed herein, each Z1 is independently a halogroup, cyanogroup, -NO2, or C1-6 alkyl group.C1-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2 12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1a; Each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted with one to five Z1a; each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted with one to five Z1a; Each Z1a is independently a halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0082] In some embodiments, a compound of formula VI is provided: VI or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: X1 is N, NR8a, O, S, or CR6a; X2 is N, NR8b, O, S, or CR6b; X3 is N, NR8c, or CR6c; X4 is N or CR6d;The conditions are that at least one of X1, X2, X3, and X4 is N, and the ring containing X1, X2, X3, and X4 is aromatic; q is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted by one to five Z1 groups; R4 is hydrogen, halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R 11, -C(O)N(R11)2, -NR 11C(O) R11, -NR11S(O)R11, -NR11S(O)2R 11, -S(O)N(R11)2, -S(O)2N(R 11)2, -NR 11C(O)N(R11)2, -NR 11S(O)N (R11)2, -NR 11S(O)2N(R 11)2, -OC(O)N(R 11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted with one to five Z1 groups; R5 represents hydrogen, halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R) 11)2、-OC(O)N(R 11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted by one to five Z1 groups; R6a, R6b, R6c and R6d are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S (O)2R 11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1 groups; R8a, R8b, and R8c are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl are independently and optionally substituted with one to five Z1 groups; or R8a and R6b, or R8b and R6c, or R6b and R6c, or R8c and R6d, or R6c and R6d together form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further be independently and optionally substituted with one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C1-6 haloalkyl. C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2 or -NR12C(O) OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a; each R11 is independently hydrogen, a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group.R12 is a group consisting of a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups. Each Z1a is independently a halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0083] In some embodiments, R is partially or entirely; wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; ring B is a C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted by one to five Z1s; and L1 is a bond, C1-4 alkylene, C2-4 alkenyl, or C2-4 alkynyl.

[0084] In some embodiments, R is partially or entirely; wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; ring B is a C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1b groups; and L1 is a bond, C1-4 alkylene, C2-4 alkenyl, or C2-4 ynylene.

[0085] In some embodiments, p is 1.

[0086] In some embodiments, q is 1 or 2.

[0087] In some embodiments, R1 is a halogroup, cyano, C1-3 alkyl, C1-3 haloalkyl, or C3-6 cycloalkyl group, optionally substituted with a cyano or methyl group.

[0088] In some embodiments, R1 is fluorine, chlorine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclobutyl, or cyclopropyl, optionally substituted with cyano or methyl.

[0089] In some embodiments, R1 is chloro, cyano, or trifluoromethyl.

[0090] In some embodiments, L1 is a bond or a C1-4 alkylene group. In some embodiments, L1 is a bond or a C1-2 alkylene group. In some embodiments, L1 is a bond or -CH2-. In some embodiments, L1 is a bond. Specification 30 / 262 pages 53 CN 122138828 A

[0091] In some embodiments, ring B is a heteroaryl group optionally substituted with one to five Z1a. In some embodimentsIn this embodiment, ring B is a heteroaryl group optionally substituted with one to five Z1a, and L1 is a bond or a C1-2 alkylene group. In some embodiments, ring B is a heteroaryl group optionally substituted with one to five Z1a, and L1 is a bond or CH2. In some embodiments, ring B is a heteroaryl group and L1 is a bond. In some embodiments, ring B is a heteroaryl group optionally substituted with one to five Z1a, L1 is a bond, q is 1, and Z1 is a C1-6 alkyl group.

[0092] In some embodiments, ring B is a heteroaryl group optionally substituted with one to five Z1b. In some embodiments, ring B is a heteroaryl group optionally substituted with one to five Z1b, and L1 is a bond or a C1-2 alkylene group. In some embodiments, ring B is a heteroaryl group optionally substituted with one to five Z1b, and L1 is a bond or CH2. In some embodiments, ring B is a heteroaryl group and L1 is a bond. In some embodiments, ring B is optionally a heteroaryl group substituted with one to five Z1b, L1 is a bond, q is 1, and Z1 is a C1-6 alkyl group.

[0093] In some embodiments, R4 is hydrogen or a C1-6 alkyl group.

[0094] In some embodiments, R4 is hydrogen or a methyl group.

[0095] In some embodiments, R5 is hydrogen or a halogroup.

[0096] In some embodiments, R5 is hydrogen or fluorine.

[0097] In some embodiments, the portion is , ...

[0099] In some embodiments, a portion is.

[0100] In some embodiments, a portion is, , , , , , , , , , , or.

[0101] In some embodiments, R6a, R6b, R6c and R6d are each independently hydrogen, halogroup, cyano, C1-6 alkyl, C1-6 haloalkyl or C3-10 cycloalkyl.

[0102] In some embodiments, a portion is, , , , , , , , , , , , , , , or; and R6a, R6b, R6c and R6d are each independently hydrogen, halogroup, cyano, C1-6 alkyl, C1-6 haloalkyl or C3-10 cycloalkyl.

[0103] In some embodiments, the portion is, , , , specification 32 / 262 pages 55 CN 122138828 A, , , , , , or; and R6a, R6b, R6c and R6d are each independently hydrogen, halogroup, cyano, C1-6 alkyl, C1-6 haloalkyl or C3-10 cycloalkyl.

[0104] In some embodiments, R6a, R6b, R6c, and R6d are each independently hydrogen, fluorine, cyano, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-methoxyethyl, cyclopropyl, or cyclopropylmethyl.

[0105] In some embodiments, each Z1 is independently a halogroup, cyano, C1-6 alkyl, C1-6 haloalkyl, heteroaryl, -OR12, or -C(O)OR12; wherein each C1-6 alkyl, C1-6 haloalkyl, or heteroaryl is optionally independently substituted with one to five hydroxyl, methoxy, or methyl groups.

[0106] In some embodiments, R is -OR7.

[0107] In some embodiments, R is -OR7, and R7 is benzyl or cyclobutyl.

[0108] In some embodiments, R is -NR2R3.

[0109] In some embodiments, R is -NR2R3, and R2 and R3 together form a heterocyclic group, which may further independently and optionally be substituted with one to five Z1 groups; wherein each Z1 is independently fluorine, bromine, cyano, methyl, trifluoromethyl, methoxy, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl-1-yl, or phenyl.

[0111] In some embodiments, R is a C1-6 alkyl group optionally substituted with one to five Z1 groups.

[0112] In some embodiments, R is a C1-6 alkyl group optionally substituted with one to five Z1 groups; wherein each Z1 is independently fluorine, methyl, trifluoromethyl, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl-1-yl, phenyl, or pyridyl.

[0113] In some embodiments, each Z1 is independently a halogroup, cyanogroup, C1-6 alkyl, C1-6 haloalkyl, heteroaryl, C1-6 alkoxy, or -C(O)O-C1-6 alkyl; wherein each C1-6 alkyl, C1-6 haloalkyl, heteroaryl is optionally independently substituted with one to five hydroxyl, methoxy, or methyl groups.

[0114] In some embodiments, a compound of formula IIA is provided: IIA or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: X3 is N or CR6c; X4 is N or CR6d; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups; R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl group is substituted with one to five Z1 groups. (Specification 33 / 262 pages 56 CN 122138828 A)R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, optionally substituted with one to five Z1 groups; R3 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; or R2 and R3 together form a heterocyclic group, which may be further optionally substituted with one to five Z1 groups; R4 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one to five Z1 groups; R5 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N (R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one to five Z1 groups; R6c and R6d are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR 11C(O)R11, -NR11S(O)R11, -NR11S(O)2R 11, -S(O)N(R11)2, -S(O)2N(R 11)2, -NR11C(O)N(R11)2, -NR 11S(O)N(R11)2, -NR 11S(O)2N(R 11)2, -OC(O)N(R 11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1 groups; R8b is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1 groups; or R8b and R6c, or R6c and R6d together form a 5-membered heterocyclic group, which may be further independently and optionally substituted by one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR 12. ‑SR12, ‑C(O)R12, ‑C(O)OR12, ‑S(O)R12, ‑S (O)2R 12. ‑C(O)N(R12)2, ‑NR 12C(O)R12, ‑NR12S(O)R12, ‑NR12S(O)2R 12. ‑S(O)N(R12)2, ‑S(O)2N (R12)2, ‑NR 12C(O)N(R12)2, ‑NR 12S(O)N(R12)2, ‑NR 12S(O)2N(R 12)2, ‑OC(O)N(R 12)2 or ‑NR12C(O) OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a; Each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted by one to five Z1a.Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted by one to five Z1b; each Z1a is independently halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R 13, -C(O)N(R13)2, -NR 13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR 13C(O)N(R13)2, -NR 13S(O)N(R13)2, -NR 13S(O)2N(R13)2, -OC(O)N(R13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1b groups; Each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1b is independently halogroup, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, - L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)--C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of Z1b and L is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, The aryl and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0115] In some embodiments, a compound of formula IIB is provided: IIB or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; X3 is N or CR6c; X4 is N or CR6d; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups; R4 is hydrogen, a halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11、-SR11、-C(O)R11、-C(O)OR11、-S(O)R11、-S(O)2R 11、-C(O)N(R11)2、-NR 11C(O) R11、-NR11S(O)R11、-NR11S(O)2R 11、-S(O)N(R11)2、-S(O)2N(R 11)2、-NR 11C(O)N(R11)2、-NR 11S(O)N Instruction manual 35 / 262 pages 58 CN 122138828 A (R11)2、-NR 11S(O)2N(R 11)2、-OC(O)N(R 11)2 or -NR11C(O)OR11; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl are optionally substituted by one to five Z1 groups; R5 is hydrogen, halogroup, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one to five Z1 groups; R6c and R6d are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, - NR11C(O)N(R11)2, -NR 11S(O)N(R11)2, -NR 11S(O)2N(R 11)2, -OC(O)N(R 11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted by one to five Z1 substitutions; R8b is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted by one to five Z1 substitutions; R8b and R6c, or R6c and R6d together, form a 5-membered heterocyclic group, which may be further independently and optionally substituted by one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR 12C(O)N(R12)2, -NR 12S(O)N(R12)2, -NR 12S(O)2N(R 12)2, -OC(O)N(R 12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; Each of the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups is independently and optionally substituted with one to five Z1a groups; each R11 is independently hydrogen, a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups is independently and optionally substituted with one to five Z1a groups; Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1a is independently a halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR 13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2, -OC(O)N(R13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1b groups; Specification 36 / 262 pages 59 CN 122138828 A Each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaromatic.The group is composed of a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is independently and optionally substituted with one to five Z1b groups; each Z1b group is independently a halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, - L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups in Z1b and L is further independently and optionally substituted by one to five independently selected substituents from the following: haloyl, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl.

[0116] In some embodiments, a compound of formula IIC is provided: IIC or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; L1 is a bond, a C1-4 alkylene group, a C2-4 alkenyl group, or a C2-4 ynylene group; ring B is a C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1b; X3 is N or CR6c; X4 is N or CR6d;R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups; R4 is hydrogen, halogroup, cyanogroup, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R 11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted by one to five Z1 groups; R5 is hydrogen, halogroup, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR 11、-SR11、-C(O)R11、-C(O)OR11、-S(O)R11、-S(O)2R 11、-C(O)N(R11)2、-NR 11C(O) Instruction manual 37 / 262 pages 60 CN 122138828 A R11、-NR11S(O)R11、-NR11S(O)2R 11、-S(O)N(R11)2、-S(O)2N(R 11)2、-NR 11C(O)N(R11)2、-NR 11S(O)N (R11)2、-NR 11S(O)2N(R 11)2、-OC(O)N(R 11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one to five Z1 groups; R6c and R6d are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11. -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1 groups; R8b is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group; wherein C1-6 Alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally substituted with one to five Z1 groups; or R8b and R6c, or R6c and R6d together form a 5-membered heterocyclic group, which may be further independently and optionally substituted with one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR 12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR 12C(O)N(R12)2, -NR 12S(O)N(R12)2, -NR 12S(O)2N(R12)2, -OC(O)N(R12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted by one to five Z1a; Each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; each R11 is independently hydrogen, a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a groups; Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaromatic.The group is composed of a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is independently and optionally substituted by one to five Z1b groups; each Z1a group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R 13)2、-NR 13C(O)N (R13)2、-NR 13S(O)N(R13)2、-NR 13S(O)2N(R 13)2、-OC(O)N(R 13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1b; each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1b; Each Z1b is independently a halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups of Z1b and L is further optionally independently substituted by one to five substituents independently selected from: halogroup, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl.

