Tetrahydroisoquinoline derivatives for the treatment of erythrocyte disorders and inflammatory diseases

Abstract

Provided herein are compounds that activate nuclear factor erythroid 2-related factor 2 (Nrf2), and compositions thereof, for treating red blood cell and inflammatory diseases.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 078,118 filed September 14, 2020, and U.S. Provisional Patent Application No. 63 / 229,338 filed August 4, 2021, which are incorporated herein by reference in their entirety, respectively, under 35 United States Code § 119(e).

[0002] This disclosure generally relates to compounds, compositions, and methods for treating red blood cells and inflammatory diseases. [Background technology]

[0003] Nuclear factor erythroid lineage 2-related factor 2 (Nrf2), also known as nuclear factor erythrocyte-derived 2-like 2, is a human transcription factor encoded by the NFE2L2 gene. Nrf2 is a basic leucine zipper (bZIP) protein that regulates the expression of antioxidant proteins that protect against oxidative damage induced by injury and inflammation. Nrf2 is at the center of a complex regulatory network and plays a crucial role in regulating metabolism, inflammation, autophagy, proteostasis, mitochondrial physiological function, and immune responses. [Overview of the project] [Problems that the invention aims to solve]

[0004] Red blood cell (RBC) disorders are conditions that affect red blood cells, which are the cells in the blood that carry oxygen from the lungs to all parts of the body. Many different types of red blood cell disorders exist: including anemia and abnormal hemoglobin disorders (e.g., sickle cell disease and thalassemia). Inflammatory diseases include, but are not limited to, asthma, rheumatoid arthritis, ulcerative colitis, and Crohn's disease. There is a great deal of unmet medical need for safe and effective oral treatments to address red blood cell and inflammatory diseases. Nrf2 activators treat red blood cell disorders by stimulating proteins that protect against oxidative damage, thereby reducing inflammation.

Means for Solving the Problems

[0005] Thus, in one aspect, what is provided herein is a compound that activates Nrf2 for use in treating erythrocyte diseases.

[0006] Thus, in another aspect, what is provided herein is a compound that activates Nrf2 for use in treating inflammatory diseases.

Modes for Carrying Out the Invention

[0007] Embodiment 1. Compound of formula (I):

Chemical formula

[0008] Embodiment 1a(i). Compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (in the formula: R is H, or -OH, C 1~6 Alkyloxy or C 1~6 C is sometimes replaced by an aryl group. 1~6 It is alkyl; R 1 is H or C 1~6 It is alkyl; R 2 is H or C 1~6 It is alkyl; R 3 is H or C 1~6 It is alkyl; Ring B is C 5~12 Arylene, or C containing 1 to 4 heteroatoms independently selected from N and O. 3~12 It is a heteroarylene, and ring B is [ka] on the condition that it is not, * represents the bond to L; n is 0, 1, 2 or 3; each R 5 is independently halo, C 1~6 alkyl or C 1~6 alkyloxy; ring A is C 5~12 arylene, or C containing 1 to 2 heteroatoms independently selected from N and O 3~12 heteroarylene; m is 1, 2, 3 or 4; each R 4 is independently H, halo, C 1~6 alkyl or C 1~6 alkoxy, and the C 1~6 alkyl and C 1~6 alkoxy groups are optionally substituted with 1 to 3 groups independently selected from halo, C 1~6 alkyloxy, amide and N,N-dimethylamide groups; L is C 4~8 alkylene, C 4~8 alkenylene, C 4~8 heteroalkylene or C 4~8 heteroalkenylene, each of which is optionally substituted with 1 or 4 groups independently selected from halo and C 1~6 alkyl, and heteroalkylene and heteroalkenylene contain 1 to 4 oxygen atoms).

[0009] Embodiment 1a(ii). Compound of formula (I):

Chemical formula

Chemical formula

[0010] Embodiment 1a (iii). Compound of formula (I): [Chemical formula] or a pharmaceutically acceptable salt thereof (wherein: R is H, or C 1~6 alkyloxy or C 6~12 alkyl optionally substituted with one substituent selected from aryl; 1~6 alkyl; R 1 is H or C 1~6 alkyl; R 2 is H or C 1~6 alkyl; R 3 is H or C 1~6 alkyl; Ring B is C 6~12 arylene, or C heteroarylene containing 1 to 4 heteroatoms independently selected from N and O; 3~12 heteroarylene; n is 0, 1, 2 or 3; Each R 5 is independently halo, C 1~6 alkyl or C 1~6 alkyloxy; Ring A is C 7~12 arylene, or 7- to 12-membered heteroarylene containing 1 to 2 heteroatoms independently selected from N and O; m is 1, 2, 3 or 4; Each R 4 is independently H, halo, C 1~6 alkyl or C 1~6 alkoxy, and the C 1~6 alkyl and C 1~6 alkoxy groups are optionally substituted with 1 to 3 groups independently selected from halo, C 1~6 alkyloxy, amide and N,N-dimethylamide groups; L is C 4~8 alkylene, C 4~8 alkenylene, C4~8 Heteroalkylene or C 4~8 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or four groups independently selected from alkyl groups (heteroalkylenes and heteroalkenylenes contain one to four oxygen atoms).

[0011] Embodiment 1b. A compound of Embodiment 1a(i), 1a(ii), or 1a(iii), or a pharmaceutically acceptable salt thereof, wherein ring B is not benzotriazole.

[0012] Embodiment 1c.L is C 5~7 Alkylene, C 5~7 Alkenylene, C 5~7 Heteroalkylene or C 5~7 These are heteroalkenylenes, and each of them is a halo and C 1~6 Compounds of Embodiment 1a(i), 1a(ii), or 1a(iii), or pharmaceutically acceptable salts thereof, optionally substituted with one or four groups independently selected from alkyl groups, wherein the heteroalkylene and heteroalkenylene contain one to two oxygen atoms.

[0013] Embodiment 1d.L includes a halo and C 1~6 C optionally substituted with one or four groups independently selected from alkyl groups 4~8 A compound of Embodiment 1a(i), 1a(ii), or 1a(iii), or a pharmaceutically acceptable salt thereof, which is an alkylene.

[0014] Embodiment 1e.L includes a halo and C 1~6 Compounds of Embodiment 1a(i), 1a(ii), or 1a(iii), or pharmaceutically acceptable salts thereof, which are C6 alkylenes optionally substituted with one or four groups independently selected from alkyl groups.

[0015] Embodiment 1f.L is C 4~8 These are alkenylenes, and each of them is a halo and C 1~6Compounds of Embodiment 1a(i), 1a(ii), or 1a(iii), or pharmaceutically acceptable salts thereof, optionally substituted with one or four groups independently selected from alkyl groups.

[0016] Embodiment 1 g.L is C 4~8 These are heteroalkylenes, each of which is a halo and C. 1~6 The heteroalkylene is optionally substituted with one or four groups independently selected from alkyl groups, and the heteroalkylene is a compound of Embodiment 1a(i), 1a(ii), or 1a(iii), or a pharmaceutically acceptable salt thereof, containing one to four oxygen atoms.

[0017] Embodiment 1h.L is C 4~8 These are heteroalkenylenes, each of which is a halo and C. 1~6 Compounds of Embodiment 1a(i), 1a(ii), or 1a(iii), or pharmaceutically acceptable salts thereof, optionally substituted with one or four groups independently selected from alkyl groups, wherein the heteroalkenylene contains one to four oxygen atoms.

[0018] Embodiment 1i.L is C 4~8 Alkenylene or C 4~8 It is a heteroalkenylene, C 4~8 Alkenylene and C 4~8 A compound of Embodiment 1a(i), 1a(ii), or 1a(iii), or a pharmaceutically acceptable salt thereof, wherein the heteroalkenylene contains one unsaturation site (i.e., one unsaturated bond).

[0019] Embodiment 2. The compound of Embodiment 1a(i), 1a(ii), or 1a(iii), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (IA): [ka] (In the formula: L' is C 4~6 Alkylene, C 4~6 Alkenylene, C4~6 heteroalkylene or C 4~6 heteroalkenylene, each of which is optionally substituted with one or two groups independently selected from halo and C 1~6 alkyl, and heteroalkylene and heteroalkenylene contain one or two oxygen atoms; X 3 is CH2 or O; n is 0, 1 or 2; X 1 and X 2 are independently CH or N).

[0020] Embodiment 2a(i). Compounds of formula (IC):

Chemical formula

[0021] Embodiment 2a(ii). Compound of formula (IC): [ka] or a pharmaceutically acceptable salt thereof (in the formula: R is H, or -OH, C 1~6 Alkyloxy and C 6~12 C optionally substituted with one substituent selected from aryl groups. 1~6 It is alkyl; R 1 is H or C 1~6 It is alkyl; R 2 is H or C 1~6 It is alkyl; R 3 is H or C 1~6 It is alkyl; n is 0, 1, 2, or 3; Each R 5 Independently, Halo, C 1~6 Alkyl or C 1~6 It is an alkyloxy; Ring A is C 6~12 Arylene, or C containing 1-2 heteroatoms independently selected from N and O. 3~12 It is a heteroarrene; m is 1, 2, 3, or 4; Each R 4 These are independently H, Halo, and C. 1~6 Alkyl or C 1~6 It is an alkoxy, C 1~6 Alkyl and C 1~6 The alkoxy group is a halo, C 1~6 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups; L is C 4~8 Alkylene, C 4~8 Alkenylene, C 4~8 Heteroalkylene or C 4~8 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or four groups independently selected from alkyl groups (heteroalkylenes and heteroalkenylenes contain one to four oxygen atoms).

[0022] Embodiment 2b.L is C 5~7 Alkylene, C 5~7 Alkenylene, C 5~7 Heteroalkylene or C 5~7 These are heteroalkenylenes, and each of them is a halo and C 1~6 Compounds of Embodiment 2a(i) or 2a(ii), or pharmaceutically acceptable salts thereof, optionally substituted with one or four groups independently selected from alkyl groups, wherein the heteroalkylene and heteroalkenylene contain one to two oxygen atoms.

[0023] Embodiment 2c.L includes a halo and C 1~6 C optionally substituted with one or four groups independently selected from alkyl groups 4~8 A compound of Embodiment 2a(i) or 2a(ii), or a pharmaceutically acceptable salt thereof, which is an alkylene.

[0024] Embodiment 2d.L includes a halo and C 1~6A compound of Embodiment 2a(i) or 2a(ii), or a pharmaceutically acceptable salt thereof, which is a C6 alkylene optionally substituted with one or four groups independently selected from alkyl groups.

[0025] Embodiment 2e.L is C 4~8 These are alkenylenes, and each of them is a halo and C 1~6 Compounds of Embodiment 2a(i) or 2a(ii), or pharmaceutically acceptable salts thereof, optionally substituted with one or four groups independently selected from alkyl groups.

[0026] Embodiment 2f.L is C 4~8 They are heteroalkylenes, and each of these is a halo and C 1~6 A compound of Embodiment 2a(i) or 2a(ii), or a pharmaceutically acceptable salt thereof, optionally substituted with one or four groups independently selected from alkyl groups, wherein the heteroalkylene contains one to four oxygen atoms.

[0027] Embodiment 2g.L is C 4~8 These are heteroalkenylenes, each of which is a halo and C. 1~6 The heteroalkenylene is optionally substituted with one or four groups independently selected from alkyl groups, and the compound of Embodiment 2a(i) or 2a(ii), or a pharmaceutically acceptable salt thereof, contains one to four oxygen atoms.

[0028] Embodiment 2h.L is C 4~8 Alkenylene or C 4~8 It is a heteroalkenylene, C 4~8 Alkenylene and C 4~8 A compound of Embodiment 2a(i) or 2a(ii), or a pharmaceutically acceptable salt thereof, wherein the heteroalkenylene contains one unsaturation site (i.e., one unsaturated bond).

[0029] Embodiment 3.X 3 The compound of Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein the compound is CH2.

[0030] Embodiment 4.X 3 The compound of Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein is O.

[0031] Embodiment 5.X 1 Any one of the compounds from Embodiments 2 to 4, or a pharmaceutically acceptable salt thereof, wherein N is present.

[0032] Embodiment 6.X 1 A compound from any one of Embodiments 2 to 4, or a pharmaceutically acceptable salt thereof, wherein CH is present.

[0033] Embodiment 7.X 2 A compound from any one of Embodiments 2 to 4, or a pharmaceutically acceptable salt thereof, wherein N is present.

[0034] Embodiment 8.X 2 A compound from any one of Embodiments 2 to 4, or a pharmaceutically acceptable salt thereof, wherein CH is present.

[0035] Embodiment 9.X 1 and X 2 However, each of the compounds from Embodiments 2 to 4, or a pharmaceutically acceptable salt thereof, is N.

[0036] Embodiment 10.X 1 and X 2 However, each of the compounds from Embodiments 2 to 4, or a pharmaceutically acceptable salt thereof, is CH.

[0037] Embodiment 11.X 1 and X 2 A compound from any one of Embodiments 2 to 4, or a pharmaceutically acceptable salt thereof, wherein one of the elements is CH and the other is N.

[0038] Embodiment 12. Any one of the compounds from Embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0039] Embodiment 13. Any one of the compounds from Embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0040] Embodiment 14. Each R 5 However, independently, C 1~4 Alkyl or C 1~4 A compound from any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, which is an alkyloxy.

[0041] Embodiment 15. Each R 5 However, independently, one of the compounds from Embodiments 1 to 14, which is methyl or methoxy, or a pharmaceutically acceptable salt thereof.

[0042] Embodiment 16. Any one of the compounds from Embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0043] Embodiment 17.L' is C 4~6 Alkylene, C 4~6 Alkenylene, C 4~6 Heteroalkylene or C 4~6 A heteroalkenylene, wherein the heteroalkylene and heteroalkenylene contain one or two oxygen atoms, one of the compounds of Embodiments 2 to 16, or a pharmaceutically acceptable salt thereof.

[0044] Embodiment 18.C 4~6 Alkenylene or C 4~6 A compound of Embodiment 17, or a pharmaceutically acceptable salt thereof, wherein the heteroalkenylene contains one unsaturated bond.

[0045] Embodiment 19.X 3 The first part is CH2, and L' is a C containing one unsaturated bond. 4~6 Alkenylene or C 4~6 A heteroalkenylene, one of the compounds of Embodiments 2-3 and 5-18, or a pharmaceutically acceptable salt thereof.

[0046] Embodiment 20.X 3is O, and L' is C containing one unsaturated bond. 4~6 Alkenylene or C 4~6 A heteroalkenylene, one of the compounds from Embodiments 2 and 4-18, or a pharmaceutically acceptable salt thereof.

[0047] Embodiment 21.X 3 CH2 is C 4~6 Alkylene or C 4~6 It is a heteroalkylene, C 4~6 The heteroalkylene is any one of the compounds of Embodiments 2-3 and 5-18, or a pharmaceutically acceptable salt thereof, comprising one or two oxygen atoms.

[0048] Embodiment 22.X 3 O is C 4~6 Alkylene or C 4~6 It is a heteroalkylene, C 4~6 The heteroalkylene is any one of the compounds from Embodiments 2 and 4-18, or a pharmaceutically acceptable salt thereof, containing one oxygen atom.

[0049] Embodiment 23.X 3 O is C 4~6 A compound that is alkylene, one of the compounds from Embodiments 2 and 4-18, or a pharmaceutically acceptable salt thereof.

[0050] Embodiment 24.X 3 CH2 is C 4~6 A compound that is alkylene, one of the compounds of Embodiments 2-3 and 5-18, or a pharmaceutically acceptable salt thereof.

[0051] Embodiment 25. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (IB): [ka] (In the formula: L'' is C 4~6 Alkylene, C 4~6Alkenylene, C 4~6 Heteroalkylene or C 4~6 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or two groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one to two oxygen atoms; Ring B'' is, [ka] Selected from, * This shows the binding to L'';X 4 CR 5 , CH or N; ring B'' is -(R 5 ) n It is replaced by n, where n is 0, 1, 2, or 3; each R 5 Independently, Halo, C 1~4 Alkyl or C 1~4 It is an alkyloxy. Note that ring B'' contains methylene, which is contained within L in formula I.

[0052] Embodiment 25a. Ring B'' is [ka] A compound of Embodiment 25, or a pharmaceutically acceptable salt thereof, selected from the above (wherein, * This shows the binding to L'';X 4 CR 5 , CH or N; ring B'' is -(R 5 ) n It is replaced by n, where n is 0, 1, 2, or 3; each R 5 Independently, Halo, C 1~4 Alkyl or C 1~4 It is an alkyloxy, and the ring is, [ka] (Provided that it is not the case.)

