Tetrahydroisoquinoline derivatives for the treatment of red cell disorders and inflammatory diseases

Abstract

This article provides compounds and compositions thereof for activating nuclear factor erythroid 2-associated factor 2 (Nrf2) for the treatment of erythrocyte diseases and inflammatory diseases.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 078,118, filed September 14, 2020, and U.S. Provisional Application No. 63 / 229,338, filed August 4, 2021, pursuant to 35 USC §119(e), each of which is incorporated herein by reference in its entirety. Technical Field

[0003] This application generally relates to compounds, compositions, and methods for treating erythrocyte and inflammatory diseases. Background Technology

[0004] Nuclear factor erythroid 2-associated factor 2 (Nrf2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor encoded by the NFE2L2 gene in humans. Nrf2 is a basic leucine zipper (bZIP) protein that regulates the expression of antioxidant proteins that prevent oxidative damage induced by injury and inflammation. Nrf2 is central to a complex regulatory network and plays a crucial role in the regulation of metabolism, inflammation, autophagy, protein homeostasis, mitochondrial physiology, and immune responses.

[0005] Red blood cell (RBC) disorders are conditions affecting red blood cells, which carry oxygen from the lungs to all parts of the body. Many different types of RBC disorders exist, including anemia and hemoglobinopathies (such as sickle cell disease and thalassemia). Inflammatory diseases include, but are not limited to, asthma, rheumatoid arthritis, ulcerative colitis, and Crohn's disease. Currently, there is a significant unmet medical need for safe and effective oral therapies to treat RBC disorders and inflammatory conditions. Nrf2 activators stimulate proteins that prevent oxidative damage to reduce inflammation and treat RBC disorders.

[0006] Therefore, in one respect, this article provides compounds that activate Nrf2 for the treatment of erythrocyte diseases.

[0007] Therefore, on the other hand, this article provides compounds that activate Nrf2 for the treatment of inflammatory diseases. Summary of the Invention

[0008] Implementation Scheme 1. A compound of formula (I):

[0009]

[0010] Or its pharmaceutically acceptable salt, wherein:

[0011] R is H or optionally -OH, C 1-6 Alkoxy or C 1-6 aryl-substituted C 1-6alkyl;

[0012] R 1 Is it H or C? 1-6 alkyl;

[0013] R 2 Is it H or C? 1-6 alkyl;

[0014] R 3 Is it H or C? 1-6 alkyl;

[0015] Ring B is C 5-12 arylene or C containing 1 to 4 heteroatoms independently selected from N and O 3-12 heteroaryl;

[0016] n is 0, 1, 2, or 3;

[0017] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0018] Ring A is C 5-12 arylene or C containing 1-2 heteroatoms independently selected from N and O 3-12 heteroaryl;

[0019] m is 1, 2, 3, or 4;

[0020] Each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0021] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of 1 to 4 independently selected from halogens and C 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0022] Implementation scheme 1a(i). A compound of formula (I):

[0023]

[0024] Or its pharmaceutically acceptable salt, wherein:

[0025] R is H or optionally -OH, C 1-6 Alkoxy or C 1-6 aryl-substituted C 1-6 alkyl;

[0026] R 1 Is it H or C? 1-6 alkyl;

[0027] R 2 Is it H or C? 1-6 alkyl;

[0028] R 3 Is it H or C? 1-6 alkyl;

[0029] Ring B is C 5-12 arylene or C containing 1 to 4 heteroatoms independently selected from N and O 3-12 Heteroarylene, provided that cyclic B is not

[0030]

[0031] Where * represents the key connected to L;

[0032] n is 0, 1, 2, or 3;

[0033] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0034] Ring A is C 5-12 arylene or C containing 1-2 heteroatoms independently selected from N and O 3-12 heteroaryl;

[0035] m is 1, 2, 3, or 4;

[0036] Each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0037] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0038] Implementation scheme 1a(ii). A compound of formula (I):

[0039]

[0040] Or its pharmaceutically acceptable salt, wherein:

[0041] R is H or optionally replaced by a group selected from -OH, C 1-6 Alkoxy or C 6-12 Aryl substituents substituted C 1-6 alkyl;

[0042] R 1 Is it H or C? 1-6 alkyl;

[0043] R 2 Is it H or C? 1-6 alkyl;

[0044] R 3 Is it H or C? 1-6 alkyl;

[0045] Ring B is C 6-12 arylene or C containing 1 to 4 heteroatoms independently selected from N and O 3-12 Heteroarylene, provided that cyclic B is not

[0046]

[0047] Where * represents the key connected to L;

[0048] n is 0, 1, 2, or 3;

[0049] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0050] Ring A is C 6-12 arylene or C containing 1-2 heteroatoms independently selected from N and O 3-12 heteroaryl;

[0051] m is 1, 2, 3, or 4;

[0052] Each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0053] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0054] Implementation scheme 1a(iii). A compound of formula (I):

[0055]

[0056] Or its pharmaceutically acceptable salt, wherein:

[0057] R is H or optionally replaced by a group selected from -OH, C 1-6 Alkoxy or C 6-12 Aryl substituents substituted C 1-6 alkyl;

[0058] R 1 Is it H or C? 1-6 alkyl;

[0059] R 2 Is it H or C? 1-6 alkyl;

[0060] R 3 Is it H or C? 1-6 alkyl;

[0061] Ring B is C 6-12 arylene or C containing 1 to 4 heteroatoms independently selected from N and O 3-12 heteroaryl;

[0062] n is 0, 1, 2, or 3;

[0063] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0064] Ring A is C 7-12 arylene or 7- to 12-membered heteroarylene containing 1-2 independent heteroatoms selected from N and O;

[0065] m is 1, 2, 3, or 4;

[0066] Each R 4 Independently, it consists of H, halogens, and C. 1-6Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0067] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0068] Implementation scheme 1b. The compound of implementation scheme 1a(i) or 1a(ii) or 1(a)(iii), or a pharmaceutically acceptable salt thereof, wherein ring B is not benzotriazole.

[0069] Implementation scheme 1c. The compound of implementation scheme 1a(i) or 1a(ii) or 1(a)(iii), wherein L is C 5-7 Alkylene, C 5-7 imidene group, C 5-7 Heteroalkylene, or C 5-7 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 2 oxygen atoms.

[0070] Implementation scheme 1d. The compound of implementation scheme 1a(i) or 1a(ii) or 1(a)(iii), or a pharmaceutically acceptable salt thereof, wherein L is C 4-8 Alkylene, optionally composed of one or four independently selected from halogens and C 1-6 Alkyl groups are substituted.

[0071] Implementation Scheme 1e. The compound of Implementation Scheme 1a(i) or 1a(ii) or 1(a)(iii), or a pharmaceutically acceptable salt thereof, wherein L is a C6 alkylene group, optionally composed of one or four independently selected from halogens and C 1-6 Alkyl groups are substituted.

[0072] Implementation scheme 1f. The compound of implementation scheme 1a(i) or 1a(ii) or 1(a)(iii), or a pharmaceutically acceptable salt thereof, wherein L is C 4-8 Alkylenes, each of which is optionally selected independently by one or four halogens and C. 1-6 Alkyl groups are substituted.

[0073] Implementation scheme 1g. The compound of implementation scheme 1a(i) or 1a(ii) or 1(a)(iii), or a pharmaceutically acceptable salt thereof, wherein L is C 4-8 Heteroalkylene groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene group contains 1 to 4 oxygen atoms.

[0074] Implementation scheme 1h. The compound of implementation scheme 1a(i) or 1a(ii) or 1(a)(iii), or a pharmaceutically acceptable salt thereof, wherein L is C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroene group contains 1 to 4 oxygen atoms.

[0075] Implementation scheme 1i. The compound of implementation scheme 1a(i) or 1a(ii) or 1(a)(iii), or a pharmaceutically acceptable salt thereof, wherein L is C 4-8 imide or C 4-8 Heteroene derivatives, and C 4-8 imide and C 4-8 The heteroene group contains an unsaturated point (i.e., an unsaturated bond).

[0076] Implementation Scheme 2. The compound of Implementation Scheme 1a(i) or 1a(ii) or 1(a)(iii), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is the compound of Formula (IA):

[0077]

[0078] in:

[0079] L′ is C 4-6 Alkylene, C 4-6 imidene group, C 4-6 Heteroalkylene, or C 4-6 Heteroalkenyl groups, each optionally selected independently by one or two halogens and C. 1-6 Alkyl groups are substituted, and wherein the heteroalkylene and heteroeneyl groups contain one or two oxygen atoms;

[0080] X 3 It is CH2 or O;

[0081] n is 0, 1, or 2; and

[0082] X 1 and X 2 It can be CH or N independently.

[0083] Implementation scheme 2a(i). A compound of formula (IC):

[0084]

[0085] Or its pharmaceutically acceptable salt, wherein:

[0086] R is H or optionally -OH, C 1-6 Alkoxy or C 1-6 aryl-substituted C 1-6 alkyl;

[0087] R 1 Is it H or C? 1-6 alkyl;

[0088] R 2 Is it H or C? 1-6 alkyl;

[0089] R 3 Is it H or C? 1-6 alkyl;

[0090] n is 0, 1, 2, or 3;

[0091] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0092] Ring A is C 5-12 arylene or C containing 1-2 heteroatoms independently selected from N and O 3-12 heteroaryl;

[0093] m is 1, 2, 3, or 4;

[0094] Each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0095] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0096] Implementation scheme 2a(ii). A compound of formula (IC):

[0097]

[0098] Or its pharmaceutically acceptable salt, wherein:

[0099] R is H or optionally replaced by a group selected from -OH, C 1-6 Alkoxy and C 6-12 Aryl substituents substituted C 1-6 alkyl;

[0100] R 1 Is it H or C? 1-6 alkyl;

[0101] R 2 Is it H or C? 1-6 alkyl;

[0102] R 3 Is it H or C? 1-6 alkyl;

[0103] n is 0, 1, 2, or 3;

[0104] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0105] Ring A is C 6-12 arylene or C containing 1-2 heteroatoms independently selected from N and O 3-12 heteroaryl;

[0106] m is 1, 2, 3, or 4;

[0107] Each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0108] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0109] Implementation scheme 2b. A compound of implementation scheme 2a(i) or 2a(ii), wherein L is C 5-7 Alkylene, C5-7 imidene group, C 5-7 Heteroalkylene, or C 5-7 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 2 oxygen atoms.

[0110] Implementation scheme 2c. The compound of implementation scheme 2a(i) or 2a(ii), or a pharmaceutically acceptable salt thereof, wherein L is C 4-8 Alkylene, optionally composed of one or four independently selected from halogens and C 1-6 Alkyl groups are substituted.

[0111] Implementation Scheme 2d. The compound of Implementation Scheme 2a(i) or 2a(ii), or a pharmaceutically acceptable salt thereof, wherein L is a C6 alkylene group, optionally composed of one or four independently selected from halogens and C6 alkylene groups. 1-6 Alkyl groups are substituted.

[0112] Implementation scheme 2e. The compound of implementation scheme 2a(i) or 2a(ii), or a pharmaceutically acceptable salt thereof, wherein L is C 4-8 Alkylenes, each of which is optionally selected independently by one or four halogens and C. 1-6 Alkyl groups are substituted.

[0113] Implementation scheme 2f. The compound of implementation scheme 2a(i) or 2a(ii), or a pharmaceutically acceptable salt thereof, wherein L is C 4-8 Heteroalkylene groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene group contains 1 to 4 oxygen atoms.

[0114] Implementation scheme 2g. The compound of implementation scheme 2a(i) or 2a(ii), or a pharmaceutically acceptable salt thereof, wherein L is C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroene group contains 1 to 4 oxygen atoms.

[0115] Implementation scheme 2h. The compound of implementation scheme 2a(i) or 2a(ii), or a pharmaceutically acceptable salt thereof, wherein L is C 4-8 imide or C 4-8 Heteroene derivatives, and C 4-8 imide and C 4-8 The heteroene group contains an unsaturated point (i.e., an unsaturated bond).

[0116] Implementation Scheme 3. The compound of Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein X3 It is CH2.

[0117] Implementation Scheme 4. The compound of Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein X 3 It is O.

[0118] Implementation Scheme 5. A compound of any one of Implementation Schemes 2 to 4, or a pharmaceutically acceptable salt thereof, wherein X 1 It is N.

[0119] Implementation Scheme 6. A compound of any one of Implementation Schemes 2 to 4, or a pharmaceutically acceptable salt thereof, wherein X 1 It is CH.

[0120] Implementation Scheme 7. A compound of any one of Implementation Schemes 2 to 4, or a pharmaceutically acceptable salt thereof, wherein X 2 It is N.

[0121] Implementation Scheme 8. A compound of any one of Implementation Schemes 2 to 4, or a pharmaceutically acceptable salt thereof, wherein X 2 It is CH.

[0122] Implementation Scheme 9. A compound of any one of Implementation Schemes 2 to 4, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is N.

[0123] Implementation Scheme 10. A compound of any one of Implementation Schemes 2 to 4, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is CH.

[0124] Implementation Scheme 11. A compound of any one of Implementation Schemes 2 to 4, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 One is CH and the other is N.

[0125] Implementation scheme 12. A compound of any one of implementation schemes 1 to 11, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0126] Implementation Scheme 13. The compound of any one of Implementation Schemes 1 to 11, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0127] Implementation Scheme 14. A compound of any one of Implementation Schemes 1 to 13, or a pharmaceutically acceptable salt thereof, wherein each R 5 C is independent 1-4 Alkyl or C 1-4 Alkyl group.

[0128] Implementation Scheme 15. A compound of any one of Implementation Schemes 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each R 5 It is either methyl or methoxy.

[0129] Implementation Scheme 16. A compound of any one of Implementation Schemes 1 to 11, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0130] Implementation Scheme 17. A compound of any one of Implementation Schemes 2 to 16, or a pharmaceutically acceptable salt thereof, wherein L′ is C 4-6 Alkylene, C 4-6 imidene group, C 4-6 Heteroalkylene, or C 4-6 Heteroalkenyl groups, wherein heteroalkylene groups and heteroalkenyl groups contain one or two oxygen atoms.

[0131] Implementation Scheme 18. The compound of Implementation Scheme 17, or a pharmaceutically acceptable salt thereof, wherein C 4-6 imide or C 4-6 The heteroene group contains an unsaturated bond.

[0132] Implementation Scheme 19. A compound of any one of Implementation Schemes 2 to 3 and 5 to 18, or a pharmaceutically acceptable salt thereof, wherein X 3 It is CH2, and L′ is a C containing one unsaturated bond. 4-6 imide or C 4-6 Heteroene group.

[0133] Implementation Scheme 20. A compound of any one of Implementation Schemes 2 and 4 to 18, or a pharmaceutically acceptable salt thereof, wherein X 3 It is O, and L′ is C containing one unsaturated bond. 4-6 imide or C 4-6 Heteroene group.

[0134] Implementation Scheme 21. A compound of any one of Implementation Schemes 2 to 3 and 5 to 18, or a pharmaceutically acceptable salt thereof, wherein X 3 It is CH2 and L′ is C 4-6 Alkylene or C 4-6 Heteroalkylene, wherein C 4-6 Heteroalkylene groups contain one or two oxygen atoms.

[0135] Implementation Scheme 22. A compound of any one of Implementation Schemes 2 and 4 to 18, or a pharmaceutically acceptable salt thereof, wherein X 3 It is O and L′ is C 4-6 Alkylene or C 4-6 Heteroalkylene, wherein C 4-6 Heteroalkylene contains one oxygen atom.

[0136] Implementation Scheme 23. A compound of any one of Implementation Schemes 2 and 4 to 18, or a pharmaceutically acceptable salt thereof, wherein X 3 It is O and L′ is C 4-6 Alkylene.

[0137] Implementation Scheme 24. A compound of any one of Implementation Schemes 2 to 3 and 5 to 18, or a pharmaceutically acceptable salt thereof, wherein X 3 It is CH2 and L′ is C 4-6 Alkylene.