[0117] In some embodiments, L1 is a bond.

[0118] In some embodiments, R1 is a halogroup or optionally a C1-6 alkyl group substituted with one to five halogroups.

[0119] In some embodiments, R1 is a halogroup or a C1-6 haloalkyl group. In some embodiments, R1 is a halogroup or CF3.

[0120] In some embodiments, R4 is hydrogen.

[0121] In some embodiments, R5 is hydrogen or a halogroup.

[0122] In some embodiments, X3 is CR6c.

[0123] In some embodiments, X4 is N.

[0124] In some embodiments, X3 is CR6c; and X4 is N.

[0125] In some embodiments, R8b is a C1-6 alkyl group. In some embodiments, R8b is methyl.

[0126] In some embodiments, a compound of formula IID is provided: IID or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; L1 is a bond, a C1-4 alkylene group, a C2-4 alkenyl group, or a C2-4 ynylene group; ring B is a C3-10 cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the C3-10 cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally substituted with one to five Z1b groups; R1 is a halogroup, a cyanogroup, a C1-3 alkyl group, a C2-3 alkenyl group, a C2-3 ynylene group, or a C3-6 cycloalkyl group; wherein the C1-6 alkyl group, C2-6 alkenyl group, C2-6 ynylene group, or C3-10 cycloalkyl group is optionally substituted with one to five Z1 groups; R5 is hydrogen or a halogroup; R8b is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally replaced by one to five Z1 derivatives (see specification 39 / 262, page 62, CN 122138828 A).Each Z1 is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR 12S(O)2N(R 12)2, -OC(O)N(R 12)2, or -NR12C(O) OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted with one to five Z1a; each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted with one to five Z1b; Each Z1a is independently a halogenated group, cyano group, -NO2 group, C1-6 alkyl group, C2-6 alkenyl group, C2-6 ynyl group, C3-10 cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2. 13)2, -OC(O)N(R 13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1b; each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted with one to five Z1b;Each Z1b is independently a halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups in Z1b and L is further independently and optionally substituted by one to five independently selected substituents from the following: haloyl, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl.

[0127] In some embodiments, a compound of formula IIE is provided: IIE or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; ring B is a C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one to five Z1b groups; R1 is a halogroup, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl group is optionally substituted with one to five Z1 groups; R5 is hydrogen or a halogroup;R8b is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR 12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR 12C(O)N(R12)2, -NR 12S(O)N(R12)2, -NR 12S(O)2N(R12)2, -OC(O)N(R12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted by one to five Z1a; Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1a is independently a halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR 13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR 13C(O)N(R13)2, -NR 13S(O)N(R13)2, -NR 13S(O)2N(R13)2, -OC(O)N(R13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1b groups;Each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1b is independently halogroup, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, - L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups in Z1b and L is further independently and optionally substituted by one to five independently selected substituents: haloyl, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl.

[0128] In some embodiments, R8b is a C1-6 alkyl group. In some embodiments, R8b is a methyl group.

[0129] In some embodiments, ring B is an oxadiazole optionally substituted with one to five Z1b groups.

[0130] In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 0. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments...In this case, q is 3.

[0131] In some embodiments, a compound of formula IIF is provided: IIF or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five Z1 groups; R5 is hydrogen or a halogroup; R8b is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 Alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally substituted with one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N (R12)2, -NR 12C(O)N(R12)2, -NR 12S(O)N(R12)2, -NR 12S(O)2N(R 12)2, -OC(O)N(R 12)2 or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently and optionally substituted by one to five Z1a. Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1a is independently a halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR 13C(O)R13, ​​‑NR13S(O)R13, ​​‑NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2, -OC(O)N(R13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted with one to five Z1b groups; each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group. (See page 42 / 262 of the specification, 65 CN 122138828 A) The group is alkyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1b is independently a halogroup, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Z1c is hydrogen or Z1b; Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups in Z1b and L is further independently and optionally substituted by one to five independently selected substituents from the following: halogroup, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkoxyAlkyl, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0132] In some embodiments, each Z1 is independently a halogroup, cyano, C1-6 alkyl, C1-6 haloalkyl, heteroaryl, -OR12, or -C(O)OR12; wherein each C1-6 alkyl, C1-6 haloalkyl, or heteroaryl is independently optionally substituted with one to five hydroxyl, methoxy, or methyl groups.

[0133] In some embodiments, each Z1b is independently a halogroup, cyano, C1-6 alkyl, or C1-6 haloalkyl; wherein each C1-6 alkyl or C1-6 haloalkyl is independently optionally substituted with a hydroxyl or methoxy group.

[0134] In some embodiments, a compound of formula IIG is provided: IIG or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein: R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, or C3-6 cycloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl is optionally substituted with one to five halogroups; R5 is hydrogen or a halogroup; Z1c is hydrogen or Z1b; Z1b is a halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N (C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, - Specification 43 / 262 pages 66 CN 122138828 AC(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of Z1b and L is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic group,The aryl and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0135] In some embodiments, compounds selected from Table 1 or pharmaceutically acceptable salts, isotopically enriched analogs, prodrugs, stereoisomers, or mixtures of stereoisomers thereof are provided: Table 1 Specification 44 / 262 pages 67 CN 122138828 A Specification 45 / 262 pages 68 CN 122138828 A Specification 46 / 262 pages 69 CN 122138828 A Specification 47 / 262 pages 70 CN 122138828 A Specification 48 / 262 pages 71 CN 122138828 A Specification 49 / 262 pages 72 CN 122138828 A Specification 50 / 262 pages 73 CN 122138828 A Specification 51 / 262 pages 74 CN 122138828 A Specification 52 / 262 pages 75 CN 122138828 A Instruction Manual 53 / 262 pages 76 CN 122138828 A Instruction Manual 54 / 262 pages 77 CN 122138828 A Instruction Manual 55 / 262 pages 78 CN 122138828 A Instruction Manual 56 / 262 pages 79 CN 122138828 A Instruction Manual 57 / 262 pages 80 CN 122138828 A Instruction Manual 58 / 262 pages 81 CN 122138828 A Instruction Manual 59 / 262 pages 82 CN 122138828 A Instruction Manual 60 / 262 pages 83 CN 122138828 A Instruction Manual 61 / 262 pages 84 CN 122138828 A Instruction Manual 62 / 262 pages 85 CN 122138828 A Instruction manual 63 / 262 pages 86 CN 122138828 A Instruction manual 64 / 262 pages 87 CN 122138828 A Instruction manual 65 / 262 pages 88 CN 122138828 A Instruction manual 66 / 262 pages 89 CN 122138828 A Instruction manual 67 / 262 pages 90 CN 122138828 A (Description)Instruction manual 68 / 262 pages 91 CN 122138828 A Instruction manual 69 / 262 pages 92 CN 122138828 A Instruction manual 70 / 262 pages 93 CN 122138828 A Instruction manual 71 / 262 pages 94 CN 122138828 A Instruction manual 72 / 262 pages 95 CN 122138828 A Instruction manual 73 / 262 pages 96 CN 122138828 A Instruction manual 74 / 262 pages 97 CN 122138828 A Instruction manual 75 / 262 pages 98 CN 122138828 A Instruction manual 76 / 262 pages 99 CN 122138828 A Instruction manual 77 / 262 pages 100 CN 122138828 A Instruction manual 78 / 262 pages 101 CN 122138828 A Specification 79 / 262 pages 102 CN 122138828 A Specification 80 / 262 pages 103 CN 122138828 A Specification 81 / 262 pages 104 CN 122138828 A Specification 82 / 262 pages 105 CN 122138828 A Specification 83 / 262 pages 106 CN 122138828 A Specification 84 / 262 pages 107 CN 122138828 A Specification 85 / 262 pages 108 CN 122138828 A Specification 86 / 262 pages 109 CN 122138828 A In some embodiments, compounds selected from Table 2 or pharmaceutically acceptable salts thereof are provided.

[0136] Table 2 Specification 87 / 262 pages 110 CN 122138828 A Specification 88 / 262 pages 111 CN 122138828 A Specification 89 / 262 pages 112 CN 122138828 A Specification 90 / 262 pages 113 CN 122138828 A Specification 91 / 262 pages 114 CN 122138828 A Specification 92 / 262 pages 115 CN 122138828 A Specification 93 / 262 pages 116 CN 122138828 A Specification 94 / 262 pages 117 CN 122138828 A Specification 95 / 262 pages 118 CN 122138828 A Specification 96 / 262 pages119 CN 122138828 A Instruction Manual 97 / 262 pages 120 CN 122138828 A Instruction Manual 98 / 262 pages 121 CN 122138828 A Instruction Manual 99 / 262 pages 122 CN 122138828 A Instruction Manual 100 / 262 pages 123 CN 122138828 A Instruction Manual 101 / 262 pages 124 CN 122138828 A Instruction Manual 102 / 262 pages 125 CN 122138828 A Instruction Manual 103 / 262 pages 126 CN 122138828 A Instruction Manual 104 / 262 pages 127 CN 122138828 A Instruction Manual 105 / 262 pages 128 CN 122138828 A Instruction manual 106 / 262 pages 129 CN 122138828 A; Instruction manual 107 / 262 pages 130 CN 122138828 A; Instruction manual 108 / 262 pages 131 CN 122138828 A; Instruction manual 109 / 262 pages 132 CN 122138828 A; Instruction manual 110 / 262 pages 133 CN 122138828 A; Instruction manual 111 / 262 pages 134 CN 122138828 A; Instruction manual 112 / 262 pages 135 CN 122138828 A; Instruction manual 113 / 262 pages 136 CN 122138828 A; Instruction manual 114 / 262 pages 137 CN 122138828 A; Instruction manual 115 / 262 pages 138 CN 122138828 A Instruction Manual 116 / 262 pages 139 CN 122138828 A Instruction Manual 117 / 262 pages 140 CN 122138828 A Instruction Manual 118 / 262 pages 141 CN 122138828 A Instruction Manual 119 / 262 pages 142 CN 122138828 A Instruction Manual 120 / 262 pages 143 CN 122138828 A Instruction Manual 121 / 262 pages 144 CN 122138828 A Instruction Manual 122 / 262 pages 145 CN 122138828 A Instruction Manual 123 / 262 pages 146 CN 122138828 A Instruction Manual 124 / 262 pages 147 CN 122138828 A Instruction ManualBook 125 / 262 pages 148 CN 122138828 A Instruction manual 126 / 262 pages 149 CN 122138828 A Instruction manual 127 / 262 pages 150 CN 122138828 A Instruction manual 128 / 262 pages 151 CN 122138828 A 3. Method "treatment" is a method for obtaining a beneficial or desired outcome (including clinical outcomes). Favorable or desired clinical outcomes may include one or more of the following: a) suppressing the disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder and / or alleviating the severity of the disease or disorder); b) slowing or halting the development of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the worsening or progression of the disease or disorder and / or preventing or delaying the spread of the disease or disorder (e.g., metastasis)); and / or c) alleviating the disease, even if clinical symptoms subside (e.g., improving the disease state, providing partial or overall remission of the disease or disorder, enhancing the effect of another drug therapy, delaying the progression of the disease, improving quality of life and / or prolonging survival).

[0137] "Prevention" means any treatment of a disease or disorder that causes the clinical symptoms of the disease or disorder to not develop. In some embodiments, the compound may be administered to a subject (including humans) who is at risk of the disease or disorder or has a family history of the disease or disorder.

[0138] "Subject" means an animal, such as a mammal (including humans), that has been or will be the subject of treatment, observation or experimentation. The methods described herein are applicable to human therapeutic and / or veterinary applications. In some embodiments, the subject information 129 / 262 pages 152 CN 122138828 A is a mammal. In some embodiments, the subject is a human.

[0139] The term “therapeutic effective amount” or “effective amount” for the compound described herein or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug means an amount sufficient to achieve treatment to provide therapeutic benefit (e.g., improvement of symptoms or slowing of disease progression) when administered to a subject. For example, a therapeutic effective amount may be an amount sufficient to alleviate symptoms of a disease or ailment as described herein. Therapeutic effective amounts may vary depending on the subject to be treated and the disease or ailment, the subject’s weight and age, the severity of the disease or ailment, and the manner of administration, and may be readily determined by one of ordinary skill in the art.

