GCN2 and PERK kinase modulators and their methods of use

Abstract

This specification describes compounds that are modulators of GCN2 kinase or PERK kinase, and methods for treating diseases, including diseases related to GCN2 kinase or PERK kinase, with said compounds.

Claims

1. Compound represented by formula I-A: 【Chemistry 1】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, X １ and X ４ However, each is independently selected from the group consisting of CH and N, X ２ However, selected from the group consisting of C and N, X ３ However, CR ４ and NR ４ Selected from the group consisting of, However, X １ , X ２ , X ３ , and X ４ are subject to the condition that two or fewer of them are N X ５ However, CR ５ Selected from the group consisting of and N, R １ and R ２ However, each is independently selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen. R ３ However, it is selected from the group consisting of H, alkyl, alkoxy, cyano, and halogen, R ４ However, it is selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl, alkynyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, R ５ However, it is selected from the group consisting of H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclylalkyl, R ６ , R ７ , and R ８ However, each is independently selected from the group consisting of H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl. R ９ However, it is selected from the group consisting of H, halogens, and alkyls. however, i) X ２ If C, 【Chemistry 2】 but, 【Transformation 3】 Instead, In the formula, R ６ However, selected from the group consisting of halogens, alkoxys, and alkyls, R ８ However, it is selected from the group consisting of H, halogens, and alkyls. R １０ However, it is selected from the group consisting of H, alkyl, and acyl, ii) X ２ C is X ３ NR ４ If that is the case, 【Chemistry 4】 but, 【Transformation 5】 Instead, In the formula, R ６ H is, R ７ However, H, Cl, and OCH ３ Selected from the group consisting of, R ８ However, it is H or Br, R ９ However, it is H, iii) X ２ C is X ３ NR ４ If that is the case, 【Transformation 6】 but, 【Transformation 7】 Instead, In the formula, R ５ However, H, F, Cl, CH ３ , OCH ３ CF ３ Selected from the group consisting of , and CN, R ６ However, it is H or F, R ７ However, H, F, Cl, Br, I, CH ３ , OCH3, OCH ２ CH ３ , OCH(CH ３ ) ２ CF ３ OH, and OCF ３ Selected from the group consisting of, R ８ However, H, F, Cl, CH ３ , OCH ３ CF ３ Selected from the group consisting of , and CN, R ９ A compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, provided that the element is H or F.

2. R １ , R ２ and R ３ The compound according to claim 1, wherein at least one of them is a halogen.

3. R １ , R ２ and R ３ The compound according to claim 1 or 2, wherein at least one of the elements is fluoro.

4. R １ The compound according to any one of claims 1 to 3, wherein it is fluoro.

5. X １ The compound according to any one of claims 1 to 4, wherein N is present.

6. X ２ The compound according to any one of claims 1 to 4, wherein N is present.

7. Compound represented by formula I-B: 【Transformation 8】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, X ５ However, CR ５ Selected from the group consisting of and N, R １ and R ２ However, each is independently selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen. R ３ However, it is selected from the group consisting of H, alkyl, and halogen, R ４ However, it is selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl, alkynyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, R ５ However, it is selected from the group consisting of H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclylalkyl, R ６ , R ７ , and R ８ However, each is independently selected from the group consisting of H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl. R ９ However, it is selected from the group consisting of H, halogens, and alkyls. however, i) 【Chemistry 9】 but, 【Chemistry 10】 Instead, In the formula, R ６ However, selected from the group consisting of halogens, alkoxys, and alkyls, R ８ However, it is selected from the group consisting of H, halogens, and alkyls. R １０ However, it is selected from the group consisting of H, alkyl, and acyl, ii) 【Chemistry 11】 but, 【Chemistry 12】 Instead, In the formula, R ６ H is, R ７ However, H, Cl, and OCH ３ Selected from the group consisting of, R ８ However, it is H or Br, R ９ However, it is H, iii) 【Chemistry 13】 but, 【Chemistry 14】 Instead, In the formula, R ５ However, H, F, Cl, CH ３ , OCH ３ CF ３ Selected from the group consisting of , and CN, R ６ However, it is H or F, R ７ is selected from the group consisting of H, F, Cl, Br, I, CH ３ , OCH ３ , OCH ２ CH ３ , OCH(CH ３ ) ２ , CF ３ , OH, and OCF ３ ; and is selected from the group consisting of R ８ is selected from the group consisting of H, F, Cl, CH ３ , OCH ３ , CF ３ , and CN; R ９ A compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, provided that it is H or F.