[0053] Embodiment 26. Ring B'' is [ka] The compound of Embodiment 25, or a pharmaceutically acceptable salt thereof (in the formula, * This shows the binding to L'';X 4 is N; ring B is -(R 5 ) n It is replaced by n, where n is 0, 1, or 2; each R 5 Independently, Halo, C 1~4 Alkyl or C 1~4 (It is an alkyloxy.)

[0054] Embodiment 27.X 4 The compound of Embodiment 25, or a pharmaceutically acceptable salt thereof, wherein is CH.

[0055] Embodiment 28.X 4 A compound of Embodiment 25, or a pharmaceutically acceptable salt thereof, wherein N is present.

[0056] Embodiment 29.X 4 CR 5 The compound of Embodiment 25, or a pharmaceutically acceptable salt thereof.

[0057] Embodiment 30. Any one of the compounds from Embodiments 25 to 29, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0058] Embodiment 31. Any one of the compounds from Embodiments 25 to 29, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0059] Embodiment 32. Each R 5 However, independently, C 1~4 Alkyl or C 1~4 An alkoxy compound, one of the compounds from Embodiments 25 to 31, or a pharmaceutically acceptable salt thereof.

[0060] Embodiment 33. Each R 5However, independently, one of the compounds from Embodiments 25 to 32, which is methyl or methoxy, or a pharmaceutically acceptable salt thereof.

[0061] Embodiment 34. Any one of the compounds from Embodiments 25 to 29, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0062] Embodiment 35.L'' is C 4~6 Alkylene, C 4~6 Alkenylene, C 4~6 Heteroalkylene or C 4~6 A heteroalkenylene, and a heteroalkenylene is any one of the compounds of Embodiments 25 to 34, or a pharmaceutically acceptable salt thereof, containing one to two oxygen atoms.

[0063] Embodiment 36.L'' is C 4~6 Alkenylene or C 4~6 It is a heteroalkenylene, and the heteroalkenylene contains one oxygen atom, C 4~6 Alkenylene and C 4~6 The heteroalkylene is any one of the compounds from Embodiments 25 to 35, or a pharmaceutically acceptable salt thereof, containing one unsaturated bond.

[0064] Embodiment 37.L'' is C 4~6 Alkylene or C 4~6 It is a heteroalkylene, C 4~6 The heteroalkylene is any one of the compounds from Embodiments 25 to 35, or a pharmaceutically acceptable salt thereof, comprising one or two oxygen atoms.

[0065] Embodiment 38.L'' is C 4~6 A compound from any one of embodiments 25 to 35, or a pharmaceutically acceptable salt thereof, which is an alkylene.

[0066] Embodiment 39. Each R 5 However, independently, Hello, C 1~4 Alkyl or C 1~4An alkyloxy compound, one of the compounds from Embodiments 25 to 38, or a pharmaceutically acceptable salt thereof.

[0067] Embodiment 40. Each R 5 However, independently, one of the compounds from Embodiments 25 to 39, which is F, Cl, or methyl, or a pharmaceutically acceptable salt thereof.

[0068] Embodiment 41. Any one of the compounds from Embodiments 25 to 40, or a pharmaceutically acceptable salt thereof, wherein ring A is phenylene, indolylene, pyrrolopyridinylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridadinylene, naphthalenylene, quinolinylene, benzimidazoylene, or benzofuranylene.

[0069] Embodiment 42. Ring A is [ka] The compound is one of any of the compounds from Embodiments 1 to 41, or a pharmaceutically acceptable salt thereof (in the formula, * This indicates a bond to L, L', or L'', and ring A is -(R 4 ) m It is replaced by m, where m is 1, 2, 3 or 4; each R 4 These are independently H, Halo, and C. 1~6 Alkyl or C 1~6 It is an alkoxy, C 1~6 Alkyl and C 1~6 The alkoxy group is a halo, C 1~6 (Optionally substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups).

[0070] Embodiment 43. Ring A is [ka] The compound is one of any of the compounds from Embodiments 1 to 42, or a pharmaceutically acceptable salt thereof (in the formula, * This indicates a bond to L, L', or L'', and ring A is -(R 4) m It is replaced by m, where m is 1 or 2; each R 4 These are independently H, Halo, and C. 1~4 Alkyl or C 1~4 It is an alkoxy, C 1~4 Alkyl and C 1~4 The alkoxy group is a halo, C 1~4 (Optionally substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups).

[0071] Embodiment 44. Ring A is [ka] The compound is one of any of the compounds from Embodiments 1 to 42, or a pharmaceutically acceptable salt thereof (in the formula, * This indicates a bond to L, L', or L'', and ring A is -(R 4 ) m It is replaced by m, where m is 1 or 2; each R 4 These are independently H, Halo, and C. 1~4 Alkyl or C 1~4 It is an alkoxy, C 1~4 Alkyl and C 1~4 The alkoxy group is a halo, C 1~4 (Optionally substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups).

[0072] Embodiment 45. Ring A is [ka] The compound is one of any of the compounds from Embodiments 1 to 42, or a pharmaceutically acceptable salt thereof (in the formula, * This indicates a bond to L, L', or L'', and ring A is -(R 4 ) m It is replaced by m, where m is 1, 2, 3 or 4; each R 4 These are independently H, Halo, and C. 1~4 Alkyl or C 1~4 It is an alkoxy, C 1~4Alkyl and C 1~4 The alkoxy group is a halo, C 1~4 (Optionally substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups).

[0073] Embodiment 46. Each R 4 However, H, Haro, C 1~4 Alkyl and C 1~4 Selected independently from alkoxy, C 1~4 Alkyl and C 1~4 The alkoxy group is a halo, C 1~4 Any one of the compounds from Embodiments 1 to 45, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups.

[0074] Embodiment 47a. Each R 4 However, H, Haro, C 1~4 Alkyl and C 1~4 Selected independently from alkoxy, each C 1~4 Alkyl and C 1~4 Any one of the compounds from Embodiments 1 to 46, or a pharmaceutically acceptable salt thereof, wherein the alkoxy group is optionally substituted with 1 to 3 groups independently selected from F, Cl, methyl, methoxy, amide, and N,N-dimethylamide groups.

[0075] Embodiment 47b. Each R 4 However, H, Haro, C 1~4 Alkyl and C 1~4 Selected independently from alkoxy, each C 1~4 Alkyl and C 1~4 Any one of the compounds from Embodiments 1 to 46, or a pharmaceutically acceptable salt thereof, wherein the alkoxy group is optionally substituted with 1 to 3 groups independently selected from F, Cl, methoxy, amide, and N,N-dimethylamide groups.

[0076] Embodiment 48. Each R 4However, H, methyl, isobutyl, F, Cl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy 、 Any one of the compounds from Embodiments 1 to 47, independently selected from N,N-dimethylamide, 3,3,3-trifluoropropyl, 2,2-difluoroethyl, 3-fluoropropyl, and methoxyethyl, or a pharmaceutically acceptable salt thereof.

[0077] Embodiment 49. A compound from any one of Embodiments 1 to 48, or a pharmaceutically acceptable salt thereof, wherein R is H, methyl, ethyl, 2-hydroxyethyl, or benzyl.

[0078] Embodiment 50. Any one of the compounds from Embodiments 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R is H.

[0079] Embodiment 51.R 1 However, H or C 1~4 A compound from any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof, which is alkyl.

[0080] Embodiment 52.R 1 The compound is one of any of the compounds from Embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, wherein the compound is H or methyl.

[0081] Embodiment 53.R 1 A compound from any one of Embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0082] Embodiment 54.R 2 However, H or C 1~4 A compound from any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt thereof, which is alkyl.

[0083] Embodiment 55.R 2 The compound is one of any of the compounds from Embodiments 1 to 54, or a pharmaceutically acceptable salt thereof, which is H or methyl.

[0084] Embodiment 56.R3 However, H or C 1~4 A compound from any one of Embodiments 1 to 55, or a pharmaceutically acceptable salt thereof, which is alkyl.

[0085] Embodiment 57.R 3 The compound is one of any of Embodiments 1 to 56, or a pharmaceutically acceptable salt thereof, which is H or methyl.

[0086] Embodiment 58.R 2 and R 3 One of the compounds from Embodiments 1 to 54 and 56, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is H and the other is C1-4 alkyl.

[0087] Embodiment 59.R 2 and R 3 A compound from any one of Embodiments 1 to 58, or a pharmaceutically acceptable salt thereof, wherein one atom is H and the other is methyl.

[0088] Embodiment 60.R 2 and R 3 However, each of these compounds is H, one of the compounds from Embodiments 1 to 57, or a pharmaceutically acceptable salt thereof.

[0089] Embodiment 61.R 2 and R 3 However, each of the compounds from Embodiments 1 to 57, or a pharmaceutically acceptable salt thereof, is methyl.

[0090] Embodiment 62. A compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

[0091] Embodiment 63. A compound selected from the compounds in Table 2, or a pharmaceutically acceptable salt thereof.

[0092] Embodiment 63a. A compound selected from the compounds in Table 2a, or a pharmaceutically acceptable salt thereof.

[0093] Embodiment 63b. A compound selected from the compounds in Table 3, or a pharmaceutically acceptable salt thereof.

[0094] Embodiment 64. A pharmaceutical composition comprising one of the compounds from Embodiments 1 to 63, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0095] Embodiment 65. A method for activating Nrf2, comprising contacting Nrf2 with an effective amount of any one compound from Embodiments 1 to 63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 64.

[0096] Embodiment 66. A method for treating sickle cell disease in a subject requiring it, comprising administering to the subject a therapeutically effective amount of any one compound from Embodiments 1 to 63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 64.

[0097] explanation definition The following description outlines exemplary embodiments of the technology. However, it should be noted that such descriptions are not intended to limit the scope of this disclosure, but rather are provided solely as descriptions of exemplary embodiments.

[0098] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the claimed subject matter belongs. The general descriptions set forth herein and those detailed below are illustrative and explanatory only and should be understood as not restricting any claimed subject matter. If any material incorporated herein by reference conflicts with the express content of this disclosure, the express content shall prevail. In this application, the use of the singular form includes the plural unless otherwise specified. As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple references unless the context clearly indicates otherwise. 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 limited to these.

[0099] References to “certain embodiments,” “an embodiment,” “one embodiment,” or “other embodiments” in this specification mean that certain features, structures, or characteristics described in relation to an embodiment are included in at least some embodiments, but not necessarily in all embodiments of this disclosure.

[0100] As used herein, ranges and quantities are expressed as "approximately" a specific value or range. "Approximately" also includes the exact quantity. Thus, "approximately 5 μL" means "approximately 5 μL" and also "5 μL". In general, the term "approximately" includes quantities that are expected to be within, for example, 15%, 10%, or 5% of the experimental error.

[0101] The section headings used herein are for structural purposes only and should not be construed as limiting the subject matter described herein.

[0102] A dash ("-") that is not between two letters or symbols is used to indicate the attachment point for a substituent. For example, -C(O)NH2 is attached via a carbon atom. Dashes before or after a chemical group are for convenience only; chemical groups may be shown with or without one or more dashes without losing their usual meaning. A wavy line drawn through a line in a structure indicates the attachment point of a group. Unless chemically or structurally required, orientation or stereochemistry is not indicated or suggested by the order in which chemical groups are listed or named.

[0103] Prefix “C” u~v " indicates that the following group has u to v carbon atoms. For example, "C 1~6 The term "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0104] In this specification, references to values ​​or parameters "about" include (and describe) embodiments relating to that value or parameter itself. In certain embodiments, the term "about" includes ±10% of the indicated amount. In certain embodiments, the term "about" includes ±5% of the indicated amount. In certain embodiments, the term "about" includes ±1% of the indicated amount. Also, the term "about X" includes the description of "X". Furthermore, the singular forms "a" and "the" include multiple references unless the context clearly indicates otherwise. Thus, for example, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes one or more assays and their equivalents known to those skilled in the art.

[0105] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain with 1 to 20 carbon atoms (i.e., C 1~ C 20 Alkyl), 1 to 10 carbon atoms (i.e., C 1~ C 10 Alkyl), 1 to 6 carbon atoms (i.e., C 1~C6 alkyl) or 1 to 3 carbon atoms (i.e., C 1~ It has 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 encompass 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).

[0106] "Alkenyl" contains at least one carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C 2~20 Alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 Alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 Alkenyls), or 2-4 carbon atoms (i.e., C 2~4 This refers to an alkyl group having an alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0107] "Alkoxy" or "alkyloxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0108] "Amide" is a "C-amide" group (group-C(O)NR y R z(referring to) and the "N-amide" group (group-NR) y C(O)R z It refers to both of the following (which refers to), and in the formula, R y and R z This is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which may be substituted as needed.

[0109] "Amino" is the base -NR y R z It refers to, and in the formula, R y and R z This is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, or heteroaryl, each of which may be substituted as needed.

[0110] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings including a condensed system (e.g., bicyclic or tricyclic). As used herein, aryl refers to a ring with 6 to 20 carbon atoms (i.e., C 6~20 aryl), 6-12 carbocyclic atoms (i.e., C 6~12 aryl) or 6-10 carbon ring atoms (i.e., C 6~10 It has an aryl atom. In certain embodiments, the aryl atom has 6 to 18 carbon ring atoms (i.e., C 6~18 It contains an aryl group. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl never encompasses or overlaps with heteroaryls as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0111] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodine.

[0112] "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. Heteroatom 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 heterocyclyl, each of which may 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 be substituted. Examples of heteroalkylene groups include -OCH2-, -CH2OCH2-, -OCH2CH2O-, -OCH2OCH2-, -SCH3, -CH2SCH2-, -NR'CH2-, and -CH2NR'CH2-, where R' is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be substituted as provided herein. In certain embodiments, examples of heteroalkyl groups include -CH2SCH3 and -CH2NR'CH3, and examples of heteroalkylene groups include -CH2SCH2- and -CH2NR'CH2-, where R' is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be substituted as provided herein. As used herein, a heteroalkyl group comprises 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 certain embodiments, the term “heteroalkyl” requires that the attachment points to the remainder of the molecule are through carbon atoms.

[0113] "Heteroalkenyl" refers to a monovalent heteroalkyl group, and "heteroalkenylene" refers to a divalent heteroalkyl group 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 one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. The terms "heteroalkenyl" and "heteroalkenylene" 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., where R' is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be substituted as applicable. Examples of heteroalkenyl groups include -OCHCH2, -CH2OCHCH2, -SCHCH2, -CH2SCHCH2, -NR'CHCH2, and -CH2NR'CHCH2, and examples of heteroalkenylene groups include -OCHCH-, -CH2OCHCH-, -SCHCH-, -CH2SCHCH-, -NR'CHCH-, and -CH2NR'CHCH-, where R' is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be substituted as applicable. As used herein, heteroalkenyls and heteroalkenylenes include 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.

[0114] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or multiple fused rings and one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a group having 1 to 20 ring carbon atoms (i.e., C 1~20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 Heteroaryl) or 3 to 8 carbon ring atoms (i.e., C 3~8Heteroaryls; and also comprising 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the term “heteroaryl” refers to a 5 to 14-membered ring system. In certain embodiments, the heteroaryl comprises 1 to 13 ring carbon atoms (i.e., C 1~13Includes heteroaryl groups. In certain embodiments, the heteroaryl group contains 1 to 6 heteroatoms. Examples of heteroaryl groups include pyrimidinyl, prinyl, pyridyl, pyridadinyl, benzothiazolyl, and pyrazolyl. Examples of condensed heteroaryl rings, though not limited to these, include benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, and the heteroaryl group can be linked via any of the rings in the condensed system. In certain embodiments, examples of heteroaryl groups include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxynyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, i This includes ndazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyradinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadiniyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).Any aromatic ring having one or more fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryls do not encompass or overlap with aryls as defined above. The term “heteroarylene” refers to a divalent heteroaryl group, and examples of heteroarylenes, though not limited to these, include indolylene, pyrrolopyridinylene, pyridinylene, pyradinylene, pyrimidinylene, pyridadinylene, quinolinylene, benzimidazoylene, and benzofuranylene.

[0115] Certain commonly used alternative chemical names may be used. For example, divalent groups, such as divalent "alkyl" groups, divalent "phenyl" groups, divalent "heteroaryl" groups, and divalent "heterocyclyl" groups, may also be referred to as "alkylene" groups, "phenylene" groups, "heteroarylene" groups, or "heterocyclylene" groups, respectively.

[0116] The terms "depending on" or "depending on" mean that the event or situation described thereafter may or may not occur, and that the description includes both the cases in which such event or situation occurs and the cases in which it does not occur. The term "depending on" means that any one or more hydrogen atoms on the specified atom or group may or may not be replaced by a non-hydrogen portion.