[0140] The methods described herein can be applied to in vivo or ex vivo cell populations. “In vivo” means in a living individual, such as in an animal or human. In such cases, the methods described herein can be used therapeutically in individuals. (“Ex vivo”)This refers to the external environment of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained using methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine the optimal administration schedule and / or dosing of the compounds disclosed herein for a given indication, cell type, individual, and other parameters. Information gathered from such uses can be used for experimental purposes or in a clinic to establish medical protocols for in vivo treatment. Other ex vivo uses of the compounds and compositions described herein that may be suitable are described below or will become apparent to those skilled in the art. The compounds may be further characterized to examine safety or tolerable doses in human or non-human subjects. Such properties can be examined using methods commonly known to those skilled in the art.

[0141] In some embodiments, compounds that inhibit the activity of a 1 (SARM1) protein containing a sterile α and TIR motif are provided, as well as pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof. In some embodiments, the compounds provided herein, as well as pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, inhibit SARM1.

[0142] In some embodiments, a method for inhibiting SARM1 activity is provided, comprising contacting cells with an effective amount of the compounds disclosed herein, as well as pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof. Inhibition may be in vitro or in vivo.

[0143] In some embodiments, compounds as disclosed herein, as well as pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, are provided for inhibiting SARM1 activity (e.g., in vitro or in vivo).

[0144] In some embodiments, this disclosure provides the use of compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, in the manufacture of pharmaceutical agents for inhibiting SARM1 activity (e.g., in vitro or in vivo).

[0145] In some embodiments, compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, are provided for inhibiting NADase activity of SARM1. In some embodiments, methods for inhibiting SARM1 NADase activity in a subject of need and / or treating neurodegeneration or neurological diseases or conditions are provided, comprising administering to the subject of need a therapeutically effective amount of the compounds disclosed herein.The compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0146] In some embodiments, a method for treating a disease or ailment at least partially mediated by SARM1 is provided, comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0147] In some embodiments, a method for treating a disease or ailment at least partially mediated by SARM1 is provided, comprising administering to a subject in need a therapeutically effective amount of a compound of formula I: I or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X1 is N, NR8a, O, S, or CR6a; X2 is N, NR8b, O, S, or CR6b; X3 is N, NR8c, or CR6c; X4 is N or CR6d; provided that at least one of X1, X2, X3, and X4 is N, and the ring containing X1, X2, X3, and X4 is aromatic; R is -NR2R3, -OR7, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, or heterocyclic; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C3-10 cycloalkyl are optionally substituted with one to five Z1 groups; R1 is a halogroup, cyanogroup, C1-3 alkyl, C2-3 alkenyl, C2-3 ynyl, C1-3 alkoxy, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-3 alkoxy, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted with one to five Z1 groups; R2 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted with one to five Z1 groups. R3 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; or R2 and R3 together form a heterocyclic group, which may be further independently and optionally substituted with one to five Z1 groups; R4 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally substituted with one to five Z1 groups; R5 is hydrogen, haloyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N (R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2 or -NR11C(O)OR11; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl groups are independently and optionally substituted by one to five Z1 groups; R6a, R6b, R6c and R6d are each independently hydrogen, halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R 11. -C(O)N(R11)2, -NR 11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR 11C(O)N(R11)2, -NR 11S(O)N(R11)2, -NR 11S(O)2N(R 11)2, -OC(O)N(R 11)2 or -NR11C(O) Instruction manual 131 / 262 pages 154 CN 122138828 AOR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; R7 is a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1 groups; R8a, R8b, and R8c are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl are independently and optionally substituted with one to five Z1 groups; or R8a and R6b, or R8b and R6c, or R6b and R6c, or R8c and R6d, or R6c and R6d together form a 5-membered heterocyclic group, which may further be independently and optionally substituted with one to five Z1 groups; each Z1 group is independently a halogroup, cyanogroup, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, or C1-6 haloalkyl. C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2 or -NR12C(O) OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a; each R10 is independently a C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally substituted with one to five Z1a; Each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted by one to five Z1a.Each R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1a is independently a halogroup, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, ​​-C(O)OR13, -S(O)R13, ​​-S(O)2R13, -C(O)N(R13)2, -NR 13C(O)R13, ​​-NR13S(O)R13, ​​-NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR 13C(O)N(R13)2, -NR 13S(O)N(R13)2, -NR 13S(O)2N(R13)2, -OC(O)N(R13)2 or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl or heteroaryl group is independently and optionally substituted by one to five Z1b groups; Each R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl is independently and optionally substituted by one to five Z1b; each Z1b is independently halogroup, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 ynyl, - L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 ynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 ynyl)-, (See page 132 / 262 of the specification, 155 CN) 122138828 A-C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; wherein each of Z1b and L is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclic, The aryl and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogenated, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0148] In some embodiments, a method of treating axonal degeneration in a subject of need is provided, comprising administering to the subject of need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug. In some embodiments, the compound or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers, or a prodrug inhibits axonal degeneration, including axonal degeneration caused by a reduction or depletion of NAD+. In some embodiments, the compound or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof prevents axonal degeneration distal to axonal injury.

[0149] In some embodiments, a method for treating degeneration of neurons or a portion thereof in the peripheral nervous system is provided, comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0150] In some embodiments, a method for treating degeneration of neurons or a portion thereof in the central nervous system is provided, comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0151] In some embodiments, the treatment includes reducing one or more symptoms or features of neurodegeneration.

[0152] In some embodiments, a method for inhibiting axonal degeneration is provided, the method comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0153] In some embodiments, a method for treating neurodegeneration or neurological diseases or conditions is provided, wherein...The method includes administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

[0154] In some embodiments, a method is provided for treating neurodegeneration or neurological diseases or conditions associated with axonal degeneration, axonal damage, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI) (see Ziogas et al., J. Neuroscience, 2018, 38(16):4031-4032 and WO2020191257), leukoencephalopathy, or leukodystrophy, said method comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

[0155] In some embodiments, compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, are provided for treating at least partially SARM1-mediated diseases or disorders in a subject of need.

[0156] In some embodiments, compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, are provided for inhibiting axonal degeneration in a subject of need. Specification 133 / 262 pages 156 CN 122138828 A

[0157] In some embodiments, this disclosure provides the use of compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, in the manufacture of medicaments for inhibiting axonal degeneration in a subject of need.

[0158] In some embodiments, this disclosure provides the use of compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, in the manufacture of medicaments for treating neurodegeneration or neurological diseases or conditions, such as those associated with axonal degeneration, axonal damage, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI), leukodystrophy, or leukodystrophy.

[0159] In some embodiments, the disease or condition is an acute condition. In some embodiments, the disease or condition is a chronic condition.

[0160] In some embodiments, the disease or condition is characterized by involvement of the central nervous system, peripheral nervous system, optic nerve,Axonal degeneration in cranial nerves or combinations thereof.

[0161] In some embodiments, the disease or disorder is or includes acute injury to the central nervous system, such as, but not limited to, spinal cord injury and / or traumatic brain injury (TBI). In some embodiments, the disease or disorder is or includes chronic injury to the central nervous system, such as, but not limited to, spinal cord injury, traumatic brain injury (TBI), and / or traumatic axonal injury (TAI). In some embodiments, the disease or disorder is or includes chronic traumatic encephalopathy (CTE).

[0162] In some embodiments, the disease or disorder is a chronic disorder affecting the central nervous system, such as, but not limited to, Parkinson's disease (see, for example, Sajadi, A. et al. Curr. Biology. 2004, 14, 326-330; and Hasbani, DM et al. Exp. Neurology. 2006, 202, 93-99), amyotrophic lateral sclerosis (see, for example, White, MA et al. Acta Neuropath. Comm. 2019, 7(1), 166), multiple sclerosis, Huntington's disease, or Alzheimer's disease.

[0163] In some embodiments, the disease or disorder is acute peripheral neuropathy. In some embodiments, the disease or disorder is chemotherapy-induced peripheral neuropathy (CIPN). See, for example, Geisler, S. et al. Brain. 2016, 139, 3092-3108; Turkiew, E. et al. J. Peripher. Nerv. Syst. 2017, 22, 162-171; Geisler, S. et al. JCI Insight. 2019, 4(17), e129920; and Cetinkaya-Fisgin, A. et al. Sci. Rep. 2020, 21889. Chemotherapy-induced peripheral neuropathy (CIPN) is an example of acute peripheral neuropathy that can be associated with a variety of drugs, such as, but not limited to, thalidomide, epothilone (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinblastine alkaloids (e.g., vinblastine, vinblastine...).Rebinolbine, vincristine, and vindesine, proteasome inhibitors (e.g., bortezomib), or platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0164] In some embodiments, the disease or ailment is a chronic condition affecting the peripheral nervous system, such as, but not limited to, diabetic neuropathy, HIV neuropathy, Charcot Marie Tooth disease, or amyotrophic lateral sclerosis.

[0165] In some embodiments, the disease or ailment is glaucoma (see, for example, Ko, K.W. et al. J. Cell Bio. 2020, 219(8), e201912047).

[0166] In some embodiments, the disease or disorder is an acute disorder affecting the optic nerve, such as, but not limited to, diabetic optic neuropathy, acute optic neuropathy (AON), or acute angle-closure glaucoma.

[0167] In some embodiments, the disease or disorder is a chronic disorder affecting the optic nerve, such as, but not limited to, diabetic optic neuropathy, Leber congenital amaurosis, Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma, or autosomal dominant optic atrophy.

[0168] In some embodiments, the disease or disorder is associated with retinal degeneration. In some embodiments, the disease or disorder is Leber congenital amaurosis, such as Leber congenital amaurosis type 9 (LCA9) (see, for example, Sasaki, Y. et al., eLife. 2020, 9, e62027).

[0169] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat one or more neurodegenerative diseases, conditions, or disorders selected from the group consisting of neuropathy or axonopathy. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat neuropathy or axonopathy associated with axonotropy. In some embodiments, the neuropathy associated with axonotropy is a hereditary or congenital neuropathy or axonopathy. In some embodiments, the neuropathy associated with axonotropy is caused by de novo mutation or somatic mutation. In some embodiments, the neuropathy associated with axonotropy is selected from the list contained herein. In some embodiments, the neuropathy or axonopathy is associated with axonotropy, including but not limited to Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, focal ischemia, etc.Wind, chemical injury, thermal injury, or AIDS.

[0170] In some embodiments, one or more compounds or compositions as described herein are characterized by reducing one or more symptoms or features of neurodegeneration when administered to a subject population. For example, in some embodiments, the associated symptoms or features may be selected from the group consisting of: the degree, rate, and / or timing of neuronal damage. In some embodiments, neuronal damage may be or include axonal degeneration, synaptic loss, dendritic loss, synaptic density loss, dendritic dendrite loss, axonal branching loss, neuronal density loss, myelination loss, neuronal cell body loss, synaptic enhancement loss, action potential difference loss, cytoskeleton stability loss, axonal transport loss, ion channel synthesis and switching loss, neurotransmitter synthesis loss, neuronal release and reuptake capacity loss, axonal potential propagation loss, neuronal hyperexcitability, and / or neuronal hypoexcitability. In some embodiments, neuronal damage is characterized by the inability to maintain an appropriate resting neuronal membrane potential. In some embodiments, neuronal damage is characterized by the presence of inclusion bodies, plaques, and / or neurofibrillary tangles. In some embodiments, neuronal damage is characterized by the presence of stress granules. In some embodiments, neuronal destruction is characterized by intracellular activation of one or more members of the cysteine-aspartate protease (caspase) family. In some embodiments, neuronal destruction is characterized by neurons undergoing programmed cell death (e.g., apoptosis, telogen effluvium, ferruginous apoptosis and / or necrosis) and / or inflammation.

[0171] In some embodiments, neurodegeneration or neurological diseases or conditions are associated with axonal degeneration, axonal damage, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by leukodystrophy, or leukodystrophy. In some implementations, neurodegeneration or neurological diseases or conditions include spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, Krabbe's disease, Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS), and Lou Gehrig's disease.Diseases), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher's disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (e.g., chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, glaucoma, retinitis pigmentosa, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis (e.g., Leber congenital amaurosis 9) Type 9 (LCA9), neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Shamadudine disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, Noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonal neuropathy, Guillain-Barré syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, infectious cavernous encephalopathy, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic hemiplegia, familial spastic paraplegia, French settlement disease.

