MRGPRX2 inhibitor and method of use thereof

Abstract

Compounds, compositions, and methods useful for preventing or treating MRGPRX2-mediated diseases or disorders are disclosed.

Claims

1. Equation (Ia) or (Ib): 【Chemistry 1】 A compound or a pharmaceutically acceptable salt thereof, wherein the formula is X is N or CR ｘ And, X １ , X ２ , and X ３ Each of these independently determines N or CR ｘ And, R ｘ However, each entity is independently hydrogen, fluoro, or chloro. Y is C(=O), C(=O)CH ２ ,CH ２ , or a combination, R １ is -OR １ａ or -CH ２ R １ａ where R １ａ is phenyl, (C １ -C ６ )alkyl, a 5- or 6-membered heteroaryl, or (C ３ -C ８ )cycloalkyl(C １ -C ６ )alkyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of fluoro, chloro, (C １ -C ６ )alkyl, (C ３ -C ８ )cycloalkyl, and (C １ -C ６ )alkoxy R ２ However, 4, 5, or 6-membered heterocycloalkyls, 9 or 10-membered bicyclic heterocycloalkyls, 5 or 6-membered heteroaryls, 9 or 10-membered bicyclic heteroaryls, (C ３ ~C ８ ) Cycloalkyl or phenyl, where these are fluoro, chloro, cyano, hydroxy, (C) １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , -NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, (C １ ~C ６ ) Halohydroxyalkyl, (C １ ~C ６ ) Hydroxylalkoxy, (C １ ~C ６ ) Carboxyalkyl (C １ ~C ６ ) Haloalkoxy, (C ３ ~C ８ ) optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 4- to 7-membered heterocycloalkyl groups, (C １ ~C ６ ) Alkyl is phenyl, 4-7 member heterocycloalkyl, or -NHR ２ａ It is optionally replaced by R ２ However, (C １ ~C ６ ) is alkyl, R ２ａ However, C(=O)R ２ｂ , (C １ ~C ６ ) alkyl, or (C ３ ~C ８ ) is cycloalkyl, (C １ ~C ６ ) alkyl or (C ３ ~C ８ ) The cycloalkyl group is optionally substituted by one or more independent entities of the halo. R ２ｂ However, (C １ ~C ６ ) is alkyl, R ３ and R ４ Each of them independently produces hydrogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkoxyalkyl, or (C １ ~C ６ ) are haloalkyl or, together with the carbon atoms to which they are bonded, (C ３ ~C ６ ) forms a cycloalkyl group, R ５ is hydrogen, (C １ ~C ６ )-alkyl, (C １ ~C ６ )-alkoxyalkyl, or (C １ ~C ６ )-haloalkyl, or R ５ is, together with R ３ or R ４ forming -(CH ２ ) ｎ -, n is 1, 2, or 3, R ６ and R ７ each independently, for each occurrence, is hydrogen or (C １ -C ６ )alkyl, or R ６ and R ７ together with the carbon atom to which they are attached form (C ３ -C ６ )cycloalkyl, said compound or a pharmaceutical salt thereof.