[0117] The term "substituted" means that any one or more hydrogen atoms (e.g., 1 to 5 or 1 to 3) on the indicated atom or group are replaced by one or more substituents other than hydrogen, provided that the normal valency of the indicated atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof.

[0118] Polymers or similar obscure structures achieved by defining substituents having an infinitely increasing number of further substituents (e.g., substituted aryls having a substituted alkyl, which itself is substituted with a substituted aryl group (which is further substituted with a substituted heteroalkyl group, etc.)) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, the consecutive substitution of a substituted aryl group having two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryls. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms, or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may describe other chemical groups as defined herein. Unless otherwise specified, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in certain embodiments, the term “substituted alkyl” refers to alkyl groups having one or more substituents, including hydroxy, halo, alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0119] In many cases, the compounds of this disclosure can form acidic and / or basic salts based on the presence of an amino and / or carboxyl group or a similar group.

[0120] This disclosure also includes “deuterated analogues” of the compounds described herein, in which 1 to n hydrogen atoms attached 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): pp. 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0121] This specification also provides pharmaceutically acceptable salts, hydrates, solvates, tautomers, and stereoisomers of the compounds described herein. “pharmaceutically acceptable” or “physiologically acceptable” refers to compounds, salts, compositions, dosage forms, and other materials useful in the manufacture of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0122] The term "pharmaceutically acceptable salt" of 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 salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Furthermore, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acidic salt. Conversely, if the product is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, using the usual procedure for producing acid addition salts from a base compound. Those skilled in the art will understand the various synthetic methodologies that can be used to produce non-toxic pharmaceutically acceptable addition salts. pharmaceutically acceptable acid addition salts can be produced from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids 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, but are not limited to, 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)), and dialkenylamines (i.e., HN(alkenyl)2). These include trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di- or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, but are not limited to, isopropylamine, trimethylamine, dielthiamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0123] The term "hydrate" refers to a complex formed by combining the compound of formula (I) with water.

[0124] A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0125] Some compounds exist as tautomers. Tautomers exist in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with imido acid tautomers. Regardless of which tautomers are shown and regardless of the nature of the equilibrium between the tautomers, those skilled in the art will understand that a compound contains both amide and imido acid tautomers. Thus, amide-containing compounds are understood to contain their imido acid tautomers. Similarly, imido acid-containing compounds are understood to contain their amide tautomers.

[0126] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, contain chiral centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined with respect to absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. This disclosure includes 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 separated using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or separation of racemic compounds (or racemic compounds of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). When a compound described herein contains an olefinic double bond or other geometrically asymmetrical centers, and unless otherwise specified, the compound is intended to include both E and Z geometric isomers. Similarly, all tautomer forms are also intended to be included.

[0127] "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space, and include enantiomers and diastereoisomers. In certain embodiments, "stereoisomers" refer to compounds that have different three-dimensional structures but are composed of the same atoms bonded together by the same bonds, but are not interchangeable. This disclosure intends various stereoisomers and mixtures thereof, and includes "enantiomers" which refer to two stereoisomers whose molecules are mirror images of each other and cannot be superimposed.

[0128] An "enantiomer" is a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A mixture of a pair of enantiomers in a 1:1 ratio is called a "racemic" mixture.

[0129] A "diastereoisomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other.

[0130] The absolute stereochemistry is determined according to the Kahn-Ingold prelogue-RS system. If the compound is a pure enantiomer, the stereochemistry at each chiral carbon is determined by either R or S. Split compounds with an unknown absolute configuration are denoted as (+) or (-) by the direction in which the plane of polarization is rotated (dextrorotatory or levorotatory) at the wavelength of the sodium D line.

[0131] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable additive” or “additive” includes all kinds of solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is intended unless any common media or agent is incompatible with the active ingredient. Auxiliary active ingredients may also be incorporated into the composition.

[0132] The “effective amount” or dose of a compound or composition refers to the amount of the compound or composition that produces the desired result based on the disclosure herein. The effective amount is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining the LD50 (a dose that is lethal to 50% of the population) and ED50 (a dose that is therapeutically effective to 50% of the population).

[0133] The “therapeutic effective dose” or dosage of a compound or composition refers to the amount of the compound or composition that produces a reduction or inhibition of symptoms or an extension of survival in the subject (i.e., a human patient). Results may require multiple administrations of the compound or composition.

[0134] In this context, "treating" or "treating" a disease means: 1) preventing the onset of the disease in patients who are susceptible to or do not further exhibit symptoms of the disease; 2) inhibiting or suppressing the onset of the disease; or 3) restoring or causing regression of the disease. As used herein, "treating" or "treating" refers to an approach to obtain beneficial or desired outcomes, including clinical outcomes. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms resulting from a disease or condition; reducing the severity of a disease or disability; stabilizing a disease or disability (e.g., preventing or delaying the worsening of a disease or disability); delaying the onset or recurrence of a disease or disability; delaying or slowing the progression of a disease or disability; restoring a disease or disability condition; achieving remission of a disease or disability (partial or total); reducing the dose of one or more other medicines required to treat a disease or disability; enhancing the effect of another medicine used to treat a disease or disability; delaying the progression of a disease or disability; increasing the quality of life; and / or extending the survival of the subject. Reduction of the pathological consequences of a disease or disability is also included in “treatment.” The methods of this disclosure are intended to be any one or more of these aspects of treatment.

[0135] As used herein, the terms “individual,” “subject,” and “patient” mean 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.

[0136] While various features of this disclosure are described in the context of a single embodiment, features may be provided separately or in any suitable combination. Conversely, while this disclosure may be described herein for clarification in relation to other embodiments, this disclosure is also practiced in a single embodiment.

[0137] compound In one embodiment, a compound of formula (I) [ka] Or a pharmaceutically acceptable salt thereof is provided herein: R is C, which may be substituted with H or benzyl. 1~6 It is alkyl; R 1 is H or C 1~6 It is alkyl; R 2 is H or C 1~6 It is alkyl; R 3 is H or C 1~6 It is alkyl; Ring B is C 5~12 Arylene, or C containing 1 to 4 heteroatoms selected from N and O. 3~12 It is a heteroarrene; n is 0, 1, 2, or 3; Each R 5 Independently, Halo, C 1~6 Alkyl or C 1~6 It is an alkyloxy; Ring A is C 5~12 Arylene, or C containing 1-2 heteroatoms selected from N and O. 3~12 It is a heteroarrene; m is 1, 2, 3, or 4; Each R 4 These are independently H, Halo, and C. 1~6 Alkyl or C 1~6 It is an alkoxy, C 1~6 Alkyl and C 1~6 The alkoxy group is a halo, C 1~6 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups; L is C 4~8 Alkylene, C 4~8 Alkenylene, C 4~8 Heteroalkylene or C4~8 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or four groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one to four oxygen atoms.

[0138] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts thereof, are provided herein: R is optionally substituted with H or phenyl. 1~6 It is alkyl; R 1 is H or C 1~6 It is alkyl; R 2 is H or C 1~6 It is alkyl; R 3 is H or C 1~6 It is alkyl; Ring B is C 6~12 Arylene, or C containing 1 to 4 heteroatoms selected from N and O. 3~12 It is a heteroarrene; n is 0, 1, 2, or 3; Each R 5 Independently, Halo, C 1~6 Alkyl or C 1~6 It is an alkyloxy; Ring A is C 6~12 Arylene, or C containing 1-2 heteroatoms selected from N and O. 3~12 It is a heteroarrene; m is 1, 2, 3, or 4; Each R 4 These are independently H, Halo, and C. 1~6 Alkyl or C 1~6 It is an alkoxy, C 1~6 Alkyl and C 1~6 The alkoxy group is a halo, C 1~6 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups; L is C 4~8 Alkylene, C4~8 Alkenylene, C 4~8 Heteroalkylene or C 4~8 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or four groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one to four oxygen atoms.

[0139] In some embodiments, the compound of formula (I): [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided: R is H, or -OH, C 1~6 Alkyloxy or C 1~6 C is sometimes replaced by an aryl group. 1~6 It is alkyl; R 1 is H or C 1~6 It is alkyl; R 2 is H or C 1~6 It is alkyl; R 3 is H or C 1~6 It is alkyl; Ring B is C 5~12 Arylene, or C3 containing 1 to 4 heteroatoms independently selected from N and O 12 It is a heteroarylene, and ring B is [ka] Provided that it is not the case, * This displays the binding to L; n is 0, 1, 2, or 3; Each R 5 Independently, Halo, C 1~6 Alkyl or C 1~6 It is an alkyloxy; Ring A is C 5~12 Arylene, or C containing 1-2 heteroatoms independently selected from N and O. 3~12 It is a heteroarrene; m is 1, 2, 3, or 4; Each R 4 These are independently H, Halo, and C. 1~6 Alkyl or C 1~6 It is an alkoxy, C 1~6 Alkyl and C 1~6 The alkoxy group is a halo, C 1~6 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups; L is C 4~8 Alkylene, C 4~8 Alkenylene, C 4~8 Heteroalkylene or C 4~8 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or four groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one to four oxygen atoms.

[0140] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts thereof, are provided: R is H, or -OH, C 1~6 Alkyloxy or C 6~12 C optionally substituted with one substituent selected from aryl groups. 1~6 It is alkyl; R 1 is H or C 1~6 It is alkyl; R 2 is H or C 1~6 It is alkyl; R 3 is H or C 1~6 It is alkyl; Ring B is C 6~12 Arylene, or C3 containing 1 to 4 heteroatoms independently selected from N and O 12 It is a heteroarylene, and ring B is [ka] Provided that it is not the case, *This displays the binding to L; n is 0, 1, 2, or 3; Each R 5 Independently, Halo, C 1~6 Alkyl or C 1~6 It is an alkyloxy; Ring A is C 6~12 Arylene, or C containing 1-2 heteroatoms independently selected from N and O. 3~12 It is a heteroarrene; m is 1, 2, 3, or 4; Each R 4 These are independently H, Halo, and C. 1~6 Alkyl or C 1~6 It is an alkoxy, C 1~6 Alkyl and C 1~6 The alkoxy group is a halo, C 1~6 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups; L is C 4~8 Alkylene, C 4~8 Alkenylene, C 4~8 Heteroalkylene or C 4~8 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or four groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one to four oxygen atoms.

[0141] In some embodiments, ring B is not benzotriazole.

[0142] In some embodiments, L is C 5~7 Alkylene, C 5~7 Alkenylene, C 5~7 Heteroalkylene or C 5~7 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or four groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one to two oxygen atoms. In some embodiments, L is C 5~7Alkylene, C 5~7 Alkenylene, C 5~7 Heteroalkylene or C 5~7 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or four groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one oxygen atom. In some embodiments, L is C 5~7 Alkylene, C 5~7 Alkenylene, C 5~7 Heteroalkylene or C 5~7 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or four groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain two oxygen atoms.

[0143] In some embodiments, L is C 4~8 Alkenylene or C 4~8 It is a heteroalkenylene, C 4~8 Alkenylene and C 4~8 Heteroalkenylenes contain one unsaturation site (i.e., one unsaturated bond).

[0144] In some embodiments, L is [ka] Selected from, * This indicates the bond to ring B.

[0145] In some embodiments, the compound of formula (I) is the compound of formula (IA): [ka] Or a pharmaceutically acceptable salt thereof: L' is C 4~6 Alkylene, C 4~6 Alkenylene, C 4~6 Heteroalkylene or C 4~6 These are heteroalkenylenes, each of which is a halo and C.1~6 Heteroalkylenes and heteroalkenylenes are optionally substituted with one or two groups independently selected from alkyl groups, and contain one or two oxygen atoms; X 3 is either CH2 or O; n is 0, 1, or 2; each X 1 and X 2 These are independently CH or N; Ring A, R, R 1 , R 2 , R 3 , R 4 , R 5 m and n are as described for the compound of formula (I).

[0146] In some embodiments, the compound of formula (IC) [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided: R is H, or -OH, C 1~6 Alkyloxy or C 1~6 C is sometimes replaced by an aryl group. 1~6 It is alkyl; R 1 is H or C 1~6 It is alkyl; R 2 is H or C 1~6 It is alkyl; R 3 is H or C 1~6 It is alkyl; n is 0, 1, 2, or 3; Each R 5 Independently, Halo, C 1~6 Alkyl or C 1~6 It is an alkyloxy; Ring A is C 5~12 Arylene, or C containing 1-2 heteroatoms independently selected from N and O. 3~12 It is a heteroarrene; m is 1, 2, 3, or 4; Each R 4 These are independently H, Halo, and C. 1~6 Alkyl or C 1~6 It is an alkoxy, C 1~6 Alkyl and C 1~6 The alkoxy group is a halo, C 1~6 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups; L is C 4~8 Alkylene, C 4~8 Alkenylene, C 4~8 Heteroalkylene or C 4~8 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or four groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one to four oxygen atoms.

[0147] In some embodiments, compounds of formula (IC), or pharmaceutically acceptable salts thereof, are provided: R is H, or -OH, C 1~6 Alkyloxy and C 6~12 C optionally substituted with one substituent selected from aryl groups. 1~6 It is alkyl; R 1 is H or C 1~6 It is alkyl; R 2 is H or C 1~6 It is alkyl; R 3 is H or C 1~6 It is alkyl; n is 0, 1, 2, or 3; Each R 5 Independently, Halo, C 1~6 Alkyl or C 1~6 It is an alkyloxy; Ring A is C 6~12 Arylene, or C containing 1-2 heteroatoms independently selected from N and O. 3~12 It is a heteroarrene; m is 1, 2, 3, or 4; Each R 4 These are independently H, Halo, and C. 1~6 Alkyl or C 1~6 It is an alkoxy, C 1~6 Alkyl and C 1~6 The alkoxy group is a halo, C 1~6 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups; L is C 4~8 Alkylene, C 4~8 Alkenylene, C 4~8 Heteroalkylene or C 4~8 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or four groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one to four oxygen atoms.

[0148] In some embodiments, X 3 is CH2. In some embodiments, X 3 It is O.

[0149] In some embodiments, X 1 In some embodiments, X 1 is CH. In some embodiments, X 2 In some embodiments, X 2 is CH. In some embodiments, X 1 and X 2 These are N, respectively. In some embodiments, X 1 and X 2 These are CH, respectively. In some embodiments, X 1 and X 2 One of them is CH, and the other is N.

[0150] In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 0.

[0151] Some implementation methods, each R 5 Independently, C1~4 Alkyl or C 1~4 It is an alkoxy. In some embodiments, each R 5 These are independently methyl or methoxy.

[0152] In some embodiments, L' is C 4~6 Alkylene, C 4~6 Alkenylene, C 4~6 Heteroalkylene or C 4~6 These are heteroalkenylenes, and heteroalkenylenes contain one or two oxygen atoms. In some embodiments, C 4~6 Alkenylene and C 4~6 Heteroalkenylenes contain one unsaturation site (i.e., one unsaturated bond).

[0153] In some embodiments, X 3 is CH2, and L' is a C containing one unsaturation point (i.e., one unsaturated bond). 4~6 Alkenylene or C 4~6 It is a heteroalkenylene.

[0154] In some embodiments, X 3 is O, and L' is C containing one unsaturation point (i.e., one unsaturated bond). 4~6 Alkenylene or C 4~6 It is a heteroalkenylene. In some embodiments, X 3 is CH2, and L' is C 4~6 Alkylene or C 4~6 It is a heteroalkylene, C 4~6 Heteroalkylenes contain one or two oxygen atoms. In some embodiments, X 3 is O, and L' is C 4~6 Alkylene or C 4~6 It is a heteroalkylene, C 4~6 Heteroalkylenes contain one oxygen atom. In some embodiments, X 3 is O, and L' is C 4~6 It is an alkylene. 3 is CH2, and L' is C 4~6It is alkylene.

[0155] In some embodiments, the compound of formula (I) is the compound of formula (IB): [ka] Or a pharmaceutically acceptable salt thereof: L'' is C 4~6 Alkylene, C 4~6 Alkenylene, C 4~6 Heteroalkylene or C 4~6 These are heteroalkenylenes, each of which is a halo and C. 1~6 They are optionally substituted with one or two groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one to two oxygen atoms; Ring B'' is, [ka] Selected from, * This shows the binding to L'';X 4 CR 5 , CH or N; Ring A, R, R 1 , R 2 , R 3 , R 4 , R 5 m and n are as described for the compound of formula (I).

[0156] In some embodiments, ring B'' is [ka] Selected from, * This shows the binding to L or L''; X 4 CR 5 , CH or N-; ring B or ring B'' is -(R 5 ) n It is replaced by n, where n is 0, 1, 2, or 3; each R 5 Independently, Halo, C 1~4 Alkyl or C 1~4It is an alkyloxy.