[0172] In some embodiments, this disclosure provides SARM1 activity inhibitors for treating neurodegeneration or neurological diseases or conditions involving axonal degeneration or axonal lesions. This disclosure also provides methods for treating, preventing, or improving axonal degeneration, axonal lesions, and neurodegeneration or neurological diseases or conditions involving axonal degeneration using SARM1 activity inhibitors. In some embodiments, this disclosure provides methods for inhibiting axonal degeneration, the methods comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0173] In some embodiments, this disclosure provides methods for treating neurodegeneration or neurological diseases or conditions associated with axonal degeneration, axonal damage, axonopathy, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by leukodystrophy, or leukodystrophy.

[0174] In some embodiments, neuropathy and axonopathy include any disease or condition involving neurons and / or supporting cells such as glial cells, muscle cells, or fibroblasts, particularly those involving axonal damage. Axonal damage can be caused by traumatic injury or non-mechanical injury caused by disease, condition, or exposure to toxic molecules or drugs. The result of such damage can be axonal degeneration or dysfunction and loss of functional neuronal activity. Diseases and conditions that produce or are associated with such axonal damage are among a large number of neurological diseases and conditions. Such neuropathy can include peripheral neuropathy, central neuropathy, or a combination thereof. Furthermore, peripheral neuropathy can result from diseases primarily affecting the central nervous system, while central nervous system manifestations can result from substantially peripheral or systemic diseases.

[0175] In some embodiments, peripheral neuropathy may involve damage to the peripheral nerves and / or may be caused by neurological diseases or as a result of systemic diseases. Some such diseases include diabetes, uremia, infectious diseases such as AIDS or leprosy, nutritional deficiencies such as vascular or collagen diseases of atherosclerosis, or autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa. In some embodiments, peripheral neuropathy is caused by traumatic (mechanical) damage to the nerves as well as chemical or thermal damage to the nerves. Such disorders of peripheral nerve damage include compression or entrapment injuries, such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injury, contusion.Injury, fracture, or dislocation; pressure involving superficial nerves (ulnar, radial, or peroneal nerves), which may be caused by prolonged use of crutches or maintaining one posture for too long, or tumors; intraneural hemorrhage; local ischemia; exposure to cold or radiation, or certain drugs or toxic substances, such as herbicides or pesticides. In particular, nerve damage may be caused by chemical damage from cytotoxic anticancer agents (such as paclitaxel, cisplatinin, proteasome inhibitors, or vinca alkaloids, such as vincristine). Typical symptoms of such peripheral neuropathy include weakness, numbness, paresthesia (abnormal sensations, such as burning, itching, tingling, or numbing sensations), and pain in the arms, hands, legs, and / or feet. In some embodiments, the neuropathy is associated with mitochondrial dysfunction. Such neuropathy may manifest as a decrease in energy levels, i.e., a decrease in NAD and ATP levels.

[0176] In some embodiments, peripheral neuropathy is a metabolic and endocrine neuropathy that includes a wide range of peripheral neuropathy symptoms associated with systemic diseases of metabolic origin. These diseases include, for example, diabetes, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia vera, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorders, nutritional / vitamin deficiencies, or mitochondrial diseases. A common hallmark of these diseases is the structural or functional alteration of myelin and axons due to metabolic pathway dysregulation, thereby affecting the peripheral nerves.

[0177] In some embodiments, neuropathy includes optic neuropathy, such as glaucoma; retinal ganglion degeneration, such as those associated with retinitis pigmentosa and external retinal neuropathy; optic neuritis and / or degeneration, including those associated with multiple sclerosis; traumatic injury to the optic nerve, which may include, for example, injury during tumor resection; hereditary optic neuropathy, such as Kjer's disease and Leber's hereditary optic neuropathy (LHON); focal ischemic optic neuropathy, such as those secondary to giant cell arteritis; metabolic optic neuropathy, such as neurodegenerative diseases, including Leber's neuropathy; nutritional deficiencies, such as vitamin B12 or folic acid deficiency; and poisoning, such as poisoning by ethambutol or cyanide; neuropathy caused by adverse drug reactions and neuropathy caused by vitamin deficiencies. Focal ischemic optic neuropathy also includes non-arterial anterior focal ischemic optic neuropathy.

[0178] In some embodiments, neurodegenerative diseases associated with neuropathy or axonal lesions in the central nervous system include a variety of diseases. Such diseases include those involving: progressive dementia, such as Alzheimer's disease, senile dementia, Pick's disease, and Huntington's disease; central nervous system diseases affecting muscle function, such as…Parkinson's disease; motor neuron diseases and progressive ataxias, such as amyotrophic lateral sclerosis; demyelinating diseases, such as multiple sclerosis; viral encephalitis, such as those caused by enteroviruses, arboviruses, and herpes simplex viruses; and prion disease. Mechanical injuries (such as glaucoma or traumatic injuries to the head and spine) also cause nerve damage and degeneration in the brain and spinal cord. In addition, local ischemia and stroke, as well as disorders such as nutritional deficiencies and chemical toxicity (such as chemotherapeutic agents), can cause central nervous system neuropathy.

[0179] In some embodiments, this disclosure provides methods for treating neuropathy or axonal lesions associated with axonal degeneration. In some embodiments, the neuropathy or axonal lesion associated with axonal degeneration may be any of a variety of neuropathies or axonal lesions, such as those that are hereditary or congenital or associated with Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, ischemic stroke, chemical injury, thermal injury, and AIDS. Furthermore, neurodegenerative diseases not mentioned above, as well as subsets of the aforementioned diseases, may also be treated using the methods of this disclosure. Such subsets of diseases may include Parkinson's disease or Alzheimer's disease.

[0180] In some embodiments, the method includes administering to a subject in need an effective amount of the compound and / or composition described herein (e.g., compound of formula I). ​​In some such embodiments, the subject is at risk of developing a disease characterized by axonal degeneration. In some embodiments, the subject has a disease characterized by axonal degeneration. In some embodiments, the subject has been diagnosed with a disease characterized by axonal degeneration. In some embodiments, the subject is at risk of developing a disease characterized by axonal degeneration. In some embodiments, for example, the subject is identified as having axonal degeneration risk based on the subject's genotype, diagnosis of a disease associated with axonal degeneration, and / or exposure to agents and / or diseases that induce axonal degeneration.

[0181] In some embodiments, the subject is at risk of developing a neurodegenerative disease. In some embodiments, the subject is an older person. In some embodiments, the subject is known to have genetic risk factors for neurodegeneration. In some embodiments, the subject has a family history of neurodegenerative disease. In some embodiments, the subject exhibits one or more copies of a known genetic risk factor for neurodegeneration. In some embodiments, the subject comes from a population with a high incidence of neurodegeneration. In some embodiments, the subject has a hexanucleotide repeat amplification in open reading frame 72 of chromosome 9. In some embodiments, the subject has one or more copies of the ApoE4 allele.

[0182] In some embodiments, the neurodegenerative disease, condition, or disorder may be or include traumatic neuronal injury. In some embodiments, traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to concussion and / or explosive force, penetrating injury to the brain cavity or a nerve-innervated area of ​​the body. In some embodiments, traumatic neuronal injury is a force that causes axonal degeneration, stretching, compression, or tearing. In some embodiments, the disease or disorder is traumatic brain injury (TBI).

[0183] In some embodiments, the subject has engaged in or is engaged in activities identified as risk factors for neurodegeneration, such as contact sports or occupations with a high chance of developing traumatic neuronal injury or TBI.

[0184] In some embodiments, a method of treating a neurodegenerative disease, condition, or disorder is provided, comprising administering to a patient in need one or more of the compounds described herein and DLK inhibitors or NAMPT inhibitors. In some embodiments, a combination therapy is provided comprising the compounds described herein and DLK inhibitors and / or NAMPT inhibitors. In some embodiments, a combination therapy is provided comprising the compounds described herein, DLK inhibitors, and one or more additional therapeutic agents. In some embodiments, a combination therapy is provided comprising a compound as described herein, an NAMPT inhibitor, and one or more additional therapeutic agents. In some embodiments, a combination therapy is provided comprising a compound as described herein, a DLK inhibitor, an NAMPT inhibitor, and one or more additional therapeutic agents.

[0185] In some embodiments, the DLK inhibitor is a small molecule, peptide, peptide fragment, nucleic acid (e.g., siRNA, antisense oligonucleotide, microRNA, or aptamer), antibody, dominant / negative inhibitor, or ribozyme. In some embodiments, the DLK inhibitor is a small molecule. In some embodiments, the DLK inhibitor is siRNA. In some embodiments, the DLK inhibitor is an antisense oligonucleotide. In some embodiments, the DLK inhibitor is a peptide. In some embodiments, the DLK inhibitor is a peptide fragment. In some embodiments, the DLK inhibitor is a nucleic acid. In some embodiments, the DLK inhibitor is an antisense oligonucleotide.

[0186] Exemplary DLK inhibitors are provided in WO2013174780, WO2014111496, WO2014177524, WO2014177060, WO2015091889, WO2016142310, US20180057507, WO2018107072, WO2019241244, WO2020168111 and CN104387391A, all of which are hereby incorporated by reference in their entirety.

[0187] In some embodiments, the NAMPT inhibitor is a small molecule, peptide, peptide fragment, nucleic acid (e.g., siRNA, antisense oligonucleotide, microRNA, or aptamer), antibody, dominant / negative inhibitor, or ribozyme. In some embodiments, the NAMPT inhibitor is a small molecule. In some embodiments, the NAMPT inhibitor is siRNA. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide. In some embodiments, the NAMPT inhibitor is a peptide. In some embodiments, the NAMPT inhibitor is a nucleic acid. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide.

[0188] In some embodiments, the NAMPT inhibitor prevents the formation of nicotinamide mononucleotide (NMN). In some embodiments, inhibition of NAMPT inhibits the mammalian NAD+ rescue pathway.

[0189] In some embodiments, a composition comprising compounds as described herein is provided, formulated for administration in combination with a DLK inhibitor and / or a NAMPT inhibitor to a subject.

[0190] In some embodiments, a composition comprising the compounds described herein is provided for use in combination with a DLK inhibitor and / or a NAMPT inhibitor. In some embodiments, such a composition is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0191] In some embodiments, the subject may be a subject who has received, is receiving, or has been prescribed chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, but are not limited to, thalidomide, epothilone (e.g., ixaprazole), taxanes (e.g., paclitaxel and docetaxel), vinblastine alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), and platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0192] In some embodiments, SARM1 inhibition as described herein may be used in combination with one or more other therapies to treat an associated disease, condition, or disorder. In some embodiments, the administration of the SARM1 inhibitor is altered when used in combination therapy compared to when administered as a monotherapy; alternatively or additionally, the therapy administered in combination with SARM1 inhibitor as described herein is administered according to a regimen or medical regimen different from that when administered alone or in combination with one or more therapies other than SARM1 inhibitor. In some embodiments, the composition includes an additional therapeutic agent, which, together with the provided compound, may act synergistically. In some embodiments, the combination regimen utilizes...One or both therapies are administered at a lower level or less frequently than when used as a monotherapy.

[0193] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs or compositions are administered in combination with NAD+ or NAD+ precursors (e.g., nicotinamide riboside (NR), nicotinic acid (NA), nicotinic acid ribose (NaR), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinic acid mononucleotide (NaMN), tryptophan (TRP), nicotinic acid adenine dinucleotide (NAAD), or vitamin B3).

[0194] In some embodiments, compounds as disclosed herein or their pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs are provided for inhibiting the activity (e.g., in vitro or in vivo) of protein 1 (SARM1) containing sterile α and TIR motifs.

[0195] In some embodiments, this disclosure provides for the use of compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, in the manufacture of agents for inhibiting the activity of protein 1 (SARM1) containing sterile α and TIR motifs (e.g., in vitro or in vivo) and supplementing axonal NAD+ levels.

[0196] Axonal degeneration is associated with various types of neurodegenerative diseases and is considered an important indicator of disease progression and an attractive target for therapeutic treatment of these diseases. Similarly, axonal degeneration has been observed in subjects with traumatic brain injury and peripheral neuropathy.

[0197] In some embodiments, a method for treating a disease or ailment at least partially mediated by SARM1 is provided, comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug in combination with NAD+ or a NAD+ precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0198] In some embodiments, this disclosure provides the use of a compound as disclosed herein or a pharmaceutically acceptable description thereof (pages 139 / 262, CN 122138828 A), a salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug in combination with NAD+ or a NAD+ precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3) in the manufacture of a medicament for treating or preventing neurodegenerative diseases in a subject of need.