[0138] Implementation Scheme 25. The compound of Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (IB):

[0139]

[0140] in:

[0141] L″ is C 4-6 Alkylene, C 4-6 imidene group, C 4-6 Heteroalkylene, or C 4-6 Heteroalkenyl groups, each optionally selected independently by one or two halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 2 oxygen atoms;

[0142] Ring B″ is selected from

[0143]

[0144] Where * represents the key connected to L″; X 4 It is CR 5 CH, or N; ring B” is –(R 5 ) n Replace, where n is 0, 1, 2, or 3; and each R 5 Independently, halogen, C 1-4 Alkyl, or C 1-4 Alkyl group. It should be noted that ring B″ includes a methylene group, which is included in L in formula I.

[0145] Implementation Scheme 25a. The compound of Implementation Scheme 25, or a pharmaceutically acceptable salt thereof, wherein ring B″ is selected from...

[0146]

[0147] Where * represents the key connected to L″; X 4 It is CR 5 CH, or N; ring B″ is –(R5 ) n Replace, where n is 0, 1, 2, or 3; and each R 5 Independently, halogen, C 1-4 Alkyl, or C 1-4 Alkyl groups, provided the ring is not alkoxy.

[0148] Implementation Scheme 26. The compound of Implementation Scheme 25, or a pharmaceutically acceptable salt thereof, wherein ring B″ is

[0149] Where * represents the key connected to L″; X 4 It is N; ring B is -(R) 5 ) n Replace, where n is 0, 1, or 2; and each R 5 Independently, halogen, C 1-4 Alkyl, or C 1-4 Alkyl group.

[0150] Implementation Scheme 27. The compound of Implementation Scheme 25, or a pharmaceutically acceptable salt thereof, wherein X 4 It is CH.

[0151] Implementation Scheme 28. The compound of Implementation Scheme 25, or a pharmaceutically acceptable salt thereof, wherein X 4 It is N.

[0152] Implementation Scheme 29. The compound of Implementation Scheme 25, or a pharmaceutically acceptable salt thereof, wherein X 4 It is CR 5 .

[0153] Implementation scheme 30. The compound of any one of implementation schemes 25 to 29, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0154] Implementation scheme 31. The compound of any one of Implementation schemes 25 to 29, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0155] Implementation Scheme 32. The compound of any one of Implementation Schemes 25 to 31, or a pharmaceutically acceptable salt thereof, wherein each R 5 C is independent 1-4 Alkyl or C 1-4 Alkyl group.

[0156] Implementation Scheme 33. The compound of any one of Implementation Schemes 25 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 5 It is either methyl or methoxy.

[0157] Implementation Scheme 34. The compound of any one of Implementation Schemes 25 to 29, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0158] Implementation Scheme 35. The compound of any one of Implementation Schemes 25 to 34, or a pharmaceutically acceptable salt thereof, wherein L″ is C 4-6 Alkylene, C 4-6 imidene group, C 4-6 Heteroalkylene, or C 4-6 Heteroalkenyl groups, wherein heteroalkylene groups and heteroalkenyl groups contain 1 to 2 oxygen atoms.

[0159] Implementation Scheme 36. The compound of any one of Implementation Schemes 25 to 35, or a pharmaceutically acceptable salt thereof, wherein L″ is C 4-6 imide or C 4-6 Heteroeneyl group, wherein the heteroeneyl group contains one oxygen atom, and wherein C 4-6 imide and C 4-6 Heteroalkylene compounds contain one unsaturated bond.

[0160] Implementation Scheme 37. The compound of any one of Implementation Schemes 25 to 35, or a pharmaceutically acceptable salt thereof, wherein L″ is C 4-6 Alkylene or C 4-6 Heteroalkylene, wherein C 4-6 Heteroalkylene groups contain one or two oxygen atoms.

[0161] Implementation Scheme 38. The compound of any one of Implementation Schemes 25 to 35, or a pharmaceutically acceptable salt thereof, wherein L″ is C 4-6 Alkylene.

[0162] Implementation Scheme 39. The compound of any one of Implementation Schemes 25 to 38, or a pharmaceutically acceptable salt thereof, wherein each R 5 Independently, halogen, C 1-4 Alkyl, or C 1-4 Alkyl group.

[0163] Implementation Scheme 40. The compound of any one of Implementation Schemes 25 to 39, or a pharmaceutically acceptable salt thereof, wherein each R 5 It can be F, Cl, or methyl on its own.

[0164] Implementation Scheme 41. The compound of any one of Implementation Schemes 25 to 40, or a pharmaceutically acceptable salt thereof, wherein ring A is phenylene, indolylene, pyrrolopyridylene, pyridylene, pyrazinylene, pyrimidinylene, pyridazinylene, naphthylene, quinolinylene, benzimidazolylene, or benzofuranylene.

[0165] Implementation Scheme 42. The compound of any one of Implementation Schemes 1 to 41, or a pharmaceutically acceptable salt thereof, wherein ring A is

[0166]

[0167]

[0168] Where * represents a key connected to L, L′, or L″, and ring A is –(R 4 ) m Replacement, where m is 1, 2, 3, or 4; and each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups.

[0169] Implementation Scheme 43. The compound of any one of Implementation Schemes 1 to 42, or a pharmaceutically acceptable salt thereof, wherein ring A is

[0170]

[0171]

[0172] Where * represents a key connected to L, L′, or L″, and ring A is –(R 4 ) m Replace, where m is 1 or 2; and each R 4 Independently, it consists of H, halogens, and C. 1-4 Alkyl, or C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-4 Substitution of alkoxy, amide, and N,N-dimethylamide groups.

[0173] Implementation Scheme 44. A compound of any one of Implementation Schemes 1 to 42, or a pharmaceutically acceptable salt thereof, wherein ring A is Where * represents a key connected to L, L′, or L″, and ring A is –(R 4 ) m Replace, where m is 1 or 2; and each R 4 Independently, it consists of H, halogens, and C. 1-4 Alkyl, or C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C1-4 Substitution of alkoxy, amide, and N,N-dimethylamide groups.

[0174] Implementation Scheme 45. A compound of any one of Implementation Schemes 1 to 42, or a pharmaceutically acceptable salt thereof, wherein ring A is

[0175] And where * represents a key connected to L, L′, or L″, ring A is –(R 4 ) m Replacement, where m is 1, 2, 3, or 4; and each R 4 Independently, it consists of H, halogens, and C. 1-4 Alkyl, or C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-4 Substitution of alkoxy, amide, and N,N-dimethylamide groups.

[0176] Implementation Scheme 46. A compound of any one of Implementation Schemes 1 to 45, or a pharmaceutically acceptable salt thereof, wherein each R 4 Independently selected from H, halogens, C 1-4 Alkyl and C 1-4 Alkoxy, where C 1-4 Alkyl and C 1-4 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-4 Substitution of alkoxy, amide, and N,N-dimethylamide groups.

[0177] Implementation scheme 47a. A compound of any one of Implementation schemes 1 to 46, or a pharmaceutically acceptable salt thereof, wherein each R 4 Independently selected from H, halogens, C 1-4 Alkyl and C 1-4 Alkoxy groups, where each C 1-4 Alkyl and C 1-4 The alkoxy group is optionally substituted by 1 to 3 groups independently selected from F, Cl, methyl, methoxy, amide and N,N-dimethylamide.

[0178] Implementation scheme 47b. A compound of any one of Implementation schemes 1 to 46, or a pharmaceutically acceptable salt thereof, wherein each R 4 Independently selected from H, halogens, C 1-4 Alkyl and C 1-4 Alkoxy groups, where each C 1-4 Alkyl and C 1-4 The alkoxy group is optionally substituted with 1 to 3 groups independently selected from F, Cl, methoxy, amide and N,N-dimethylamide.

[0179] Implementation Scheme 48. A compound of any one of Implementation Schemes 1 to 47, or a pharmaceutically acceptable salt thereof, wherein each R 4 It is independently selected from H, methyl, isobutyl, F, Cl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, N,N-dimethylamido, 3,3,3-trifluoropropyl, 2,2-difluoroethyl, 3-fluoropropyl and methoxyethyl.

[0180] Implementation Scheme 49. The compound of any one of Implementation Schemes 1 to 48, or a pharmaceutically acceptable salt thereof, wherein R is H, methyl, ethyl, 2-hydroxy-ethyl, or benzyl.

[0181] Implementation scheme 50. The compound of any one of implementation schemes 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R is H.

[0182] Implementation Scheme 51. A compound of any one of Implementation Schemes 1 to 50, or a pharmaceutically acceptable salt thereof, wherein R 1 Is it H or C? 1-4 alkyl.

[0183] Implementation Scheme 52. The compound of any one of Implementation Schemes 1 to 51, or a pharmaceutically acceptable salt thereof, wherein R 1 It is H or methyl.

[0184] Implementation Scheme 53. The compound of any one of Implementation Schemes 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R 1 It is H.

[0185] Implementation Scheme 54. A compound of any one of Implementation Schemes 1 to 53, or a pharmaceutically acceptable salt thereof, wherein R 2 Is it H or C? 1-4 alkyl.

[0186] Implementation Scheme 55. The compound of any one of Implementation Schemes 1 to 54, or a pharmaceutically acceptable salt thereof, wherein R 2 It is H or methyl.

[0187] Implementation Scheme 56. A compound of any one of Implementation Schemes 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R 3 Is it H or C? 1-4 alkyl.

[0188] Implementation Scheme 57. A compound of any one of Implementation Schemes 1 to 56, or a pharmaceutically acceptable salt thereof, wherein R 3 It is H or methyl.

[0189] Implementation Scheme 58. A compound of any one of Implementation Schemes 1 to 54 and 56, or a pharmaceutically acceptable salt thereof, wherein R2 and R 3 One is H and the other is C. 1-4 alkyl.

[0190] Implementation Scheme 59. A compound of any one of Implementation Schemes 1 to 58, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 One is H and the other is methyl.

[0191] Implementation Scheme 60. A compound of any one of Implementation Schemes 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each is H.

[0192] Implementation Scheme 61. A compound of any one of Implementation Schemes 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each is a methyl group.

[0193] Implementation Scheme 62. A compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

[0194] Implementation Scheme 63. A compound selected from the compounds in Table 2, or a pharmaceutically acceptable salt thereof.

[0195] Implementation scheme 63a. A compound selected from the compounds in Table 2a, or a pharmaceutically acceptable salt thereof.

[0196] Implementation scheme 63b. A compound selected from the compounds in Table 3, or a pharmaceutically acceptable salt thereof.

[0197] Implementation Scheme 64. A pharmaceutical composition comprising a compound of any one of Implementation Schemes 1 to 63, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0198] Implementation Scheme 65. A method for activating Nrf2, comprising contacting an effective amount of a compound of any one of Implementation Schemes 1-63 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Implementation Scheme 64, with Nrf2.

[0199] Implementation Scheme 66. A method of treating sickle cell disease in a subject in need, comprising administering to the subject a therapeutically effective amount of any one of the compounds of Implementation Schemes 1-63 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Implementation Scheme 64.

[0200] describe

[0201] definition

[0202] The following description illustrates exemplary embodiments of the present technology. However, it should be understood that such description is not intended to limit the scope of this application, but is provided as a description of exemplary embodiments.

[0203] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. It should be understood that the general description above and the detailed description below are merely exemplary and illustrative and do not limit any of the claimed subject matter. In the event of any discrepancy between any material incorporated herein by reference and the explicit content of this application, the explicit content shall prevail. In this application, the singular is used to include the plural unless otherwise specified. It must be noted that, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” as used in the specification and appended claims include the plural referent. In this application, the use of “or” means “and / or” unless otherwise specified. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “(included)” is not restrictive.

[0204] References to “some embodiments,” “implementation,” “one embodiment,” or “other embodiments” in the specification mean that a specific feature, structure, or characteristic described in connection with an embodiment is included in at least some, but not necessarily all, embodiments of this application.

[0205] As used herein, ranges and quantities can be expressed as “about” for a specific value or range. “About” also includes the exact quantity. Therefore, “about 5 μL” means “about 5 μL” as well as “5 μL”. Typically, the term “about” includes quantities expected to be within experimental error, such as, for example, within 15%, 10%, or 5%.

[0206] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics described.

[0207] 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 a carbon atom. 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 usual meaning. A wavy line drawn through a line in the structure indicates the 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.

[0208] prefix "C" u-v"Indicates that the following groups have u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that an alkyl group has 1 to 6 carbon atoms.

[0209] The use of the term "about" in this document includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes a specified amount ±10%. In some embodiments, the term "about" includes a specified amount ±5%. In some embodiments, the term "about" includes a specified amount ±1%. Additionally, the term "about X" includes a description of "X". Furthermore, the singular forms "a" and "the" include the plural forms unless the context clearly indicates otherwise. Thus, for example, reference to "compound" includes multiple such compounds, and reference to "assay" includes reference to one or more assays and their equivalents known to those skilled in the art.

[0210] "Alkyl" refers to a non-branched or branched saturated hydrocarbon chain. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C1-C2). 20 Alkyl groups, 1 to 10 carbon atoms (i.e., C1-C1) 10 Alkyl groups are alkyl groups with 1 to 6 carbon atoms (i.e., C1-C6 alkyl) or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of alkyl groups include 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 its chemical name or identified by its molecular formula, it may include all positional isomers having that number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), isobutyl (i.e., -CH2CH(CH3)2), sec-butyl (i.e., -CH(CH3)CH2CH3), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0211] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2O4 ... 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 2-4 Alkyl groups (alkenyl). Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0212] "Alkoxy" or "alkyloxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0213] "Acylamino" refers to the "C-amide group" (which refers to the group -C(O)NR). y R z ) and "N-amide" group (which refers to the -NR group) y C(O)R z Both, of which R y and R z It is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which may be optionally substituted.

[0214] "Amino" refers to the -NR group. y R z , where R y and R z It is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, or heteroaryl, each of which may be optionally substituted.

[0215] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) comprising a fused system. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C64 ... 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 Aryl group). In some embodiments, the aryl group has 6 to 18 carbon ring atoms (i.e., C646-C ... 6-18 Aryl groups. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracene. However, aryl groups do not include heteroaryl groups as defined below or any combination thereof with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl group. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic group.

[0216] "Halogen" or "halogenated" includes fluorine, chlorine, bromine, and iodine.

[0217] "Heteroalkyl" refers to a monovalent alkyl group, and "heteroalkylene" refers to a divalent alkyl group having one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. The terms "heteroalkyl" and "heteroalkylene" include unbranched or branched saturated chains having carbon and heteroatoms. Heteroatomic groups include, but are not limited to, -NR'-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R' is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic, each of which may optionally be substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NR'CH3, and -CH2NR'CH3, where R' is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may optionally be substituted. Examples of heteroalkylene groups include -OCH2-, -CH2OCH2-, -OCH2CH2O-, -OCH2OCH2-, -SCH3, -CH2SCH2-, -NR'CH2-, and -CH2NR'CH2-, wherein R' is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may optionally be substituted. In some embodiments, examples of heteroalkyl groups include -CH2SCH3 and -CH2NR'CH3, and examples of heteroalkylene groups include -CH2SCH2- and -CH2NR'CH2-, wherein R' is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted, as defined herein. As used herein, heteroalkyl groups comprise 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In some implementations, the term "heteroalkyl" requires that the connection point with the rest of the molecule is through a carbon atom.

