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US-20260125389-A1 - MEMBRANE-ASSOCIATED TYROSINE AND THREONINE KINASE INHIBITOR AND USE THEREOF

US20260125389A1US 20260125389 A1US20260125389 A1US 20260125389A1US-20260125389-A1

Abstract

The present disclosure relates to a PKMYT1 inhibitor compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof, and use thereof in preventing or treating a PKMYT1-related disease. X 1 to X 5 , R 1 to R 4 , R 7 , and R 8 in formula (I) are as defined in the specification.

Inventors

  • Dongxing ZHU
  • Jianbin XUE
  • Weikun WANG
  • Lang Liu
  • Xiang HUAN
  • Yike Zhou
  • Tao Wang
  • Wei Zhu
  • Zhengtao LI

Assignees

  • HAINAN SIMCERE ZAIMING PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260507
Application Date
20230922
Priority Date
20220923

Claims (20)

  1. 1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 is selected from the group consisting of N and CR 9 ; represents a single bond or a double bond; X 2 is selected from the group consisting of CR 5 R 6 , NR 5 , CR 5 , and N; X 3 is selected from the group consisting of CR 5 ′R 6 ′, NR 5 ′, CR 5 ′, and N; X 4 and X 5 are independently selected from the group consisting of (C(R 10 ) 2 ) n , NR 10 , and O; R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, amino, nitro, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 9 cycloalkyl-O—, 4-9 membered heterocyclyl-O—, C 1 -C 6 alkyl-C(O)O—, C 3 -C 9 cycloalkyl-C(O)O—, 4-9 membered heterocyclyl-C(O)O—, P(O)(OH) 2 O, and NH 2 C(O)O—, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 9 cycloalkyl-O—, 4-9 membered heterocyclyl-O—, C 1 -C 6 alkyl-C(O)O—, C 3 -C 9 cycloalkyl-C(O)O—, 4-9 membered heterocyclyl-C(O)O—, P(O)(OH) 2 O, or NH 2 C(O)O— is optionally substituted with one or more R 11 ; R 2 is selected from the group consisting of hydrogen, cyano, halogen, C 1 -C 6 alkyl, C 3 -C 9 cycloalkyl, 4-9 membered heterocyclyl, C 6 -C 10 aryl, 5-9 membered heteroaryl, C(═O)H, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein the C 1 -C 6 alkyl, C 3 -C 9 cycloalkyl, 4-9 membered heterocyclyl, C 6 -C 10 aryl, 5-9 membered heteroaryl, C(═O)H, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R a ; or R 1 and R 2 , together with the atoms linked thereto, form a 5-8 membered heterocyclic ring or 5-9 membered heteroaromatic ring; R 4 , R 6 , R 6 ′, and R 10 are independently selected from the group consisting of hydrogen, deuterium, amino, hydroxy, sulfydryl, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 9 cycloalkyl, 4-9 membered heterocyclyl, C 6 -C 10 aryl, 5-9 membered heteroaryl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and —C(═O)NH 2 , wherein the amino, hydroxy, sulfydryl, C 1 -C 6 alkyl, C 3 -C 9 cycloalkyl, 4-9 membered heterocyclyl, C 6 -C 10 aryl, 5-9 membered heteroaryl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or —C(═O)NH 2 is optionally substituted with one or more R a ; R 5 and R 5 ′, together with the atoms linked thereto, form a C 3 -C 9 saturated or partially saturated carbon ring, a C 6 -C 10 aromatic ring, a 5-8 membered heterocyclic ring, or a 5-9 membered heteroaromatic ring, wherein the C 3 -C 9 saturated or partially saturated carbon ring, C 6 -C 10 aromatic ring, 5-8 membered heterocyclic ring, or 5-9 membered heteroaromatic ring is optionally substituted with one or more R a ; R 7 and R 8 are independently selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with deuterium; R 9 is selected from the group consisting of hydrogen, hydroxy, amino, cyano, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C(═O)H, wherein the hydroxy, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C(═O)H is optionally substituted with one or more R a ; R 11 is selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 9 cycloalkyl, 4-9 membered heterocyclyl, C 1 -C 6 alkoxy, C 3 -C 9 cycloalkyl-O—, 4-9 membered heterocyclyl-O—, C 1 -C 6 alkyl-C(O)O—, C 3 -C 9 cycloalkyl-C(O)O—, 4-9 membered heterocyclyl-C(O)O—, P(O)(OH) 2 O, NH 2 C(O)O—, and C 1 -C 6 alkyl-OC(O)O—; n is selected from the group consisting of 0, 1, and 2; R a is independently selected from the group consisting of deuterium, halogen, oxo, hydroxy, amino, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 6 -C 10 aryl, and 5-9 membered heteroaryl, wherein the hydroxy, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 6 -C 10 aryl, or 5-9 membered heteroaryl is optionally substituted with one or more R b ; R b is independently selected from the group consisting of halogen, hydroxy, amino, cyano, C 1 -C 3 alkyl, NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, and 5-9 membered heteroaryl, wherein the C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, or 5-9 membered heteroaryl is optionally substituted with one or more R c ; R c is independently selected from the group consisting of halogen, hydroxy, amino, cyano, and C 1 -C 3 alkyl.
  2. 2 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein X 2 is selected from the group consisting of CR 5 R 6 , NR 5 , and CR 5 ; or X 2 is selected from the group consisting of CR 5 R 6 and CR 5 ; or X 2 is CR 5 R 6 ; or X 2 is CR 5 .