[0157] In some embodiments, the ring is [ka] isn't it.

[0158] In some embodiments, ring B'' is [ka] And, * This shows the binding to L'';X 4 CR 5 , CH or N; ring B'' is -(R 5 ) n It is replaced by n, where n is 0, 1, or 2; each R 5 Independently, Halo, C 1~4 Alkyl or C 1~4 It is an alkyloxy.

[0159] In some embodiments, ring B'' is [ka] And, * This shows the binding to L'';X 4 is N; ring B'' is -(R 5 ) n It is replaced by n, where n is 0, 1, or 2; each R 5 Independently, Halo, C 1~4 Alkyl or C 1~4 It is an alkyloxy.

[0160] In some embodiments, X 4 is CH. In some embodiments, X 4 In some embodiments, X 4 CR 5 That is the case.

[0161] In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 0.

[0162] Some implementation methods, each R 5 C 1~4 Alkyl or C 1~4 It is an alkoxy. In some embodiments, each R 5 It is either methyl or methoxy.

[0163] In some embodiments, L'' is C 4~6 Alkylene, C 4~6 Alkenylene, C 4~6 Heteroalkylene or C 4~6 Heteroalkylenes are heteroalkenylenes, and heteroalkylenes contain 1 to 2 oxygen atoms.

[0164] In some embodiments, L'' is C 4~6 Alkenylene or C 4~6 It is a heteroalkenylene, and a heteroalkenylene contains one oxygen atom and C 4~6 Alkenylene and C 4~6 A heteroalkylene contains one unsaturation site (i.e., one unsaturated bond). In some embodiments, L'' is C 4~6 Alkylene or C 4~6 It is a heteroalkylene, and each C 4~6 Heteroalkylenes contain one or two oxygen atoms. In some embodiments, L'' is C 4~6 It is alkylene.

[0165] Some implementation methods, each R 5 Independently, Halo, C 1~4 Alkyl or C 1~4 It is an alkoxy. In some embodiments, each R 5 These are independently F, Cl, or methyl.

[0166] In some embodiments, ring A is phenylene, indolylene, pyrrolopyridinylene, pyridinylene, pyradinylene, pyrimidinylene, pyridadinylene, naphthalenylene, quinolinylene, benzimidazoylene, or benzofuranylene.

[0167] In some embodiments of the compounds of formula (I), formula (IA), and / or formula (IB), ring A is [ka] And, * This indicates a bond to L, L', or L'', and ring A is -(R 4 ) m It is replaced by m, where m is 1, 2, 3 or 4; each R 4 These are independently H, Halo, and C. 1~6 Alkyl or C 1~6 It is an alkoxy, C 1~6 Alkyl and C 1~6 The alkoxy group is a halo, C 1~6 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups.

[0168] In some embodiments of the compounds of formula (I), formula (IA), and / or formula (IB), ring A is [ka] And, * This indicates a bond to L, L', or L'', and ring A is -(R 4 ) m It is replaced by m, where m is 1 or 2; each R 4 These are independently H, Halo, and C. 1~4 Alkyl or C 1~4 It is an alkoxy, C 1~4 Alkyl and C 1~4 The alkoxy group is a halo, C 1~4 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups.

[0169] In some embodiments, ring A is [ka] And, *This indicates a bond to L, L', or L'', and ring A is -(R 4 ) m It is replaced by m, where m is 1, 2, 3 or 4; each R 4 These are independently H, Halo, and C. 1~6 Alkyl or C 1~6 It is an alkoxy, C 1~6 Alkyl and C 1~6 The alkoxy group is a halo, C 1~6 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups.

[0170] In some embodiments of the compounds of formula (I), formula (IA), and / or formula (IB), ring A is [ka] And, * This indicates a bond to L, L', or L'', and ring A is -(R 4 ) m It is replaced by m, where m is 1 or 2; each R 4 These are independently H, Halo, and C. 1~4 Alkyl or C 1~4 It is an alkoxy, C 1~4 Alkyl and C 1~4 The alkoxy group is a halo, C 1~4 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups.

[0171] In some embodiments of the compounds of formula (I), formula (IA), and / or formula (IB), ring A is [ka] And, * This indicates a bond to L, L', or L'', and ring A is -(R 4 ) m It is replaced by m, where m is 1, 2, 3 or 4; each R 4 These are independently H, Halo, and C. 1~4 Alkyl or C 1~4It is an alkoxy, C 1~4 Alkyl and C 1~4 The alkoxy group is a halo, C 1~4 It may be substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups.

[0172] Some implementation methods, each R 4 H, Halo, C 1~4 Alkyl, C 1~4 Selected independently from alkoxy, C 1~4 Alkyl and C 1~4 The alkoxy group is a halo, C 1~4 They are optionally substituted with 1 to 3 groups independently selected from alkoxy, amide, and N,N-dimethylamide groups. In some embodiments, each R 4 H, Halo, C 1~4 Alkyl, C 1~4 Selected independently from alkoxy, C 1~4 Alkyl and C 1~4 Each alkoxy group is optionally substituted with 1 to 3 groups independently selected from F, Cl, methyl, methoxy, amide, and N,N-dimethylamide groups. In some embodiments, each R 4 H, Halo, C 1~4 Alkyl, C 1~4 Selected independently from alkoxy, C 1~4 Alkyl and C 1~4 Each alkoxy group is optionally substituted with 1 to 3 groups independently selected from F, Cl, methoxy, amide, and N,N-dimethylamide groups. In some embodiments, each R 4 The compound is independently selected from H, methyl, isobutyl, F, Cl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, N,N-dimethylamide, 3,3,3-trifluoropropyl, 2,2-difluoroethyl, 3-fluoropropyl, and methoxyethyl.

[0173] In some embodiments, R is H, or -OH, C 1~6 Alkyloxy or C 6~12A C1-4 alkyl group optionally substituted with one substituent selected from aryl groups. In some embodiments, R is H, or -OH, C 1~6 It is a C1-4 alkyl group, optionally substituted with one substituent selected from alkyloxy or phenyl. In some embodiments, R is H, methyl, or benzyl. In some embodiments, R is H.

[0174] In some embodiments, R 1 is H or C 1~4 It is alkyl. In some embodiments, R 1 is H or methyl. In some embodiments, R 1 H is H.

[0175] In some embodiments, R 2 is H or C 1~4 It is alkyl. In some embodiments, R 2 is H or methyl. In some embodiments, R 3 is H or C 1~4 It is alkyl. In some embodiments, R 3 is H or methyl. In some embodiments, R 2 and R 3 One of them is H, and the other is C 1~4 It is alkyl. In some embodiments, R 2 and R 3 One of them is H and the other is methyl. In some embodiments, R 2 and R 3 These are H, respectively. In some embodiments, R 2 and R 3 These are methyl compounds.

[0176] In some embodiments, pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive are disclosed herein.

[0177] In this specification, it is understood that any description, variation, embodiment, or aspect of any part may be combined with any description, variation, embodiment, or aspect of any part, in the same way as each and every combination of the description is specifically and individually listed. For example, with respect to L of formula (I), any description, variation, embodiment, or aspect provided herein may be combined with any and every combination of rings A, B, R, R, in the same way as each and every combination of the description is specifically and individually listed. 1 , R 2 , R 3 , R 4 , R 5 Any description, variation, embodiment, or aspect of m and n may be combined with any other description, variation, embodiment, or aspect of formula (I). It is also understood that all descriptions, variations, embodiments, or aspects of formula (I) are equally applicable to any other formula detailed herein, where applicable, and that each and every description, variation, embodiment, or aspect is described in the same way as if it were listed separately and individually for all formulas. For example, all descriptions, variations, embodiments, or aspects of formula (I) are equally applicable to any formula detailed herein, such as formula (IA) or formula (IB), where applicable, and that each and every description, variation, embodiment, or aspect is described in the same way as if it were listed separately and individually for all formulas.

[0178] 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. Certain compounds described in this disclosure, including those in Tables 1, 2, 2a, and 3, are presented as specific stereoisomers and / or non-stereochemical forms, but it is understood that any or all stereochemical forms, including any enantiomer or diastereoisomer forms, and any tautomer or other forms, of any of the compounds in this disclosure, including those in Tables 1, 2, 2a, and 3, are described herein. In some embodiments, compounds selected from the compounds in Table 2, 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. Certain compounds described in this disclosure, including those in Table 3, are presented as specific stereoisomers and / or non-stereochemical forms, but it is understood that any or all stereochemical forms of any of the compounds in this disclosure, including those in Table 3, including any enantiomer or diastereoisomer forms, and any tautomer or other forms, are described herein.

[0179] Also provided herein are the following compounds listed in Tables 1, 2, 2a, and 3.

[0180] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64 Table 65 Table 66 Table 67 Table 68 Table 69 Table 70 Table 71 Table 72 Table 73 Table 74 Table 75 Table 76 Table 77 Table 78 Table 79 Table 80 Table 81 Table 82 Table 83 Table 84 Table 85 Table 86 Table 87 Table 88 Table 89 Table 90 Table 91 Table 92 Table 93 [Table 94] [Table 95] [Table 96] [Table 97] [Table 98] [Table 99] [Table 100] [Table 101] [Table 102] [Table 103] [Table 104]

[0181] Synthesis method Generally, compounds of formula (I) are prepared using known synthesis methods, and in some embodiments, using the methods generally shown in scheme 1A-4.

[0182] In general scheme 1A, Q 1 and Q 2 When bonded together, the corresponding alkene substituent Q 3This is a terminal alkene that forms a ring. Component compound 1-C is prepared, for example, by Miyaura 1,4-addition of a desired alkene (compound 1-B) to dioxaborolane (compound A). In some embodiments, ring A is coupled to compound 1-C using an amide coupling reaction after the BOC protecting group is removed under standard conditions of compound 1-C. Once ring A is incorporated into the molecule, the macrocyclic molecule 1-E can be prepared, for example, by a Grubbs metathesis reaction, thereby adding an L, L', or L'' group to embodiments containing a single double bond (i.e., substituent Q). 3 ) is formed. Hydrogenation of alkenylene to alkylene yields embodiments of the compound of formula (I) in which L, L', or L'' is an alkylene group or a heteroalkylene group. The final acetate compound (i.e., R is H) is achieved by saponification carried out after the hydrogenation reaction or after the metathesis reaction in embodiments in which the L, L', or L'' group contains a single double bond.

[0183] The constituent compound C is prepared, for example, by Miyaura 1,4-addition of a desired alkene (compound B) to dioxaborolane (compound A). In some embodiments, ring A is coupled to compound C using an amide coupling reaction after the BOC protecting group is removed. Schemes 1B, 2, and 3 show several different ring A groups coupled to compound C.

[0184] Once ring A is incorporated into the molecule, the final macrocyclic molecule can be prepared, for example, using a Grubbs metathesis reaction to form embodiments in which the L, L', or L'' group contains a single double bond. Hydrogenation of the alkenylene to an alkylene yields embodiments in which the L, L', or L'' group contains an alkylene group or a heteroalkylene group. The final acetate compound is achieved in embodiments in which the L, L', or L'' group contains a single double bond by saponification carried out after the hydrogenation reaction or after the metathesis reaction, as shown in the scheme below.

[0185] Scheme 4 shows that, in some embodiments, the chiral compound is produced in the same general manner as shown in Schemes 1-3, by including a chiral separation step before the inclusion of ring A.

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] [ka]

[0190] [ka]

[0191] It is understood that the synthesis processes disclosed herein can be modified to arrive at the various compounds of this disclosure by selecting appropriate reagents and starting materials.

[0192] All compounds of formula (I) or any variation thereof described herein, existing in free base or acid form, are converted to pharmaceutically acceptable salts thereof by treatment with a suitable inorganic or organic base or acid by methods known to those skilled in the art. Salts of the compounds of this disclosure are converted to their free base or acid form by standard techniques.

[0193] 1. Pharmaceutical compositions and preparations In another embodiment, the foregoing provides a pharmaceutical composition of any of the compounds detailed herein. Thus, the herein provides a pharmaceutical composition comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions according to the herein may be in a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or in a form suitable for inhalation administration. The pharmaceutical compositions according to the herein provide a compound of formula (I), or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or excipients.

[0194] The compounds described herein are used in the manufacture of compositions, such as pharmaceutical compositions, by combining the compounds as active ingredients with pharmaceutically acceptable additives. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; surfactants, e.g., polysorbate 80 (i.e., Tween 80); tragacanth powder; malt; gelatin; talc; additives, e.g., cocoa butter and suppository wax; oils, e.g., peanut oil, cottonseed oil, safflower oil, Sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; water free of pyrogens; isotonic saline; Ringer's solution; ethyl alcohol; pH buffer solutions; polyesters, polycarbonates, and / or polyacid anhydrides; and other non-toxic, suitable substances used in pharmaceutical formulations. Pharmaceutical formulations are manufactured by known pharmaceutical methods. Suitable formulations are found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005), which is incorporated herein by reference.

[0195] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, and fragrances, preservatives, and antioxidants may also be present in the composition.

[0196] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0197] The formulations of this disclosure include those suitable for oral, nasal, topical (including oral buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may be conveniently presented in unit dosage forms and may be manufactured by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form varies depending on the host being treated and the specific mode of administration. Generally, the amount of active ingredient that can be combined with a carrier material to produce a single dosage form is that amount of the compound that produces the therapeutic effect. Generally, this amount is in the range of about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.

[0198] In certain embodiments, the formulations of the Disclosure include cyclodextrins, liposomes, micellar-forming agents such as bile acids, and polymer carriers such as polyesters and polyacid anhydrides; as well as compounds of the Disclosure. In certain embodiments, the formulations make the compounds of the Disclosure orally bioavailable.

[0199] Formulations of the present disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as flavored tablets (using an inert base, e.g., gelatin and glycerin or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of the compound of the present disclosure as an active ingredient. The compound of the present disclosure may also be administered as a bolus, lick, or paste.

[0200] In the solid dosage forms of the present disclosure for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.), the active ingredient is contained in one or more pharmaceutically acceptable carriers, e.g., sodium citrate or dicalcium phosphate and / or any of the following: fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; humectants, e.g., glycerin; disintegrants, For example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; dissolution retarders, e.g., paraffin; absorption enhancers, e.g., quaternary ammonium compounds; wetting agents, e.g., cetyl alcohol, glyceryl monostearate and nonionic surfactants; absorbents, e.g., kaolin and bentonite clay; lubricants, e.g., 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 buffers. Similar types of solid compositions may also be used as fillers in soft-shell and hard-shell gelatin capsules, using additives such as lactose and high molecular weight polyethylene glycol.

[0201] Tablets may be prepared by compression or molding, sometimes with one or more auxiliary components. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert excipients, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), surfactants, or dispersants. Molded tablets may be prepared in a suitable machine in which a mixture of powdered compounds is moistened with an inert liquid excipient.

[0202] Tablets and other solid dosage forms of the pharmaceutical compositions of this disclosure, e.g., sugar-coated tablets, capsules, pills, and granules, may optionally be etched or manufactured with coatings and shells, e.g., enteric coatings and other coatings known in the art of pharmaceutical formulation. These may also be formulated to achieve sustained or controlled release of the active ingredient therein, for example, using a variable proportion of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to achieve a desired release profile. These may be formulated for rapid release and, for example, lyophilized. These may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifiers and may be compositions that release only or preferentially the active ingredient, optionally in a delayed manner, in a specific portion of the gastrointestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in a microencapsulated form, accompanied by one or more of the above-mentioned additives, where appropriate.

[0203] Liquid dosage forms for oral administration of the compounds of this disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredients, the liquid dosage forms may contain inert excipients commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, as well as mixtures thereof.

[0204] In addition to inert excipients, oral compositions may also contain adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances and preservatives.

[0205] The suspension may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0206] Formulations of the pharmaceutical compositions of the present disclosure for rectal or vaginal administration may be presented as suppositories that can be prepared by mixing one or more of the compounds of the present disclosure with one or more suitable non-irritating additives or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity to release the active compound.

[0207] Dosage forms for topical or transdermal administration of the compounds of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compounds may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0208] In addition to the active compounds of this disclosure, ointments, pastes, creams, and gels may contain additives such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0209] The powders and sprays may contain, in addition to the compounds of the Disclosure, additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0210] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include one or more compounds of the present disclosure in combination with one or more pharmaceutically acceptable sterile and isotonic aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, or sterile powders, which may contain sugars, alcohols, antioxidants, buffers, antibacterial agents, solutes isotonic with the blood of the recipient to whom the formulation is intended, or suspending agents or thickeners.