[0218] "Heteroalkenyl" refers to a monovalent heteroalkyl group, and "heteroalkenyl" refers to a divalent heteroalkyl group, each containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms, and having one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. The terms "heteroalkenyl" and "heteroalkenyl" include unbranched or branched saturated chains having carbon and heteroatoms. Heteroatom groups include, but are not limited to, -NR'-, -O-, -S-, -S(O)-, -S(O)2-, etc., wherein R' is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic, each of which may optionally be substituted. Examples of heteroalkenyl groups include -OCHCH2, -CH2OCHCH2, -SCHCH2, -CH2SCHCH2, -NR'CHCH2, and -CH2NR'CHCH2, and examples of heteroalkenyl groups include -OCHCH-, -CH2OCHCH-, -SCHCH-, -CH2SCHCH-, -NR'CHCH-, and -CH2NR'CHCH-, wherein R' is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may optionally be substituted. As used herein, heteroalkenyl and heteroalkenyl groups comprise 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0219] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 cyclic carbon atoms (i.e., C64 ... 1-20 (heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 The heteroaryl group; and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatom, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the term "heteroaryl" refers to a 5-14 membered ring system. In some embodiments, the heteroaryl group comprises 1 to 13 cyclic carbon atoms (i.e., C14, C24, C34, C44, C54, C64, C7 ... 1-13 (Heteroaryl). In some embodiments, the heteroaryl group comprises 1 to 6 heteroatoms. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophene, indazole, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group may be linked via any ring of the fused system. In some embodiments, examples of heteroaryl groups include aza-... acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazolyl 1,4-benzodioxane, benzonaphthylfuranyl, benzooxazolyl, benzodioxane-pentenyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl (benzothienyl) (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, cenolinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanoneyl, isothiazolyl, imidazoyl, indazoleyl, indoleyl, indazoleyl, isoindoleyl, indolinyl, isoindolinyl, isoquinolinyl, indoleazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoazadiazolyl The following are listed: aryl, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrazinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroloyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrroloyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of its connection to the rest of the molecule (i.e., through any of these fused rings). Heteroaryls do not include aryl groups as defined above or are not superimposed with aryl groups as defined above. The term "heteroaryl" refers to a divalent heteroaryl group, and examples of heteroaryl groups include, but are not limited to, indoleyl, pyrrolopyridyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, benzimidazolyl, and benzofuranyl.

[0220] Certain commonly used alternative chemical names can be used. For example, divalent groups, such as divalent "alkyl" groups, divalent "phenyl" groups, divalent "heteroaryl" groups, and divalent "heterocyclic" groups, can also be referred to as "alkylene" groups, "phenylene" groups, "heteroarylene" groups, or "heterocyclic" groups, respectively.

[0221] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both the scenario where said event or situation occurs and the scenario where said event or situation does not occur. Additionally, the term “optionally substituted” means that any one or more hydrogen atoms on a specified atom or group may or may not be substituted with any of the components other than hydrogen.

[0222] The term "substituted" means that any one or more hydrogen atoms (e.g., 1 to 5 or 1 to 3) on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the substitution does not exceed the normal valence of the specified atom. Such one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidyl, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidinyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof.

[0223] Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of additional substituents (e.g., a substituted aryl group having a substituted alkyl group, the substituted alkyl group itself being replaced by a substituted aryl group, the substituted aryl group being further replaced by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, an aryl group that is consecutively substituted with two other substituted aryl groups is limited to an aryl group substituted with ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include permissible substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such permissible 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. Unless otherwise stated, in cases where a group is described as optionally substituted, any substituted elements of that group are themselves not substituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halogen, alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. In other embodiments, the one or more substituents may be further substituted with halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is substituted. In other embodiments, these substituents may be further substituted with halogen, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is not substituted.

[0224] In many cases, the compounds of this application are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0225] This application also includes “deuterated analogues” of the compounds described herein, wherein one to n hydrogen atoms bonded to a carbon atom are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound when administered to mammals, particularly humans. 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 of methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0226] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, and stereoisomers of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0227] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Additionally, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared according to conventional methods for preparing acid addition salts from base 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 prepared from inorganic and organic acids. Inorganic acids from which the salts are derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids that derive salts include acetic acid, propionic 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, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as 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), and 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, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0228] The term "hydrate" refers to a complex formed by combining a compound of formula (I) with water.

[0229] "Solvate" refers to an association or complex of one or more solvent molecules and a compound of this application. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0230] Some of these compounds exist as tautomers. The tautomers are in equilibrium with each other. For example, compounds containing amides can exist in equilibrium with imine tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between the tautomers, those skilled in the art will understand that the compound contains both amide and imine tautomers. Therefore, compounds containing amides should be understood to include their imine tautomers. Similarly, compounds containing imines should be understood to include their amide tautomers.

[0231] The compounds disclosed herein, or their pharmaceutically acceptable salts, contain asymmetric centers and thus can produce enantiomers, diastereomers, and other stereoisomers, which can be defined according to absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. This application is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise stated, these compounds are intended to include both E and Z geometric isomers. Similarly, it aims to include all tautomer forms.

[0232] "Stereoisomers" are isomers that differ only in the spatial arrangement of their atoms, and include enantiomers and diastereomers. In some embodiments, "stereoisomers" refer to compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This application envisions various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0233] "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture.

[0234] A “diastereomer” is a stereoisomer that has at least two asymmetric atoms that are not mirror images of each other.

[0235] Absolute stereochemistry is defined according to the Cahn Ingold Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as R or S. Resolved compounds with unknown absolute configurations are designated as (+) or (-) depending on their orientation (right-handed or left-handed) in the plane of polarization at the wavelength of the sodium D line.

[0236] As used herein, "pharmaceuticalally acceptable carrier," "pharmaceuticalally acceptable excipient," or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption-delaying agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition should be considered. Additional active ingredients may also be incorporated into the composition.

[0237] An “effective amount” or dose of a compound or composition means the amount of a compound or composition that produces the intended results based on the disclosure herein. An effective amount can be determined in cell cultures or laboratory animals by standard pharmaceutical procedures, including but not limited to determining the LD50 (the dose that is lethal to 50% of the population) and ED50 (the dose that is therapeutically effective in 50% of the population).

[0238] The "therapeuticly effective amount" or dose of a compound or composition refers to the amount of the compound or composition that results in a reduction or suppression of symptoms or a prolongation of survival in a subject (i.e., a human patient). These results may require multiple doses of the compound or composition.

[0239] The term "treatment" in this context refers to 1) preventing the onset of a disease in a susceptible patient or in whom no symptoms of the disease have yet been observed; 2) suppressing or halting the progression of the disease; or 3) improving or resolving the disease. As used herein, "treatment" is a method for achieving a beneficial or desired outcome (including clinical outcomes). For the purposes of this application, beneficial or desired outcomes include, but are not limited to, one or more of the following: reducing one or more symptoms caused by the disease or disorder; reducing the severity of the disease or disorder; stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder); delaying the onset or recurrence of the disease or disorder; delaying or slowing the progression of the disease or disorder; improving the state of the disease or disorder; providing relief from the disease or disorder (whether partial or complete); reducing the dosage of one or more other medications required to treat the disease or disorder; enhancing the effect of another medication used to treat the disease or disorder; delaying the progression of the disease or disorder; improving quality of life; and / or prolonging the survival of the subject. "Treatment" also includes reducing the pathological outcomes of the disease or disorder. The methods of this application consider any one or more of these aspects of treatment.

[0240] As used herein, the terms “(multiple) individuals,” “(multiple) subjects,” and “(multiple) patients” refer to any mammal. Examples include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cattle, and humans. In some embodiments, the mammal is a human.

[0241] While various features of this application may be described in the context of a single embodiment, these features may also be provided individually or in any suitable combination. Conversely, although this application may be described herein in the context of a single embodiment for clarity, this application may also be implemented in a single embodiment.

[0242] compound

[0243] In one respect, this paper provides compounds of formula (I).

[0244]

[0245] Or its pharmaceutically acceptable salt, wherein:

[0246] R is H or C optionally substituted with benzyl. 1-6 alkyl;

[0247] R 1 Is it H or C? 1-6 alkyl;

[0248] R 2 Is it H or C?1-6 alkyl;

[0249] R 3 Is it H or C? 1-6 alkyl;

[0250] Ring B is C 5-12 arylene or C containing 1 to 4 heteroatoms selected from N and O 3-12 heteroaryl;

[0251] n is 0, 1, 2, or 3;

[0252] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0253] Ring A is C 5-12 arylene or C containing 1-2 heteroatoms selected from N and O 3-12 heteroaryl;

[0254] m is 1, 2, 3, or 4;

[0255] Each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0256] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0257] In some embodiments, this document provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0258] R is H or C optionally substituted with phenyl. 1-6 alkyl;

[0259] R 1 Is it H or C? 1-6 alkyl;

[0260] R 2 Is it H or C? 1-6 alkyl;

[0261] R 3 Is it H or C? 1-6 alkyl;

[0262] Ring B is C 6-12 arylene or C containing 1 to 4 heteroatoms selected from N and O 3-12 heteroaryl;

[0263] n is 0, 1, 2, or 3;

[0264] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0265] Ring A is C 6-12 arylene or C containing 1-2 heteroatoms selected from N and O 3-12 heteroaryl;

[0266] m is 1, 2, 3, or 4;

[0267] Each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0268] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0269] In some implementations, compounds of formula (I) are provided:

[0270]

[0271] Or its pharmaceutically acceptable salt, wherein:

[0272] R is H or optionally -OH, C 1-6 Alkoxy or C 1-6 aryl-substituted C 1-6 alkyl;

[0273] R 1 Is it H or C? 1-6 alkyl;

[0274] R 2 Is it H or C? 1-6 alkyl;

[0275] R 3 Is it H or C? 1-6 alkyl;

[0276] Ring B is C 5-12 arylene or C containing 1 to 4 heteroatoms independently selected from N and O 3-12 Heteroarylene, provided that cyclic B is not

[0277]

[0278] Where * represents the key connected to L;

[0279] n is 0, 1, 2, or 3;

[0280] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0281] Ring A is C 5-12 arylene or C containing 1-2 heteroatoms independently selected from N and O 3-12 heteroaryl;

[0282] m is 1, 2, 3, or 4;

[0283] Each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0284] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0285] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0286] R is H or optionally replaced by a group selected from -OH, C 1-6 Alkoxy or C6-12 Aryl substituents substituted C 1-6 alkyl;

[0287] R 1 Is it H or C? 1-6 alkyl;

[0288] R 2 Is it H or C? 1-6 alkyl;

[0289] R 3 Is it H or C? 1-6 alkyl;

[0290] Ring B is C 6-12 arylene or C containing 1 to 4 heteroatoms independently selected from N and O 3-12 Heteroarylene, provided that cyclic B is not

[0291]

[0292] Where * represents the key connected to L;

[0293] n is 0, 1, 2, or 3;

[0294] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0295] Ring A is C 6-12 arylene or C containing 1-2 heteroatoms independently selected from N and O 3-12 heteroaryl;

[0296] m is 1, 2, 3, or 4;

[0297] Each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0298] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0299] In some implementations, cyclic B is not benzotriazole.

[0300] In some implementations, L is C 5-7 Alkylene, C 5-7 imidene group, C 5-7 Heteroalkylene, or C 5-7 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain one to two oxygen atoms. In some embodiments, L is C 5-7 Alkylene, C 5-7 imidene group, C 5-7 Heteroalkylene, or C 5-7 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain one oxygen atom. In some embodiments, L is C 5-7 Alkylene, C 5-7 imidene group, C 5-7 Heteroalkylene, or C 5-7 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 2 oxygen atoms.

[0301] In some implementations, L is C 4-8 imide or C 4-8 Heteroene derivatives, and C 4-8 imide and C 4-8 The heteroene group contains an unsaturated point (i.e., an unsaturated bond).

[0302] In some implementation schemes, L is selected from

[0303] * indicates the key connected to ring B.

[0304] In some embodiments, the compound of formula (I) is the same as the compound of formula (IA):

[0305]

[0306] Or its pharmaceutically acceptable salt, wherein:

[0307] L′ is C 4-6 Alkylene, C 4-6 imidene group, C 4-6 Heteroalkylene, or C 4-6 Heteroalkenyl groups, each optionally selected independently by one or two halogens and C.1-6 Alkyl groups are substituted, and the heteroalkylene and heteroeneyl groups contain one or two oxygen atoms;

[0308] X 3 It is CH2 or O;

[0309] n is 0, 1, or 2;

[0310] Each X 1 and X 2 Independently, it is CH or N; and

[0311] Rings A, R, R 1 R 2 R 3 R 4 R 5 m and n are as described for compounds of formula (I).

[0312] In some implementations, compounds of formula (IC) are provided.

[0313]

[0314] Or its pharmaceutically acceptable salt, wherein:

[0315] R is H or optionally -OH, C 1-6 Alkoxy or C 1-6 aryl-substituted C 1-6 alkyl;

[0316] R 1 Is it H or C? 1-6 alkyl;

[0317] R 2 Is it H or C? 1-6 alkyl;

[0318] R 3 Is it H or C? 1-6 alkyl;

[0319] n is 0, 1, 2, or 3;

[0320] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0321] Ring A is C 5-12 arylene or C containing 1-2 heteroatoms independently selected from N and O 3-12 heteroaryl;

[0322] m is 1, 2, 3, or 4;

[0323] Each R 4Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0324] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0325] In some embodiments, a compound of formula (IC) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0326] R is H or optionally replaced by a group selected from -OH, C 1-6 Alkoxy and C 6-12 Aryl substituents substituted C 1-6 alkyl;

[0327] R 1 Is it H or C? 1-6 alkyl;

[0328] R 2 Is it H or C? 1-6 alkyl;

[0329] R 3 Is it H or C? 1-6 alkyl;

[0330] n is 0, 1, 2, or 3;

[0331] Each R 5 Independently, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0332] Ring A is C 6-12 arylene or C containing 1-2 heteroatoms independently selected from N and O 3-12 heteroaryl;

[0333] m is 1, 2, 3, or 4;

[0334] Each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups; and

[0335] L is C 4-8 Alkylene, C 4-8 imidene group, C 4-8 Heteroalkylene, or C 4-8 Heteroalkenyl groups, each optionally composed of one or four independently selected from halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 4 oxygen atoms.

[0336] In some implementation schemes, X 3 It is CH2. In some implementations, X 3 It is O.

[0337] In some implementation schemes, X 1 It is N. In some implementations, X 1 It is CH. In some implementations, X 2 It is N. In some implementations, X 2 It is CH. In some implementations, X 1 and X 2 Each is N. In some implementations, X 1 and X 2 Each is CH. In some implementations, X 1 and X 2 One is CH and the other is N.

[0338] In some implementations, n is 2. In some implementations, n is 1. In some implementations, n is 0.

[0339] In some implementations, each R 5 C is independent 1-4 Alkyl or C 1-4 Alkyl groups. In some embodiments, each R 5 It is either methyl or methoxy.

[0340] In some implementations, L′ is C 4-6 Alkylene, C 4-6 imidene group, C 4-6 Heteroalkylene, or C 4-6 Heteroalkenyl groups, wherein the heteroalkylene group and the heteroalkenyl group contain one or two oxygen atoms. In some embodiments, C 4-6 imide and C 4-6 The heteroene group contains an unsaturated point (i.e., an unsaturated bond).

[0341] In some implementation schemes, X 3 It is CH2, and L′ is a C containing one unsaturation point (i.e., one unsaturated bond). 4-6 imide or C 4-6 Heteroene group.

[0342] In some implementation schemes, X 3 It is O, and L′ is a C containing one unsaturation point (i.e., one unsaturated bond). 4-6 imide or C 4-6 Heteroene derivatives. In some embodiments, X 3 It is CH2 and L′ is C 4-6 Alkylene or C 4-6 Heteroalkylene, wherein C 4-6 The heteroalkylene group contains one or two oxygen atoms. In some embodiments, X 3 It is O and L′ is C 4-6 Alkylene or C 4-6 Heteroalkylene, wherein C 4-6 The heteroalkylene group contains one oxygen atom. In some embodiments, X 3 It is O and L′ is C 4-6 Alkylene. In some embodiments, X 3 It is CH2 and L′ is C 4-6 Alkylene.

[0343] In some embodiments, the compound of formula (I) is a compound of formula (IB):

[0344]

[0345] Or its pharmaceutically acceptable salt, wherein:

[0346] L″ is C 4-6 Alkylene, C 4--6 imidene group, C 4-6 Heteroalkylene, or C 4-6 Heteroalkenyl groups, each optionally selected independently by one or two halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain 1 to 2 oxygen atoms;

[0347] Ring B″ is selected from

[0348]

[0349] Where * represents the key connected to L″; X 4 It is CR 5 CH, or N; and

[0350] Rings A, R, R 1 R2 R 3 R 4 R 5 m and n are as described for compounds of formula (I).