8. Compounds represented by formula I-C: 【Chemistry 15】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, X １ and X ４ However, each is independently selected from the group consisting of CH and N, X ２ However, selected from the group consisting of C and N, X ３ However, CR ４ and NR ４ Selected from the group consisting of, However, X １ , X ２ , X ３ , and X ４ The condition is that two or fewer of them are N, R １ and R ２ However, each is independently selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen. R ３ However, it is selected from the group consisting of H, alkyl, and halogen, R ４ However, it is selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl, alkynyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, R ６ , R ７ , and R ８ However, each is independently selected from the group consisting of H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl. R ９ However, it is selected from the group consisting of H, halogens, and alkyls. however, X ２ C is X ３ NR ４ And R ６ H is R ８ is H or Br, R ９ If H, then R ７ is H, Cl, or OCH ３ A compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, provided that it is not a compound.

9. X １ The compound according to claim 8, wherein N is present.

10. X ２ The compound according to claim 8, wherein N is present.

11. Compounds represented by formulas I-D: 【Chemistry 16】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, X １ and X ４ However, each is independently selected from the group consisting of CH and N, X ３ However, CR ４ and NR ４ Selected from the group consisting of, However, X １ , X ３ , and X ４ The condition is that one or less of them is N, X ５ However, CR ５ Selected from the group consisting of and N, R １ and R ２ However, each is independently selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen. R ３ However, it is selected from the group consisting of H, alkyl, and halogen, R ４ However, it is selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl, alkynyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, R ５ However, it is selected from the group consisting of H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclylalkyl, R ６ , R ７ , and R ８ However, each is independently selected from the group consisting of H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl. R ９ A compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, provided that it is selected from the group consisting of H, halogens, and alkyls.

12. X １ CH is, X ３ CR ４ X ４ The compound according to claim 11, wherein is N.

13. Compounds represented by formula (I-E): 【Chemistry 17】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, X ５ However, CR ５ Selected from the group consisting of and N, R １ and R ２ However, each is independently selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen. R ３ However, it is selected from the group consisting of H, alkyl, and halogen, R ４ However, it is selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl, alkynyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, R ５ However, it is selected from the group consisting of H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclylalkyl, R ６ , R ７ , and R ８ However, each is independently selected from the group consisting of H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl. R ９ A compound selected from the group consisting of H, halogens, and alkyls, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

14. Compounds represented by formula I-F: [Chemistry 18] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the formula, R １ and R ２ However, each is independently selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen. R ３ However, it is selected from the group consisting of H, alkyl, and halogen, R ４ However, it is selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl, alkynyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, R ６ , R ７ , and R ８ Each of these is independently selected from the group consisting of H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl. R ９ It is selected from the group consisting of H, halogens, and alkyls. R １１ This refers to a compound selected from the group consisting of H and acyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