[0199] In some embodiments, a method for treating any disease caused by SARM1 activity is provided, comprising...Administer to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug in combination with NAD+ or a NAD+ precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0200] In some embodiments, the disease or ailment may be a disease or ailment of the central nervous system and / or may be caused by or related to a pathogen or traumatic injury. It should be understood that these general embodiments, defined according to a broad range of diseases, symptoms, and ailments, are not mutually exclusive.

[0201] In some embodiments, a method for treating neurodegenerative diseases is provided, comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug in combination with NAD+ or an NAD+ precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0202] Other embodiments include the use of the compounds disclosed herein in a therapy.

[0203] 4. Kit Kits are also provided herein that comprise a compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug, and suitable packaging. In some embodiments, the kit also includes instructions for use. In one aspect, the kit includes a compound of the present disclosure or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a label and / or instructions regarding the indication for treatment of the use of the compound (including the diseases or ailments described herein).

[0204] Articles comprising a compound of the present disclosure or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof contained in a suitable container. The container may be a vial, can, ampoule, pre-filled syringe, or intravenous bag.

[0205] 5. Pharmaceutical Composition and Administration The compounds provided herein are generally administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions comprising one or more of the compounds of the present disclosure or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and one or more pharmaceutically acceptable media selected from carriers, adjuvants, and excipients are also provided herein. Suitable pharmaceutically acceptable media may include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, and adjuvants. Such components are prepared in a manner well known in pharmaceutical technology. See, for example, Remington's Pharmaceutical Sciences, Maclean's.Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GS Banker and CT Rhodes).

[0206] The pharmaceutical composition may be administered in a single dose or multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, rectal, buccal, intranasal, and percutaneous routes. In some embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhaler.

[0207] One mode of administration is parenteral administration, for example by injection. Forms of pharmaceutical compositions described herein for administration by injection may include, for example, aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextran, or sterile aqueous solutions and similar pharmaceutical carriers. Instructions for Use, 140 / 262 pages, 163 CN 122138828 A

[0208] Oral administration may be another route of administration for the compounds described herein. Administration may be carried out, for example, by capsules or enteric-coated tablets. In the preparation of pharmaceutical compositions comprising at least one of the compounds described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the active ingredient is typically diluted with and / or encapsulated in a carrier, which may be in the form of capsules, sachets, paper, or other containers. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material, serving as a medium, carrier, or medium for the active ingredient. Therefore, the composition may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of an active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0209] Some examples of suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may additionally include lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives, such as methylparaben and propylparaben; sweeteners; and flavoring agents.

[0210] Compositions including at least one compound described herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug can be formulated using procedures known in the art.To provide rapid, sustained, or delayed release of the active ingredient after administration to a subject. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation used in the methods disclosed herein employs a percutaneous delivery device (“patch”). Such percutaneous patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of percutaneous patches for delivering pharmaceutical agents are well known in the art. Such patches can be configured for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0211] To prepare solid compositions (e.g., tablets), a major active ingredient may be mixed with a pharmaceutical excipient to form a solid preformed composition containing a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or a homogeneous mixture of a prodrug or the compound described herein or thereof. When these preformed compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition, making it easy to subdivide the composition into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0212] Tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action or protection against the acidic conditions of the stomach. For example, tablets or pills may include an internal dose and an external dose component, the latter in the form of a coating over the former. The two components may be separated by an enteric coating layer, which is used to resist disintegration in the stomach and allows the internal component to enter the duodenum intact or to delay release. A variety of substances may be used for such enteric coatings or coatings, including a variety of polymeric acids and mixtures of polymeric acids with substances such as shellac, cetyl alcohol, and cellulose acetate.

[0213] Compositions for inhalation or blowing may include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered via oral or nasal inhalation for local or systemic action. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be connected to a face mask tent or an intermittent positive pressure ventilator. In one embodiment, the solution, suspension, or powder composition may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0214] The amount of compounds in the pharmaceutical composition or formulation may vary within the full range applicable to those skilled in the art. Typically, based on weight percentage (wt%), the formulation will contain approximately 0.01–99.99 wt% of the components of this disclosure based on the total formulation.The compound, the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt%. Representative pharmaceutical formulations are described below.

[0215] Formulation Example 1 - Tablet Formulation The following ingredients are thoroughly mixed and compressed into single-score tablets.

[0216] Formulation Example 2 - Capsule Formulation The following ingredients are thoroughly mixed and loaded into hard-shell gelatin capsules.

[0217] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form a suspension for oral administration.

[0218] Formulation Example 4 - Injectable Formulation The following ingredients are mixed to form an injectable formulation. Instructions for Use 142 / 262 pages 165 CN 122138828 A

[0219] Formulation Example 5 - Suppository Formulation A suppository with a total weight of 2.5 g is prepared by mixing the compounds of this disclosure with Wiptsol® H-15 (a triglyceride of saturated vegetable fatty acids; Riches-Nelson, Inc., New York), and having the following composition:

[0220] 6. Dosage The specific dose level of the compounds of this application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate of the subject undergoing treatment, drug combination and the severity of the specific disease. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of the subject's body weight. A dose between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 to 100 mg / kg may be appropriate. In other embodiments, doses between 0.5 and 60 mg / kg may be appropriate. In some embodiments, doses of about 0.0001 to about 100 mg / kg body weight, about 0.001 to about 50 mg compound / kg body weight, or about 0.01 to about 10 mg compound / kg body weight may be appropriate daily. Normalization to the body weight of the subject is particularly useful when adjusting the dose among subjects with large differences in body size, for example when the drug is used in both children and adults, or when an effective dose for a non-human subject (e.g., a dog) is converted to a dose suitable for a human subject.

[0221] 7. The compounds can be prepared using the methods disclosed herein and their conventional modifications (which will be apparent in light of the disclosure herein and methods well known in the art). Conventional and well-known synthetic methods may also be used in addition to the teachings herein. The synthesis of typical compounds described herein may be carried out as described in the following examples. Reagents and starting materials may be commercially available from (e.g.) Sigma Aldrich or other chemical suppliers, if available.

[0222] It should be understood that, unless otherwise stated, other process conditions may be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0223] Furthermore, conventional protecting groups (“PG”) may be necessary to prevent certain functional groups from undergoing unwanted reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in Wuts, PGM, Greene, TW and Greene, T.W. (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience and the references cited therein. Protecting groups for alcohols, such as hydroxyl groups, include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsiloxymethyl (TOM), and triisopropylsilyl (TIPS) ether), which can be removed by acid or fluoride ions such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt3. Other protecting groups for alcohols include acetyl, removed by acid or base; benzoyl, removed by acid or base; benzyl, removed by hydrogenation; methoxyethoxymethyl ether, removed by acid; dimethoxytriphenylmethyl, removed by acid; methoxymethyl ether, removed by acid; tetrahydropyranyl or tetrahydrofuranyl, removed by acid; and triphenylmethyl, removed by acid. Examples of protecting groups used for amines include benzyloxycarbonyl, removed by hydrolysis; p-methoxybenzylcarbonyl, removed by hydrolysis; tert-butoxycarbonyl, removed by concentrated strong acid (e.g., HCl or CF3COOH) or by heating to above about 80°C; 9-fluorenylmethyloxycarbonyl, removed by a base (e.g., hexahydropyridine); acetyl, removed by treatment with a base; benzoyl, removed by treatment with a base; benzyl, removed by hydrolysis; carbamate, removed by acid and gentle heating; p-methoxybenzyl, removed by hydrolysis; 3,4-dimethoxybenzyl, removed by hydrolysis; p-methoxyphenyl, removed by cerium ammonium nitrate (IV); toluenesulfonyl, removed by concentrated acid (e.g., HBr or H2SO4) and a strong reducing agent (sodium or naphthyl sodium in liquid ammonia); troc (trichloroethyl chloroformate), removed by Zn insertion in the presence of acetic acid.To remove; and sulfonamides (Nosyl and Nps), removed by samarium iodide or tributyltin hydride.

[0224] Furthermore, the compounds of this disclosure may contain one or more palmate centers. Thus, such compounds may be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as mixtures of enriched stereoisomers, if desired. Unless otherwise stated, all such stereoisomers (and mixtures of enriched stereoisomers) are included within the scope of this disclosure. Pure stereoisomers (or mixtures of enriched stereoisomers) may be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds may be separated using, for example, palmate column chromatography, palmate resolving agents, etc.

[0225] The starting materials used in the following reactions are generally known compounds or may be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Other preparations can be made using procedures or obvious modifications thereof, as described in, for example, the following standard references: Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1–15 (John Wiley, and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989); organic Reactions, Volumes 1–40 (John Wiley, and Sons, 1991); March's Advanced Organic Chemistry (John Wiley, and Sons, 5th edition, 2001); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0226] General Synthesis Scheme I illustrates a general method that can be used to synthesize the compounds described herein (e.g., Formula I), wherein X1, X2, X3, X4, R, R1, R4, and R5 are each independently as defined herein, and each LG is independently a detachable group (e.g., a halogroup, alkoxy group, etc.).

[0227] Scheme IIn Scheme I, the compound of Formula I can be prepared by contacting compound I-1 with compound I-2 under suitable coupling reaction conditions, followed by optional functionalization or deprotection if desired. Alternatively, the compound of Formula I can be prepared by contacting compound I-3 with compound I-4 under suitable coupling reaction conditions, followed by optional functionalization or deprotection if desired. Alternatively, the compound of Formula I can be prepared by contacting compound I-5 with a suitable functionalized precursor of part A under suitable coupling reaction conditions, followed by optional functionalization or deprotection if desired. After each reaction is completed, each of the intermediates or the final compound can be recovered and optionally purified by conventional techniques (e.g., neutralization, extraction, precipitation, chromatography, filtration, etc.).

[0228] Further derivatization of the compound or any intermediate provided by the steps outlined in Scheme I provides additional compounds of Formula I. It should be understood that any of the compounds or intermediates shown in Scheme I can be prepared using conventional methods or purchased from commercial sources. Furthermore, any intermediate or product obtained by the process outlined in Scheme I can be derivatized at any step to provide various Formula I compounds. In some embodiments, various substituents of the compounds or intermediates used in Scheme I are as defined for Formula I.

[0229] In some embodiments, a Formula I compound (where R is -OR7) or a Formula IA or IB compound can be prepared according to Scheme II, wherein X1, X2, X3, X4, R1, R2, R3, R4, R5, and R7 are each independently as defined herein, and each LG is independently a detachable group (e.g., a halogenated group, alkoxy group, etc.).

[0230] Scheme II Specification 145 / 262 pages 168 CN 122138828 A In Scheme II, a compound of formula IA can be prepared by contacting compound I-1 with compound II-1 under suitable coupling reaction conditions to provide an acylation intermediate, followed by contacting the acylation intermediate with compound II-2 or a salt thereof. A compound of formula I (where R is -OR7, i.e., compound II-4) can be prepared by contacting compound I-1 with compound II-1 under suitable coupling reaction conditions to provide an acylation intermediate, followed by contacting the acylation intermediate with compound II-3. After each reaction is completed, each of the intermediates or the final compound can be recovered and optionally purified by conventional techniques (e.g., neutralization, extraction, precipitation, chromatography, filtration, etc.).

[0231] It should be understood that any of the compounds or intermediates shown in Scheme II can be prepared using conventional methods or obtained from commercial sources. Furthermore, any intermediate or product obtained by the process outlined in Scheme II can be derivatized at any step to provide various compounds of formula I or IA. In some implementations, such as the compound used in Scheme II, orVarious substituents in the intermediates are as defined for formula I or IA.

[0232] After each reaction is completed, each of the intermediates or final compounds can be recovered and optionally purified by conventional techniques (e.g., neutralization, extraction, precipitation, chromatography, filtration, etc.).

[0233] In some embodiments, a process for providing a compound of formula I is provided, comprising: 1) contacting compound I-1: I-1 with compound I-2: I-2 under conditions sufficient to provide a compound of formula I; wherein X1, X2, X3, X4, R, R1, R4 and R5 are each independently as defined herein as on pages 146 / 262 of the specification, 169 CN 122138828 A.