[0351] In some implementations, ring B″ is selected from

[0352]

[0353] Where * represents a key connected to L or L″; X 4 It is CR 5 CH, or N-; ring B or ring B″ is –(R 5 ) n Replace, where n is 0, 1, 2, or 3; and each R 5 Independently, halogen, C 1-4 Alkyl, or C 1-4 Alkyl group.

[0354] In some implementation schemes, the ring is not

[0355] In some implementation schemes, ring B″ is Where * represents the key connected to L″; X 4 It is CR 5 CH, or N; ring B″ is –(R 5 ) n Replace, where n is 0, 1, or 2; and each R 5 Independently, halogen, C 1-4 Alkyl, or C 1-4 Alkyl group.

[0356] In some implementation schemes, ring B″ is Where * represents the key connected to L″; X 4 It is N; ring B″ is –(R) 5 ) n Replace, where n is 0, 1, or 2; and each R 5 Independently, halogen, C 1-4 Alkyl, or C 1-4 Alkyl group.

[0357] In some implementation schemes, X 4 It is CH. In some implementations, X 4 It is N. In some implementations, X 4 It is CR 5 .

[0358] In some implementations, n is 2. In some implementations, n is 1. In some implementations, n is 0.

[0359] In some implementations, each R 5 It is C 1-4 Alkyl or C 1-4 Alkyl groups. In some embodiments, each R 5 It is methyl or methoxy.

[0360] In some implementations, L″ is C 4-6 Alkylene, C 4-6 imidene group, C 4-6 Heteroalkylene, or C 4-6 Heteroalkenyl groups, wherein heteroalkylene groups and heteroalkenyl groups contain 1 to 2 oxygen atoms.

[0361] In some implementations, L″ is C 4-6 imide or C 4-6 Heteroeneyl group, wherein the heteroeneyl group contains one oxygen atom, and wherein C 4-6 imide and C 4-6 The heteroene group contains an unsaturated site (i.e., an unsaturated bond). In some embodiments, L″ is C 4-6 Alkylene or C 4-6 Heteroalkylene, wherein each C 4-6 The heteroalkylene group contains one or two oxygen atoms. In some embodiments, L″ is C 4-6 Alkylene.

[0362] In some implementations, each R 5 Independently, halogen, C 1-4 Alkyl, or C 1-4 Alkyl groups. In some embodiments, each R 5 It can be F, Cl, or methyl on its own.

[0363] In some embodiments, ring A is phenylene, indolene, pyrrolopyridyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, naphthylene, quinolinyl, benzimidazolyl, or benzofuranyl.

[0364] In some embodiments of compounds of formula (I), formula (IA), and / or formula (IB), ring A is

[0365]

[0366] Where * represents a key connected to L, L′, or L″, and ring A is –(R 4 ) m Replacement, where m is 1, 2, 3, or 4; and each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups.

[0367] In some embodiments of compounds of formula (I), formula (IA), and / or formula (IB), ring A is

[0368]

[0369] Where * represents a key connected to L, L′, or L″, and ring A is -(R 4 ) m Replace, where m is 1 or 2; and each R 4 Independently, it consists of H, halogens, and C. 1-4 Alkyl, or C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-4 Substitution of alkoxy, amide, and N,N-dimethylamide groups.

[0370] In some implementations, ring A is

[0371]

[0372] Where * represents a key connected to L, L′, or L″, and ring A is –(R 4 ) m Replacement, where m is 1, 2, 3, or 4; and each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl, or C 1-6 Alkoxy, where C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, amide, and N,N-dimethylamide groups.

[0373] In some embodiments of compounds of formula (I), formula (IA), and / or formula (IB), ring A is

[0374] Where * represents a key connected to L, L′, or L″, and ring A is –(R 4 ) m Replace, where m is 1 or 2; and each R 4 Independently, it consists of H, halogens, and C.1-4 Alkyl, or C 1-4 Alkoxy, where C 1-4 Alkyl and C 1-4 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-4 Substitution of alkoxy, amide, and N,N-dimethylamide groups.

[0375] In some embodiments of compounds of formula (I), formula (IA), and / or formula (IB), ring A is

[0376] Where * represents a key connected to L, L′, or L″, and ring A is –(R 4 ) m Replacement, where m is 1, 2, 3, or 4; and each R 4 Independently, it consists of H, halogens, and C. 1-4 Alkyl, or C 1-4 Alkoxy, where C 1-4 Alkyl and C 1-4 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-4 Substitution of alkoxy, amide, and N,N-dimethylamide groups.

[0377] In some implementations, each R 4 Independently selected from H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, where C 1-4 Alkyl and C 1-4 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-4 Alkoxy, amide, and N,N-dimethylamide groups are substituted. In some embodiments, each R 4 Independently selected from H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, where C 1-4 Alkyl and C 1-4 Each alkoxy group is optionally substituted with one to three groups independently selected from F, Cl, methyl, methoxy, amide, and N,N-dimethylamide. In some embodiments, each R 4 Independently selected from H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, where C 1-4 Alkyl and C 1-4 Each alkoxy group is optionally substituted with one to three groups independently selected from F, Cl, methoxy, amide, and N,N-dimethylamide. In some embodiments, each R 4It is independently selected from H, methyl, isobutyl, F, Cl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, N,N-dimethylamido, 3,3,3-trifluoropropyl, 2,2-difluoroethyl, 3-fluoropropyl, and methoxyethyl.

[0378] In some implementations, R is H or optionally is selected from -OH, C 1-6 Alkoxy or C 6-12 Aryl substituents substituted C 1-4 Alkyl group. In some embodiments, R is H or optionally surrounded by a group selected from -OH, C. 1-6 The C-substituent of alkoxy or phenyl 1-4 Alkyl group. In some embodiments, R is H, methyl, or benzyl. In some embodiments, R is H.

[0379] In some implementation schemes, R 1 Is it H or C? 1-4 Alkyl group. In some embodiments, R 1 It is H or methyl. In some embodiments, R 1 It is H.

[0380] In some implementation schemes, R 2 Is it H or C? 1-4 Alkyl group. In some embodiments, R 2 It is H or methyl. In some embodiments, R 3 Is it H or C? 1-4 Alkyl group. In some embodiments, R 3 It is H or methyl. In some embodiments, R 2 and R 3 One is H and the other is C. 1-4 Alkyl group. In some embodiments, R 2 and R 3 One is H and the other is methyl. In some embodiments, R 2 and R 3 Each is H. In some implementations, R 2 and R 3 Each is a methyl group.

[0381] In some embodiments, this document discloses pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0382] In the description herein, it should be understood that each description, variation, embodiment, or aspect of a part may be combined with each description, variation, embodiment, or aspect of other parts, as if each and each combination described were specifically and individually listed. For example, each description, variation, embodiment, or aspect of L with respect to formula (I) provided herein may be combined with rings A, B, R, R 1 R 2 R 3 R 4 R 5 Each description, variation, embodiment, or aspect combination of m and n is described as if each and each combination were specifically and individually listed. It should also be understood that, where applicable, all descriptions, variations, embodiments, or aspects of formula (I) are equally applicable to other chemical formulas detailed herein, and are described equally as if each and each description, variation, embodiment, or aspect were separately and individually listed for all chemical formulas. For example, where applicable, all descriptions, variations, embodiments, or aspects of formula (I) are equally applicable to any chemical formula as detailed herein, such as formula (IA) or formula (IB), and are described equally as if each and each description, variation, embodiment, or aspect were separately and individually listed for all chemical formulas.

[0383] In some embodiments, compounds selected from the compounds in Table 1 or pharmaceutically acceptable salts thereof are provided. In some embodiments, compounds selected from the compounds in Table 2 or pharmaceutically acceptable salts thereof are provided. Although some compounds described in this application (including those in Tables 1, 2, 2a, and 3) are presented as specific stereoisomers and / or non-stereochemical forms, it should be understood that any or all stereochemical forms (including any enantiomers or diastereomers) and any tautomers or other forms of any compound of this application (including those in Tables 1, 2, 2a, and 3) described herein are provided. In some embodiments, compounds selected from the compounds in Table 2a or pharmaceutically acceptable salts thereof are provided. In some embodiments, compounds selected from the compounds in Table 3 or pharmaceutically acceptable salts thereof are provided. Although some compounds described in this application (including those in Table 3) are presented as specific stereoisomers and / or non-stereochemical forms, it should be understood that any or all stereochemical forms (including any enantiomers or diastereomers) and any tautomers or other forms of any compound described herein (including those in Table 3) are described.

[0384] This article also provides the following compounds in Tables 1, 2, 2a and 3.

[0385] Table 1.

[0386]

[0387] Or its pharmaceutically acceptable salt.

[0388] Table 2.

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474] Or its pharmaceutically acceptable salt.

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497] Or its pharmaceutically acceptable salt.

[0498] Synthesis method

[0499] Generally, compounds of formula (I) can be prepared using known synthetic methods, and in some embodiments, they are prepared using those methods shown in general schemes 1A-4.

[0500] In general scheme 1A, Q 1 and Q 2 These are terminal olefins, which, when linked together, form the corresponding olefin substituent Q. 3 The building block compound 1-C can be prepared, for example, by adding the desired olefin (compound 1-B) to dioxaborhexacyclopentane (compound A) using a Miyaura 1,4-addition reaction. In some embodiments, after removing the BOC protecting group under standard conditions of compound 1-C, ring A is coupled to compound 1-C using an amide coupling reaction. Once ring A is introduced into the molecule, macrocycle 1-E can be prepared, for example, using a Grubbs metathesis reaction, to form a macrocycle where the L, L', or L” group contains a double bond (i.e., substituent Q). 3 An embodiment of (I) is provided by hydrogenating an alkenyl group to an alkylene group, wherein L, L', or L" comprises an alkylene or heteroalkylene group. In an embodiment in which the L, L', or L" group comprises a double bond, the final acetic acid compound (i.e., wherein R is H) is obtained by saponification, which may be carried out after hydrogenation or after metathesis.

[0501] The building block compound C can be prepared, for example, by adding the desired olefin (compound B) to dioxaborhexacyclopentane (compound A) using a Miyaura 1,4-addition reaction. In some embodiments, ring A is coupled to compound C using an amide coupling reaction after removing the BOC protecting group. Schemes 1B, 2, and 3 show several different ring A groups that can be coupled to compound C.

[0502] Once ring A is introduced into the molecule, the final macrocycle can be prepared, for example, using a Grubbs metathesis reaction to form an embodiment in which the L, L', or L” group contains a double bond. Hydrogenating the alkenyl group to an alkylene group provides an embodiment in which the L, L', or L” group contains an alkylene or heteroalkylene group. In embodiments in which the L, L', or L” group contains a double bond, the final acetic acid compound is obtained by saponification, which can be carried out after a hydrogenation reaction as shown in the following scheme or after a metathesis reaction.

[0503] Scheme 4 shows that, in some embodiments, the chiral compound can be prepared in the same general manner as shown in Schemes 1-3 by including a chiral separation step prior to containing ring A.

[0504] General Plan 1A

[0505]

[0506] General Plan 1B

[0507]

[0508] General Option 2

[0509]

[0510] General Scheme 3

[0511]

[0512] General Scheme 4

[0513]

[0514] It should be understood that the synthetic methods disclosed herein can be modified by selecting appropriate reagents and starting materials to obtain various compounds of this application.

[0515] Compounds of all formula (I) as described herein, or any variant thereof, existing in free base or acid form, can be converted into their pharmaceutically acceptable salts by treatment with suitable inorganic or organic bases or acids using methods known to those skilled in the art. Salts of the compounds of this application can be converted into their free base or acid forms using standard techniques.

[0516] Pharmaceutical compositions and formulations

[0517] On the other hand, this document provides pharmaceutical compositions of any of the compounds detailed herein. Therefore, this application includes pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients. Pharmaceutical compositions according to this application may be in forms suitable for oral, sublingual, parenteral, nasal, topical, or rectal administration, or suitable for inhalation administration. Pharmaceutical compositions of this application comprise compounds of formula (I) or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents, or excipients.

[0518] The compounds described herein can be used to prepare compositions, such as pharmaceutical compositions, by combining the compounds as active ingredients with pharmaceutically acceptable excipients. Some examples of materials that can be used as pharmaceutically acceptable excipients include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; surfactants, such as polysorbate 80 (i.e., Tween 80); powdered tragali gum; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffer solutions; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic and compatible substances used in pharmaceutical formulations. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005), which is incorporated herein by reference.

[0519] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and aromatizers, preservatives and antioxidants may also be present in the composition.

[0520] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbate palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0521] The formulations of this application include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations can conveniently exist in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces the therapeutic effect. Typically, this amount will range from about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.

[0522] In some embodiments, the formulations of this application comprise excipients selected from the group consisting of cyclodextrins, liposomes, micelle forming agents (e.g., bile acids) and polymer carriers (e.g., polyesters and polyanhydrides); and the compounds of this application. In some embodiments, the above formulations enable the compounds of this application to be orally bioavailable.

[0523] Formulations of this application suitable for oral administration may be in the form of capsules, flat capsules, pills, tablets, lozenges (using a flavoring matrix, typically sucrose and gum arabic or tragacanth), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as elixirs or syrups, or as soft lozenges (using an inert matrix, such as gelatin and glycerin or sucrose and gum arabic), and / or as mouthwashes, each containing a predetermined amount of the compound of this application as the active ingredient. The compounds of this application may also be administered as large pills, granules, or pastes.

[0524] In the solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) of this application for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silica; binders, such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; humectants, such as glycerin; disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; solution blocking agents, such as paraffin; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glyceryl monostearate and nonionic surfactants; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft-shell and hard-shell gelatin capsules that use excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol.

[0525] Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared in suitable machinery, in which a mixture of powdered compounds is wetted with an inert liquid diluent.

[0526] The pharmaceutical compositions of this application, in tablet and other solid dosage forms such as sugar-coated pills, capsules, pellets, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings known in the pharmaceutical formulation art. They may also be formulated using, for example, hydroxypropyl methylcellulose in varying proportions to provide desired release characteristics, other polymer matrices, liposomes, and / or microspheres to provide slow or controlled release of the active ingredient therein. They may be formulated for rapid release, for example, by lyophilization. They may be sterilized by, for example, filtration through a bacterial trapping filter or by incorporation with a sterilizing agent in the form of a sterile solid composition, which may be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain a light-blocking agent and may be compositions that optionally release one or more active ingredients in a delayed manner only or preferably in a portion of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymeric substances and waxes. Where appropriate, the active ingredient may also be in a microencapsulated form having one or more of the excipients described above.

[0527] Liquid dosage forms for oral administration of the compounds of this application include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art (such as, for example, water or other solvents), solubilizers and emulsifiers (such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol), oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters and mixtures thereof of sorbitol.

[0528] In addition to inert diluents, oral compositions may also contain excipients such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents and preservatives.

[0529] In addition to the active compound, the suspension may also contain suspending agents, such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0530] Formulations of the pharmaceutical compositions of this application for rectal or vaginal administration may be in the form of suppositories, which can be prepared by mixing one or more compounds of this application with one or more suitable non-irritating excipients or carriers (including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate), and are solid at room temperature but liquid at body temperature, and thus will melt in the rectal or vaginal cavity and release the active compound.

[0531] Dosage forms for topical or transdermal administration of the compounds of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compounds may be mixed under sterile conditions with pharmaceutically acceptable carriers and any preservatives, buffers, or propellants that may be required.

[0532] In addition to the active compounds of this application, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0533] In addition to the compounds of this application, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0534] The pharmaceutical compositions of this application suitable for parenteral administration comprise one or more compounds of this application in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, or sterile powders. These sterile powders may be reconstituted into sterile injectable solutions or dispersions prior to use, and may contain sugars, alcohols, antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0535] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of this application include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. For example, by using a coating material such as lecithin, the desired particle size can be maintained in the case of a dispersion, and by using a surfactant, appropriate flowability can be maintained.

[0536] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. By including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenyl sorbic acid, it is possible to ensure protection against microbial action on the subject compound. It is also desirable to include isotonic agents, such as sugars and sodium chloride, in the composition. Furthermore, prolonged absorption of injectable drug forms can be achieved by including agents with delayed absorption, such as aluminum monostearate and gelatin.