15. R ２ However, H is R ３ The compound according to any one of claims 7 to 14, wherein H is present.

16. R １ F is R ２ H is R ３ The compound according to any one of claims 7 to 14, wherein is H.

17. R ２ However, F is R ３ The compound according to any one of claims 7 to 14, wherein H is present.

18. R ２ However, H is R ３ The compound according to any one of claims 7 to 14, wherein F is present.

19. R ４ The compound according to any one of claims 1 to 18, wherein the compound is selected from the group consisting of H, alkyl, (C2-C8)alkenyl, (C2-C8)alkenyl-(C1-C4)alkyl, (C2-C8)alkynyl, (C2-C8)alkynyl-(C1-C4)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl-(C1-C4)alkyl, alkoxy-(C1-C4)alkyl, (C3-C8)cycloalkenyl, (C3-C8)cycloalkenyl-(C1-C4)alkyl, alkylamino, amide, thio-(C1-C4)alkyl, heterocyclyl, heterocyclyl-(C1-C4)alkyl, aryl, heteroaryl, and heteroaryl-(C1-C4)alkyl, wherein the alkyl component of the alkylamino is optionally substituted with an alkoxy.

20. R ４ The compound according to any one of claims 1 to 19, wherein the compound is selected from the group consisting of H, alkyl, (C3-C8)cycloalkyl, alkylamino, amide, thio-(C1-C4)alkyl, heterocyclyl, and heteroaryl, and the alkyl component of the alkylamino is optionally substituted with a (C1-C6)alkoxy.

21. R ４ The compound according to any one of claims 1 to 20, wherein H and the following are selected from the group. 【Chemistry 19】

22. R ５ The compound according to any one of claims 1 to 7, 11 to 13, and 15 to 21, which is selected from the group consisting of H, alkyl, (C3-C8) cycloalkyl, alkylamino, hydroxy-(C1-C4) alkyl, hydroxy-(C3-C8) cycloalkyl, alkoxy-(C1-C4) alkyl, alkoxy-(C3-C8) cycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, amino-(C1-C4) alkyl, amino-(C3-C8) cycloalkyl, aminocarbonyl, acylamino, acyloxy-(C1-C4) alkyl, hydroxyimino, alkoxyimino, cyano-(C1-C4) alkyl, heterocyclyl, (C3-C8) cycloalkylamino, (C1-C4) alkoxycarbonyl, and heterocyclyl-(C1-C4) alkyl.

23. R ５ The compound according to any one of claims 1 to 7, 11 to 13, and 15 to 22, which is selected from the group consisting of H, alkyl, alkylamino, hydroxy-(C1-C4)alkyl, alkoxy-(C1-C4)alkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, amino-(C1-C4)alkyl, acyloxy-(C1-C4)alkyl, hydroxyimino, alkoxyimino, cyano-(C1-C4)alkyl, heterocyclyl, and alkoxycarbonyl.

24. R ５ The compound according to any one of claims 1 to 7, 11 to 13, and 15 to 23, wherein the compound is selected from the group consisting of H, fluoro, chloro, bromo, CF3, and the following. 【Chemistry 20】

25. R ６ , R ７ , and R ８ The compound according to any one of claims 1 to 24, wherein each of the elements is independently selected from the group consisting of H, alkyl, alkoxy, hydroxy, cyano, halogen, haloalkyl, alkylamino, (C3-C8)cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxy-(C1-C4)alkyl.

26. R ６ , R ７ , and R ８ The compound according to any one of claims 1 to 25, wherein each of the elements is independently selected from the group consisting of H, alkyl, alkoxy, hydroxy, halogen, and hydroxy-(C1-C4)alkyl.

27. R ６ The compound according to any one of claims 1 to 26, wherein the compound is selected from the group consisting of H, methyl, methoxy, fluoro, and chloro.

28. R ７ However, H, methoxy, fluoro, bromo and 【Chemistry 21】 A compound according to any one of claims 1 to 27, selected from the group consisting of the following.

29. R ９ The compound according to any one of claims 1 to 28, selected from the group consisting of H, halogens, and alkyl groups.

30. R ９ The compound according to any one of claims 1 to 29, wherein the compound is selected from the group consisting of H and fluoro.

31. R １１ The compound according to claim 14, wherein H and the following are selected from the group. 【Chemistry 22】

32. R １１ The compound according to claim 14, wherein the compound is selected from the group consisting of H, fluoro, and chloro.