[0211] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerin, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Appropriate fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin), by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0212] These compositions may also contain adjuvants, such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action by the target compound can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenyl, and sorbic acid. It is also desirable to include isotonic agents, such as sugars and sodium chloride, in the composition. Furthermore, sustained absorption of the injectable pharmaceutical form can be achieved by including absorption-delaying agents, such as aluminum monostearate and gelatin.

[0213] In some cases, it is desirable to slow down the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effects. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The rate of drug absorption is determined by its dissolution rate, which can be determined by the crystal size and crystalline form. Alternatively, delayed absorption of drug forms administered parenterally is achieved by dissolving or suspending the drug in an oil vehicle.

[0214] Injectable depot formulations are prepared by forming a microcapsule matrix of the target compound in a biodegradable polymer, such as polylactide-polyglycolide. The rate of drug release can be controlled by the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(acid anhydrides). Depot injection formulations are also prepared by capturing the drug in liposomes or microemulsions that are compatible with body tissues.

[0215] Instructions for use / processing The compounds and compositions detailed herein, for example, pharmaceutical compositions containing the compounds of any formulation provided herein, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or additives, are used in the administration and treatment methods provided herein. The compounds and compositions are also used in in vitro methods, for example, in which the compounds or compositions are administered to cells for screening purposes and / or to perform quality control assays.

[0216] In some embodiments, methods for activating Nrf2 are disclosed herein, which include contacting Nrf2 with an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0217] In some embodiments, methods for treating sickle cell disease in subjects requiring it are disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0218] In some embodiments, methods for treating inflammatory diseases in subjects requiring such treatment are disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0219] 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 18, 21, 30, 50, 60, 65, 70, 80, or 85 years old, or any of these. In some embodiments, the human is a child. In some embodiments, the human is about 21, 18, 15, 10, 5, 4, 3, 2, or less than 1 year old, or any of these.

[0220] Dosage interval and method of administration When used herein, the terms “parenteral administration” and “administering parenterally” typically mean, but are not limited to, methods of administration other than enteral and topical administration, by injection, including, but are not limited to, intravenous, intramuscular, intra-arterial, subarachnoid, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0221] The terms “systemic administration,” “administered systemically,” “peripheral administration,” and “peripherally administered,” as used herein, mean the administration of a compound, drug, or other material, such as subcutaneous administration, to a patient’s system, and thus subject to metabolism and other similar processes, other than directly to the central nervous system.

[0222] These compounds may be administered to humans and other animals for therapeutic purposes by any suitable route of administration, including orally, nasally (e.g., by spray, rectally, vaginally, parenterally, intracisional, and intraoral buccal and sublingual), and topically (e.g., by powder, ointment or drop).

[0223] Regardless of the route of administration selected, the compounds or pharmaceutical compositions of the Disclosure are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0224] The actual dose levels of the active ingredient in the pharmaceutical compositions of this disclosure may be varied to obtain an amount of the active ingredient effective in achieving a desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0225] The selected dosage level is determined by a variety of factors, including the activity of the specific compound used in this disclosure, or its ester, salt, or amide; the route of administration; the time of administration; the excretion rate or metabolism of the specific compound used; the duration of treatment; other drugs; compounds and / or materials used in combination with the specific compound used; the age, sex, weight, condition, overall health and medical history of the patient being treated; and similar factors well known in medicine. Daily, weekly, or monthly dosages (or other time intervals) may be used.

[0226] A physician or veterinarian with ordinary skill in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start the dose of the compound of the present disclosure used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and then gradually increase the dose until the desired effect is achieved.

[0227] Generally, the appropriate daily dose of the compounds of this disclosure is the lowest dose of the compound that is effective in producing a therapeutic effect (e.g., inhibition of necrosis). Such an effective dose is generally determined by the factors described above. Generally, the dose of the compounds of this disclosure for a patient, when used for the indicated effect, is in the range of about 0.0001 to about 100 mg per kg of body weight per day. Preferably, the daily dose is in the range of 0.001 to 50 mg of the compound per kg of body weight, and more preferably, 0.01 to 10 mg of the compound per kg of body weight.

[0228] If necessary, the effective daily dose of the active compound may be administered as two, three, four, five, six or more partial doses, each administered separately at appropriate intervals throughout the day in unit dosage form.

[0229] When the compounds of this disclosure are administered to humans and animals as pharmaceuticals, they can be given, either by themselves or in combination with a pharmaceutically acceptable carrier, as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient.

[0230] The compounds or compositions of this application may be administered once, twice, three times, or four times daily using any suitable mode described above. Furthermore, administration or treatment with the compounds may last for several days; for example, generally, treatment lasts for at least 7, 14, or 28 days for one treatment cycle. Treatment cycles are well known and frequently alternate with rest periods of about 1 to 28 days, generally about 7 or about 14 days. Treatment cycles may also be continuous in certain embodiments.

[0231] When administered orally, the total daily dose for human subjects may be 1 mg to 1,000 mg, approximately 1,000 to 2,000 mg / day, approximately 10 to 500 mg / day, approximately 50 to 300 mg / day, approximately 75 to 200 mg / day, or approximately 100 to 150 mg / day.

[0232] The daily dose may also be expressed as the total amount of the compound described herein administered per dose or per day. The daily dose of the compound may be approximately 1 mg to 4,000 mg, approximately 2,000 to 4,000 mg / day, approximately 1 to 2,000 mg / day, approximately 1 to 1,000 mg / day, approximately 10 to 500 mg / day, approximately 20 to 500 mg / day, approximately 50 to 300 mg / day, approximately 75 to 200 mg / day, or approximately 15 to 150 mg / day.

[0233] In certain embodiments, the method involves administering to a subject an initial daily dose of about 1 to 800 mg of the compound described herein, and increasing the dose by a fixed amount until clinical efficacy is achieved. The dose can be increased using increases of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg. The dose can be increased daily, every other day, twice a week, or once a week.

[0234] In certain embodiments, the compound or pharmaceutical product is administered orally. In certain embodiments, the compound or pharmaceutical product is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0235] Products of the present disclosure may be administered orally, parenterally, topically, or rectally. These may, of course, be administered in a form suitable for each route of administration. For example, they may be administered by injection, infusion, or inhalation, such as in tablet or capsule form, by injection, by inhalation, by eye drops, ointment, or suppository; topically by lotion or ointment; and rectally by suppository. In certain embodiments, administration is orally.

[0236] Manufacturing kits / manufactured products Also provided herein are kits comprising the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, and appropriate packaging. In certain embodiments, the kit further includes instructions for use. In one embodiment, the kit includes the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, and labels and / or instructions for the use of the compounds in the treatment of indications, including diseases or conditions described herein.

[0237] Also provided herein are products containing the compounds described herein, or pharmaceutically acceptable salts thereof, in a suitable container. The containers may be vials, jars, ampoules, pre-filled syringes, and intravenous bags.

[0238] The kit may also contain instructions for using the compound as described herein. The kit may be compartmentalized and receive the containers tightly sealed. As used herein, a kit, e.g., a compartmentalized kit, includes any kit in which the compound or drug is contained in separate containers. Descriptive examples of such containers include, but are not limited to, small glass containers, plastic containers, or plastic or paper strips. Particularly preferred types of containers allow those skilled in the art to efficiently transfer reagents from one compartment to another, without cross-contamination of samples and reagents, and allow the drug or solution in each container to be added quantitatively from one compartment to another. Such containers include, but are not limited to, containers that accept the compound or combination of compounds and / or other drugs of this disclosure. One or more compounds or drugs may be provided as powder (e.g., lyophilized powder) or precipitate. Such compounds may be provided as part of a kit or may be available separately, and can be resuspended in solution before administration. The kit may contain compounds or agents in other forms, such as liquids, gels, or solids, as described herein. Different compounds and / or agents may be provided in different forms in a single kit. [Examples]

[0239] The following embodiments are included to illustrate specific embodiments of the Disclosure. Those skilled in the art should recognize that the techniques disclosed in subsequent embodiments represent techniques that function well in the practice of the Disclosure and thus constitute a particular mode of that practice. However, those skilled in the art should recognize that, in light of the Disclosure, many variations can be made in the specific embodiments disclosed, and similar or equivalent results can still be obtained without departing from the spirit and scope of the Disclosure.

[0240] Synthesis example General procedure for synthesis examples. General Procedure 6B: Amide Coupling

[0241] The variable shown in the following scheme is specific to this general procedure.

[0242] [ka]

[0243] A 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 alkene and a small amount of isomers, typically with a shifted double bond) was added and stirred at room temperature for 1-18 hours. Water was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine (3×), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The impurities were purified by flash column chromatography (silica, typically heptane / ethyl acetate = 1:0 to 0:1) to obtain the desired amide, typically an isomer with a shifted double bond, as a small amount of byproduct.

[0244] General Procedure 7: Grubbs Metathesis The variable shown in this scheme is specific to this general procedure.

[0245] [ka]

[0246] An amide (1.0 equivalent) (consisting of a terminal alkene and small amounts of isomers, typically with a shifted double bond) was dissolved in anhydrous toluene (2.0–3.0 mM), and the solvent was degassed with nitrogen for 20 minutes. Grubbs second-generation catalyst (0.1 equivalent) was added, and the reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was concentrated under reduced pressure. Impurities were purified by flash column chromatography (silica, CH2Cl2 / MeOH = 1:0 to 9:1) to obtain macrocyclic molecules (typically together with a one-carbon-less analog as a byproduct) as a brown form.

[0247] General procedure 8: Hydrogenation The variable shown in this scheme is specific to this general procedure.

[0248] [ka]

[0249] An unsaturated macrocyclic molecule (1.0 equivalent) (typically containing a small amount of a macrocyclic molecule analog with one less carbon atom) was dissolved in MeOH (0.05-0.2 M) under an inert atmosphere. Pd / C (10% w / w, 0.1 equivalent) was added, and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1-24 hours. The reaction mixture was filtered (through a nylon filter or Celite), and the filtrate was concentrated under reduced pressure to obtain a saturated macrocyclic molecule (typically, together with an analog with one less carbon atom as a byproduct) as a brown oil.

[0250] General procedure 9: Saponification The variable shown in this scheme is specific to this general procedure.

[0251] [ka]

[0252] Methyl esters (typically containing small amounts of macrocyclic molecular analogs with one carbon atom shorter) were dissolved in MeOH (0.05-0.2 M), and aqueous 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 to pH < 5 with aqueous HCl (2 N) and purified by preparative LC (acid or base) to typically obtain both desired macrocyclic molecular carboxylic acids. The main and lesser (one carbon atom shorter) macrocyclic molecular analogs were separable by preparative LC and obtained as two distinct final compounds.

[0253] General Procedure 14: Amide Coupling The variable shown in this scheme is specific to this general procedure.

[0254] [ka]

[0255] 1.2 equivalents of carboxylic acid, 1.2 equivalents of HATU, and 3-10 equivalents of Et3N were dissolved in anhydrous DMF (0.05-0.2 M) and stirred at room temperature for 10-60 minutes. 1 equivalent of amine HCl salt (consisting of a terminal alkene and a small amount of isomers, typically with a shifted double bond) was added and stirred at room temperature for 1-18 hours. Water was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine (3×), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The impurities were purified by flash column chromatography (silica, typically heptane / ethyl acetate = 1:0 to 0:1) to obtain the desired amide, typically isomers with a shifted double bond, as small by-products.

[0256] General Procedure 15: Grubbs Metathesis The variable shown in this scheme is specific to this general procedure.

[0257] [ka]

[0258] An amide (1.0 equivalent) (consisting of a terminal alkene and typically a small amount of a migrated double bond isomer) was dissolved in anhydrous toluene (2.0–3.0 mM), and the solvent was degassed with nitrogen for 20 minutes. Grubbs second-generation catalyst (0.1 equivalent) was added, and the reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was concentrated under reduced pressure. Impurities were purified by flash column chromatography (silica, CH2Cl2 / MeOH = 1:0 to 9:1) to obtain macrocyclic molecules (typically together with a one-carbon analog as a byproduct) as a brown form.

[0259] General procedure 16: Hydrogenation The variable shown in this scheme is specific to this general procedure.

[0260] [ka]

[0261] An unsaturated macrocyclic molecule (1.0 equivalent) (typically containing a small amount of a macrocyclic molecule analog with one less carbon atom) was dissolved in MeOH (0.05-0.2 M) under an inert atmosphere. Pd / C (10% w / w, 0.1 equivalent) was added, and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1-5 hours. The reaction mixture was filtered (through a nylon filter or Celite), and the filtrate was concentrated under reduced pressure to obtain a saturated macrocyclic molecule (typically, together with an analog with one less carbon atom as a byproduct) as a brown oil.

[0262] General procedure 17: Saponification The variable shown in this scheme is specific to this general procedure.

[0263] [ka]

[0264] Methyl esters (typically containing small amounts of macrocyclic molecular analogs with one carbon atom shorter) were dissolved in MeOH (0.05-0.2 M), and aqueous 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 to pH < 5 with aqueous HCl (2 N) and purified by preparative LC (acid or base) to typically obtain both desired macrocyclic molecular carboxylic acids. Note: The main and lesser (one carbon atom shorter) macrocyclic molecular analogs were separable by preparative LC and obtained as two different final compounds.

[0265] General Procedure 24: Mitsunobu Reaction The variable shown in this scheme is specific to this general procedure.

[0266] [ka]

[0267] Benzotriazole alcohol (1.0 equivalent) and hydroxytert-butylbenzoate (1.1 equivalents) were dissolved in anhydrous toluene (0.05-0.2 M) and degassed with argon for 20 minutes. Then, cyanomethylenetributylphosphoran (1.4 equivalents) was added, and the mixture was stirred under reflux (115°C) for 16 hours. The reaction mixture was concentrated under reduced pressure. Impurities were purified using preparative HPLC (method: preparative base) or flash column chromatography (silica, CH2Cl2 / MeOH = 1:0 to 9:1) to obtain diethers.

[0268] General Procedure 39: Debenzylation and Alkene Reduction The variable shown in this scheme is specific to this general procedure.

[0269] [ka]

[0270] An unsaturated macrocyclic molecule (1.0 equivalent) was dissolved in MeOH / CH2Cl2 (4:1, 0.05-0.2 M), and the solution was degassed with nitrogen. Pd(OH)2 (0.1 equivalent) was added to the carbon atom, and H2 was bubbling into the suspension for 5 minutes. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2-16 hours. The reaction mixture was filtered through Celite, and the filter was rinsed with CH2Cl2 and MeOH. The filtrate was concentrated, and the residue was dissolved in a mixture of DMSO, MeOH, and aqueous HCl (2 M), and purified by preparative LC (acid or base) to obtain the desired macrocyclic carboxylic acid molecule.

[0271] General Procedure 70: Mitsunobu Reaction The variable shown in this scheme is specific to this general procedure.

[0272] [ka]

[0273] Boc-protected THIQ core (1 equivalent) and hydroxytert-butylbenzoate (1.1 equivalents) were dissolved in anhydrous toluene (0.05-0.2 M) and degassed with argon for 20 minutes. Then, cyanomethylene tributylphosphorane (1.4 equivalents) was added, and the mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was then purified by flash column chromatography (silica, heptane: siRNA = 1:0-0:1). After evaporation, the product was obtained as a white solid.

[0274] General Procedure 71: Deprotection, Amide Coupling - Macrocyclic and Saponification The variable shown in this scheme is specific to this general procedure.

[0275] [ka]

[0276] The reaction was carried out in the same reaction vessel, and the intermediate was not isolated.

[0277] Step 1: Boc-amine and R 2 (R 2 Simultaneous deprotection of carboxylates (=tBu, OAll, Me).

[0278] To the product containing Boc-amine and tBu-carboxylate in CH2Cl2 (0.1M), HCl (4M in dioxane, 10-40 equivalents) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure. 2 In the case of =All, the carboxylate was deprotected before Boc using Pd(PPh3)4 (0.15 equivalents) and morpholine (10 equivalents) in THF (0.1M). The reaction was carried out under nitrogen for 16 hours. The intermediate was purified by flash column chromatography (silica, DCM:MeOH = 1:0~9:1). 2 In the case of =Me, the carboxylate was saponified before Boc using an aqueous solution of NaOH (2.5 equivalents) in MeOH (0.1M). The reaction was carried out at room temperature for 5 minutes. The intermediate mixture was then neutralized with HCl 2M (2.5 equivalents), then evaporated and redissolved in DCM before Boc deprotection.

[0279] Step 2: Macrocyclic formation by amide coupling. The above mixture, containing both a carboxylic acid and an amine in the same (1 equivalent) substrate, 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.