[0537] In some cases, to prolong the effect of a drug, it is desirable to slow the absorption of drugs administered subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oil-based medium.

[0538] Injectable depot formulations are prepared by forming a microcapsule matrix of the subject compound in a biodegradable polymer such as poly(lactide-polyglycolic acid). The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable depot formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0539] Methods of use / treatment

[0540] The compounds and compositions detailed herein, such as pharmaceutical compositions comprising any of the chemical formulas provided herein or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or excipients, may be used in the administration and treatment methods provided herein. These compounds and compositions may also be used in in vitro methods, such as administering the compounds or compositions to cells for screening purposes and / or for quality control assays.

[0541] In some embodiments, this document discloses a method for activating Nrf2, which includes contacting an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, with Nrf2.

[0542] In some embodiments, this document discloses a method for treating sickle cell disease in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0543] In some implementations, this document discloses methods for treating inflammatory diseases in subjects in need, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0544] In some embodiments, the subject is a mammal. In some embodiments, the subject is a primate, dog, cat, rabbit, or rodent. In some embodiments, the subject is a primate. In some embodiments, the subject is a human. In some embodiments, the human is at least about or about 18, 21, 30, 50, 60, 65, 70, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than or about 21, 18, 15, 10, 5, 4, 3, 2, or 1 year old.

[0545] Administration and method of administration

[0546] As used herein, the phrases “parenteral administration” and “prescription” refer to administration methods other than enteral and local administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0547] As used herein, the phrases “systemic administration,” “systemic delivery,” “peripheral administration,” and “peripheral delivery” refer to the administration of a compound, drug, or other material not directly to the central nervous system, but to its entry into the patient’s system and thus subject it to metabolism and other similar processes, such as subcutaneous administration.

[0548] These compounds can be administered to humans and other animals for treatment via any suitable route of administration, including oral, nasal, such as by spray, rectal, vaginal, parenteral, intracerebrospinal, and topical, such as by powder, ointment, or drops, including sublingual and intralingual administration.

[0549] Regardless of the chosen route of administration, the compounds or pharmaceutical compositions of this application are formulated into pharmaceutically acceptable dosage forms using conventional methods known to those skilled in the art.

[0550] The actual dose level of the active ingredient in the pharmaceutical composition of this application can be varied in order to obtain an amount of active ingredient that is non-toxic to the patient and effectively achieves the desired therapeutic response for a particular patient, composition, and administration mode.

[0551] The selected dose level will depend on a variety of factors, including the activity of the specific compound of this application or its esters, salts or amides, the route of administration, the time of administration, the excretion or metabolic rate of the specific compound, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical field. Daily, weekly or monthly doses (or other time intervals) may be used.

[0552] Physicians or veterinarians with ordinary skills in the art can easily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start with a dose of the compound of this application used in the pharmaceutical composition at a level below that required to achieve the desired therapeutic effect, and then gradually increase the dose until the desired effect is achieved.

[0553] Generally, the appropriate daily dose of the compound of this application will be the amount of the lowest dose of the compound that effectively produces a therapeutic effect (e.g., inhibition of necrosis). Such an effective dose will generally depend on the factors described above. Typically, when used for the indicated effect, the dose of the compound of this application for a patient will be in the range of about 0.0001 to about 100 mg / kg body weight / day. Preferably, the daily dose will be in the range of 0.001 to 50 mg compound / kg body weight and even more preferably 0.01 to 10 mg compound / kg body weight.

[0554] If desired, the effective daily dose of the active compound can be administered as two, three, four, five, six or more sub-dose, administered at appropriate intervals throughout the day, optionally in unit dosage form.

[0555] When the compounds of this application are administered to humans and animals as drugs, they may be administered either on their own or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of an active ingredient in combination with a pharmaceutically acceptable carrier.

[0556] The compounds or compositions thereof of this application may be administered once, twice, three or four times daily in any suitable manner as described above. Additionally, administration or treatment with the compounds may continue for several days; for example, for a treatment cycle, treatment typically lasts at least 7, 14, or 28 days. Treatment cycles are well known and are often alternated between cycles with intervals of about 1 to 28 days, typically about 7 days or about 14 days. In some embodiments, treatment cycles may also be continuous.

[0557] When administered orally, the total daily dose for human subjects may be from 1 mg to 1,000 mg, about 1,000-2,000 mg / day, about 10-500 mg / day, about 50-300 mg / day, about 75-200 mg / day, or about 100-150 mg / day.

[0558] The daily dose can also be described as the total amount of the compound described herein administered per dose or per day. The daily dose of the compound can be from about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0559] In some embodiments, the method includes administering an initial daily dose of about 1 to 800 mg of the compound described herein to the subject and increasing the dose in increments until clinical efficacy is achieved. The dose may be increased in increments of about 5, 10, 25, 50, or 100 mg. The dose may be increased daily, every other day, twice a week, or once a week.

[0560] In some embodiments, the compound or drug formulation is administered orally. In some embodiments, the compound or drug formulation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0561] The formulations of this application may be administered orally, parenterally, topically, or rectally. They are, of course, administered in a form suitable for each route of administration. For example, they may be administered in tablet or capsule form, by injection, inhalation, eye wash, ointment, suppository, etc.; by injection, infusion, or inhalation; topically by lotion or ointment; and rectally by suppository. In some embodiments, administration is orally.

[0562] reagent kits / products

[0563] This document also provides a kit comprising a compound of this application or a pharmaceutically acceptable salt thereof and suitable packaging. In some embodiments, the kit further includes instructions for use. In one aspect, the kit comprises a compound of this application or a pharmaceutically acceptable salt thereof, along with labeling and / or instructions for use in treating indications (including the diseases or conditions described herein).

[0564] This article also provides preparations containing the compounds described herein or pharmaceutically acceptable salts thereof in suitable containers. Containers may be vials, wide-mouth bottles, ampoules, pre-filled syringes, and intravenous bags.

[0565] The kit may also contain instructions for using the compounds according to this application. The kit may be compartmentalized to accommodate tightly sealed containers. As used herein, kits such as compartmentalized kits include any kit in which compounds or agents are contained in individual containers. Illustrative examples of such containers include, but are not limited to, small glass containers, plastic containers, or plastic strips or paper. Particularly preferred types of containers allow technicians to efficiently transfer reagents from one compartment to another without cross-contamination of these samples and reagents, and allow these reagents or solutions in each container to be added quantitatively from one compartment to another. Such containers include, but are not limited to, containers that will receive compounds or combinations of compounds and / or other agents of this application. One or more compounds or agents may be provided as powders (e.g., lyophilized powders) or precipitates. One or more such compounds may be resuspended in a solution prior to administration, which may be provided as part of the kit or separately. The kit may contain compounds or agents in other forms, such as liquids, gels, solids, as described herein. Different compounds and / or agents may be provided in different forms in a single kit. Example

[0566] The following embodiments are included to illustrate specific implementations of this application. 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 application and can therefore be considered to constitute specific models of its practice. However, those skilled in the art will understand that, based on this application, many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of this application, and similar or analogous results can still be obtained.

[0567] Synthesis Examples

[0568] A general procedure for synthesizing embodiments.

[0569] General Procedure 6B: Amide Coupling

[0570] The variables shown in the following scheme are specific to this general program.

[0571]

[0572] Carboxylic acid (1 equivalent), HATU (1 equivalent), and NEt3 (2–10 equivalents) were dissolved in anhydrous DMF (0.05–0.2 M) and stirred at room temperature for 10–60 minutes. An amine HCl salt (1 equivalent) (consisting of a terminal olefin and usually a small amount of migrating double bond isomers) was added and stirred at room temperature for 1–18 hours. Water was added and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine (3×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The impure product was purified by rapid column chromatography (silica, usually heptane / EtOAc = 1:0 → 0:1) to obtain the desired amide, with usually migrating double bond isomers as minor byproducts.

[0573] General Program 7: Grubbs Decomposition

[0574] The variables shown in this scheme are specific to this general program.

[0575]

[0576] The amide (1.0 equivalent) (consisting of a terminal olefin and usually a small amount of migrating double bond isomers) was dissolved in anhydrous toluene (2.0–3.0 mM), and the solvent was degassed with nitrogen for 20 min. A Grubbs second-generation catalyst (0.1 equivalent) was added, and the reaction mixture was stirred at 80 °C for 18 h. The reaction mixture was concentrated under reduced pressure. The impure product was purified by rapid column chromatography (silica, CH₂Cl₂ / MeOH = 1:0 → 9:1) to obtain a large ring in the form of brown foam (usually accompanied by a smaller analogue of one carbon atom as a byproduct).

[0577] General Procedure 8: Hydrogenation

[0578] The variables shown in this scheme are specific to this general program.

[0579]

[0580] Unsaturated macrocycles (1.0 equivalent) (often contaminated with small amounts of shorter macrocycle analogs with one carbon atom) are dissolved in MeOH (0.05–0.2 M) under an inert atmosphere. Pd / C (10% w / w, 0.1 equivalent) is added, and the reaction mixture is stirred at room temperature under a hydrogen atmosphere for 1–24 hours. The reaction mixture is filtered (using a nylon or diatomaceous earth filter), and the filtrate is concentrated under reduced pressure to obtain saturated macrocycles (often accompanied by smaller macrocycle analogs with one carbon atom as byproducts) as a brown oil.

[0581] General Procedure 9: Saponification

[0582] The variables shown in this scheme are specific to this general program.

[0583]

[0584] The methyl ester (often contaminated with small amounts of a shorter macrocyclic analog with one carbon atom) was dissolved in MeOH (0.05–0.2 M) and an aqueous solution of NaOH (1 N; 3–10 equivalents) was added. The reaction mixture was stirred at room temperature for 1–18 hours. The reaction mixture was acidified with an aqueous solution of HCl (2 N) until pH < 5 and purified by preparative LC (acid or base) to obtain the two generally desired macrocyclic carboxylic acids. The major and minor (shorter one carbon atom) macrocyclic analogs were separated by preparative LC and obtained as two distinct final compounds.

[0585] General Procedure 14: Amide Coupling

[0586] The variables shown in this scheme are specific to this general program.

[0587]

[0588] Carboxylic acid (1.2 equivalents), HATU (1.2 equivalents), and Et3N (3–10 equivalents) were dissolved in anhydrous DMF (0.05–0.2 M) and stirred at room temperature for 10–60 minutes. An amine HCl salt (1 equivalent) (consisting of a terminal olefin and usually a small amount of migrating double bond isomers) was added and stirred at room temperature for 1–18 hours. Water was added and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine (3×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The impure product was purified by rapid column chromatography (silica, usually heptane / EtOAc = 1:0 → 0:1) to obtain the desired amide, with usually migrating double bond isomers as minor byproducts.

[0589] General Program 15: Grubbs Decomposition

[0590] The variables shown in this scheme are specific to this general program.

[0591]

[0592] The amide (1.0 equivalent) (consisting of a terminal olefin and usually a small amount of migrating double bond isomers) was dissolved in anhydrous toluene (2.0–3.0 mM), and the solvent was degassed with nitrogen for 20 min. A Grubbs second-generation catalyst (0.1 equivalent) was added, and the reaction mixture was stirred at 80 °C for 18 h. The reaction mixture was concentrated under reduced pressure. The impure product was purified by rapid column chromatography (silica, CH₂Cl₂ / MeOH = 1:0 → 9:1) to obtain a large ring in the form of brown foam (usually accompanied by a smaller analogue of one carbon atom as a byproduct).

[0593] General Procedure 16: Hydrogenation

[0594] The variables shown in this scheme are specific to this general program.

[0595]

[0596] Unsaturated macrocycles (1.0 equivalent) (often contaminated with small amounts of shorter macrocycle analogs with one carbon atom) are dissolved in MeOH (0.05–0.2 M) under an inert atmosphere. Pd / C (10% w / w, 0.1 equivalent) is added, and the reaction mixture is stirred at room temperature under a hydrogen atmosphere for 1–5 hours. The reaction mixture is filtered (using a nylon or diatomaceous earth filter), and the filtrate is concentrated under reduced pressure to obtain saturated macrocycles (often accompanied by smaller macrocycle analogs with one carbon atom as byproducts) as a brown oil.

[0597] General Procedure 17: Saponification

[0598] The variables shown in this scheme are specific to this general program.

[0599]

[0600] The methyl ester (often contaminated with small amounts of a shorter macrocyclic analog with one carbon atom) was dissolved in MeOH (0.05–0.2 M) and an aqueous solution of NaOH (1 N; 3–10 equivalents) was added. The reaction mixture was stirred at room temperature for 1–18 hours. The reaction mixture was acidified with an aqueous solution of HCl (2 N) until pH < 5 and purified by preparative LC (acid or base) to obtain the two generally desired macrocyclic carboxylic acids. Note: The major and minor (shorter one carbon atom) macrocyclic analogs were separated by preparative LC and obtained as two distinct final compounds.

[0601] General Procedure 24: Phototensive Reaction (Mitsunobu)

[0602] The variables shown in this scheme are specific to this general program.

[0603]

[0604] Benzotriazol (1.0 equivalent) and tert-butyl hydroxybenzoate (1.1 equivalent) were dissolved in anhydrous toluene (0.05–0.2 M) and degassed with argon for 20 min. Then, cyanomethylenetributylphosphine (1.4 equivalent) was added, and the mixture was stirred under reflux (115 °C) for 16 h. The reaction mixture was concentrated under reduced pressure. The impure product was purified by preparative HPLC (method: preparative base) or rapid column chromatography (silica, CH₂Cl₂ / MeOH = 1:0 → 9:1) to obtain diethers.

[0605] General Procedure 39: Debenzylation and Olefin Reduction

[0606] The variables shown in this scheme are specific to this general program.

[0607]

[0608] Unsaturated macrocyclic compounds (1.0 equivalents) were dissolved in MeOH / CH₂Cl₂ (4:1, 0.05–0.2 M), and the solution was degassed with nitrogen. Pd(OH)₂ (0.1 equivalents) was added to carbon, and H₂ was bubbled through the suspension for 5 min. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2–16 h. The reaction mixture was filtered through diatomaceous earth, and the filter was washed with CH₂Cl₂ and MeOH. The filtrate was concentrated, and the residue was dissolved in a mixture of DMSO, MeOH, and an aqueous solution of HCl (2 M), and purified by preparative LC (acid or base) to obtain the desired macrocyclic carboxylic acid.

[0609] General Procedure 70: Phototensive Reaction

[0610] The variables shown in this scheme are specific to this general program.

[0611]

[0612] The Boc-protected THIQ core (1 equivalent) and tert-butyl hydroxybenzoate (1.1 equivalent) were dissolved in anhydrous toluene (0.05–0.2 M) and degassed with argon for 20 min. Cyanomethylene tributylphosphine (1.4 equivalent) was then added, and the mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by rapid column chromatography (silica, heptane:EtOAc = 1:0 to 0:1) to give a product as a white solid after evaporation.

[0613] General Procedure 71: Deprotection, Amide Coupling-Macrocyclization and Saponification

[0614] The variables shown in this scheme are specific to this general program.

[0615]

[0616] The reaction takes place in the same reaction vessel, and the intermediates are not separated.

[0617] Step 1: Boc-amine and R 2 (R 2 Simultaneous deprotection of (tBu, OAll, Me)-carboxylic acid esters.

[0618] HCl (4 M, in dioxane, 10⁻⁴⁰ equivalents) was added to the product (0.1 M) containing Boc-amine and tBu-carboxylic acid ester in CH₂Cl₂, and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure. R 2 In the case of =All, prior to Boc removal, the carboxylic acid ester was deprotected using Pd(PPh3)4 (0.15 equivalents) and morpholine (10 equivalents) in THF (0.1 M). The reaction was carried out under nitrogen for 16 hours. The intermediate was purified by rapid column chromatography (silica, DCM:MeOH = 1:0 to 9:1). R 2 In the case of Me, prior to Boc, the carboxylic acid ester is saponified using an aqueous solution of NaOH (2.5 equivalents) in MeOH (0.1M). The reaction is carried out at room temperature for 5 min. The intermediate mixture is then neutralized with HCl 2M (2.5 equivalents), evaporated, and redissolved in DCM, followed by Boc deprotection.