2. Equation (Ia) or (Ib): 【Chemistry 2】 A compound or a pharmaceutically acceptable salt thereof, wherein the formula is X is N or CR ｘ And, X １ , X ２ , and X ３ Each of these independently determines N or CR ｘ And, R ｘ However, each entity is independently hydrogen, fluoro, or chloro. Y is C(=O), C(=O)CH ２ ,CH ２ , or a combination, R １ However, -OR １ａ or -CH ２ R １ａ And R １ａ However, phenyl, 5-6 member heteroaryl, or (C ３ ~C ８ ) Cycloalkyl (C １ ~C ６ ) are alkyl, and these are fluoro, chloro, and (C) respectively. １ ~C ６ ) alkyl, (C ３ ~C ８ ) cycloalkyl and (C １ ~C ６ ) It is optionally substituted by one or more substituents independently selected from the group consisting of alkoxys, R ２ However, these are 5 or 6-membered heterocycloalkyls, 9 or 10-membered bicyclic heterocycloalkyls, 5 or 6-membered heteroaryls, 9 or 10-membered bicyclic heteroaryls, or phenyls, and these are each fluoro, chloro, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, and (C １ ~C ６ ) optionally substituted by one or more substituents independently selected from the group consisting of haloalkoxys, (C １ ~C ６ ) Alkyl is phenyl or -NHR ２ａ It is optionally replaced by R ２ａ However, it is optionally replaced by one or more independent entities of the halo (C ３ ~C ８ ) It is a cycloalkyl, R ３ and R ４ Each of them independently produces hydrogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkoxyalkyl, or (C １ ~C ６ ) are haloalkyl or, together with the carbon atoms to which they are bonded, (C ３ ~C ６ ) forms a cycloalkyl group, R ５ However, hydrogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkoxyalkyl, or (C １ ~C ６ ) Haloalkyl or R ５ However, R ３ Or R ４ Together with, - (CH ２ ) ｎ - is formed, and n is 1, 2, or 3. R ６ and R ７ However, each entity independently contains hydrogen or (C １ ~C ６ ) Alkyl or R ６ and R ７ However, together with the carbon atoms to which they are bonded, (C ３ ~C ６ ) The compound or a pharmaceutically acceptable salt thereof that forms a cycloalkyl group.

3. The aforementioned compound is of formula (Ia): 【Transformation 3】 The compound according to claim 1 or 2.

4. X １ The compound according to claim 3, wherein N is present.

5. X １ The compound according to claim 3, wherein the compound is CH.

6. X ２ The compound according to any one of claims 3 to 5, wherein the compound is CH.

7. X ３ The compound according to any one of claims 3 to 6, wherein the compound is CH.

8. X １ However, N is X ２ However, it is CH, and X ３ The compound according to claim 3, wherein the compound is CH.

9. X １ However, it is CH, and X ２ However, it is CH, and X ３ The compound according to claim 3, wherein the compound is CH.

10. The aforementioned compound is of formula (Ib): 【Chemistry 4】 The compound according to claim 1 or 2.

11. The compound according to claim 10, wherein X is CH.

12. The compound according to any one of claims 1 to 11, wherein Y is C (= O).

13. R １ However, -OR １ａ The compound according to any one of claims 1 to 12.

14. R １ａ The compound according to any one of claims 1 to 13, wherein the compound is a phenyl optionally substituted with one or two fluoro or chloro entities.

15. R １ａ The compound according to claim 14, wherein the compound is 4-fluorophenyl.

16. R １ａ The compound according to claim 14, wherein the compound is 2,4-difluorophenyl.

17. R １ａ The compound according to claim 14, wherein the compound is 4-chlorophenyl.

18. R １ａ The compound according to any one of claims 1 to 13, wherein the compound is a six-membered heteroaryl optionally substituted with one or two fluoro or chloro entities.

19. R １ａ The compound according to claim 18, wherein the pyridyl is optionally substituted with one or two fluoro or chloro groups.

20. R １ａ The compound according to claim 17 or 19, wherein the compound is 4-fluoropyridyl.

21. R １ａ However, (C ３ ~C ８ ) Cycloalkyl (C １ ~C ６ The compound according to any one of claims 1 to 13, wherein it is alkyl.

22. R １ａ The compound according to any one of claims 1 to 13, wherein the compound is cyclopropylmethyl.

23. R ２ However, fluoro, chloro, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , -NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, (C １ ~C ６ ) Halohydroxyalkyl, (C １ ~C ６ ) Hydroxylalkoxy, (C １ ~C ６ ) Carboxyalkyl (C １ ~C ６ ) Haloalkoxy, (C ３ ~C ８ ) A 9 or 10-membered bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyls and 4- to 7-membered heterocycloalkyls, (C １ ~C ６ ) Alkyl is phenyl, 4-7 member heterocycloalkyl, or -NHR ２ａ A compound according to any one of claims 1 to 22, which is optionally substituted by the compound.