[0280] Step 3: Saponification The above mixture was dissolved in MeOH:THF (4:1, 0.05-0.2M), treated with aqueous LiOH (1M, 3-10 equivalents), and the mixture was stirred at room temperature for 1-18 hours. The reaction mixture was acidified to pH < 5 with aqueous HCl (2M), and purified by preparative HPLC (method: preparative acid or preparative base) to obtain the desired macrocyclic carboxylic acid.

[0281] General procedure 86: Deprotection The variable shown in this scheme is specific to this general procedure.

[0282] [ka]

[0283] Simultaneous deprotection of Boc-amine and tBu-carboxylate: To a feed containing Boc-amine and tBu-carboxylate dissolved in CH2Cl2 (0.05-0.20 M), HCl (4 M in dioxane, 10-70 equivalents) was added, 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.

[0284] General Procedure 90: Amide Coupling - Macrocyclic Formation The variable shown in this scheme is specific to this general procedure.

[0285] [ka]

[0286] The carboxylic acid and amine from the same substrate (1 equivalent) were dissolved in CH2Cl2 (0.01-0.05 M), and NEt3 (3-10 equivalents) and HATU (1 equivalent) were added. 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 flash column chromatography (silica, CH2Cl2 / MeOH = 1:0 → 95:5). The desired fractions were combined and concentrated under reduced pressure to obtain the amide.

[0287] General procedure 91: Debenzylation The variable shown in this scheme is specific to this general procedure.

[0288] [ka]

[0289] An amide (1 equivalent) was dissolved in MeOH (0.01-0.2 M) and flushed with N2. PdOH (20%, 0.1 equivalent) was added, and the resulting reaction mixture was stirred at room temperature under an 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.

[0290] Synthesis Example 1: 2-(5,33-dimethyl-2-oxo-1,5,15,16,17-pentazaheptacyclo[22.5.3.26,9.118,22.03,7.015,19.027,31]pentatriaconta-3,6,8,16,18(33),19,21,24(32),25,27(31),34-undecaen-23-yl)acetic acid (compound 362) [ka]

[0291] Details: The title compound was manufactured in four steps:

[0292] Step 1: Starting with methyl 3-(4-methyl-1-(penta-4-en-1-yl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate dihydrochloride (200 mg, 0.407 mmol) and 1-methyl-5-vinyl-1H-indole-3-carboxylic acid (98 mg, 0.488 mmol), followed by general procedure 6B: amide coupling to obtain the corresponding amide (250 mg, 0.253 mmol, 95%).

[0293] Step 2: General Procedure 7: Following Grubbs metathesis, an unsaturated macrocyclic molecule (100 mg, 0.163 mmol, y: 65%, py: 93.6%) was obtained.

[0294] Step 3: General Procedure 8: Following hydrogenation, the corresponding saturated macrocyclic molecule (100 mg, 0.162 mmol, y: 93%, py: 93.2%) was obtained.

[0295] Step 4: General Procedure 9: After saponification, the title compound (15.0 mg, 0.027 mmol, 15%) was obtained as a white solid.

[0296] Yield: The final compound was isolated as a white solid (15.0 mg, 0.027 mmol, 8.6% after 4 steps).

[0297] Analysis: LCMS (Method N): t R = 1.49 min; m / z calculated for [M+H] + = 562.2, found = 562.4; 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (bs, 1H), 7.62 (s, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.26 - 7.12 (m, 2H), 7.02 (dd, J = 8.4, 1.6 Hz, 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, 6.9 Hz, 1H), 2.95 (dd, J = 16.0, 8.8 Hz, 1H), 2.83 (q, J = 5.6 Hz, 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).

[0298] Synthesis Example 2: 2-(34-methyl-22-oxo-17-oxa-8,9,10,19,23,32-hexaazahexacyclo[21.5.3.218,21.13,7.06,10.026,30]tetratriaconta-1(29),3,5,7(34),8,18,20,26(30),27,32-decaen-2-yl)acetic acid (compound 379) [ka]

[0299] Details: The title compound was manufactured in four steps:

[0300] Step 1: Starting with methyl 3-(1-(buta-3-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate dihydrochloride (200 mg, 0.419 mmol) and 5-(buta-3-en-1-yloxy)pyrazine-2-carboxylic acid, followed by general procedure 6B: amide coupling to obtain the corresponding amide (158 mg, 0.272 mmol, 65%).

[0301] Step 2: General Procedure 7: Following Grubbs metathesis, the corresponding (main) crude unsaturated macrocyclic molecule (64 mg, 0.12 mmol, 42%) was obtained.

[0302] Step 3: General Procedure 8: After hydrogenation, the corresponding saturated coarse cyclic molecule was obtained. The product was used when 100% conversion was achieved.

[0303] Step 4: General Procedure 9: After saponification, the title compound (23.1 mg, 0.042 mmol, 55%) was obtained as a white solid.

[0304] Yield: The final compound was isolated as a white solid (23.1 mg, 0.042 mmol, 10% after 4 steps).

[0305] Analysis: LCMS (Method T): tR = .967 min; m / z calculated for [M+H]+ = 540.3, found = 541.4; 1H NMR (400 MHz, DMSO) δ 8.19 - 8.14 (m, 2H), 7.60 (q, J = 8.7 Hz, 2H), 7.31 (dd, J = 8.0, 1.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.40 (d, J = 1.9 Hz, 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 = 16.8 Hz, 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).

[0306] Synthesis Example 3: 2-(20,32-difluoro-34-methyl-22-oxo-14,17-dioxa-8,9,10,23-tetrazahexacyclo[21.5.3.218,21.13,7.06,10.026,30]tetratriaconta-1(29),3(34),4,6,8,18(33),19,21(32),26(30),27-decaen-2-yl)acetic acid (compound 368) [ka]

[0307] Details: The title compound was manufactured in four steps:

[0308] Step 1: Starting with tert-butyl 7-(3-(benzyloxy)-1-(1-(3-(2-hydroxyethoxy)propyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.5 g, 2.386 mmol) and tert-butyl 2,6-difluoro-4-hydroxybenzoate, the corresponding di-ether (1.73 g, 1.646 mmol, py: 80%, y: 69%) was obtained after general procedure 24: Mitsunobu reaction by flash column chromatography purification (CH2Cl2 / MeOH = 1:0 → 97:3).

[0309] Step 2: General procedure 86: After deprotection, starting with 100 mg, 0.119 mmol of diether, free amino acids (81 mg, 0.119 mmol, 100%) were obtained.

[0310] Step 3: General Procedure 90: Amide Coupling - Macrocyclization was followed. A portion of additional Et3N (5.0 equivalents) and HATU (0.5 equivalents) were added to obtain the amide (26 mg, 0.035 mmol, py: 90%, y: 30%) as a beige oil.

[0311] Step 4: After debenzylation using a total of 0.7 equivalents of palladium carbon hydroxide and preparative acid (general procedure 91), the title macrocyclic molecule (3.45 mg, 0.006 mmol, 15%) was obtained as a white solid.

[0312] Yield: The final compound was isolated as a white solid (3.45 mg, 0.006 mmol, 3.1% after 4 steps). Analysis: LCMS (Method R): t R = 1.38 min; m / z calculated for [M+H] + = 577.2, found = 577.4; 1H NMR (400 MHz, DMSO) δ 7.62 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 10.9 Hz, 1H), 6.42 (d, J = 10.8 Hz, 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 - 3.52 (m, 3H), 3.05 - 2.85 (m, 2H), 2.83 (t, J = 6.4 Hz, 2H), 2.53 (s, 3H), 2.14 (p, J = 6.8 Hz, 2H).

[0313] Synthesis Example 4: 2-[(12E)-20-oxo-15-oxa-8,9,10,21-tetrazahexacyclo[19.5.3.216,19.13,7.06,10.024,28]dotriaconta-1(27),3,5,7(32),8,12,16(31),17,19(30),24(28),25-undecaen-2-yl]acetic acid (compound 419) [ka]

[0314] Details: The title compound was manufactured in a single step:

[0315] Step 1: Starting with methyl 3-(1-(buta-3-en-1-yl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate dihydrochloride (287 mg, 0.62 mmol) and 4-(allyloxy)benzoic acid, followed by general procedure 6B: amide coupling to obtain the corresponding amide (240 mg, 0.62 mmol, 100%).

[0316] Step 2: General Procedure 7: Following Grubbs metathesis, an unsaturated macrocyclic molecule (150 mg, 0.29 mmol, 47%) was obtained.

[0317] Step 3: General procedure 9: Saponification in MeCN instead of MeOH. Following this, the title compound (less macrocyclic molecule, 7.8 mg, 0.016 mmol, 12%) was obtained as a white solid as a mixture of E and Z isomers in a 3:1 ratio.

[0318] Yield: The final compound was isolated as a white solid (7.8 mg, 0.016 mmol, 5.6% after 3 steps). Analysis: LCMS (Method J): tR = 2.32 min; m / z calculated for [M+H]+ = 495.2, found = 495.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 7.90 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 9.0 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 5.98 (d, J = 1.9 Hz, 1H), 5.94 - 5.79 (m, 2H), 5.52 - 5.35 (m, 2H), 4.72 (q, J = 16.8 Hz, 2H), 4.60 (t, J = 7.8 Hz, 1H), 4.17 - 4.04 (m, 2H), 3.99 (d, J = 16.4 Hz, 1H), 3.51 (dt, J = 13.9, 7.3 Hz, 1H), 3.03 (qd, J = 15.7, 7.6 Hz, 2H), 2.92 - 2.76 (m, 2H).

[0319] Synthesis Example 5: 2-[(2R)-33-methyl-21-oxo-8,10,22-triazahexacyclo[20.5.3.217,20.13,7.06,10.025,29]tritriaconta-1(28),3,5,7(33),8,17(32),18,20(31),25(29),26-decaen-2-yl]acetic acid (compound 385) [ka]

[0320] Details: The title compound was manufactured in four steps:

[0321] Step 1: Starting with rel-methyl(R)-3-(1-(hexa-5-en-1-yl)-4-methyl-1H-benzo[d]imidazol-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate trihydrochloride (obtained from the second eluted enantiomer of the constituent components, 0.285 g, 0.527 mmol) and 4-vinylbenzoic acid, followed by general procedure 6B: amide coupling to obtain the corresponding amide (90 mg, 0.146 mmol, 27%).

[0322] Step 2: Subsequently, general procedure 7: Grubbs metathesis was performed using an additional Grubbs second-generation catalyst, followed by stirring for 2 days to obtain an unsaturated macrocyclic molecule (25 mg, 0.044 mmol, 27%).

[0323] Step 3: General Procedure 8: Following hydrogenation, the corresponding saturated macrocyclic molecule (27 mg, 0.048 mmol, 100%) was obtained.

[0324] Step 4: General procedure 9: Saponification in 4N NaOH aqueous solution, and after stirring for 5 days, the title compound (less analogue, 7.8 mg, 0.013 mmol, 27%) was obtained as a white solid.

[0325] 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): tR = 1.06 min; m / z calculated for [M+H] + = 522.3, found = 522.4; 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.35 - 7.24 (m, 2H), 7.18 - 7.04 (m, 4H), 7.01 (d, J = 7.9 Hz, 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, 6.7 Hz, 1H), 2.98 - 2.82 (m, 2H), 2.77 (t, J = 6.0Hz, 2H), 2.69 - 2.58 (m, 1H), 2.39 (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).

[0326] Synthesis Example 6: 2-(4-oxo-31,32,33,34-tetrahydro-6,11-dioxa-3(7,2)-isoquinolina-1(5,2)-pyridina-5(1,4)-benzenacycloundecafan-2-yl)acetic acid (compound 211) [ka]

[0327] Details: The title compound was manufactured in two steps:

[0328] Step 1: Starting with tert-butyl 7-(1-(6-(4-(4-(tert-butoxycarbonyl)phenoxy)butoxy)pyridine-3-yl)-3-methoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (200 mg, 0.413 mmol) and tert-butyl 4-hydroxybenzoate, the corresponding product (260 mg, 0.390 mmol, 94%) was obtained after General Procedure 70: Mitsunobu reaction.

[0329] Step 2: General Procedure 71: Following deprotection, amide coupling-macrocyclicization, and saponification, the title macrocyclic molecule (15 mg, 0.031 mmol, 7.8%) was obtained as a white solid.

[0330] Yield: The final compound was isolated as a white solid (15 mg, 0.031 mmol, 7.3% in two steps). Analysis: LC-MS (Method T): t R = 0.988 min; m / z calculated for [M+H] + = 473.2, found = 473.4; 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.7, 2.5 Hz, 1H), 7.28 (dd, J = 7.8, 1.8 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 8.4 Hz, 2H), 6.43 (s, 1H), 4.48 (dp, J = 21.8, 5.6 Hz, 2H), 4.36 (t, J = 7.9 Hz, 1H), 4.17 (d, J = 3.8 Hz, 2H), 4.12 (t, J = 7.5 Hz, 2H), 3.90 (dt, J = 13.0, 6.5 Hz, 1H), 3.70 (dt, J = 13.2, 6.9 Hz, 1H), 2.96 (d, J = 8.0 Hz, 2H), 2.88 (t, J = 6.7 Hz, 2H), 1.76 (th, J = 13.4, 6.9, 6.0 Hz, 4H).

[0331] Synthesis Example 7: 2-(2-oxo-12-oxa-1,14,28-triazapentacyclo[16.5.3.23,6.213,16.021,25]triaconta-3,5,13(28),14,16(27),18(26),19,21(25),29-nonaen-17-yl)acetic acid (compound 277) [ka]

[0332] Details: The title compound was manufactured in four steps:

[0333] Step 1: Started with 7-(3-methoxy-3-oxo-1-(2-(penta-4-en-1-yloxy)pyrimidine-5-yl)propyl)-1,2,3,4-tetrahydroisoquinoline-2-ium chloride (350 mg, 0.837 mmol) and 4-vinylbenzoic acid, followed by general procedure 14: amide coupling to obtain the corresponding amide (270 mg, 0.528 mmol, 63%).

[0334] Step 2: Next, general procedure 15: Grubbs metathesis was performed to obtain the corresponding (main) unsaturated macrocyclic molecule (141 mg, 0.108 mmol, 20%).

[0335] Step 3: General Procedure 16: Following hydrogenation, the corresponding saturated macrocyclic molecule (130 mg, 0.088 mmol, 82%) was obtained.

[0336] Step 4: General Procedure 17: After saponification, a portion of DCM was added along with the preparative acid for solubility, and the title compound (15.5 mg, 0.033 mmol, 37%) was obtained as a white solid.

[0337] Yield: The final compound was isolated as a white solid (15.5 mg, 0.033 mmol, 3.8% after 4 steps). Analysis: LC-MS (Method H): t R= 3.33 min; m / z calculated for [M+H]+ = 472.2, found = 472.4; 1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.37 (s, 2H), 7.31 - 7.16 (m, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.03 (q, J = 8.0 Hz, 4H), 6.10 (s, 1H), 4.48 (dt, J = 11.0, 5.4 Hz, 1H), 4.44 - 4.31 (m, 2H), 4.26 (d, J = 16.2 Hz, 1H), 4.12 (d, J = 16.2 Hz, 1H), 4.04 (dt, J = 12.3, 5.9 Hz, 1H), 3.60 (dt, J = 13.5, 7.0 Hz, 1H), 2.96 (dt, J = 16.4, 8.1 Hz, 2H), 2.90 - 2.77 (m, 2H), 2.62 (q, J = 7.3, 6.9 Hz, 2H), 1.75 (t, J = 7.4 Hz, 2H), 1.70 - 1.45 (m, 2H), 1.19 (td, J = 15.3, 14.2, 6.3 Hz, 2H).

[0338] Synthesis example 8: 2-(33-メチル-2-オキソ-15-オキサ-1,7,17,33-テトラザヘキサシクロ[19.5.3.216,19.13,6.15,9.024 ,28]Torotron-3,5,7,9(32),16,18,21(29),22,24(28),30-デカエン-20-イル) anthioic acid (compound 158)

change

[0339] Details: Table title compound を3 engineering and manufacturing した:

[0340] Step 1: Starting with benzyl 3-(6-(penta-4-en-1-yloxy)pyridine-3-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate 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), followed by general procedure 14: amide coupling to obtain the corresponding amide (86 mg, 0.134 mmol, 37%).

[0341] Step 2: Next, general procedure 15: Grubbs metathesis was performed to obtain the corresponding (main) unsaturated macrocyclic molecule (63 mg, 0.068 mmol, y: 51%).

[0342] Step 3: General Procedure 39: After debenzylation, alkene reduction using Pd / C, and purification by preparative HPLC (Method: Preparative Acid), the compound was obtained as a racemic mixture (4.63 mg, 0.0086 mmol, 8%).