33. Compounds selected from the following group: 【Chemistry 23-1】 【Chemistry 23-2】 Furthermore, pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

35. A method for treating a disease caused by dysregulation of the integrated stress response and / or endoplasmic reticulum stress response in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34.

36. The method according to claim 35, wherein the dysregulation of the integrated stress response and / or the endoplasmic reticulum stress response is caused by a kinase selected from the group consisting of PKR-like ER kinase (PERK kinase) and GCN2 (general control nonderepressible 2) kinase.

37. The method according to claim 35 or 36, wherein the dysregulation of the integrated stress response and / or the endoplasmic reticulum stress response is caused by GCN2 kinase.

38. The method according to claim 35 or 36, wherein the dysregulation of the integrated stress response and / or the endoplasmic reticulum stress response is caused by PERK kinase.

39. A method for regulating the activity of GCN2 kinase in a patient requiring regulation of GCN2 kinase activity, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34.

40. A method for regulating the activity of PERK kinase in a patient requiring regulation of PERK kinase activity, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34.

41. A method for treating cancer in a patient requiring cancer treatment, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34.

42. The method according to claim 41, wherein the cancer is selected from the group consisting of colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small intestine cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, hematological cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenström macroglobulinemia, light chain amyloidosis, and malignant lymphoma.

43. A method for treating amyloidosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34.

44. A method for treating light chain amyloidosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34.

45. The method according to any one of claims 35 to 44, further comprising administering a therapeutically effective amount of one or more therapeutic agents to the patient.

46. The method according to claim 45, wherein the one or more therapeutic agents are selected from the group consisting of IMiD agents, proteasome inhibitors, steroids, anti-CD38 agents, anti-CD20 agents, Bcl-2 inhibitors, PI3K inhibitors, bispecific antibodies, nucleoside analogs, BTK inhibitors, DNA alkylating agents, EZH2 inhibitors, anthracyclines, topoisomerase inhibitors, platin, tyrosine kinase inhibitors, HDAC inhibitors, nuclear export inhibitors, microtubule inhibitors, L-asparaginase, pegylated asparaginase, PERK inhibitors, mTOR inhibitors, immunomodulators, anti-angiogenic drugs, EGFR inhibitors, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors.

47. The one or more of the above-mentioned therapeutic agents include L-asparaginase, pegaspargase, caraspargase pegol-mnkl, bortezomib, carfilzomib, ixazomib, thalidomide, pomalidomide, lenalidomide, dexamethasone, prednisone, daratumumab, daratumumab / hyaluronidase, isatuximab, rituximab, obinutuzumab, venetoclax, idelalisib, copanlisib, duberisib, umbralicib, gemcitabine, and sita. Rabin, ibrutinib, acalabrutinib, zanubrutinib, bendamustine, cyclophosphamide, tazemetostat, doxorubicin, daunorubicin, etoposide, oxaloplatin, carboplatin, cisplatin, bosutinib, dasatinib, imatinib, nilotinib, ponatinib, panobinostat, selinexol, vincristine, JZP-458, eryaspase, PF745 (JZP-341), asparaginase Erwinia The method according to claim 45, selected from the group consisting of chrysanthemia (chrysanthase), Escherichia coli asparaginase (collaspase), erlotinib, gefitinib, osimertinib, afatinib, cetuximab, bevacizumab, axitinib, sunitinib, sorafenib, cabozantinib, pazopanib, lenvatinib, vandetanib, regorafenib, nintedanib, apatinib, anti-PD1 agents, anti-PDL1 agents, and anti-CTLA4 agents.

48. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34, for use in the treatment of a disease caused by dysregulation of the integrated stress response and / or endoplasmic reticulum stress response in a patient who requires such treatment.

49. The compound or composition according to claim 48, wherein the dysregulation of the integrated stress response and / or the endoplasmic reticulum stress response is caused by a kinase selected from the group consisting of PERK kinase and GCN2 kinase.

50. The compound or composition according to claim 48 or 49, wherein the dysregulation of the integrated stress response and / or the endoplasmic reticulum stress response is caused by GCN2 kinase.