24. R ２ However, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyrazine, [1,2,4]triazolo[1,5-a]pyrimidine, [1,2,4]triazolo[4,3-a]pyrimidine, [1,2,4]triazolo[1,5-b]pyridazine, 1H-pyrazolo[3,4-b]pyridine7-oxide, 3H-imidazo[4,5-b]pyridine4 -Oxide, benzo[d]oxazole, 1H-benzo[d]imidazole, benzo[d]thiazole, 1H-benzo[d][1,2,3]triazole, [1,2,3]oxadiazolo[4,5-b]pyridine, oxazolo[4,5-b]pyridine, 1H-indazole, 1H-pyrazolo[3,4-b]pyridine, or oxoisoindorin-1-yl, which are fluoro, chloro, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , -NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, (C １ ~C ６ ) Halohydroxyalkyl, (C １ ~C ６ ) Hydroxylalkoxy, (C １ ~C ６ ) Carboxyalkyl (C １ ~C ６ ) Haloalkoxy, (C ３ ~C ８ ) optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 4- to 7-membered heterocycloalkyl groups, (C １ ~C ６ ) Alkyl is phenyl, 4-7 member heterocycloalkyl, or -NHR ２ａ The compound according to claim 23, which is optionally substituted by [the specified agent].

25. R ２ However, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyrazine, [1,2,4]triazolo[1,5-a]pyrimidine, [1,2,4]triazolo[4,3-a]pyrimidine, [1,2,4]triazolo[1,5-b]pyridazine, 1H-pyrazolo[3,4-b]pyridine7-oxide, 3H -Imidazol[4,5-b]pyridine 4-oxide, benzo[d]oxazole, 1H-benzo[d]imidazole, benzo[d]thiazole, 1H-benzo[d][1,2,3]triazole, [1,2,3]oxadiazolo[4,5-b]pyridine, oxazolo[4,5-b]pyridine, or 1H-indazole, which are fluoro, chloro, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , -NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, (C １ ~C ６ ) Halohydroxyalkyl, (C １ ~C ６ ) Hydroxylalkoxy, (C １ ~C ６ ) Carboxyalkyl (C １ ~C ６ ) Haloalkoxy, (C ３ ~C ８ ) optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 4- to 7-membered heterocycloalkyl groups, (C １ ~C ６ ) Alkyl is phenyl, 4-7 member heterocycloalkyl, or -NHR ２ａ The compound according to claim 22, which is optionally substituted by the compound.

26. R ２ However, fluoro, chloro, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , -NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, (C １ ~C ６ ) Halohydroxyalkyl, (C １ ~C ６ ) Hydroxylalkoxy, (C １ ~C ６ ) Carboxyalkyl (C １ ~C ６ ) Haloalkoxy, (C ３ ~C ８ ) A 9 or 10-membered bicyclic heterocycloalkyl group optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl groups and 4- to 7-membered heterocycloalkyl groups, (C １ ~C ６ ) Alkyl is phenyl, 4-7 member heterocycloalkyl, or -NHR ２ａ A compound according to any one of claims 1 to 22, which is optionally substituted by the compound.

27. R ２ However, 6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, 4,5,6,7-tetrahydro-1H-benzo[d]imidazole, 4,5,6,7-tetrahydro These are lobenzo[d]oxazole, 4,5,6,7-tetrahydro-1l2-benzo[d][1,2,3]triazole, 6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxazine, 4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole, isoindorin-1-one, or 7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidine, which are fluoro, chloro, cyano, hydroxy, (C) respectively. １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , -NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, (C １ ~C ６ ) Halohydroxyalkyl, (C １ ~C ６ ) Hydroxylalkoxy, (C １ ~C ６ ) Carboxyalkyl (C １ ~C ６ ) Haloalkoxy, (C ３ ~C ８ ) optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 4- to 7-membered heterocycloalkyl groups, (C １ ~C ６ ) Alkyl is phenyl, 4-7 member heterocycloalkyl, or -NHR ２ａ The compound according to claim 26, which is optionally substituted by [the specified agent].