[0619] Step 2: Macrocyclization via amide coupling.

[0620] The mixture containing both carboxylic acids and amines in the same substrate (1 equivalent) was redissolved in CH2Cl2:DMF (20:1, 0.001 M), and NEt3 (3–10 equivalents) was added. Then, HATU (1.1 equivalents) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was used as is.

[0621] Step 3: Saponification

[0622] The above mixture was dissolved in MeOH:THF (4:1, 0.05–0.2 M) and treated with an aqueous LiOH solution (1 M, 3–10 equivalents), and the mixture was stirred at room temperature for 1–18 hours. The reaction mixture was acidified with an aqueous HCl solution (2 M) until pH < 5, and the desired macrocyclic carboxylic acid was obtained by preparative HPLC (method: prep acid or prep base).

[0623] General Procedure 86: Unprotection

[0624] The variables shown in this scheme are specific to this general program.

[0625]

[0626] Simultaneous deprotection of Boc-amine and tBu-carboxylic acid ester: HCl (4 M, in dioxane, 10-70 equivalents) was added to a feed (0.05–0.20 M) containing Boc-amine and tBu-carboxylic acid ester dissolved in CH2Cl2, and the mixture was stirred at room temperature for 1–24 hours. The mixture was then concentrated under reduced pressure and stripped twice with CH2Cl2 to obtain the free amine and carboxylic acid.

[0627] General Procedure 90: Amide Coupling - Macrocyclization

[0628] The variables shown in this scheme are specific to this general program.

[0629]

[0630] The carboxylic acid and amine (1 equivalent) from the same substrate were dissolved in CH₂Cl₂ (0.01–0.05 M), NEt₃ (3–10 equivalents) and HATU (1 equivalent) were added, and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica, CH₂Cl₂ / MeOH = 1:0 → 95:5). The desired fractions were combined and concentrated under reduced pressure to obtain the amide.

[0631] General Procedure 91: Debenzylation

[0632] The variables shown in this scheme are specific to this general program.

[0633]

[0634] The amide (1 equivalent) was dissolved in MeOH (0.01–0.2 M) and washed with N2. PdOH (20%, 0.1 equivalent) was added, and the resulting reaction mixture was stirred at room temperature under H2 atmosphere for 1–16 hours. The reaction mixture was filtered and purified by preparative HPLC (method: preparative acid or preparative base) to obtain the desired macrocyclic carboxylic acid.

[0635] Synthesis Example 1:

[0636] 2-(5,33-dimethyl-2-oxo-1,5,15,16,17-pentazaheptane[22.5.3.26,9.118,22.03,7.015,19.027,31]tridecano-3,6,8,16,18(33),19,21,24(32),25,27(31),34-undecen-23-yl)acetic acid (compound 362)

[0637]

[0638] Details: Preparation of the title compound in 4 steps:

[0639] Step 1: Following the general procedure 6B: amide coupling, starting with methyl 3-(4-methyl-1-(pent-4-en-1-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propionate dihydrochloride (200 mg, 0.407 mmol) and 1-methyl-5-vinyl-1H-indole-3-carboxylic acid (98 mg, 0.488 mmol) to obtain the corresponding amide (250 mg, 0.253 mmol, 95%).

[0640] Step 2: Follow General Procedure 7: Grubbs metathesis to obtain unsaturated macrocycles (100 mg, 0.163 mmol, yield: 65%, purity: 93.6%).

[0641] Step 3: Hydrogenation according to general procedure 8 to obtain the corresponding saturated macrocycle (100 mg, 0.162 mmol, yield: 93%, purity: 93.2%).

[0642] Step 4: Saponify according to general procedure 9 to obtain the title compound as a white solid (15.0 mg, 0.027 mmol, 15%).

[0643] Yield: The final compound was isolated as a white solid (15.0 mg, 0.027 mmol, 8.6%, after 4 steps).

[0644] Analysis: LCMS (Method N): t R=1.49min; calculated m / z value [M+H] + =562.2, measured value =562.4; 1 HNMR (400MHz, DMSO-d6) δ12.17(bs,1H),7.62(s,1H),7.49(d,J=8.7Hz,1H),7.38–7.29(m,2H),7.26–7. 12(m,2H),7.02(dd,J=8.4,1.6Hz,1H),6.95(s,1H),6.15(bs,1H),4.80–4.55(m,3H),4.55–4.35(m,2H), 3.83–3.71(m,4H),3.70–3.59(m,1H),3.11(dd,J=16.0,6.9Hz,1H),2.95(dd,J=16.0,8.8Hz,1H),2.83(q ,J=5.6Hz,2H),2.65(s,3H),2.48–2.30(m,2H),2.11–1.85(m,2H),1.68–1.34(m,2H),0.88–0.61(m,2H).

[0645] Synthesis Example 2:

[0646] 2-(34-methyl-22-oxo-17-oxa-8,9,10,19,23,32-hexaazahexanecyclo[21.5.3.218,21.13,7.06,10.026,30]tetradecano-1(29),3,5,7(34),8,18,20,26(30),27,32-decaen-2-yl)acetic acid (compound 379)

[0647]

[0648] Details: Preparation of the title compound in 4 steps:

[0649] Step 1: Following the general procedure 6B: amide coupling, starting with methyl 3-(1-(but-3-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propionate dihydrochloride (200 mg, 0.419 mmol) and 5-(but-3-en-1-yloxy)pyrazin-2-carboxylic acid, to obtain the corresponding amide (158 mg, 0.272 mmol, 65%).

[0650] Step 2: Follow the general procedure 7: Grubbs metathesis to obtain the corresponding (major) unsaturated macrocyclic crude product (64 mg, 0.12 mmol, 42%).

[0651] Step 3: Hydrogenate according to general procedure 8 to obtain the corresponding crude saturated macrocyclic compound. When using the product, assume 100% conversion.

[0652] Step 4: Saponify according to general procedure 9 to obtain the title compound as a white solid (23.1 mg, 0.042 mmol, 55%).

[0653] Yield: The final compound was isolated as a white solid (23.1 mg, 0.042 mmol, 10%, after 4 steps).

[0654] Analysis: LCMS (method T): tR = 0.967 min; calculated m / z [M+H]+ = 540.3, measured value = 541.4; 1H NMR (400MHz, DMSO) δ 8.19–8.14 (m, 2H), 7.60 (q, J = 8.7Hz, 2H), 7.31 (dd, J = 8.0, 1.8Hz, 1H), 7.10 (d, J = 7.8Hz, 1H), 6.40 (d, J = 1.9Hz, 1H), 4.78–4.62 (m, 3H), 4.62–4.54 (m, 1H) ,4.39(d,J=16.8Hz,1H),4.30–4.21(m,1H),4.21–4.12(m,1H),4.09(d,J=16.8Hz,1H),3.42–3.34(m,0H),3.03–2.89(m ,2H),2.84–2.76(m,2H),2.55–2.51(m,4H),1.89–1.67(m,2H),1.56–1.35(m,2H),1.32–1.07(m,3H),0.87–0.72(m,1H).

[0655] Synthesis Example 3:

[0656] 2-(20,32-difluoro-34-methyl-22-oxo-14,17-dioxa-8,9,10,23-tetraazahexanecyclo[21.5.3.218,21.13,7.06,10.026,30]tetradecano-1(29),3(34),4,6,8,18(33),19,21(32),26(30),27-decaen-2-yl)acetic acid (compound 368)

[0657]

[0658] Details: Preparation of the title compound in 4 steps:

[0659] Step 1: Following general procedure 24: photoelectrophoresis, starting with tert-butyl 7-(3-(benzyloxy)-1-(1-(3-(2-hydroxyethoxy)propyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.5 g, 2.386 mmol) and tert-butyl 2,6-difluoro-4-hydroxybenzoate, purified by rapid column chromatography (CH2Cl2 / MeOH = 1:0 → 97:3) to obtain the corresponding diether (1.73 g, 1.646 mmol, purity: 80%, yield: 69%).

[0660] Step 2: Following the general procedure 86: Deprotection, begin with 100 mg, 0.119 mmol diether to obtain free amino acids (81 mg, 0.119 mmol, 100%).

[0661] Step 3: Follow the general procedure 90: amide coupling-macrocyclization. Add some additional Et3N (5.0 equivalents) and HATU (0.5 equivalents) to obtain an amide in the form of a beige oil (26 mg, 0.035 mmol, purity: 90%, yield: 30%).

[0662] Step 4: Following general procedure 91: debenzylation, with a total of 0.7 equivalents of palladium hydroxide on carbon with a preparative acid to obtain a title macrocycle as a white solid (3.45 mg, 0.006 mmol, 15%).

[0663] Yield: The final compound, separated as a white solid (3.45 mg, 0.006 mmol, 3.1%, after 4 steps), was analyzed by LCMS (Method R): t R =1.38min; calculated m / z value [M+H] + =577.2, measured value =577.4; 1 H NMR (400MHz, DMSO) δ7.62(d,J=8.7Hz,1H),7.39(d,J=8.7Hz,1H),7.34(d,J=7.8Hz,1H ),7.14(d,J=7.8Hz,1H),6.71(d,J=10.9Hz,1H),6.42(d,J=10.8Hz,1H),6.23(s,1H), 4.79–4.66(m,3H),4.20–4.08(m,3H),4.05–3.90(m,2H),3.74–3.62(m,2H),3.63–3.5 2(m,3H),3.05–2.85(m,2H),2.83(t,J=6.4Hz,2H),2.53(s,3H),2.14(p,J=6.8Hz,2H).

[0664] Synthesis Example 4:

[0665] 2-[(12E)-20-oxo-15-oxa-8,9,10,21-tetraazahexane[19.5.3.216,19.13,7.06,10.024,28]tetane-1(27),3,5,7(32),8,12,16(31),17,19(30),24(28),25-undecen-2-yl]acetic acid (compound 419)

[0666]

[0667] Details: Preparation of the title compound in 3 steps:

[0668] Step 1: Following the general procedure 6B: amide coupling, starting with methyl 3-(1-(but-3-en-1-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propionate dihydrochloride (287 mg, 0.62 mmol) and 4-(allyloxy)benzoic acid to obtain the corresponding amide (240 mg, 0.62 mmol, 100%).

[0669] Step 2: Follow the general procedure 7: Grubbs metathesis to obtain unsaturated macrocycles (150 mg, 0.29 mmol, 47%).

[0670] Step 3: Following general procedure 9: saponification in MeCN instead of MeOH to obtain the title compound (minor macrocycle, 7.8 mg, 0.016 mmol, 12%) as a 3:1 mixture of E and Z isomers, in the form of a white solid.

[0671] Yield: The final compound was separated as a white solid (7.8 mg, 0.016 mmol, 5.6%, after 3 steps). Analysis: LCMS (Method J): tR = 2.32 min; calculated m / z [M+H]+ = 495.2, measured m / z = 495.1; 1H NMR (400MHz, DMSO-d6) δ12.25(s,1H),7.90(s,1H),7.70(d,J=8.6Hz,1H),7.31(d,J=7.7Hz,1H),7.25(d ,J=9.0Hz,1H),7.12(d,J=7.9Hz,1H),6.81(d,J=8.6Hz,2H),6.67(d,J=8.6Hz,2H),5.98(d,J=1.9Hz,1H ),5.94–5.79(m,2H),5.52–5.35(m,2H),4.72(q,J=16.8Hz,2H),4.60(t,J=7.8Hz,1H),4.17–4.04(m,2H ), 3.99 (d, J = 16.4Hz, 1H), 3.51 (dt, J = 13.9, 7.3Hz, 1H), 3.03 (qd, J = 15.7, 7.6Hz, 2H), 2.92–2.76 (m, 2H).

[0672] Synthesis Example 5:

[0673] 2-[(2R)-33-methyl-21-oxo-8,10,22-triazahexane[20.5.3.217,20.13,7.06,10.025,29]tetratec-1(28),3,5,7(33),8,17(32),18,20(31),25(29),26-decen-2-yl]acetic acid (compound 385)

[0674]

[0675] Details: Preparation of the title compound in 4 steps:

[0676] Step 1: Following the general procedure 6B: amide coupling, starting with rel-(R)-3-(1-(hex-5-en-1-yl)-4-methyl-1H-benzo[d]imidazol-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propionate trihydrochloride (obtained from the second eluted enantiomer of the building unit, 0.285 g, 0.527 mmol) and 4-vinylbenzoic acid, to obtain the corresponding amide (90 mg, 0.146 mmol, 27%).

[0677] Step 2: Following General Procedure 7: Grubbs metathesis, with an additional portion of Grubbs Generation 2 catalyst and stirring for 2 days, to obtain unsaturated macrocyclic compounds (25 mg, 0.044 mmol, 27%).

[0678] Step 3: Hydrogenate according to general procedure 8 to obtain the corresponding saturated macrocycle (27 mg, 0.048 mmol, 100%).

[0679] Step 4: Following general procedure 9: saponification with 4N NaOH aqueous solution and stirring for 5 days to obtain the title compound (minor analog, 7.8 mg, 0.013 mmol, 27%) as a white solid.

[0680] Yield: The final compound was isolated as a white solid (7.8 mg, 0.013 mmol, 2.0%, after 4 steps). Analysis: LCMS (Method R): t R =1.06min; calculated m / z value [M+H] + =522.3, measured value =522.4; 1H NMR (400MHz, DMSO-d6) δ 8.06(s,1H), 7.35–7.24(m,2H), 7.18–7.04(m,4H), 7.01(d,J=7.9Hz,2H), 6.05(s,1H), 4.70(t,1H), 4.35–4.24(m,2H), 4.16–4.02(m,3H), 3.51(dt) ,J=13.0,6.7Hz,1H),2.98–2.82(m,2H),2.77(t,J=6.0Hz,2H),2.69–2.58(m,1H),2.3 9(s,3H),1.73–1.48(m,3H),1.28–1.00(m,3H),0.74–0.61(m,1H),0.57–0.42(m,1H).

[0681] Synthesis Example 6:

[0682] 2-(4-oxo-31,32,33,34-tetrahydro-6,11-dioxa-3(7,2)-isoquinolino-1(5,2)-pyridaza-5(1,4)-benzocycloundecane-2-yl)acetic acid (compound 211)

[0683]

[0684] Details: The title compound was prepared in two steps:

[0685] Step 1: Following general procedure 70: photoelectrophoresis, starting with 7-(1-(6-(4-(4-(tert-butoxycarbonyl)phenoxy)butoxy)pyridin-3-yl)-3-methoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (200 mg, 0.413 mmol) and 4-hydroxybenzoate tert-butyl ester to obtain the corresponding product (260 mg, 0.390 mmol, 94%).

[0686] Step 2: Following general procedure 71: deprotection, amide coupling-macrocyclization and saponification, to obtain the title macrocycle as a white solid (15 mg, 0.031 mmol, 7.8%).

[0687] Yield: The final compound, separated as a white solid (15 mg, 0.031 mmol, 7.3%, after 2 steps), was analyzed by LCMS (method T): t R =0.988min; calculated m / z value [M+H] + =473.2, measured value =473.4; 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),8.10(d,J=2.4Hz,1H),7.44(dd,J=8.7,2.5Hz,1H),7.28(dd,J=7.8,1.8Hz,1 H),7.13(d,J=7.7Hz,1H),6.83(d,J=8.4Hz,2H),6.72(d,J=8.5Hz,1H),6.56(d,J=8.4Hz,2H),6.43(s,1H),4.48(d p,J=21.8,5.6Hz,2H),4.36(t,J=7.9Hz,1H),4.17(d,J=3.8Hz,2H),4.12(t,J=7.5Hz,2H),3.90(dt,J=13.0,6.5Hz ,1H),3.70(dt,J=13.2,6.9Hz,1H),2.96(d,J=8.0Hz,2H),2.88(t,J=6.7Hz,2H),1.76(th,J=13.4,6.9,6.0Hz,4H).