  3. 3 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein X 3 is selected from the group consisting of CR 5 ′R 6 ′, NR 5 ′, and CR 5 ′; or X 3 is selected from the group consisting of CR 5 ′R 6 ′ and CR 5 ′; or X 3 is CR 5 ′R 6 ′ or X 3 is CR 5 ′.
  4. 4 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein X 4 and X 5 are independently selected from the group consisting of a bond, C(R 10 ) 2 , and O; or X 4 is a bond, —CH 2 —, —CH(CH 3 )—, or or X 5 is a bond, —O—, —CH(CH 3 )—, —C(CH 3 ) 2 —, or or X 4 and X 5 are both bonds; or X 4 is —CH 2 — and X 5 is a bond.
  5. 5 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 and R 3 are independently selected from the group consisting of hydrogen and hydroxy; or R 1 is hydroxy and R 3 is hydrogen.
  6. 6 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is hydrogen.
  7. 7 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 , R 6 , R 6 ′, and R 10 are independently selected from the group consisting of hydrogen, amino, hydroxy, sulfydryl, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 9 cycloalkyl, 4-9 membered heterocyclyl, C 6 -C 10 aryl, 5-9 membered heteroaryl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and —C(═O)NH 2 , wherein the amino, hydroxy, sulfydryl, C 1 -C 6 alkyl, C 3 -C 9 cycloalkyl, 4-9 membered heterocyclyl, C 6 -C 10 aryl, 5-9 membered heteroaryl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or —C(═O)NH 2 is optionally substituted with one or more R a ; or R 4 , R 6 , R 6 ′, and R 10 are independently selected from the group consisting of hydrogen, amino, hydroxy, C 1 -C 6 alkyl, C 3 -C 9 cycloalkyl, 4-9 membered heterocyclyl, C 6 -C 10 aryl, and 5-9 membered heteroaryl, wherein the amino, hydroxy, C 1 -C 6 alkyl, C 3 -C 9 cycloalkyl, 4-9 membered heterocyclyl, C 6 -C 10 aryl, or 5-9 membered heteroaryl is optionally substituted with one or more R a , or R 4 , R 6 , R 6 ′, and R 10 are independently selected from the group consisting of hydrogen, amino, hydroxy, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the amino, hydroxy, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl is optionally substituted with one or more R a ; or R 4 is selected from the group consisting of hydrogen, amino, hydroxy, C 1 -C 6 alkyl, C 3 -C 9 cycloalkyl, 4-9 membered heterocyclyl, C 6 -C 10 aryl, and 5-9 membered heteroaryl, wherein the amino, hydroxy, C 1 -C 6 alkyl, C 3 -C 9 cycloalkyl, 4-9 membered heterocyclyl, C 6 -C 10 aryl, or 5-9 membered heteroaryl is optionally substituted with one or more R a ; or R 4 is selected from the group consisting of —H, —CH 3 , —CH(CH 3 ) 2 , —OCH 3 , —N(CH 3 ) 2 , —CF 3 , —CHF 2 , —C(CH 3 ) 2 (OH), or R 4 is selected from the group consisting of H and methyl; or each R 10 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl.
  8. 8 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 5 and R 5 ′, together with the atoms linked thereto, form a C 4 -C 7 saturated or partially saturated carbon ring, a benzene ring, a 5-6 heterocyclic ring, or a 5-6 membered heteroaromatic ring, wherein the C 4 -C 7 saturated or partially saturated carbon ring, benzene ring, 5-6 heterocyclic ring, or 5-6 membered heteroaromatic ring is optionally substituted with one or more R a , or R 5 and R 5 ′, together with the atoms linked thereto, form a benzene ring or a 5-6 membered heteroaromatic ring, wherein the benzene ring or 5-6 membered heteroaromatic ring is optionally substituted with one or more R a ; or X 2 is CR 5 , X 3 is CR 5 ′, and R 5 and R 5 ′, together with the atoms linked thereto, form a benzene ring or a 5-6 membered heteroaromatic ring, wherein the benzene ring or 5-6 membered heteroaromatic ring is optionally substituted with one or more R a ; or X 2 is CR 5 , X 3 is CR 5 ′, and R 5 and R 5 ′, together with the atoms linked thereto, form a benzene ring, a pyridine ring, a pyrazole ring, a thiazole ring, an isothiazole ring, a pyrrole ring, or a furan ring, wherein the benzene ring, pyridine ring, pyrazole ring, thiazole ring, isothiazole ring, pyrrole ring, or furan ring is optionally substituted with one or more R a .
  9. 9 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 7 and R 8 are independently selected from the group consisting of halogen and C 1 -C 6 alkyl; or R 7 and R 8 are independently selected from the group consisting of C 1 -C 3 alkyl; or R 7 and R 8 are both methyl.
  10. 10 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein X 1 is N; or X 1 is CR 9 , and R 9 is selected from the group consisting of hydrogen, hydroxy, amino, halogen, and C 1 -C 3 alkyl, wherein the hydroxy, amino, and C 1 -C 3 alkyl are each optionally substituted with one or more R a ; or R 9 is selected from the group consisting of hydrogen and methyl.
  11. 11 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein n is selected from the group consisting of 0 and 1.