28. R ２ However, 6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, 4,5,6,7 -Tetrahydro-1H-benzo[d]imidazole, 4,5,6,7-tetrahydrobenzo[d]oxazole, 4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole, 6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxazine, 4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole, or isoindorin-1-one, which are fluoro, chloro, cyano, hydroxy, (C) respectively. １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , -NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, (C １ ~C ６ ) Halohydroxyalkyl, (C １ ~C ６ ) Hydroxylalkoxy, (C １ ~C ６ ) Carboxyalkyl (C １ ~C ６ ) Haloalkoxy, (C ３ ~C ８ ) optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 4- to 7-membered heterocycloalkyl groups, (C １ ~C ６ ) Alkyl is phenyl, 4-7 member heterocycloalkyl, or -NHR ２ａ The compound according to claim 27, which is optionally substituted by the compound.

29. R ２ These are pyridine-2(1H)-one, pyridine oxide, pyrimidine oxide, 1,5-dihydro-2H-pyrrole-2-one, phenyl, isoindorin-1-one, 1H-indazole, tetrahydro-2H-pyran, pyridine, 1H-pyrazole, 2-oxo-2,3-dihydro-1H-imidazole, 5-oxomorpholine, tetrahydropyrimidine-2(1H)-one, piperidine-2-one, pyrimidine-2(1H)-one, pyridazine-3(2H)-one, or pyrazine-2(1H)-one, and these are fluoro, chloro, cyano, hydroxy, (C) respectively. １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, and (C １ ~C ６ ) optionally substituted by one or more substituents independently selected from the group consisting of haloalkoxys, (C １ ~C ６ ) Alkyl is phenyl or -NHR ２ａ A compound according to any one of claims 1 to 22, which is optionally substituted by the compound.

30. R ２ These are pyridine-2(1H)-one, pyridine oxide, pyrimidine oxide, 1,5-dihydro-2H-pyrrole-2-one, phenyl, isoindorin-1-one, 1H-indazole, tetrahydro-2H-pyran, pyridine, 1H-pyrazole, 2-oxo-2,3-dihydro-1H-imidazole, or 5-oxomorpholine, and these are fluoro, chloro, cyano, hydroxy, (C) respectively. １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, and (C １ ~C ６ ) optionally substituted by one or more substituents independently selected from the group consisting of haloalkoxys, (C １ ~C ６ ) Alkyl is phenyl or -NHR ２ａ A compound according to any one of claims 1 to 22, which is optionally substituted by the compound.

31. R ２ These are pyridine-2(1H)-one, pyridine oxide, pyrimidine oxide, 1,5-dihydro-2H-pyrrole-2-one, phenyl, isoindorin-1-one, 1H-indazole, tetrahydro-2H-pyran, pyridine, or 1H-pyrazole, and these are fluoro, chloro, cyano, hydroxy, (C) respectively. １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, and (C １ ~C ６ ) optionally substituted by one or more substituents independently selected from the group consisting of haloalkoxys, (C １ ~C ６ ) Alkyl is phenyl or -NHR ２ａ A compound according to any one of claims 1 to 22, which is optionally substituted by the compound.

32. R ２ However, these are pyridine-2(1H)-one or pyridine oxide, and these are fluoro, chloro, cyano, hydroxy, and (C) respectively. １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkenyl, -C(=O)NH ２ , (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Hydroxyalkyl, and (C １ ~C ６ ) optionally substituted by one or more substituents independently selected from the group consisting of haloalkoxys, (C １ ~C ６ ) Alkyl is phenyl or -NHR ２ａ The compound according to claim 29, which is optionally substituted by [the specified agent].

33. R ２ The compound according to claim 29, wherein the compound is an unsubstituted pyridine-2(1H)-one or pyridine oxide.

34. R ２ However, (C １ ~C ６ The compound according to claim 29, wherein the pyrazine-2(1H)-one is optionally substituted with a hydroxyalkyl group.

35. R ２ａ The compound according to any one of claims 1 to 34, wherein the compound is methyl.

36. R ２ａ The compound according to any one of claims 1 to 34, wherein the compound is a cyclobutyl atom optionally substituted with at least one fluoropolymer.