51. The compound or composition according to claim 48 or 49, wherein the dysregulation of the integrated stress response and / or the endoplasmic reticulum stress response is caused by PERK kinase.

52. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34, for use in regulating the activity of GCN2 kinase in patients who require it.

53. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34, for use in regulating the activity of PERK kinase in patients who require it.

54. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34, for use in the treatment of patients who require it.

55. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34, for use in the treatment of cancer in patients who require it.

56. The compound or composition for use according to claim 55, wherein the cancer is selected from the group consisting of colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small intestine cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, hematological cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenström macroglobulinemia, and malignant lymphoma.

57. The compound or composition according to claim 55 or 56, wherein the cancer is leukemia.

58. The compound or composition according to claim 55 or 56, wherein the cancer is acute myeloid leukemia.

59. The compound or composition according to claim 55 or 56, wherein the cancer is acute lymphoblastic leukemia.

60. The compound or composition according to claim 55 or 56, wherein the cancer is a fibrosarcoma.

61. The compound or composition according to claim 55 or 56, wherein the cancer is multiple myeloma.

62. The compound or composition according to claim 55 or 56, wherein the cancer is lymphoma.

63. The compound or composition according to claim 55 or 56, wherein the cancer is B-cell lymphoma.

64. The compound or composition according to claim 55 or 56, wherein the cancer is T-cell lymphoma.

65. The compound or composition for use according to claim 55 or 56, wherein the cancer is renal cancer.

66. The compound or composition for use according to claim 55 or 56, wherein the cancer is lung cancer.

67. The compound or composition for use according to claim 55 or 56, wherein the cancer is colorectal cancer.

68. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34, for use in the treatment of amyloidosis in patients who require it.

69. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34, for use in the treatment of light chain amyloidosis in patients who require it.

70. A compound or composition for use according to any one of claims 48 to 69, further comprising the use of one or more therapeutic agents.

71. The compound or composition according to claim 70, wherein the one or more therapeutic agents are selected from the group consisting of IMiD agents, proteasome inhibitors, steroids, anti-CD38 agents, anti-CD20 agents, Bcl-2 inhibitors, PI3K inhibitors, bispecific antibodies, nucleoside analogs, BTK inhibitors, DNA alkylating agents, EZH2 inhibitors, anthracyclines, topoisomerase inhibitors, platin, tyrosine kinase inhibitors, HDAC inhibitors, nuclear export inhibitors, microtubule inhibitors, L-asparaginase, pegylated asparaginase, PERK inhibitors, mTOR inhibitors, immunomodulators, anti-angiogenic drugs, EGFR inhibitors, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors.

72. The one or more of the above-mentioned therapeutic agents include L-asparaginase, pegaspargase, caraspargase pegol-mnkl, bortezomib, carfilzomib, ixazomib, thalidomide, pomalidomide, lenalidomide, dexamethasone, prednisone, daratumumab, daratumumab / hyaluronidase, isatuximab, rituximab, obinutuzumab, venetoclax, idelalisib, copanlisib, duberisib, umbralicib, gemcitabine, and sita. Rabin, ibrutinib, acalabrutinib, zanubrutinib, bendamustine, cyclophosphamide, tazemetostat, doxorubicin, daunorubicin, etoposide, oxaloplatin, carboplatin, cisplatin, bosutinib, dasatinib, imatinib, nilotinib, ponatinib, panobinostat, selinexol, vincristine, JZP-458, eryaspase, PF745 (JZP-341), asparaginase Erwinia A compound or composition according to claim 70, selected from the group consisting of chrysanthemia (chrysanthase), Escherichia coli asparaginase (colaspase), erlotinib, gefitinib, osimertinib, afatinib, cetuximab, bevacizumab, axitinib, sunitinib, sorafenib, cabozantinib, pazopanib, lenvatinib, vandetanib, regorafenib, nintedanib, apatinib, anti-PD1 agent, anti-PDL1 agent, and anti-CTLA4 agent.

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