[0688] Synthesis Example 7:

[0689] 2-(2-oxo-12-oxa-1,14,28-triazapentane[16.5.3.23,6.213,16.021,25]triacont-3,5,13(28),14,16(27),18(26),19,21(25),29-nonen-17-yl)acetic acid (compound 277)

[0690]

[0691] Details: Preparation of the title compound in 4 steps:

[0692] Step 1: Following General Procedure 14: Amide Coupling, starting with 7-(3-methoxy-3-oxo-1-(2-(pent-4-en-1-yloxy)pyrimidin-5-yl)propyl)-1,2,3,4-tetrahydroisoquinoline-2-onium chloride (350 mg, 0.837 mmol) and 4-vinylbenzoic acid, to obtain the corresponding amide (270 mg, 0.528 mmol, 63%).

[0693] Step 2: Follow the general procedure 15: Grubbs metathesis to obtain the corresponding (major) unsaturated macrocycle (141 mg, 0.108 mmol, 20%).

[0694] Step 3: Hydrogenate according to general procedure 16 to obtain the corresponding saturated macrocycle (130 mg, 0.088 mmol, 82%).

[0695] Step 4: Following general procedure 17: saponification, using a preparative acid, add some DCM for dissolution to obtain the title compound as a white solid (15.5 mg, 0.033 mmol, 37%).

[0696] Yield: The final compound, separated as a white solid (15.5 mg, 0.033 mmol, 3.8%, after 4 steps), was analyzed by LCMS (Method H): t R =3.33min; calculated m / z value [M+H]+ = 472.2, measured value = 472.4; 1H NMR (400MHz, DMSO-d6) δ 12.34(s,1H), 8.37(s,2H), 7.31–7.16(m,1H), 7.13(d,J=7.8Hz,1H), 7.03(q,J=8.0Hz,4H), 6.10(s,1H), 4.48(dt,J=11.0,5.4Hz,1H), 4.44–4.31(m,2H), 4.26(d,J=16.2Hz,1H), 4.12(d,J=16.2Hz) ,1H),4.04(dt,J=12.3,5.9Hz,1H),3.60(dt,J=13.5,7.0Hz,1H),2.96(dt,J=16.4,8.1Hz,2H),2.90–2.77(m, 2H), 2.62 (q, J=7.3, 6.9Hz, 2H), 1.75 (t, J=7.4Hz, 2H), 1.70–1.45 (m, 2H), 1.19 (td, J=15.3, 14.2, 6.3Hz, 2H).

[0697] Synthesis Example 8:

[0698] 2-(33-methyl-2-oxo-15-oxa-1,7,17,33-tetraazahexane[19.5.3.216,19.13,6.15,9.024,28]tetratec-3,5,7,9(32),16,18,21(29),22,24(28),30-decaen-20-yl)acetic acid (compound 158)

[0699]

[0700] Details: Preparation of the title compound in 3 steps:

[0701] Step 1: Following General Procedure 14: Amide Coupling, starting with 3-(6-(pent-4-en-1-yloxy)pyridin-3-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propionate hydrochloride (192 mg, 0.363 mmol) and 1-methyl-5-vinyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (88 mg, 0.435 mmol) to obtain the corresponding amide (86 mg, 0.134 mmol, 37%).

[0702] Step 2: Follow the general procedure 15: Grubbs metathesis to obtain the corresponding (major) unsaturated macrocycle (63 mg, 0.068 mmol, yield: 51%).

[0703] Step 3: Following general procedure 39: debenzylation and olefin reduction, the compound was purified with Pd / C and by preparative HPLC (method: preparative acid) to give the compound as a racemic mixture (4.63 mg, 0.0086 mmol, 8%).

[0704] Yield: The final compound was isolated as a white solid (4.63 mg, 0.0086 mmol, 2%, after 3 steps). Analysis: LCMS (method T): t R =1.08min; calculated m / z value [M+H] + =525.2, measured value =525.4; 1H NMR (400MHz, DMSO) δ8.18(d,J=2.0Hz,1H),8.06(d,J=2.5Hz,1H),7.49(d,J=2.0Hz,1H),7.39( dd,J=8.5,2.5Hz,1H),7.30(d,J=7.8Hz,1H),7.18(d,J=7.8Hz,1H),6.72(d,J=8.5Hz,1H),6.54 (s,1H),5.85(s,1H),4.49(s,2H),4.44–4.31(m,2H),4.24–4.15(m,1H),4.14–4.04(m,1H),3.8 1–3.71(m,5H),2.96–2.82(m,4H),2.72(t,J=6.2Hz,2H),1.84–1.63(m,4H),1.33–1.25(m,2H).

[0705] Synthesis Example 9:

[0706] 2-[(2S)-33-methyl-21-oxo-8,9,10,22-tetraazahexane[20.5.3.217,20.13,7.06,10.025,29]tetratec-1(28),3,5,7(33),8,17(32),18,20(31),25(29),26-decen-2-yl]acetic acid (compound 223)

[0707]

[0708] Details: Preparation of the title compound in 4 steps:

[0709] Step 1: Following the general procedure 6B: amide coupling, starting with rel-(S)-3-(4-methyl-1-(pent-4-en-1-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propionate dihydrochloride (obtained from the first eluted enantiomer of the building unit, 564 mg, 1.15 mmol) and 4-allylbenzoic acid to obtain the corresponding amide (510 mg, 0.91 mmol, 79%).

[0710] Step 2: Follow General Procedure 7: Grubbs metathesis to obtain unsaturated macrocycles (480 mg, 0.90 mmol, 99%).

[0711] Step 3: Hydrogenate according to general procedure 8 to obtain the corresponding saturated macrocycle (480 mg, 0.89 mmol, 100%).

[0712] Step 4: Saponify according to general procedure 9 to obtain the title compound (main analog, 126 mg, 0.24 mmol, 27%) as a white solid.

[0713] Yield: The final compound was isolated as a white solid (126 mg, 0.24 mmol, 21%, after 4 steps). Analysis: LCMS (Method H): t R =3.12min; calculated m / z value [M+H] + =523.3, measured value =523.4; chiral SFC method IC isotropicity: ee = 100%; t R(主要) =6.15min,t R(次要) =8.31min;1H NMR (400MHz, DMSO-d6) δ12.30(s,1H),7.58(d,J=8.6Hz,1H),7.35–7.28(m,2H),7.18–7.06(m,3H),6.96(d,J=7.8Hz,2H),6.04(d,J=1. 9Hz,1H),4.80–4.69(m,2H),4.64(ddd,J=14.3,11.4,3.2Hz,1H),4.23(d,J=16.7Hz,1H),4.13(d,J=16.6Hz,1H),3.89(dt,J=11.8,5.7H z,1H),3.70(dt,J=12.7,6.3Hz,1H),3.06(dd,J=15.8,6.8Hz,1H),2.91(dd,J=15.7,8.8Hz,1H),2.79(t,J=6.1Hz,2H),2.64–2.54(m,4H ),2.37–2.23(m,1H),1.86–1.76(m,1H),1.73–1.59(m,1H),1.59–1.43(m,1H),1.33–1.00(m,3H),0.75–0.59(m,1H),0.56–0.40(m,1H).

[0714] Synthesis Example 10:

[0715] (2S)-2-[(17S)-2-oxo-12-oxa-1,14-diazapentane[16.5.3.23,6.213,16.021,25]triacont-3,5,13,15,18(26),19,21(25),27,29-nonen-17-yl]propionic acid (compound 127)

[0716]

[0717] Details: Preparation of the title compound in 3 steps:

[0718] Step 1: Following General Procedure 14: Amide Coupling, starting with 2-methyl-3-(6-(pent-4-en-1-yloxy)pyridin-3-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propionate hydrochloride (444 mg, 0.876 mmol) and 4-vinylbenzoic acid, to obtain the corresponding amide (440 mg, 0.718 mmol, 82%).

[0719] Step 2: Following general procedure 15: Grubbs metathesis, the corresponding (major) unsaturated macrocycle was obtained (520 mg, 0.908 mmol, purity: unknown, yield: 124%).

[0720] Step 3: Following general procedure 39: debenzylation and olefin reduction, purification was performed with Pd / C and via preparative HPLC (method: preparative acid) to obtain a diastereomeric mixture. The cis and trans products were separated by preparative HPLC (method: preparative acid 2) to give the corresponding macrocyclic carboxylic acid (4.41 mg, 0.0087 mmol, 1%) as the first eluent.

[0721] Yield: The final compound was isolated as a white solid (4.41 mg, 0.0087 mmol, 10%, after 3 steps). The structure was deduced based on the separation as the first elution product. Analysis: LCMS (Method H): t R =3.72 min; calculated m / z value [M+H] + =485.2, measured value =485.4; 1 H NMR (400MHz, DMSO) δ8.10(d,J=2.6Hz,1H),7.29–7.18(m,2H),7.09(d,J=7.8Hz,1H),6.98(q,J=8.0Hz ,4H),6.56(d,J=8.4Hz,1H),6.30(s,1H),4.62–4.52(m,1H),4.34(d,J=16.3Hz,1H),4.30–4.20(m,1H) ,4.18–4.05(m,2H),3.94(d,J=11.4Hz,1H),3.47–3.42(m,1H),3.09–2.99(m,1H),2.92–2.76(m,2H), 2.70–2.61(m,1H),2.61–2.53(m,1H),1.85–1.47(m,4H),1.20(p,J=7.5Hz,2H),1.01(d,J=6.8Hz,3H).

[0722] Synthesis Example 11:

[0723] 2-(27-methyl-2-oxo-12-oxa-1,14-diazapentane[16.5.3.23,6.213,16.021,25]triacont-3,5,13,15,18(26),19,21(25),27,29-nonen-17-yl)acetic acid (compound 80)

[0724]

[0725] Details: Preparation of the title compound in 4 steps:

[0726] Step 1: Following General Procedure 14: Amide Coupling, starting with methyl 3-(4-methyl-6-(pent-4-en-1-yloxy)pyridin-3-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propionate dihydrochloride (200 mg, 0.428 mmol) and 4-vinylbenzoic acid, to obtain the corresponding amide (114 mg, 0.217 mmol, 51%).

[0727] Step 2: Follow the general procedure 15: Grubbs metathesis to obtain unsaturated macrocycles (69 mg, 0.139 mmol, 64%).

[0728] Step 3: Hydrogenate according to general procedure 16 to obtain the corresponding saturated macrocycle (55 mg, 0.110 mmol, 79%).

[0729] Step 4: Following general procedure 17: saponification in MeOH / DMSO instead of MeOH to obtain the title compound as a white solid (39 mg, 0.080 mmol, 72%).

[0730] Yield: The final compound was isolated as a white solid (39 mg, 0.080 mmol, 19%, after 4 steps). Analysis: LCMS (Method R): t R =1.60min; calculated m / z value [M+H] +=485.2, actual measured value =485.4; 1H NMR (400MHz, DMSO) δ12.24(s,1H),8.00(s,1H),7.27(dd,J=7.8,1.9Hz,1H),7.10(d,J=7.8Hz,1H),7.06(d,J=7.9Hz,2H),6.99(d,J=7.9Hz ,2H),6.51(s,1H),6.11(d,J=1.8Hz,1H),4.79(ddd,J=11.5,8.3,3.4Hz,1H),4.40(t,J=7.9Hz,1H),4.26(d,J=16.1Hz,1H),4.19(dt,J=12 .1,5.6Hz,1H),4.00(d,J=16.1Hz,1H),3.94(ddd,J=10.6,6.3,3.7Hz,1H),3.42(d,J=6.3Hz,1H),2.99(dd,J=15.9,8.0Hz,1H),2.93–2.76 (m,3H),2.72–2.62(m,1H),2.59–2.52(m,1H),1.96(s,3H),1.85–1.74(m,1H),1.73–1.58(m,2H),1.58–1.42(m,1H),1.21(p,J=7.7Hz,2H).

[0731] Synthesis Example 12:

[0732] The remaining compounds in Tables 1 and 2 were prepared using suitable reagents and modifications known to those skilled in the art according to the synthetic procedures described above. Standard techniques known in the art, such as... 1 The compounds described in this paper were characterized by 1H NMR and mass spectrometry.

[0733] Biological Examples

[0734] Nrf2-Keap1 Biochemical Assay Protocol

[0735] Material

[0736] • Pf-BSA (protease-free): Sigma: A3059

[0737] • Streptavidin labeled XL665: CisBio: 610SAXLA

[0738] • Terbium-labeled anti-6HIS antibody: CisBio: 61HI2TLA

[0739] • Biotin-Nrf2 (16-mer): Biosyntan: Custom Synthesis

[0740] • HIS-Keap1 full length: Biosyntan: Custom Synthesis

[0741] • Proxiplate-384Plus, white 384 microplate: Perkin Elmer: 6008280

[0742] Assay buffer

[0743] ·10mM Hepes pH 7.4(sigma H3375)

[0744] ·150mM NaCl (sigma S7653)

[0745] ·0.005%Tween-20(sigma P1379)

[0746] ·0.01% pf-BSA (sigma A3059)

[0747] Final concentration determination

[0748] HIS-Keap1 is 4.1 nm long.

[0749] • Biotin-Nrf2 (16-mer) 4.1 nM

[0750] · Anti-6HIS Terbium 0.18nM

[0751] Streptavidin XL665 10.4 nM

[0752] Measurement scheme

[0753] In the first step, the Keap1 / compound complex was prepared by adding 100 nmL of the compound via ECHO 555, followed by 5 μL of an aliquot of 2x Keap1. The mixture was incubated at room temperature for 15 minutes. In the second step, the Keap1 / Nrf2 complex was prepared by adding 5 μL of an aliquot of 2x Nrf2 to the same mixture and incubating at room temperature for another 15 minutes. Then, 5 μL of anti-HIS-Tb was added, followed by 5 μL of 4x streptavidin-XL665. After incubation at 4 °C for 2 hours, TR-FRET measurements were performed on a Pherastar FS (optical module HTRF 337 / 620 / 665 nm).

[0754] Cell assay protocol

[0755] BEAS-2B cell culture

[0756] The growth rate of BEAS-2B cells varied based on batches of BEGM SingleQuots in BEGM medium. The cell growth rate for each batch of SingleQuots was determined. Ideally, cells were thawed into medium containing fresh batches of SingleQuots and grown for two generations prior to testing; however, viable cultures cultured for two to three generations in fresh batches prior to testing were also acceptable. Cells were cultured at different densities (cells / cm²) before determining the cell growth rate. 2 Cells are seeded in multiple tissue culture flasks to avoid cell confluence exceeding 70%. Cells should not exceed 70% confluence because they differentiate when they become confluent. After cells are grown in a fresh batch of medium as described above, the number of cells to be seeded in each well of the collagen plate is determined by seeding different numbers of cells per well and incubating for 48 hours. After 48 hours, cell confluence is checked, and the number of cells just below to just above confluence is selected for future plate seeding. After 48 hours, cell confluence in the plate is measured to be 95%–100% confluence. 70% confluence in the plate after 48 hours results in greater variability in the MTT signal and ineffective Z'.

[0757] BEAS-2B cell culture medium:

[0758] The cell culture medium consisted of BEBM basal medium supplemented with BEGM SingleQuots. The SingleQuots vials were thawed in a tissue culture fume hood without the addition of GA-1000 (gentamicin-amphotericidal).

[0759] If using the complete medium immediately, warm the BEBM basal medium to room temperature in a fume hood, but not up to 37°C. When preparing medium for future use, add SingleQuots to the cold BEBM. Add the SingleQuots components (except GA-1000) to the BEBM medium one at a time. After removing each component from the vial, rinse the vial with 0.5–1 mL of BEBM (depending on the volume the vial can hold) and add it to the BEBM vial. Once all components have been added, place the label provided with the SingleQuots kit on the vial and date it. Mix the medium by gently shaking the vial. Do not filter the medium. Store the medium at 4°C and dispose of any remaining medium one month after the date the SingleQuots were added.

[0760] BEAS-2B cell lysis protocol:

[0761] First, warm the trypsin to 37°C in a water bath. Then, warm the culture medium to room temperature, but not above 37°C, by placing it in a tissue culture fume hood. Aspirate the culture medium from one or more flasks and wash them with PBS. Add 1 to 1.5 mL of warm trypsin to each flask and incubate at 37°C until the cells detach from the flasks on their own (~8-10 minutes), without vigorous tapping of the flasks to separate the cells.