[0234] In some embodiments, a process for providing a compound of formula I is provided, comprising: 1) contacting a compound of formula I-1: I-1 with a compound of formula IA-2: IA-2 under conditions sufficient to provide a compound of formula IA; wherein X1, X2, X3, X4, R1, R2, R3, R4 and R5 are each independently as defined herein. In some embodiments, the conditions include a phosgene reagent, such as triphosgene.

[0235] Examples include the following examples to illustrate specific embodiments of the present disclosure. It will be understood by those skilled in the art that the techniques disclosed in the following embodiments represent techniques that work well in the practice of the present disclosure and can therefore be considered as a particular pattern constituting its practice. However, it will be understood by those skilled in the art that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the present disclosure and similar or analogous results can still be obtained.

[0236] All solvents used in general experimental methods are commercially available and used without further purification. Anhydrous solvents are typically used in reactions under an inert nitrogen atmosphere.

[0237] NMR spectroscopy: 1H nuclear magnetic resonance (NMR) spectroscopy is performed using one of the following instruments operating at 300 MHz: a Bruker Avance III or lower equipped with a BBFO 300 MHz probe; a Bruker Avance 400 instrument equipped with a DUAL 400 MHz S1 probe; a Bruker Avance 400 instrument equipped with a 6S1 400 MHz 5mm 1H-13C ID probe; a Bruker Avance III 400 instrument with a nanobay equipped with a Broadband BBFO 5 mm direct probe; or a Bruker Mercury Plus 400 NMR spectrometer operating at 400 MHz equipped with a Bruker 400 BBO probe. All deuterated solvents typically contain 0.03% to 0.05% v / v tetramethylsilane, which is used as a reference signal (for...).Both 1H and 13C are set at δ 0.00). In some cases, unless otherwise specified, 1H nuclear magnetic resonance (NMR) spectroscopy is performed using the solvent at approximately room temperature with a Bruker Advance 400 instrument running at 400 MHz. In all cases, the NMR data are consistent with the proposed structure. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations of the peak names: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet; dt, doubletuplet; br, broad peak.

[0238] Thin-layer chromatography: where thin-layer chromatography (TLC) is used, it refers to silica TLC using silica F254 (Merck) plates, where Rf is the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent. Column chromatography is performed on a silica column using an automated flash chromatography system or on a C18 column in the case of reversed-phase chromatography. Alternatively, thin-layer chromatography (TLC) is performed on an Alugram® (silica gel 60 F254) from Mancherey-Nagel, typically using UV to visualize the spots. Other visualization methods are employed in some cases. In these cases, the TLC plate is developed using iodine (generated by adding approximately 1 g of I2 to 10 g of silica gel and mixing thoroughly), ninhydrin (commercially available from Aldrich), or Magic Stain (generated by thoroughly mixing 25 g of (NH4)6Mo7O24·4H2O and 5 g of (NH4)2Ce(IV)(NO3)6 in 450 mL of water and 50 mL of concentrated H2SO4) to visualize the compounds.

[0239] Liquid chromatography-mass spectrometry and HPLC analysis: HPLC analysis was performed on a Shimadzu 20AB HPLC system with a photodiode array detector and a Luna-C18(2) 2.0 × 50 mm (5 µm column) at a flow rate of 1.2 mL / min using a gradient solvent mobile phase A (MPA, H2O + 0.037% (v / v) TFA): mobile phase B (MPB, ACN + 0.018% (v / v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LCMS or evaporative light scattering (ELSD) detection and positive electrospray ionization (MS) were performed at 220 nm and 254 nm. Semi-preparative HPLC was performed under acidic or neutral conditions. Acidity: Luna C18 100 ×30 mm, 5 μm; MPA: HCl / H2O = 0.04% or formic acid / H2O = 0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150 × 25, 5 μm; MPA: 10 mM NH4HCO3 in H2O; MPB: ACN. Gradients for both conditions: 10% MPB over 12 min to 80% MPB at a flow rate of 20 mL / min, followed by 100% MPB over 2 min, then 10% MPB over 2 min, UV detector. SFC analysis was performed on a Thar analytical SFC system using a UV / Vis detector and a series of palmar columns, including AD, AS-H, OJ, OD, AY, and IC. The columns were 4.6 × 100 mm, 3 µm, and the flow rate was 4 mL / min. A gradient solvent was used: mobile phase A (MPA, CO2) : mobile phase B (MPB, MeOH + 0.05% (v / v) IPA) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56–5 min, 10% MPB). Preparative SFC was performed on a Thar 80 preparative SFC system equipped with a UV / Vis detector and a series of palmar preparative columns (AD-H, AS-H, OJ-H, OD-H, AY-H, and IC-H, 30 × 250 mm, 5 μm columns) at a flow rate of 65 mL / min using a gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.1 % (v / v) NH3H2O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1–10 min, 10% MPB). LC-MS data were also collected using a UPLC-MS Acquity™ system equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternating positive and negative electrospray ionization modes. The column used was a Cortecs UPLC C18, 1.6 µm, 2.1 × 50 mm. A linear gradient was applied, starting with 95% A (A: 0.1% formic acid in water) and ending with 95% B (B: 0.1% formic acid in MeCN), lasting 2.0 min, for a total run time of 2.5 min. The column temperature was 40 °C, and the flow rate was 0.8 mL / min.

[0240] Examples include the following examples to illustrate specific embodiments of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that work well in the practice of this disclosure and are therefore considered...This constitutes a specific pattern of practice. However, as will be understood by those skilled in the art based on this disclosure, many changes may be made to the specific embodiments disclosed without departing from the spirit and scope of this disclosure, and similar or related results may still be obtained.

[0241] General experimental methods include the following examples to illustrate specific embodiments of this disclosure. As will be understood by those skilled in the art, the techniques disclosed in the following embodiments represent techniques that work well in the practice of this disclosure and may therefore be considered as a specific pattern of practice. However, as will be understood by those skilled in the art based on this disclosure, many changes may be made to the specific embodiments disclosed without departing from the spirit and scope of this disclosure, and similar or related results may still be obtained.

[0242] All solvents used in the general experimental methods are commercially available and can be used without further purification. Anhydrous solvents are typically used in reactions carried out under an inert nitrogen atmosphere. Instruction manual 148 / 262 pages 171 CN 122138828 A

[0243] NMR spectroscopy: 1H nuclear magnetic resonance (NMR) spectroscopy is performed using one of the following instruments equipped with a BBFO 300 MHz probe and operating at 300 MHz: Bruker Avance 400 instrument equipped with probe DUAL 400 MHz S1, Bruker Avance 400 instrument equipped with probe 6 S1 400 MHz 5mm 1H-13C ID, Bruker Avance III 400 instrument with a nanobay equipped with a Broadband BBFO 5 mm direct probe, and Bruker Mercury Plus 400 NMR spectrometer operating at 400 MHz equipped with a Bruker 400 BBO probe. All deuterated solvents typically contain 0.03% to 0.05% v / v tetramethylsilane, which is used as a reference signal (set at δ 0.00 for both 1H and 13C). In some cases, unless otherwise specified, 1H nuclear magnetic resonance (NMR) spectroscopy is performed using the solvent at approximately room temperature with a Bruker Advance 400 instrument running at 400 MHz. In all cases, the NMR data are consistent with the proposed structure. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations of the peak names: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet; dt, doubletuplet; br, broad peak.

[0244] Thin-layer chromatography: where thin-layer chromatography (TLC) has been used, this refers to the use of silica gel F254 (Merck) plates.In silica gel TLC, Rf is the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent. Column chromatography is performed on a silica gel column using an automated flash chromatography system or on a C18 column in the case of reversed-phase chromatography. Alternatively, thin-layer chromatography (TLC) is performed on Alugram® (silica gel 60 F254) from Mancherey-Nagel, and UV is typically used to visualize the spots. Other visualization methods are also employed in some cases. In these cases, the TLC plate is developed using iodine (generated by adding approximately 1 g of I2 to 10 g of silica gel and mixing thoroughly), ninhydrin (commercially available from Aldrich), or Magic Stain (generated by thoroughly mixing 25 g of (NH4)6Mo7O24·4H2O and 5 g of (NH4)2Ce(IV)(NO3)6 in 450 mL of water and 50 mL of concentrated H2SO4) to visualize the compound.

[0245] Liquid Chromatography-Mass Spectrometry and HPLC Analysis: HPLC analysis was performed on a Shimadzu 20AB HPLC system with a photodiode array detector and a Luna-C18(2) 2.0 × 50 mm (5 µm column) at a flow rate of 1.2 mL / min using a gradient solvent mobile phase A (MPA, H2O + 0.037% (v / v) TFA): mobile phase B (MPB, ACN + 0.018% (v / v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LCMS or evaporative light scattering (ELSD) detection and positive electrospray ionization (MS) were performed at 220 nm and 254 nm. Semi-preparative HPLC was performed under acidic or neutral conditions. Acidic: Luna C18 100 × 30 mm, 5 μm; MPA: HCl / H2O = 0.04% or formic acid / H2O = 0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150 × 25, 5 μm; MPA: 10 mM NH4HCO3 in H2O; MPB: ACN. Gradients for both conditions: 10% MPB over 12 min to 80% MPB at a flow rate of 20 mL / min, followed by 100% MPB over 2 min, and 10% MPB over 2 min, with a UV detector. SFC analysis was performed on a Thar analytical SFC system using a UV / Vis detector and a series of palmar columns, including AD, AS-H, OJ, OD, AY, and IC, 4.6 × 100 mm, 3 µm column, at a flow rate of 4 mL / min.mL / min, using a gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.05% (v / v) IPA) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56–5 min, 10% MPB). Preparative SFC was performed on a Thar 80 preparative SFC system equipped with a UV / Vis detector and a series of palmar preparative columns (including AD-H, AS-H, OJ-H, OD-H, AY-H, and IC-H, 30 × 250 mm, 5 μm columns) at a flow rate of 65 mL / min using a gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.1 % (v / v) NH3H2O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1–10 min, 10% MPB). LC-MS data were also collected using a UPLC-MS Acquity™ system equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternating positive and negative electrospray ionization modes. The column used was a Cortecs UPLC C18, 1.6 µm, 2.1 × 50 mm. A linear gradient was applied, starting with 95% A (A: 0.1% formic acid in water) and ending with 95% B (B: 0.1% formic acid in MeCN), lasting 2.0 min. The total run time was 2.5 min. The column temperature was 40 °C, and the flow rate was 0.8 mL / min.

[0246] Intermediate 1: 4-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline was added to a mixture of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)aniline (1 g, 4.29 mmol) and 3-bromo-1-methyl-1,2,4-triazole (834 mg, 5.15 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) at 25 °C under N2 conditions, along with Pd(dppf)Cl2 (314 mg, 0.429 mmol) and K2CO3 (1.78 g, 12.87 mmol). The mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was then diluted with H₂O (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and then with anhydrous Na₂SO₄.The sample was dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the title compound. LCMS: m / z = 189.1 [M+H]+.

[0247] Intermediate 2, 2-cyclobutyl-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)acetamide, at 0°C under N2, was added to a mixture of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline (2 g, 8.58 mmol) in DCM (20 mL) with TEA (1.74 g, 17.16 mmol) and 2-cyclobutylacetyl chloride (1.37 g, 10.30 mmol). The mixture was stirred at 0°C for 1 h. The reaction mixture was then diluted with H2O (30 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to give the title compound. LCMS: m / z = 330.3 [M+H]+.

[0248] Intermediate 3,4-methyl-3-(5-methyl-1H-1,2,4-triazol-3-yl)aniline 2-methyl-5-nitrobenzoylhydrazine: At 25 °C under N2, NH2NH2•H2O (2.56 g, 51.24 mmol, 2.49 mL) was added to a mixture of methyl 2-methyl-5-nitrobenzoate (2 g, 10.25 mmol, CN 122138828 A, pages 150 / 262, 173) in EtOH (20 mL). The mixture was heated to 85°C and stirred for 16 h. The mixture was then concentrated under reduced pressure to give the title compound.

[0249] 5-Methyl-3-(2-methyl-5-nitrophenyl)-1H-1,2,4-triazole: K2CO3 (1.90 g, 13.73 mmol) was added to a mixture of 2-methyl-5-nitrobenzoyl hydrazine (1.34 g, 6.87 mmol) and acetamiprid hydrochloride (649 mg, 6.87 mmol) in H2O (20 mL) at 25°C under N2. The mixture was heated to 80°C and stirred for 16 h. The reaction mixture was filtered and the solid was dried under reduced pressure to give the title compound.