[0343] Yield: The final compound was isolated as a white solid (4.63 mg, 0.0086 mmol, 2% in 3 steps). Analysis: LC-MS (Method T): t R = 1.08 min; m / z calculated for [M+H] + = 525.2, found = 525.4; 1H NMR (400 MHz, DMSO) δ 8.18 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.5, 2.5 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 8.5 Hz, 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), 3.81 - 3.71 (m, 5H), 2.96 - 2.82 (m, 4H), 2.72 (t, J = 6.2 Hz, 2H), 1.84 - 1.63 (m, 4H), 1.33 - 1.25 (m, 2H).

[0344] Synthesis Example 9: 2-[(2S)-33-methyl-21-oxo-8,9,10,22-tetrazahexacyclo[20.5.3.217,20.13,7.06,10.025,29]tritriaconta-1(28),3,5,7(33),8,17(32),18,20(31),25(29),26-decaen-2-yl]acetic acid (compound 223) [ka]

[0345] Details: The title compound was manufactured in four steps:

[0346] Step 1: Starting with rel-methyl(S)-3-(4-methyl-1-(penta-4-en-1-yl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate dihydrochloride (obtained from the first eluted enantiomer of the constituent components, 564 mg, 1.15 mmol) and 4-allylbenzoic acid, followed by general procedure 6B: amide coupling to obtain the corresponding amide (510 mg, 0.91 mmol, 79%).

[0347] Step 2: General Procedure 7: Following Grubbs metathesis, an unsaturated macrocyclic molecule (480 mg, 0.90 mmol, 99%) was obtained.

[0348] Step 3: General Procedure 8: Following hydrogenation, the corresponding saturated macrocyclic molecule (480 mg, 0.89 mmol, 100%) was obtained.

[0349] Step 4: General Procedure 9: After saponification, the title compound (main analogue, 126 mg, 0.24 mmol, 27%) was obtained as a white solid.

[0350] Yield: The final compound was isolated as a white solid (126 mg, 0.24 mmol, 21% after 4 steps). Analysis: LC-MS (Method H): t R = 3.12 min; m / z calculated for [M+H] + = 523.3, found = 523.4; chiral SFC method IC isocratic: ee = 100%; t R(major) = 6.15 min, t R(minor)= 8.31 min; 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.18 - 7.06 (m, 3H), 6.96 (d, J = 7.8 Hz, 2H), 6.04 (d, J = 1.9 Hz, 1H), 4.80 - 4.69 (m, 2H), 4.64 (ddd, J = 14.3, 11.4, 3.2 Hz, 1H), 4.23 (d, J = 16.7 Hz, 1H), 4.13 (d, J = 16.6 Hz, 1H), 3.89 (dt, J = 11.8, 5.7 Hz, 1H), 3.70 (dt, J = 12.7, 6.3 Hz, 1H), 3.06 (dd, J = 15.8, 6.8 Hz, 1H), 2.91 (dd, J = 15.7, 8.8 Hz, 1H), 2.79 (t, J = 6.1 Hz, 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).

[0351] Synthesis example 10: (2S)-2-[(17S)-2-オキソ-12-オキサ-1,14-ジアザペンタシクロ[16.5.3.23,6.213,16.021,2 5]トリアコンタ-3,5,13,15,18(26),19,21(25),27,29-ノナエン-17-イル]プロパン acid (compound 127)

change

[0352] Details: Table title compound を3 engineering and manufacturing した:

[0353] Step 1: Starting with benzyl 2-methyl-3-(6-(penta-4-en-1-yloxy)pyridine-3-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate hydrochloride (444 mg, 0.876 mmol) and 4-vinylbenzoic acid, followed by general procedure 14: amide coupling to obtain the corresponding amide (440 mg, 0.718 mmol, 82%).

[0354] Step 2: Next, general procedure 15: Grubbs metathesis was performed to obtain the corresponding (main) unsaturated macrocyclic molecule (520 mg, 0.908 mmol, py: unknown, y: 124%).

[0355] Step 3: General Procedure 39: After debenzylation, alkene reduction with Pd / C, and purification by preparative HPLC (Method: Preparative Acid), a mixture of diastereoisomers was obtained. By preparative HPLC (Method: Preparative Acid 2), the syn- and anti-products were separated, and the corresponding macrocyclic molecular carboxylic acid (4.41 mg, 0.0087 mmol, 1%) was obtained as the first elution product.

[0356] Yield: The final compound was isolated as a white solid (4.41 mg, 0.0087 mmol, 10% in 3 steps). Based on the separation, the structure was identified as the first elution product. Analysis: LC-MS (Method H): t R = 3.72 min; m / z calculated for [M+H] + = 485.2, found = 485.4; 1H NMR (400 MHz, DMSO) δ 8.10 (d, J = 2.6 Hz, 1H), 7.29 - 7.18 (m, 2H), 7.09 (d, J = 7.8 Hz, 1H), 6.98 (q, J = 8.0 Hz, 4H), 6.56 (d, J = 8.4 Hz, 1H), 6.30 (s, 1H), 4.62 - 4.52 (m, 1H), 4.34 (d, J = 16.3 Hz, 1H), 4.30 - 4.20 (m, 1H), 4.18 - 4.05 (m, 2H), 3.94 (d, J = 11.4 Hz, 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 = 7.5 Hz, 2H), 1.01 (d, J = 6.8 Hz, 3H).

[0357] Synthesis Example 11: 2-(27-methyl-2-oxo-12-oxa-1,14-diazapentacyclo[16.5.3.23,6.213,16.021,25]triaconta-3,5,13,15,18(26),19,21(25),27,29-nonaen-17-yl)acetic acid (compound 80) [ka]

[0358] Details: The title compound was manufactured in four steps:

[0359] Step 1: Starting with methyl 3-(4-methyl-6-(penta-4-en-1-yloxy)pyridine-3-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate dihydrochloride (200 mg, 0.428 mmol) and 4-vinylbenzoic acid, followed by general procedure 14: amide coupling to obtain the corresponding amide (114 mg, 0.217 mmol, 51%).

[0360] Step 2: Next, general procedure 15: Grubbs metathesis was performed to obtain an unsaturated macrocyclic molecule (69 mg, 0.139 mmol, 64%).

[0361] Step 3: General Procedure 16: Following hydrogenation, the corresponding saturated macrocyclic molecule (55 mg, 0.110 mmol, 79%) was obtained.

[0362] Step 4: General procedure 17: Saponification in MeOH / DMSO instead of MeOH. The title compound (39 mg, 0.080 mmol, 72%) was obtained as a white solid.

[0363] Yield: The final compound was isolated as a white solid (39 mg, 0.080 mmol, 19% after 4 steps). Analysis: LC-MS (Method R): t R = 1.60 min; m / z calculated for [M+H] += 485.2, found = 485.4; 1H NMR (400 MHz, DMSO) δ 12.24 (s, 1H), 8.00 (s, 1H), 7.27 (dd, J = 7.8, 1.9 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 7.9 Hz, 2H), 6.99 (d, J = 7.9 Hz, 2H), 6.51 (s, 1H), 6.11 (d, J = 1.8 Hz, 1H), 4.79 (ddd, J = 11.5, 8.3, 3.4 Hz, 1H), 4.40 (t, J = 7.9 Hz, 1H), 4.26 (d, J = 16.1 Hz, 1H), 4.19 (dt, J = 12.1, 5.6 Hz, 1H), 4.00 (d, J = 16.1 Hz, 1H), 3.94 (ddd, J = 10.6, 6.3, 3.7 Hz, 1H), 3.42 (d, J = 6.3 Hz, 1H), 2.99 (dd, J = 15.9, 8.0 Hz, 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 = 7.7 Hz, 2H).

[0364] Synthesis Example 12: The remaining compounds in Tables 1 and 2 were prepared according to the above synthetic procedures using appropriate reagents and modifications known to the art. The compounds described herein are based on standard techniques known to the art, e.g. 1 It was characterized by the use of 1H NMR and mass spectroscopy.

[0365] Biological examples Nrf2-Keap1 Biochemical Assay Protocol

[0366] material • Pf-BSA (protease-free): Sigma: A3059 • XL665-labeled streptavidin: CisBio: 610SAXLA Terbium-labeled anti-6HIS antibody: CisBio: 61HI2TLA • Biotin-Nrf2(16-mer): Biosyntan: Custom Synthesis • HIS-Keap1 Overall Length: Biosyntan: Custom Synthesis • Proxiplate-384 Plus, white 384 microplate: Perkin Elmer: 6008280

[0367] Assay buffer ·10mM Hepes pH7.4(sigma H3375) • 150mM NaCl (Sigma S7653) ·0.005% Tween-20(sigma P1379) • 0.01% pf-BSA (Sigma A3059)

[0368] Final assay concentration ·HIS-Keap1 total length 4.1nM Biotin-Nrf2(16-mer)4.1nM • Anti-6HIS terbium 0.18nM • Streptoavidin XL665 10.4nM

[0369] Assay protocol In the first step, the Keap1 / compound complex was prepared by adding 100 nL of the compound with ECHO 555, followed by a 5 μL aliquot of 2 × Keap1. This mixture was incubated at room temperature for 15 minutes. In the second step, the Keap1 / Nrf2 complex was prepared by adding a 5 μL aliquot of 2 × Nrf2 to the same mixture and incubating again at room temperature for 15 minutes. 5 μL of anti-HIS-Tb was then added, followed by 5 μL of 4 × streptavidin-XL665. After incubation at 4°C for 2 hours, TR-FRET measurements were performed using a Pherastar FS (optical module HTRF 337 / 620 / 665 nM).

[0370] Cell assay protocol BEAS-2B cell culture The growth rate of BEAS-2B cells was varied based on the lot of BEGM SingleQuots in BEGM medium. The cell growth rate was determined for each lot of SingleQuots. Ideally, cells were thawed in medium with a new lot of SingleQuots and grown for two generations before testing; however, it was also acceptable to grow active cultures for two to three generations in a new lot of medium before testing. To avoid cell density exceeding 70% until the cell growth rate was determined, cells were grown at different densities (cells / cm³). 2 Cells were seeded into multiple tissue culture flasks using the above medium. Cells should not exceed 70% density because they differentiate once they become density. After the cells grew in a fresh lot of the above medium, the number of cells per well that needed to be seeded into collagen plates was determined by seeding different numbers of cells per well and incubating for 48 hours. Cell density was confirmed after 48 hours, and a number of cells slightly above or below density was selected for future plate seeding. Cell density in assay plates was 95-100% density after 48 hours. 70% density in assay plates after 48 hours resulted in a lot of variability in the MTT signal, and Z' was not obtained. BEAS-2B cell medium:

[0371] The cell culture medium consisted of BEBM basal medium with added BEGM SingleQuots. The SingleQuots vials were thawed in a tissue culture hood, and GA-1000 (gentamicin-amphotericin) was not added.

[0372] If the complete medium was to be used immediately, the BEBM basal medium was warmed to room temperature in a hood, but not as high as 37°C. If the medium was to be prepared for future use, SingleQuots was added to cold BEBM. At the same time, the SingleQuots components (except GA-1000) were added to the BEBM medium. After removing each component from the vial, the vial was rinsed with 0.5–1 mL of BEBM (depending on the volume the vial could hold) and added to the BEBM bottle. After adding all components, the label included in the SingleQuots kit was attached to the medium bottle and the date was recorded. The medium was mixed by gently shaking the bottle. The medium was not filtered. This medium was stored at 4°C with a certain amount of remaining medium to be discarded one month after the date SingleQuots was added.

[0373] BEAS-2B cell division protocol: First, the trypsin was warmed to 37°C in a water bath. The culture medium was then warmed to room temperature by placing it in a tissue culture hood, but it was not as high as 37°C. The medium was aspirated from the flask, and the flask was washed with PBS. 1-1.5 mL of warm trypsin was added to each flask, and the flask itself was incubated at 37°C until cells were removed, taking care not to detach the cells by vigorously tapping the flask (for about 8-10 minutes).

[0374] The culture medium was added to each flask until the total volume reached 8–10 mL, and then transferred to a 15 mL conical tube. The cells were spun down at 120 g for 5 minutes using a 5-stage brake. The cells may be spun down at 100–150 g. Next, the medium was aspirated, and the cell pellet was resuspended in fresh medium by pipetting up and down and moving the tube from side to side. After allowing any remaining clumps of cells to settle to the bottom of the tube, the suspension at the top was transferred to another tube, leaving approximately 1 mL of medium in the original tube. The 1 mL of medium and cell clumps were mixed with a single-channel p1000 pipette, the remaining clumps were removed, and the cells in the suspension were added to the other tube. The suspension was mixed with a pipette, the aliquots were removed, and the cells were counted. The desired cell count was calculated as follows: cells / cm³. 2 The required volume of cells was calculated and added to the tissue culture flask. For example, approximately 6000 cells / cm³. 2 The use of SingleQuots is suitable for a 3-day incubation period, with approximately 3000 cells / cm². 2 The cells were suitable for a 5-day incubation. The optimal cell density varied by lot of SingleQuots. Flasks were incubated at 37°C in 5% CO2.

[0375] Day 1: Seed BEAS-2B cells into a collagen plate: The plates were seeded with either 0.3% or 0% HSA. The protocol was similar under both conditions, but the differences are noted below in this specification.

[0376] Trypsin was warmed to 37°C in a water bath. The culture medium was warmed to room temperature by placing it in a tissue culture hood. (The medium was not warmed to 37°C.) If the collagen plate containing the compound was frozen, the plate was thawed at room temperature for 1 hour. Two multidrop standard cassettes were used: one was used to dispense medium and cells without human serum albumin (HSA), and the other was used to dispense medium with HSA.

[0377] Once the entire plate reached the desired temperature, the seal was removed from the collagen plate. Using a multidrop cassette without HSA, 20 μL of culture medium was added to each well, and the plate was sat covered at room temperature.

[0378] In this example, a single 20 μL injection was used on a 0.3% HSA plate, and two 20 μL injections were used on a 0% HSA plate.

[0379] Next, BEAS-2B cells were divided according to the BEAS-2B cell division protocol. The cells were counted first, and then switched from the multidrop cassette to the +HSA cassette.

[0380] For 0.3% HSA plates only: 20 μL each of medium, HSA in the medium, and cells were combined, and HSA was added at a 3-fold concentration. Since the final HSA concentration in the cells was 0.3%, 0.9% HSA was added to the plates. To prepare the 0.9% HSA solution, 0.9 mL of HSA stock (10%) was added to 9.1 mL of medium to obtain 10 mL of 0.9% HSA.

[0381] Using an HSA multidrop cassette, 0.9% HSA (only in 0.3% HSA plates) was added to each well in 20 μL of culture medium, and then the process was switched from the multidrop cassette to a cassette without HSA. Cells were prepared in the culture medium to the desired concentration. In one example of SingleQuots using 2500 cells / well, 20 μL was added per well, resulting in 1.25 × 10⁶ cells. 5 Cells / mL were obtained. The number of cells per well was adjusted according to the SingleQuots lot.

[0382] Using a multidrop cassette without HSA, 20 μL of cells were added to each well of both 0.3% and 0% HSA plates. The plates were left at room temperature for approximately 15–30 minutes, and then incubated at 37°C in 5% CO2 for 48 hours.

[0383] Day 3: MTT assay Because this assay is time-dependent, one plate was started simultaneously. Two clear-bottomed, white-walled plates were labeled with DMSO and DIC, and then placed in a darkroom. The Biotek washer was pre-treated with PBS- / - (minimum 200 mL). The protocol included: Pre-treatment A - 100 mL (twice) or Pre-treatment A - 250 mL. The lysis buffer was prepared immediately before use. The medium was aspirated using the BioTek and washed twice with 75 μL of PBS- / -. The Beas Wash protocol included two BioTek pre-treatments with water: W-Wash 75 μL of buffer A in two cycles, followed by washing off the PBS.

[0384] The plate was inverted onto the absorbent plate, manually pulled back to remove as much liquid as possible, and then tapped (3-4 times) on the clean spot of the absorbent pad. 50 μL of lysis buffer was added to each well, and the plate was placed in a shaker at room temperature for 8 / 1020 minutes.

[0385] 40 mL of reagent C was prepared in a light-restricted room (using red light) and then divided into two 19 mL volumes (one into a DMSO-labeled tube and the other into a DIC-labeled tube). Next, 19 μL of DMSO was added to the DMSO tube, and 19 μL of 1.5 mM dichromator ("DIC") was added to the DIC tube, and the tubes were mixed.

[0386] 40 μL of DMSO + Reagent C mixture was added to each well of a DMSO plate. After adding the DMSO + Reagent C mixture to the DMSO plate, those with MTT were protected from light. 40 μL of DIC + Reagent C mixture was added to each well of a DIC plate.