  12. 12 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R a is independently selected from the group consisting of halogen, oxo, hydroxy, amino, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 6 -C 10 aryl, and 5-9 membered heteroaryl, wherein the hydroxy, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 6 -C 10 aryl, or 5-9 membered heteroaryl is optionally substituted with one or more R b ; or R a is independently selected from the group consisting of cyano, halogen, hydroxy, amino, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein the hydroxy, amino, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl are each optionally substituted with one or more R b ; or R a is independently selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein the hydroxy, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl are each optionally substituted with one or more R b ; or R a is independently selected from the group consisting of cyano, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 alkoxy-C 1 -C 3 alkylene, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, and hydroxymethyl; or R a is independently selected from the group consisting of cyano, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; or R a is independently selected from the group consisting of —OH, —CH 3 , —C 2 H 5 , —OCH 3 , —OCH 2 CH 3 , —CH 2 CF 3 , —F, —OCF 2 H, —OCF 3 , —CN, —CF 3 , —CH 2 OH, —OCH 2 F, —CHF 2 , —CH 2 CH 2 OCH 3 , —CH(CH 3 ) 2 , —N(CH 3 ) 2 , —CH 2 N(CH 3 ) 2 , —CH 2 OCH 3 ,
  13. 13 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R b is independently selected from the group consisting of halogen, hydroxy, amino, cyano, C 1 -C 3 alkyl, NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, and 5-9 membered heteroaryl, wherein the C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, or 5-9 membered heteroaryl is optionally substituted with one or more R c ; or R b is independently selected from the group consisting of halogen, hydroxy, amino, cyano, NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, and 5-9 membered heteroaryl, wherein the C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, or 5-9 membered heteroaryl is optionally substituted with one or more R c ; or R b is independently selected from the group consisting of amino, NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, and C 1 -C 6 alkoxy, wherein the C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, and C 1 -C 6 alkoxy are each optionally substituted with one or more R c ; or R b is independently selected from the group consisting of halogen, hydroxy, C 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl, wherein the hydroxy, C 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl are each optionally substituted with one or more R c ; or R b is independently selected from the group consisting of halogen, hydroxy, C 1 -C 3 alkyl, N(C 1 -C 3 alkyl) 2 , C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, and C 1 -C 6 alkoxy, wherein the C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, and C 1 -C 6 alkoxy are each optionally substituted with one or more R c .
  14. 14 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R c is independently selected from the group consisting of halogen and C 1 -C 3 alkyl; or R c is selected from the group consisting of C 1 -C 3 alkyl; or R c is independently halogen.
  15. 15 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , selected from the group consisting of a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 5 and R 5 ′, together with the atoms linked thereto, form a C 6 -C 10 aromatic ring or a 5-9 membered heteroaromatic ring, wherein the C 6 -C 10 aromatic ring or 5-9 membered heteroaromatic ring is optionally substituted with one or more R a ; R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , X 1 , X 4 , X 5 , and R a are as defined in claim 1 .
  16. 16 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , selected from the group consisting of a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein X 6 and X 7 are independently selected from the group consisting of CH and N, wherein the CH is optionally substituted with halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy; X is selected from the group consisting of NR a and O; R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , X 1 , X 4 , X 5 , and R a are as defined in claim 1 .
  17. 17 . The compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 , selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof:
  18. 18 . A pharmaceutical composition, comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.
  19. 19 . A method for treating diseases mediated by PKMYT1 in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of the compound of formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 ; preferably, said diseases mediated by PKMYT1 are tumors, or said diseases mediated by PKMYT1 are selected from the group consisting of liver cancer and breast cancer.