[0250] 4-Methyl-3-(5-methyl-1H-1,2,4-triazol-3-yl)aniline: 5-methyl-3-(2-methyl-5-nitrophenyl)-1H-1 at 25°C2,4-triazole (200 mg, 0.92 mmol) was added to a solution of EtOAc (5 mL) with 10% Pd / C (50 mg, 0.92 mmol). The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was stirred at 25 °C under H2 (15 psi) for 0.5 h. After stirring, the reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 189.0 [M+H]+.

[0251] Intermediate 4, 4-methyl-3-(1-(trifluoromethyl)-1H-pyrazol-3-yl)aniline, 3-(2-methyl-5-nitrophenyl)-1H-pyrazol: A mixture of 2-iodo-1-methyl-4-nitrobenzene (5 g, 19.01 mmol), (1H-pyrazol-3-yl)boronic acid (4.25 g, 38.02 mmol), K2CO3 (5.25 g, 38.02 mmol), and Pd(dppf)Cl2 (1.39 g, 1.90 mmol) in 1,4-dioxane (100 mL) and H2O (10 mL) was degassed and purged three times with N2. The mixture was heated to 90 °C and stirred under N2 for 16 h. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 204.3 [M+H]+.

[0252] 1-(bromodifluoromethyl)-3-(2-methyl-5-nitrophenyl)-1H-pyrazole: NaH (457 mg, 11.42 mmol, 60% in mineral oil) was added to a mixture of 3-(2-methyl-5-nitrophenyl)-1H-pyrazole (580 mg, 2.85 mmol) in DMF (10 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h, followed by the addition of dibromo(difluoro)methane (3.59 g, 17.13 mmol) at 0 °C and stirring for another 1 h. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 332.0, 334.0 [M+H]+.

[0253] 3-(2-methyl-5-nitrophenyl)-1-(trifluoromethyl)-1H-pyrazole: At -78 °C under N2, 1-(bromodifluoromethyl)-3-(2-methyl-5-nitrophenyl)-1H-pyrazole (1.5 g,Silver tetrafluoroborate (2.64 g, 13.55 mmol) was added to a mixture of DCM (20 mL) and MeCN (4 mL). The mixture was heated to 25 °C and stirred for 12 h. The reaction mixture was adjusted to pH 7–8 by adding saturated aqueous NaHCO3 solution and then extracted with DCM (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound. LCMS: m / z = 272.1 [M+H]+.

[0254] 4-Methyl-3-(1-(trifluoromethyl)-1H-pyrazol-3-yl)aniline: 10% Pd / C (30 mg, 0.13 mmol) was added to a solution of 3-(2-methyl-5-nitrophenyl)-1-(trifluoromethyl)-1H-pyrazol (70 mg, 0.26 mmol) in EtOAc (2 mL) at 25 °C. The suspension was degassed under vacuum and purged several times with H2. The mixture was then stirred at 25 °C with H2 (15 psi) for 1 h. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 242.2 [M+H]+.

[0255] Intermediate 5 (S)-2,2-difluoro-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)cyclopropane-1-carboxamide was added to a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)aniline (1 g, 4.29 mmol) in pyridine (10 mL) at 25 °C under N2 conditions. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 9:1) to give the title compound. LCMS: m / z = 338.1 [M+H]+.

[0256] Intermediate 6 3-(1-methyl-1H-pyrazol-3-yl)-4-(1-methylcyclopropyl)aniline 2-bromo-4-nitro-1-(prop-1-en-2-yl)benzene: at 25 °C under N2, to 2-bromo-1-iodo-4-nitro-benzene (20 g, 60.99 g)K₂CO₃ (16.86 g, 121.99 mmol) and Pd(dppf)Cl₂•CH₂Cl₂ (4.98 g, 6.10 mmol) were added to a mixture of 1,4-dioxane (200 mL) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (11.27 g, 67.09 mmol) in 1,4-dioxane (200 mL) and H₂O (20 mL). The mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The crude reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE) to give the title compound.

[0257] 2-Bromo-1-(2,2-dibromo-1-methylcyclopropyl)-4-nitrobenzene: At 25°C and under N2, NaOH (33.05 g, 413 mmol, 25 mL, 50% purity, in H2O) and benzyltriethylammonium chloride (188 mg, 0.826 mmol) were added to a mixture of 2-bromo-1-isopropenyl-4-nitrobenzene (5 g, 20.66 mmol) in bromoform (50 mL). The reaction mixture was heated to 50°C and stirred for 5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was adjusted to pH = 7-8 by adding HCl (2 M), followed by extraction with MTBE (3 × 20 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: MTBE = 1:0 to 10:1) to give the title compound.

[0258] 3-Bromo-4-(1-methylcyclopropyl)aniline: At 25°C and under N2, Zn (30.81 g, 471 mmol) and NH4Cl (33.60 g, 628 mmol) were added to a mixture of 2-bromo-1-(2,2-dibromo-1-methylcyclopropyl)-4-nitrobenzene (13 g, 31.41 mmol) in EtOH (100 mL). The mixture was heated to 90°C and stirred for 5 h. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative HPLC (column: Welch Xtimate C18 250 × 70 mm × 10 μm; mobile phase: A: 10 μm in water).mM NH4HCO3, B: MeCN; purified from A (B%: 40%–70%, 10 min) to obtain the title compound. LCMS: m / z = 226.1, 228.1 [M+H]+.

[0259] 3-(1-methyl-1H-pyrazole-3-yl)-4-(1-methylcyclopropyl)aniline: At 25°C and under N2, K2CO3 (367 mg, 2.65 mmol) and Pd(dppf)Cl2 (97 mg, 0.133 mmol) were added to a mixture of 3-bromo-4-(1-methylcyclopropyl)aniline (300 mg, 1.33 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazole (414 mg, 1.99 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL). The mixture was heated to 100°C and stirred for 10 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 228.1 [M +H]+.

[0260] Intermediate 7 N-(4-cyclopropyl-3-(1-methyl-1H-pyrazol-3-yl)phenyl)-1H-imidazol-1-carboxamide was added to a mixture of CDI (91 mg, 0.56 mmol) in DCM (3 mL) at -40 °C under N2, with 4-cyclopropyl-3-(1-methyl-1H-pyrazol-3-yl)aniline (100 mg, 0.469 mmol) in DCM (3 mL). The mixture was stirred at -40 °C for 1 h and the reaction mixture was used directly in the next step.

[0261] Intermediate 8 3-fluoro-5,8-dihydro-5,8-cycloiminoquinoline hydrochloride 4-bromo-5-fluoro-3-(trimethylsilyl)pyridin-2-ol: At -78°C under N2, LDA (22.92 mmol, 2 M, 11.46 mL in THF) was added to a mixture of 4-bromo-5-fluoropyridin-2-ol (2 g, 10.42 mmol) in THF (25 mL). The mixture was stirred at -78°C for 30 min, then the reaction mixture was heated to 0°C and TMSCl (2.26 g, 20.83 mmol) was added and stirred at 0°C for 4 min.h. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 264.0, 266.0 [M+H]+.

[0262] 5-fluoro-3-(trimethylsilyl)pyridine-2-ol: 10% Pd / C (100 mg, 3.21 mmol) was added to a mixture of 4-bromo-5-fluoro-3-(trimethylsilyl)pyridine-2-ol (847 mg, 3.21 mmol) in MeOH (10 mL) at 20 °C. The mixture was stirred at 20 °C under H2 (15 psi) for 2 h. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 186.2 [M+H]+.

[0263] 5-fluoro-3-(trimethylsilyl)pyridin-2-yl trifluoromethanesulfonate: Tf2O (1.37 g, 4.86 mmol) was added to a mixture of 5-fluoro-3-(trimethylsilyl)pyridin-2-ol (450 mg, 2.43 mmol) in pyridine (5 mL) at 20 °C under N2. The mixture was heated to 20 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was adjusted to pH 7–8 by adding saturated NaHCO3 aqueous solution and then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE) to give the title compound. LCMS: m / z = 318.1 [M+H]+.

[0264] 3-Fluoro-5,8-dihydro-5,8-cycloiminoquinoline-9-carboxylic acid tert-butyl ester: CsF (191 mg, 1.26 mmol) was added to a mixture of 5-fluoro-3-(trimethylsilyl)pyridin-2-yl trifluoromethanesulfonate (200 mg, 0.63 mmol) and 1H-pyrrole-1-carboxylic acid tert-butyl ester (527 mg, 3.15 mmol) in MeCN (5 mL) at 20 °C under N2. The mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and EtOAc (3 × 10⁻⁶)Extracted with 10 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc = 3:1) to give the title compound. LCMS: m / z = 263.2 [M+H]+.

[0265] 3-Fluoro-5,8-dihydro-5,8-cycloiminoquinoline hydrochloride: A mixture of tert-butyl 3-fluoro-5,8-dihydro-5,8-cycloiminoquinoline-9-carboxylate (50 mg, 0.19 mmol) in HCl / EtOAc (3 mL, 4 M) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 163.0 [M+H]+.

[0266] Intermediate 9 4-Cyclopropyl-3-(1-methyl-1H-pyrazol-3-yl)aniline 3-bromo-4-cyclopropylaniline: At 20°C and under N2, cyclopropylboronic acid (4.32 g, 50.35 mmol), K3PO4 (21.37 g, 100.70 mmol), tricyclohexylphosphine (1.88 g, 6.71 mmol, 2.18 mL) and Pd(OAc)2 (753 mg, 3.36 mmol) were added to a solution of 3-bromo-4-iodoaniline (10 g, 33.57 mmol) in toluene (160 mL) and H2O (8 mL). The mixture was heated to 120°C and stirred for 12 h. The mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the title compound. LCMS: m / z = 212.1, 214.1 [M+H]+.

[0267] 4-Cyclopropyl-3-(1-methyl-1H-pyrazol-3-yl)aniline: At 25°C and under N2, 3-bromo-4-cyclopropyl-aniline (5.5 g, 25.93 mmol), Pd(dppf)Cl2 (1.90 g, 2.59 mmol), and K2CO3 (7.17 g, 51.87 mmol) were added to a solution of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole (13.49 g, 64.83 mmol) in 1,4-dioxane (30 mL) and H2O (3 mL). The mixture was heated to 100°C and stirred for 12 h. The mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography.(PE:EtOAc = 10:1 to 1:1) Purification yielded the title compound. LCMS: m / z = 214.2 [M+H]+.

[0268] Intermediate 10 cis-3-(3,3-difluoroazacyclobutan-1-yl)cyclobutane-1-carboxylic acid cis-3-(3,3-difluoroazacyclobutan-1-yl)cyclobutane-1-carboxylic acid benzyl ester: At 25 °C under N2, TEA (990 mg, 9.79 mmol) and HOAc (588 mg, 9.79 mmol) were added to a mixture of 3-oxocyclobutanecarboxylic acid benzyl ester (1 g, 4.90 mmol) and 3,3-difluoroazacyclobutane (1.27 g, 9.79 mmol) in DCE (10 mL). The mixture was heated to 25 °C and stirred for 30 min, then cooled to 0 °C and NaBH3CN (923 mg, 14.69 mmol) was added. The reaction mixture was heated to 25 °C and stirred for 2 h. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the title compound.

[0269] Cis-3-(3,3-difluoroazacyclobutan-1-yl)cyclobutane-1-carboxylic acid: At room temperature and under N2, 10% Pd / C (20 mg) was added to a solution of cis-3-(3,3-difluoroazacyclobutan-1-yl)cyclobutane-1-carboxylic acid benzyl ester (200 mg, 0.71 mmol) in THF (10 mL). The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was then stirred at 25 °C for 3 h under H2 (15 psi). The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 192.1 [M+H]+.

[0270] Intermediate 11 3-(1-methyl-1H-pyrazol-3-yl)-4-(trans-2-methylcyclopropyl)aniline(E)-2-bromo-4-nitro-1-(prop-1-en-1-yl)benzene: At 25°C, under N2, K2CO3 (5.06 g, 36.60 mmol) and Pd(dppf)Cl2 (892 mg, 1.22 mg) were added to a mixture of 2-bromo-1-iodo-4-nitro-benzene (4 g, 12.20 mmol) and [(E)-prop-1-en-yl]boronic acid (1.05 g, 12.20 mmol) in 1,4-dioxane (60 mL) and H2O (6 mL).The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was filtered through a Celite® pad, and the filtrate was diluted with H2O (40 mL) and extracted with MTBE (3 × 25 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (PE) to give the title compound.