[0387] While each plate was kept protected from light, 10 μL of the solution was added to each well of the first DMSO plate, and then 10 μL of the solution was added to each well of the DIC plate.

[0388] Both DMSO and DIC plates were incubated while being protected from light at room temperature for approximately 15–30 minutes. This incubation time may be shortened if the cell count increases. For example, 5000 cells / well may require only 15 minutes to develop. The plates were spun at 277g (1500 RPM) for 5 minutes to remove any air bubbles. The absorbance of both plates at 570nm was measured using Pherastar (settings: sedimentation time = 0.1 seconds, 15 flashes / well). NQO1 activation is expressed as follows: ΔOD 570 =OD 570 DMSO-OD 570 DIC

[0389] HUDEP cells Evaluation of gene expression by qPCR in HUDEP cells treated with titration of a novel compound. HUDEP compound treatment method HUDEP cells were seeded in 200 μL of maintenance medium at a rate of 25,000 cells per well in a 96-well plate. The compound was added in a 10-point dose-response starting at 10 μM using a 1 / 3 dilution scheme with an HP digital diluter. The DMSO control was standardized with DMSO in all cases. The compounds were incubated at 37°C incubator at 5% CO for 48 hours. After incubation, total RNA was isolated using the Cells to Ct kit, and gene expression was evaluated for the target gene (GOI) after standardizing for housekeeping genes. ΔΔCT was calculated and compared to the DMSO control.

[0390] Cell lysis, isolation, and gene expression materials Cells to Ct is a kit provided by Applied Biosystems. The mRNA produced using this kit can be used directly for cDNA conversion, followed by qPCR for gene expression analysis.

[0391] procedure Cell lysis and RNA preparation: For suspension cells, e.g., HUDEP, 10,000–100,000 cells (as per the kit guidelines) were used to prepare the lysate. The plates were centrifuged at 1500 rpm for 5 minutes to pellet the cells. Used medium was removed using a multichannel pipette. 200 μL of ice-cold PBS was added to all treated wells, followed by centrifugation at 1500 rpm for 5 minutes. 195 μL of cold PBS was aspirated from all treated wells without disturbing the cell monolayer.

[0392] To prepare the Cells to CT lysis solution, 49.5 μL of Cells to CT lysis buffer and 0.5 μL / well of DNase I (the DNase I reagent was returned to the -20°C freezer immediately after pipetting) were added to each well. The Cells to CT lysis solution was pipetteed into the reservoir, and 50 μL was added per well to the treated wells. (35 μL was mixed five times without foaming, and the timer was set to 5 minutes. At the end of the 5-minute incubation, 5 μL of stop solution was added using a multichannel pipette, touching the tip to the liquid. Then 35 μL was mixed five times without foaming, and the timer was set to 2 minutes.)

[0393] The plates were sealed and stored at -20°C until cDNA synthesis. In some cases, they were placed on ice to allow for direct transfer to cDNA synthesis.

[0394] cDNA synthesis: Thaw the cell lysate plate on ice if necessary and mix four times with a multichannel pipette. Combine 4 μL of Superscript IV VILO and 6 μL of nuclease-free water with each sample. 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 five times. Using a plate sealing paddle and plate sealing film, completely seal the wells, especially around the edges. Centrifuge the PCR plate to bring the samples to the bottom of the wells. Seal the lysate plate and return it to a -20°C freezer as quickly as possible. Place the PCR plate in a thermal cycler and run 20 μL at 25°C for 10 minutes, 50°C for 10 minutes, 85°C for 5 minutes, and then at 4°C.

[0395] Real-time PCR: Thaw cDNA plates at room temperature as needed, add 30 μL of nuclease-free water to each cell lysate, and then mix four times up and down with a pipette. Thaw primers for both the target gene, housekeeping gene (HKG), and target gene (GOI).

[0396] A template was prepared, and the number of wells required for each target gene (GOI) was calculated. Each sample required 2 μL of cDNA, 5 μL of Taqman Master Mix, 0.16667 μL of GOI (60-fold concentrate), 0.16667 μL of HKG (60-fold concentrate), and 2.6667 μL of nuclease-free water. When the gene was used at a 20-fold concentrate, then 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 were combined in each well.

[0397] After calculating the number of wells for each gene, GOI, HKG, Taqman Master Mix, and nuclease-free water were combined. 8 μL was pipetteed into each well of the 384-well PCR plate detailed in the template. 2 μL of cDNA was pipettered into the appropriate wells detailed in the template, and then mixed four times up and down, changing the tip between sample additions. Using a plate sealing paddle and plate sealing film, the wells were completely sealed, especially around the edges. The PCR plate was centrifuged to settle the samples to the bottom of the wells.

[0398] RTPCR was performed for 40 cycles with a sample size of 10 μL, held at 95°C for 10 minutes, then denatured at 95°C for 15 seconds, and annealed / extended at 60°C for 1 minute. Data were analyzed by standardizing to HKG, ΔΔCT was calculated, and compared with controls.

[0399] [Table 105] [Table 106] [Table 107] [Table 108] [Table 109] [Table 110] [Table 111] [Table 112] [Table 113] [Table 114] [Table 115] [Table 116] [Table 117] [Table 118]

[0400] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure belongs.

[0401] The disclosures described herein shall be put into practice appropriately without any elements or limitations not specifically disclosed herein. Thus, for example, terms such as “comprising,” “including,” and “containing” shall be interpreted broadly and not limited thereto. Further, terms and expressions used herein are descriptive and not restrictive, and in the use of such terms and expressions there is no intention to exclude any features shown or described, or any equivalents thereof, but it is understood that various modifications may be made within the scope of this disclosure.

[0402] While this disclosure is described in relation to the embodiments described above, it should be understood that the foregoing description and examples are intended to illustrate, not limit, the scope of this disclosure. Other aspects, advantages, and modifications within the scope of this disclosure will be apparent to those skilled in the art to which this disclosure relates. All patent and scientific document disclosures cited herein are incorporated herein by reference in their entirety.

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (in the formula: R is H, or -OH, C 1 ~ 6 Alkyloxy or C 6 ~ 12 Selected from the arrows A C which may be substituted with one substituent. 1 ~ 6 It is alkyl; R 1 is H or C 1 to 6 alkyl; R 2 is H or C 1 ~ 6 It is alkyl; R 3 is H or C 1 ~ 6 It is alkyl; Ring B is a monoring C 6 Arylene, or 1 to 3 hete selected independently from N and O A monocyclic carbon containing a β atom. 3 ~ 5 It is a heteroarrene; n is 0, 1, 2, or 3; Each R 5 Independently, Halo, C 1 ~ 6 Alkyl or C 1 ~ 6 It is an alkyloxy; Ring A is C 6 ~ 12 Arylene, or one or two heterozygotes independently selected from N and O C containing atoms 3 ~ 12 It is a heteroarrene; m is 1, 2, 3, or 4; Each R 4 These are H, Halo, and C independently. 1 ~ 6 Alkyl or C 1 ~ 6 It is an alkoxy, C 1 ~ 6 a Lukil and C. 1 ~ 6 Alkoxy groups are halo, C 1 ~ 6 Alkyloxy, amide and N,N - It may be substituted with one to three groups independently selected from the dimethylamide group; L is C 4 ~ 8 Alkylene, C 4 ~ 8 Alkenylene, C 4 ~ 8 Heteroalkylene or C 4 ~ 8 These are heteroalkenylenes, each of which is a halo and C. 1 ~ 6 They are optionally substituted with one or four groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one to four oxygen atoms.

2. The compound of formula (I) is the compound of formula (IA): 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof (wherein formula: L' is C 4 ~ 6 Alkylene, C 4 ~ 6 Alkenylene, C 4 ~ 6 Heteroalkylene or C 4 ~ 6 These are heteroalkenylenes, each of which is a halo and C. 1 ~ 6 They are optionally substituted with one or two groups independently selected from alkyl groups, and heteroalkylenes and heteroalkenylenes contain one or two oxygen atoms; X 3 CH 2 or O; n is 0, 1, or 2; X 1 and X 2 (Each is independently CH or N).

3. X 3 CH 2 The compound according to claim 2, or a pharmaceutically acceptable salt thereof.

4. X 3 The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein is O.

5. X 1 The compound according to any one of claims 2 to 4, wherein is N, or pharmaceutically acceptable That salt.

6. X 1 The compound according to any one of claims 2 to 4, wherein is CH, or pharmaceutically acceptable The salt that is used.

7. X 2 The compound according to any one of claims 2 to 4, wherein is N, or pharmaceutically acceptable That salt.

8. X 2 The compound according to any one of claims 2 to 4, wherein is CH, or pharmaceutically acceptable The salt that is used.

9. X 1 and X 2 The compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein each is N.

10. X 1 and X 2 The compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein each is CH.

11. X 1 and X 2 A compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein one of the members is CH and the other is N.

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

13. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein n is 1.

14. Each R 5 Independently, C 1 ~ 4 Alkyl or C 1 ~ 4 Claims 1 to 1 are alkyloxy A compound described in any one of item 3, or a pharmaceutically acceptable salt thereof.

15. Each R 5 is independently methyl or methoxy as described in any one of claims 1 to 14. The compound, or a pharmaceutically acceptable salt thereof.

16. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein n is 0.

17. L' is C 4 ~ 6 Alkylene, C 4 ~ 6 Alkenylene, C 4 ~ 6 Heteroalkylene or C 4 ~ 6 Heteroalkylenes are heteroalkenylenes, and heteroalkylenes and heteroalkenylenes are one The compound according to any one of claims 2 to 16, or a pharmaceutically acceptable salt thereof, comprising two oxygen atoms.

18. C 4 to 6 alkenylene or C 4 to 6 heteroalkenylene, the compound according to claim 17 containing one unsaturated bond, or a pharmaceutically acceptable salt thereof.

19. X 3 is CH 2 and L’ is a C containing one unsaturated bond 4 to 6 alkenylene or a C 4 to 6 heteroalkenylene, a compound according to any one of claims 2 to 3, 5 to 11 and 17, or a pharmaceutically acceptable salt thereof.

20. X 3 is O, and L' is C containing one unsaturated bond. 4 ~ 6 Alkenylene or C 4 ~ 6 A heteroalkenylene as described in any one of claims 2, 4 to 11, 17 and 18. The compound, or a pharmaceutically acceptable salt thereof.

21. X 3 CH 2 And L' is C 4 ~ 6 Alkylene or C 4 ~ 6 It is a heteroalkylene, C 4 ~ 6 The heteroalkylene is a compound according to any one of claims 2 to 5, 17, and 18, or a pharmaceutically acceptable salt thereof, comprising one or two oxygen atoms.

22. X 3 is O, and L' is C 4 ~ 6 Alkylene or C 4 ~ 6 It is a heteroalkylene, C 4 ~ 6 The heteroalkylene contains one oxygen atom, claims 2, 4 to 11, 17 and 18 A compound as described in any one of the items, or a pharmaceutically acceptable salt thereof.

23. X 3 is O, and L' is C 4 ~ 6 Alkylene, claims 2, 4 to 11, 17 and A compound as described in any one of item 18, or a pharmaceutically acceptable salt thereof.

24. X 3 CH 2 And L' is C 4 ~ 6 A compound according to any one of claims 2-3, 5-11, 17, and 18, which is an alkylene, or a pharmaceutically acceptable salt thereof.

25. Ring A is, 【Transformation 3】 In the formula, * indicates a combination to L or L', 【Chemistry 4】 The ring A selected from is -(R 4 ) m It is replaced by m, where m is 1, 2, 3, or 4; 【Transformation 5】 The ring A selected from is further -(R 4 ) m It is replaced by m, where m is 1, 2, or 3; Each R 4 These are H, Halo, and C independently. 1 ~ 6 Alkyl or C 1 ~ 6 It is an alkoxy, C 1 ~ 6 a Lukil and C. 1 ~ 6 Alkoxy groups are halo, C 1 ~ 6 Optionally substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

26. Ring A is, 【Transformation 6】 In the formula, * indicates a combination to L or L', 【Transformation 7】 The ring A selected from is -(R 4 ) m It is replaced by m, where m is 1 or 2; 【Transformation 8】 The ring A selected from is further -(R 4 ) m It is replaced by m, where m is 1; Each R 4 These are H, Halo, and C independently. 1 ~ 4 Alkyl or C 1 ~ 4 It is an alkoxy, C 1 ~ 4 a Lukil and C. 1 ~ 4 Alkoxy groups are halo, C 1 ~ 4 Optionally substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof.

27. Ring A is, 【Chemistry 9】 The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof (wherein, * This indicates a bond to L or L', and ring A is further -(R 4 ) m Replaced by Therefore, m is 1; each R 4 These are H, Halo, and C independently. 1 ~ 4 Alkyl or C 1 ~ 4 Al It is Coxi, C 1 ~ 4 Alkyl and C 1 ~ 4 Alkoxy groups are halo, C 1 ~ 4 (Optionally substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups).

28. Ring A is, 【Chemistry 10】 The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof (wherein, * This indicates a bond to L or L', and ring A is -(R 4 ) m It has been replaced with , m is 1, 2, 3 or 4; each R 4 These are H, Halo, and C independently. 1 ~ 4 Alkyl also is C 1 ~ 4 It is an alkoxy, C 1 ~ 4 Alkyl and C 1 ~ 4 Alkoxy groups are halo, C 1 ~ 4 (Optionally substituted with 1 to 3 groups independently selected from alkyloxy, amide, and N,N-dimethylamide groups).

29. Each R 4 H, Halo, C 1 ~ 4 Alkyl and C 1 ~ 4 Selected independently from alkoxy, C 1 ~ 4 Alkyl and C 1 ~ 4 Alkoxy groups are halo, C 1 ~ 4 Alkyloxy, amide and A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, optionally substituted with one to three groups independently selected from N,N-dimethylamide groups.

30. Each R 4 H, Halo, C 1 ~ 4 Alkyl and C 1 ~ 4 Selected independently from alkoxy, each C 1 ~ 4 Alkyl and C 1 ~ 4 The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein the alkoxy group is optionally substituted with one to three groups independently selected from F, Cl, methoxy, amide, and N,N-dimethylamide groups.

31. Each R 4 H, methyl, isobutyl, F, Cl, trifluoromethyl, methoxy, diph A compound according to any one of claims 1 to 30, independently selected from ruolomethoxy, trifluoromethoxy, N,N-dimethylamide, 3,3,3-trifluoropropyl, 2,2-difluoroethyl, 3-fluoropropyl, and methoxyethyl, or a pharmaceutically acceptable salt thereof.

32. R is H, methyl, ethyl, 2-hydroxyethyl, or benzyl, the compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof.

33. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R is H.

34. R 1 is H or C 1 ~ 4 The compound according to any one of claims 1 to 33, which is alkyl The substance, or its pharmaceutically acceptable salt.

35. R 1 The compound according to any one of claims 1 to 34, wherein is H or methyl, This is the pharmaceutically acceptable salt.

36. R 1 The compound according to any one of claims 1 to 35, wherein is H, or pharmaceutically acceptable The salt that is used.

37. R 2 is H or C 1 ~ 4 The compound according to any one of claims 1 to 36, which is alkyl The substance, or its pharmaceutically acceptable salt.

38. R 2 The compound according to any one of claims 1 to 37, wherein is H or methyl, This is the pharmaceutically acceptable salt.

39. R 3 is H or C 1 ~ 4 The compound according to any one of claims 1 to 38, which is alkyl The substance, or its pharmaceutically acceptable salt.

40. R 3 The compound according to any one of claims 1 to 39, wherein is H or methyl, This is the pharmaceutically acceptable salt.

41. R 2 and R 3 One of them is H, and the other is C 1 ~ 4 A compound according to any one of claims 1 to 37 and 39, which is alkyl, or a pharmaceutically acceptable salt thereof.

42. R 2 and R 3 A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is H and the other is methyl.

43. R 2 and R 3 The compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein each of the elements is H.

44. R 2 and R 3 The compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein each is methyl.

45. A compound selected from the following, or a pharmaceutically acceptable salt thereof. Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11

46. A pharmaceutical composition comprising a compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

47. A therapeutic agent for treating sickle cell disease comprising a compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 46.

48. A compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, A therapeutic agent for treating red blood cells and inflammatory diseases, comprising the pharmaceutical composition according to claim 46.

49. A therapeutic agent for treating anemia, abnormal hemoglobinosis, asthma, rheumatoid arthritis, ulcerative colitis, and Crohn's disease, comprising a compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 46.

50. A therapeutic agent for treating anemia, sickle cell disease, thalassemia, asthma, rheumatoid arthritis, ulcerative colitis, and Crohn's disease, comprising a compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 46.

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