  20. 20 . A method for treating diseases mediated by PKMYT1 in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of the pharmaceutical composition according to claim 18 ; preferably, said diseases mediated by PKMYT1 are tumors, or said diseases mediated by PKMYT1 are selected from the group consisting of liver cancer and breast cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATION The present application claims the benefit and priority to the following 4 Chinese Patent Applications, the contents of which are incorporated herein by reference in their entirety: Chinese Patent Application No. 202211163314.4 filed with China National Intellectual Property Administration on Sep. 23, 2022;Chinese Patent Application No. 202310505509.0 filed with China National Intellectual Property Administration on May 6, 2023;Chinese Patent Application No. 202310799876.6 filed with China National Intellectual Property Administration on Jun. 30, 2023; andChinese Patent Application No. 202311040531.9 filed with China National Intellectual Property Administration on Aug. 17, 2023. TECHNICAL FIELD The present application belongs to the field of medicines, and relates to a fused-ring compound or a pharmaceutically acceptable salt thereof serving as a PKMYT1 inhibitor, a preparation method therefor, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof, and use thereof in preventing or treating diseases related to PKMYT1. BACKGROUND The genomic DNA of cells is continuously exposed to various harmful factors originating from internal or external sources, which may cause DNA damage. Therefore, cells have evolved a series of complex DNA damage response mechanisms to counteract these harmful factors, thereby maintaining genomic integrity and preventing the occurrence of diseases, including tumors, caused by genomic instability. The activation of cell cycle checkpoint pathways is one of these important mechanisms. Cell cycle checkpoints include G1, S, G2, and M phase checkpoints. Unlike normal cells, the survival of tumor cells often relies on the dysregulation of DNA damage repair mechanisms. Many tumor cells, due to mutations in the p53 gene, lose their G1 checkpoint, and thus rely more on the G2 checkpoint for DNA damage repair to sustain their survival. Membrane-associated tyrosine- and threonine-protein kinase (Myt1 kinase, also known as PKMYT1) is encoded by the PKMYT1 gene. PKMYT1 inhibits the activity of cdc2 by phosphorylating Thr-14 and Tyr-15 on cdc2, thereby regulating the cell cycle. This causes the cell cycle to pause at the G2-M phase, allowing for DNA damage repair. Research has shown that inhibiting PKMYT1 leads to the activation of cdc2, forcing cells to enter mitosis prematurely without repairing DNA damage, thus killing rapidly proliferating tumor cells. Therefore, PKMYT1 inhibitors have the potential for inhibiting tumor proliferation, and the development of PKMYT1 inhibitors may provide a novel strategy for targeted tumor therapy. SUMMARY In one aspect, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, whereinX1 is selected from the group consisting of N and CR9; represents a single bond or a double bond;X2 is selected from the group consisting of CR5R6, NR5, CR5, and N;X3 is selected from the group consisting of CR5′R6′, NR5′, CR5′, and N;X4 and X5 are independently selected from the group consisting of (C(R10)2)n, NR10, and O;R1 and R3 are independently selected from the group consisting of hydrogen, hydroxy, amino, nitro, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O—, 4-9 membered heterocyclyl-O—, C1-C6 alkyl-C(O)O—, C3-C9 cycloalkyl-C(O)O—, 4-9 membered heterocyclyl-C(O)O—, P(O)(OH)2O—, and NH2C(O)O—, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O—, 4-9 membered heterocyclyl-O—, C1-C6 alkyl-C(O)O—, C3-C9 cycloalkyl-C(O)O—, 4-9 membered heterocyclyl-C(O)O—, P(O)(OH)2O—, or NH2C(O)O— is optionally substituted with one or more R11;R2 is selected from the group consisting of hydrogen, cyano, halogen, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C10 aryl, 5-9 membered heteroaryl, C(═O)H, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C10 aryl, 5-9 membered heteroaryl, C(═O)H, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more Ra;or R1 and R2, together with the atoms linked thereto, form a 5-8 membered heterocyclic ring or 5-9 membered heteroaromatic ring;R4, R6, R6′, and R10 are independently selected from the group consisting of hydrogen, deuterium, amino, hydroxy, sulfydryl, halogen, cyano, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C10 aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl, and —C(═O)NH2, wherein the amino, hydroxy, sulfydryl, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C10 aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl, or —C(═O)NH2 is optionally substituted with one or more Ra;R5 and R5′, together with the atoms linked thereto, form a C3-C9 saturated or partially saturated carbon ring, a C6-C10 aromatic ring, a 5-8 membered heterocyclic ring, and a 5-9 membered heteroaromatic ring, wherein the C3-C9 saturated or partially saturated carbon ring, C6-C10 aro