37. R ２ｂ The compound according to any one of claims 1 to 36, wherein the compound is methyl.

38. R ３ and R ４ The compound according to any one of claims 1 to 37, wherein each of them is hydrogen.

39. R ３ and R ４ Each of them operates independently, (C １ ~C ６ The compound according to any one of claims 1 to 34, wherein it is alkyl.

40. R ３ and R ４ The compound according to claim 39, wherein each of them is methyl.

41. R ３ and R ４ The compound according to any one of claims 1 to 37, wherein one of the elements is hydrogen.

42. R ３ and R ４ One of them is (C １ ~C ６ The compound according to claim 41, wherein it is a fluoroalkyl compound.

43. (C １ ~C ６ The compound according to claim 42, wherein the fluoroalkyl is trifluoromethyl.

44. R ３ and R ４ However, together with the carbon atoms to which they are bonded, (C ３ ~C ６ The compound according to any one of claims 1 to 37, wherein it forms a cycloalkyl group.

45. R ３ and R ４ The compound according to claim 44, wherein these carbon atoms, together with the carbon atoms to which they are bonded, form a cyclopropyl group.

46. R ３ and R ４ The compound according to claim 44, wherein these carbon atoms, together with the carbon atoms to which they are bonded, form cyclobutyl.

47. R ５ The compound according to any one of claims 1 to 46, wherein the compound is hydrogen.

48. R ５ However, R ３ or R ４ It combines with one of them, - (CH ２ ) ｎ A compound according to any one of claims 1 to 43, which forms a -

49. The compound according to claim 48, wherein n is 2.

50. R ６ or R ７ The compound according to any one of claims 1 to 49, wherein one of the elements is hydrogen.

51. R ６ or R ７ One of them is (C １ ~C ６ The compound according to any one of claims 1 to 50, wherein it is alkyl.

52. R ６ or R ７ The compound according to claim 51, wherein one of them is methyl.

53. R ６ or R ７ The compound according to claim 51, wherein one of them is ethyl.

54. R ６ and R ７ The compound according to any one of claims 1 to 49, wherein each of them is hydrogen.

55. R ６ and R ７ Each of them is (C １ ~C ６ The compound according to any one of claims 1 to 49, wherein it is alkyl.

56. R ６ and R ７ The compound according to claim 55, wherein each of them is methyl.

57. R ６ and R ７ However, together with the carbon atoms to which they are bonded, (C ３ ~C ６ The compound according to any one of claims 1 to 49, wherein it forms a cycloalkyl group.

58. R ６ and R ７ The compound according to claim 57, wherein these carbon atoms, together with the carbon atoms to which they are bonded, form a cyclopropyl group.

59. A compound having the following structure or a pharmaceutically acceptable salt thereof. 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】

60. A compound having the following structure or a pharmaceutically acceptable salt thereof. 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】

61. A compound having the following structure or a pharmaceutically acceptable salt thereof. 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】

62. A pharmaceutical composition comprising a compound according to any one of claims 1 to 61 and at least one pharmaceutically acceptable excipient.

63. A method for preventing or treating an MRGPRX2-mediated disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 61 to a subject in need thereof.

64. The method according to claim 63, wherein the MRGPRX2-mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, nodular prurigo, irritable bowel syndrome, chronic inductive urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, anaphylactic-like reaction, mast cell activation syndrome, mastocytosis, pruritus, neurodermatitis, contact urticaria, allergic rhinitis, asthma, acute contact dermatitis, ulcerative colitis, Crohn's disease, idiopathic chronic cough, rheumatoid arthritis, multiple sclerosis, geographic atrophy, endometriosis, seborrheic dermatitis, psoriasis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, neuropathic pruritus, periodontitis, autism, abdominal aortic aneurysm, deep vein thrombosis, amyotrophic lateral sclerosis, interstitial cystitis, coronary artery disease, cancer, sickle cell anemia, obesity, and ulcers.

65. The method according to claim 63 or 64, wherein the MRGPRX2-mediated disease or disorder is prevented.

66. The method according to claim 63 or 64, wherein the MRGPRX2-mediated disease or disorder is treated.

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