[0271] 2-Bromo-1-((trans)-2,2-dibromo-3-methylcyclopropyl)-4-nitrobenzene: At 25°C and under N2, NaOH (15 g, 0.375 mol, 50% w / w, 15 mL H2O) and benzyltriethylammonium chloride (112 mg, 0.49 mmol) were added to a mixture of (E)-2-bromo-4-nitro-1-(prop-1-en-1-yl)benzene (3 g, 12.39 mmol) in bromoform (30 mL). The mixture was heated to 50°C and stirred for 5 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was adjusted to pH 7-8 with HCl (2 M) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE) to give the title compound.

[0272] 2-Bromo-1-(trans-2-methylcyclopropyl)-4-nitrobenzene: At 25 °C under N2, Zn (7.82 g, 119.60 mmol) and NH4Cl (8.53 g, 159.46 mmol) were added to a mixture of 2-bromo-1-[(trans)-2,2-dibromo-3-methylcyclopropyl]-4-nitrobenzene (3.3 g, 7.97 mmol) in EtOH (30 mL). The mixture was heated to 90 °C and stirred for 5 h. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 226.1, 228.1 [M+H]+.

[0273] 3-(1-methyl-1H-pyrazole-3-yl)-4-(trans-2-methylcyclopropyl)aniline: 2-bromo-1-(trans-2-methylcyclopropyl)-4-nitrobenzene (410 mg, 1.81 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane-2-yl)pyrazole (565 mg) were purified at 25 °C under N2.K₂CO₃ (501 mg, 3.63 mmol) and Pd(dppf)Cl₂ (132 mg, 0.18 mmol) were added to a mixture of 1,4-dioxane (6 mL) and H₂O (0.6 mL). The mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: A: NH₄HCO₃ in water, B: MeCN; B%: 25%–55%, 10 ...

Claims

1. A compound of formula I: I Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 It is N, NR 8b O, S or CR 6b ; X 3 It is N, NR 8c or CR 6c ; X 4 Is it N or CR? 6d ; The condition is X 1 X 2 X 3 and X 4 At least one of them is N, and it contains X. 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; R is -NR 2 R 3 -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8a and R 6b 、or R 8b and R 6c 、or R 6b and R 6c 、or R 8c and R 6d 、or R 6c and R 6d Together they form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further independently and optionally undergo one to five Z-axis reactions. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The condition is that at least one of A, B, C, D, or E occurs: A. X 1 It is N and X 2 It is NR 8b ;and a. When R is C 1-6 When alkyl; the C 1-6 Alkyl groups via halogenation or C 3-10 cycloalkyl groups and optional one to four Z 1 Replace; and / or b. R 8b Not hydrogen; and / or c. When R is -OR 7 When; then R 7 Not methyl, ethyl, isopropyl, tert-butyl, 2-bromoethyl, 2-methoxyethyl, 2-cyanoethyl, 2-phenylethyl, benzyl, or 9 H -fluorene-9-ylmethyl; And the compound is not: B. X 2 Is it N or NR? 8b And R is -NR 2 R 3 ;and a. R 2 and R 3 Not both methyl; and / or b. When X 1 When it is O, then R 8b R 8c R 6c Or R 6d At least one of them is not hydrogen; And the compound is not: C. X 1 Is it N or CR? 6a X 2 It is O, X 3 Is it N or CR? 6c And X 4 It is N; and a. In R is C 1-6 In the case of alkyl groups, the C 1-6 Alkyl groups with one to five Z 1 Replace; and / or b. R 6c Not 4-amino-2-[(3,4,5-trimethoxyphenyl)amino]-5-thiazolyl, [[4-(1-pyrrolidinylmethyl)phenyl]amino]-5-thiazolyl, or [[6-(4-methyl-1-hexahydropyrazinyl)-3-pyridyl]amino]-5-thiazolyl; and / or c. When R is -OR 7 When, then R 7 Not isobutyl or tert-butyl; And the compound is not: D. X 1 It is O, X 2 Is it N or CR? 6b X 3 It is CR 6c X 4 It is N, R 6c It is not hydrogen; and R is -NR. 2 R 3 , where R 2 and R 3 Together they form a heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 Replace; and at least one of the following a. through d. appears: a. X 2 It is N; b. R 1 Not methyl; c. R 2 and R 3 Forming an optionally substituted bridging heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; d. R 2 and R 3 Form a optionally substituted monocyclic 7-membered heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; And the compound is not: E. R is , where q is 0, 1, 2, 3, 4 or 5; and p is 0, 1, 2 or 3.

2. A compound of formula II: II Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 3 Is it N or CR? 6c ; X 4 Is it N or CR? 6d ; R is -NR 2 R 3 -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; wherein the C 1-6 Alkyl groups via halogenation or C 3-10 cycloalkyl groups and optional one to four Z 1 Replace; and where said C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 8b It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8b and R 6c 、or R 6c and R 6d Together they form a 5-membered heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The conditions are: When R is -OR 7 When; then R 7 Not methyl, ethyl, isopropyl, tert-butyl, 2-bromoethyl, 2-methoxyethyl, 2-cyanoethyl, 2-phenylethyl, benzyl, or 9 H -fluorene-9-ylmethyl; and the compound is not: 。 3. A compound of formula III: III Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 Is it N or NR? 8b ; X 3 It is N, NR 8c or CR 6c ; X 4 Is it N or CR? 6d ; The condition is that it contains X 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 6a and R 8b R 8b and R 6c 、or R 8c and R 6d 、or R 6c and R 6d Together they form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further independently and optionally undergo one to five Z-axis reactions. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The conditions are: R 2 and R 3 Not both methyl; When X 1 When it is O, then R 8b R 8c R 6c Or R 6d At least one of them is not hydrogen; and The compound is not: 。 4. A compound of formula IV: IV Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 Is it N or CR? 6a ; X 3 Is it N or CR? 6c ; R is -NR 2 R 3 -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; wherein the C 1-6 Alkyl groups with one to five Z 1 Replace; and where said C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a and R 6c Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The conditions are: R 6c Not 4-amino-2-[(3,4,5-trimethoxyphenyl)amino]-5-thiazolyl, [[4-(1-pyrrolidinylmethyl)phenyl]amino]-5-thiazolyl, or [[6-(4-methyl-1-hexahydropyrazinyl)-3-pyridyl]amino]-5-thiazolyl; and When R is -OR 7 When, then R 7 Not isobutyl or tert-butyl; and the compound is not: 。 5. A compound of formula V: V Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 2 Is it N or CR? 6b ; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6b It contains hydrogen, halogen, cyano, -NO2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 6c It is a halogenated group, a cyano group, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 6b and R 6c Together they form a 5-membered heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The condition is that at least one of the following occurs: X 2 It is N; or R 1 Not methyl; or R 2 and R 3 Forming an optionally substituted bridging heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; or R 2 and R 3 Form a optionally substituted monocyclic 7-membered heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; And the compound is not: 。 6. The compound according to any one of claims 1-5, wherein R or the said portion yes It can be optionally fused to a C6 aryl group; wherein: q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; X is CH2, CHZ 1 C(Z) 1 2. NR 9 , O or S; and R 9 Is it H or Z? 1 .

7. A compound of formula VI: WE Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 It is N, NR 8b O, S or CR 6b ; X 3 It is N, NR 8c or CR 6c ; X 4 Is it N or CR? 6d ; The condition is X 1 X 2 X 3 and X 4 At least one of them is N, and it contains X. 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; q is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are independently and optionally derived from one to five Z-shaped groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8a and R 6b 、or R 8b and R 6c 、or R 6b and R 6c 、or R 8c and R 6d 、or R 6c and R 6d Together they form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further independently and optionally undergo one to five Z-axis reactions. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

8. The compound according to any one of claims 1-5 or 7, wherein R, the portion or the part described yes ;in: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1b Replace; and L 1 It is key, C 1-4 Alkylene, C 2-4 imide or C 2-4 Alynyl group.

9. The compound of claim 7 or 8, wherein p is 1.

10. The compound of claim 6, 7 or 8, wherein q is 1 or 2.

11. The compound as claimed in any of the preceding claims, wherein R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl, optionally substituted with cyano or methyl.

12. The compound as claimed in any of the preceding claims, wherein R 1 It is fluorine, chlorine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclobutyl, or cyclopropyl, optionally substituted with cyano or methyl.

13. The compound as claimed in any of the preceding claims, wherein R 1 It is chloro, cyano, or trifluoromethyl.

14. The compound as claimed in any of the preceding claims, wherein R 4 Is it hydrogen or C? 1-6 alkyl.

15. The compound as claimed in any of the preceding claims, wherein R 4 It is either hydrogen or methyl.

16. The compound as claimed in any of the preceding claims, wherein R 5 It is either hydrogen or a halogroup.

17. The compound as claimed in any of the preceding claims, wherein R 5 It is either hydrogen or fluorine.

18. The compound of claim 1 or 7, wherein the portion yes , , , , , , , , , , , , , , , , , , , , , , , or .

19. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

20. A compound selected from Table 2 or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising any of the compounds of the preceding claims or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer or a mixture of stereoisomers, and a pharmaceutically acceptable carrier.

22. A method for inhibiting SARM1 activity, the method comprising contacting cells with an effective amount of the compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a tautomer or a mixture of stereoisomers, or the pharmaceutical composition of claim 21.

23. The method of claim 22, wherein the contact is within the body.

24. A method for treating a disease or ailment at least partially mediated by SARM1, the method comprising administering to a subject in need an effective amount of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers thereof, or a pharmaceutical composition of claim 21.

25. A method for inhibiting axonal degeneration, the method comprising administering to a subject in need an effective amount of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers, or a pharmaceutical composition of claim 21.

26. A method for treating neurodegeneration or a neurological disease or condition, the method comprising administering to a subject in need an effective amount of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers, or a pharmaceutical composition of claim 21.

27. The method of claim 26, wherein the neurodegeneration or neurological disease or condition is associated with axonal degeneration, axonal damage, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI), leukodystrophy, or leukodystrophy.

28. The method of claim 24, wherein the disease or disorder is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukodystrophy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Peyreke-Métrich disease, periventricular leukomalacia, or globular leukodystrophy. Labo's disease, Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Luke-Jaliger's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty Sachs disease, Gaucher's disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B1 12 Vitamin deficiency syndrome, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, retinitis pigmentosa, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunney virus encephalitis, etc. Subviral encephalitis, pediatric viral encephalitis, essential tremor, Shamadoosan disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axononeuropathy (AMAN).

29. A method for treating chemotherapy-induced peripheral neuropathy (CIPN), the method comprising administering to a subject in need an effective amount of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers thereof, or a pharmaceutical composition of claim 21.

30. Use of the compound of any one of claims 1-20 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21, for the treatment of a disease or ailment at least in part mediated by SARM1.

31. The use as described in claim 29, wherein the disease or ailment is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukodystrophy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Peyreke-Meyer's disease, periventricular leukomalacia, or globular leukodystrophy. Labo's disease, Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Luke-Jaliger's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty Sachs disease, Gaucher's disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B1 12 Vitamin deficiency syndrome, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalopathy Encephalitis, viral encephalitis in children, essential tremor, Shamadoosan disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axononeuropathy (AMAN).

32. The compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer or a mixture of stereoisomers thereof, or a pharmaceutical composition of claim 21, used in a therapeutic manner.

33. The compounds of any one of claims 1-20, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, tautomers, or mixtures of stereoisomers thereof, or the pharmaceutical composition of claim 21, for the treatment of spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, and other similar conditions. - Mellitus' disease, periventricular leukomalacia, globular leukodystrophy (Clapey's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lucas-Jaliger's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty Sachs disease, Gaucher's disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B 12 Vitamin deficiency syndrome, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalopathy Encephalitis, viral encephalitis in children, essential tremor, Shamadoosan disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axononeuropathy (AMAN).

34. The use of any compound of claims 1-20 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers, or the pharmaceutical composition of claim 21, for the manufacture of an agent for the treatment of: spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pygmal syndrome. Clabbe's disease, Peyrenia-Méder's disease, periventricular leukomalacia, globular leukodystrophy (Clabbe's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Luke-Jaliger's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty Sachs disease, Gaucher's disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B1 12 Vitamin deficiency syndrome, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalopathy Encephalitis, viral encephalitis in children, essential tremor, Shamadoosan disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axononeuropathy (AMAN).