[0762] Add culture medium to each flask to a total volume of 8-10 mL and transfer to one or more 15 mL conical tubes. Centrifuge the cells at 120 g for 5 minutes at level 5. Cells can be centrifuged between 100 and 150 g. Then aspirate the culture medium and resuspend the cell pellet in fresh medium by pipetting up and down and gently tapping the tube left and right. Before transferring the top suspension to another tube, allow any remaining cell clumps to settle to the bottom of the tube, leaving approximately 1 mL of culture medium in the original tube. Mix the 1 mL of culture medium and cell clumps using a single-channel P1000 pipette, removing any remaining clumps before adding the cells from the suspension to another tube. Mix the suspensions using a pipette, aliquot the sample, and count the cells. Calculate the desired cell count / cm³. 2 And add the required volume of cells to the tissue culture flask. For example, using a flask with ~6000 cells / cm³. 2 SingleQuots are suitable for three-day incubation and have a density of ~3000 cells / cm³. 2 Suitable for five-day incubation. Optimal cell density varies depending on the SingleQuots batch. Incubate the flask at 37°C in 5% CO2.

[0763] Day 1: Seed BEAS-2B cells in collagen plates:

[0764] Inoculate one or more plates with 0.3% or 0% HSA. Although the protocols are similar under both conditions, any differences are noted below.

[0765] Warm the trypsin to 37°C in a water bath. Warm the culture medium to room temperature by placing it in a tissue culture fume hood. (Do not warm the culture medium to 37°C.) If the collagen plates containing the compound have been frozen, thaw them at room temperature for 1 hour. Two multidrop standard cassettes were used: one for dispensing culture medium and cells without human serum albumin (HSA), and the other for dispensing culture medium containing HSA.

[0766] Once all materials have reached the desired temperature, remove the seal from the collagen plates. Using an HSA-free multipoint box, add 20 μL of culture medium to each well, and allow the plates to stand covered at room temperature.

[0767] In this embodiment, a single injection of 20 μL was used for a 0.3% HSA plate, and two injections of 20 μL were used for a 0% HSA plate.

[0768] Next, BEAS-2B cells were lysed according to the BEAS-2B cell lysis protocol. First, the cells were counted, and then the cells were switched from a multi-point box to a +HSA box.

[0769] For 0.3% HSA plates only: Combine 20 μL each of culture medium, HSA in the medium, and cells, and add HSA at a three-fold concentration. Since the final HSA concentration on the cells is 0.3%, add 0.9% HSA to the plate. To prepare a 0.9% HSA solution, add 0.9 mL of HSA stock solution (10%) to 9.1 mL of culture medium to obtain 10 mL of 0.9% HSA.

[0770] Using an HSA multi-point box, add 20 μL of 0.9% HSA in culture medium to each well (for 0.3% HSA plates only), and switch from the multi-point box to an HSA-free box. Prepare cells to the desired concentration in culture medium. In the example with 2500 cells / well SingleQuots, adding 20 μL per well yielded 1.25 × 10⁻⁶ cells / well. 5 Cells / mL. The number of cells per well is adjusted depending on the SingleQuots batch.

[0771] Using an HSA-free multipoint box, add 20 μL of cells to each well of 0.3% and 0% HSA plates. Incubate these plates at room temperature for approximately 15–30 minutes, then incubate them at 37°C and 5% CO2 for 48 hours.

[0772] Day 3: MTT assay

[0773] Because this assay is time-dependent, start with one plate at a time. Label the two clear-bottomed, white-walled plates DMSO and DIC, and then place them in a darker chamber. Prefill the Biotek washer with PBS - / - (minimum 200 mL). The protocol involves either prefilling A – 100 mL (twice) or prefilling A – 250 mL.

[0774] Prepare lysis buffer immediately before use. Aspirate the culture medium using BioTek and wash it twice with 75 μL of PBS - / -. The Beas washing protocol involves washing with 75 μL of buffer A for 2 cycles, followed by pre-rinsing the BioTek twice with water to remove the PBS.

[0775] Invert the plate onto the absorbent pad and pull it back to manually remove as much liquid as possible, then tap the plate gently against the clean spot on the absorbent pad (3-4 times). Add 50 μL of lysis buffer to each well and place the plate on a shaker at 8 / 10 setting for 20 minutes at room temperature.

[0776] Prepare 40 mL of reagent C in a light-limited chamber (with red light) and then divide it into two 19 mL volumes (one into a tube labeled DMSO and the other into a tube labeled DIC). Then add 19 μL of DMSO to the DMSO tube and 19 μL of 1.5 mM dicoumarol (“DIC”) to the DIC tube, and mix the tubes together.

[0777] Add 40 μL of the DMSO + Reagent C mixture to each well of the DMSO plate. Once the DMSO + Reagent C mixture is added to the DMSO plate, protect any substances containing MTT from light. Add 40 μL of the DIC + Reagent C mixture to each well of the DIC plate.

[0778] Each plate was kept in the dark, and 10 μL of pyrolysis product was first added to each well of the DMSO plate, followed by 10 μL of pyrolysis product to each well of the DIC plate.

[0779] Incubate both DMSO and DIC plates at room temperature for approximately 15-30 minutes while protecting from light. This incubation time can be reduced if the cell number increases. For example, 5000 cells / well may only require 15 minutes to form. Rotate these plates at 277g (1500RPM) for 5 minutes to remove any air bubbles. Measure the absorbance of both plates at 570nm on a Pherastar (settings: settling time = 0.1 sec, 15 flashes / well). The following indicates NQO1 activation:

[0780] ΔOD 570 =OD 570 DMSO-OD 570 DIC

[0781] HUDEP cells

[0782] Gene expression was assessed by qPCR in HUDEP cells titrated with the new compound.

[0783] HUDEP compound treatment method

[0784] HUDEP cells were seeded at 25,000 cells / well in 200 μL of maintenance medium in 96-well plates. The compound was added in 10-point dose-response patterns starting at 10 μM using a 1 / 3 dilution protocol with an HP digital diluent. A DMSO control was run to normalize for DMSO. The compound was incubated at 37°C with 5% CO2 for 48 h. After incubation, total RNA was isolated using a Cells to Ct kit, and gene expression was assessed against the target gene (GOI) after normalization against housekeeping genes. ΔΔCT was calculated and compared with the DMSO control.

[0785] Cell lysis, isolation, and gene expression materials

[0786] Cells to Ct is a kit provided by Applied Biosystems. The mRNA prepared using this kit can be directly used for cDNA transformation, followed by qPCR for gene expression analysis.

[0787] program

[0788] Cell lysis and RNA preparation: For suspension cells such as HUDEP, prepare lysates using 10,000–100,000 cells (according to kit instructions). Centrifuge the plate at 1500 rpm for 5 minutes and allow the cells to pellet. Remove used culture medium using a multichannel pipette. Add 200 μL of ice-cold PBS to all treated wells, then centrifuge at 1500 rpm for 5 minutes. Aspirate 195 μL of cold PBS from all treated wells without disturbing the cell monolayer.

[0789] To prepare the Cells to CT lysis solution, add 49.5 μL of Cells to CT lysis buffer and 0.5 μL / well of deoxyribonuclease I to each well (return the deoxyribonuclease I reagent to the -20°C freezer immediately after pipetting). Pipe the Cells to CT lysis solution into a reservoir and add 50 μL / well to the treated wells. (Mix 35 μL five times without generating bubbles and set the timer for 5 minutes. At the end of the 5-minute incubation, add 5 μL of stop solution to the liquid using a multichannel pipette, ensuring the tip is in contact with the liquid. Then mix 35 μL five times without generating bubbles and set the timer for 2 minutes.)

[0790] Seal these plates and store them at -20°C until cDNA synthesis. Optionally, place them on ice to allow direct cDNA synthesis.

[0791] cDNA Synthesis: If necessary, thaw the cell lysate plate on ice and mix 4 times with a multichannel pipette. For each sample, combine 4 μL of Superscript IV VILO and 6 μL of nuclease-free water. Pour the mixture into a reservoir and pipette 10 μL into each well of a 96-well PCR plate. Add 10 μL of the previously prepared lysate and mix 5 times. Seal these wells completely with the plate sealing film using a plate sealing paddle, especially around the edges. Centrifuge the PCR plate to settle the sample to the bottom of these wells. Seal the lysate plate and return it to a -20°C freezer as soon as possible. Place the PCR plate in a thermal cycler and run at 20 μL for 10 min at 25°C, 10 min at 50°C, 5 min at 85°C, and then at 4°C.

[0792] Real-time PCR: If necessary, thaw the cDNA plate at room temperature and add 30 μL of nuclease-free water to each cell lysate, then mix up and down four times with a pipette. Thaw the primers for both the target gene—housekeeping gene (HKG) and one or more target genes (GOI).

[0793] Prepare templates and calculate the number of wells required for each target gene (GOI). Each sample requires 2 μL of cDNA, 5 μL of Taqman Master Mix, 0.16667 μL of GOI at a 60-fold concentration, 0.16667 μL of HKG at a 60-fold concentration, and 2.6667 μL of nuclease-free water. If using a 20-fold concentration of the gene, combine 2 μL of cDNA, 5 μL of Taqman Master Mix, 0.5 μL of GOI, 0.5 μL of HKG, and 2 μL of nuclease-free water for each well.

[0794] After counting the number of wells for each gene, combine GOI, HKG, Taqman Master Mix, and nuclease-free water. As detailed in the template, pipette 8 μL into each well of a 384-well PCR plate. As detailed in the template, pipette 2 μL of cDNA into the appropriate well, then mix up and down 4 times, changing pipette tips between sample additions. Seal these wells completely with the plate sealing paddle and plate sealing film, especially around the edges. Centrifuge the PCR plate to settle the sample to the bottom of these wells.

[0795] RT-PCR was run for 40 cycles with a sample volume of 10 μL, held at 95 °C for 10 min, followed by denaturation at 95 °C for 15 sec and annealing / extension at 60 °C for 1 min. Data were analyzed by HKG normalization and ΔΔCT was calculated and compared with controls.

[0796] Table 4.

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0830] The disclosure described herein can be suitably implemented in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted broadly and without limitation. Furthermore, the terminology and expressions used herein have been used as descriptive terms rather than limiting terms, and the use of such terminology and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, but it should be recognized that various modifications are possible within the scope of this application.

[0831] It should be understood that although this application has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of this application. Other aspects, advantages, and modifications within the scope of this application will be apparent to those skilled in the art to which this application pertains. All disclosures of patents and scientific literature cited herein are expressly incorporated herein by reference in their entirety.

Claims

1. A compound of formula (IA): (IA) Or its pharmaceutically acceptable salt, wherein: R is H or optionally replaced by a group selected from -OH, C 1-6 Alkoxy or C 6-12 Aryl substituents substituted C 1-6 alkyl; R 1 Is it H or C? 1-6 alkyl; R 2 Is it H or C? 1-6 alkyl; R 3 Is it H or C? 1-6 alkyl; Each R 5 Independently, it is halogen, C 1-6 Alkyl or C 1-6 Alkoxy; X 3 It is CH2 or O; n is 0, 1, or 2; X 1 and X 2 It can be CH or N independently; Ring A is: , , , , , , , , , , , , , or ; The above The key connected to L′ is represented by ring A being –(R 4 ) m Replacement, where m is 1, 2, 3, or 4; and each R 4 Independently, it consists of H, halogens, and C. 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-6 Substitution of alkoxy, -C(O)NH2 and -C(O)N(CH3)2 groups; and L′ is C 4-6 Alkylene, C 4-6 imidene group, C 4-6 Heteroalkylene or C 4-6 Heteroalkenyl groups, each optionally selected independently by one or two halogens and C. 1-6 The alkyl group is substituted, and the heteroalkylene and heteroeneyl groups contain one or two oxygen atoms.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 It is CH2.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 It is O.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X 1 It is N.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X 1 It is CH.

6. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X 2 It is N.

7. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X 2 It is CH.

8. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is N.

9. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is CH.

10. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 One is CH and the other is N.

11. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein n is 2.

12. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein n is 1.

13. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each R 5 Independently C1-4 alkyl or C 1-4 Alkyl group.

14. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each R 5 It is either methyl or methoxy.

15. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein n is 0.

16. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L' is C 4-6 Alkylene, C 4-6 imidene group, C 4-6 Heteroalkylene or C 4-6 Heteroene groups, wherein the heteroalkylene groups and heteroene groups contain one or two oxygen atoms.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein C 4-6 The sub-alkenyl or C4-6 hetero-alkenyl contains an unsaturated bond.

18. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 3 It is CH2, and L' is a C containing one unsaturated bond. 4-6 imide or C 4-6 Heteroene group.

19. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein X 3 It is O, and L′ is C containing one unsaturated bond. 4-6 imide or C 4-6 Heteroene group.

20. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 3 It is CH2 and L′ is C 4-6 Alkylene or C 4-6 Heteroalkylene, wherein C 4-6 Heteroalkylene groups contain one or two oxygen atoms.

21. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein X 3 It is O and L′ is C 4-6 Alkylene or C 4-6 Heteroalkylene, wherein the C 4-6 Heteroalkylene contains one oxygen atom.

22. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein X 3 It is O and L′ is C 4-6 Alkylene.

23. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 3 It is CH2 and L′ is C 4-6 Alkylene.

24. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is 、 、 、 、 、 、 、 、 、 , , ,or , wherein The key connected to L′ is represented by ring A being –(R 4 ) m Replace, where m is 1 or 2; and each R 4 Independently, it consists of H, halogens, and C. 1-4 Alkyl or C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-4 Substitution with alkoxy, -C(O)NH2 and -C(O)N(CH3)2 groups.

25. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is , wherein The key connected to L′ is represented by ring A being –(R 4 ) m Replace, where m is 1 or 2; and each R 4 Independently, it consists of H, halogens, and C. 1-4 Alkyl or C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-4 Substitution with alkoxy, -C(O)NH2 and -C(O)N(CH3)2 groups.

26. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is And wherein The key connected to L′ is represented by ring A being –(R 4 ) m Replacement, where m is 1, 2, 3, or 4; and each R 4 Independently, it consists of H, halogens, and C. 1-4 Alkyl or C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group is optionally surrounded by 1-3 independently selected from halogens, C 1-4 Substitution with alkoxy, -C(O)NH2 and -C(O)N(CH3)2 groups.

27. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein each R 4 Independently selected from H, halogens, C1-4 alkyl groups and C 1-4 Alkoxy, wherein the C1-4 alkyl and C 1-4 The alkoxy group is optionally substituted with 1 to 3 groups independently selected from halogens, C1-4 alkoxy groups, -C(O)NH2 and -C(O)N(CH3)2.

28. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein each R 4 Independently selected from H, halogens, C1-4 alkyl groups and C 1-4 alkoxy groups, wherein each C1-4 alkyl group and C 1-4 The alkoxy group is optionally substituted by 1 to 3 groups independently selected from F, Cl, methoxy, -C(O)NH2 and -C(O)N(CH3)2.

29. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each R 4 It is independently selected from H, methyl, isobutyl, F, Cl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, 3,3,3-trifluoropropyl, 2,2-difluoroethyl, 3-fluoropropyl and methoxyethyl.

30. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R is H, methyl, ethyl, 2-hydroxy-ethyl or benzyl.

31. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R is H.

32. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 1 Is it H or C? 1-4 alkyl.

33. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 1 It is H or methyl.

34. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 1 It is H.

35. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 Is it H or C? 1-4 alkyl.

36. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 It is H or methyl.

37. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 3 Is it H or C? 1-4 alkyl.

38. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 3 It is H or methyl.

39. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 One is H and the other is C. 1-4 alkyl.

40. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 One is H and the other is methyl.

41. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each is H.

42. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each is a methyl group.

43. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from:

44. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from:

45. A pharmaceutical composition comprising the compound of any one of claims 1-44 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

46. ​​Use of the compound of any one of claims 1-44 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 45 in the preparation of a medicament for activating Nrf2.

47. Use of the compound of any one of claims 1-44 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 45 in the preparation of a medicament for treating sickle cell disease.

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