Tricyclic heteroaromatic inhibitors of KLK5

By developing tricyclic system compounds with specific structures to inhibit KLK5 activity, the skin disease problem caused by excessive KLK5 was solved, providing an effective treatment solution.

CN122070129APending Publication Date: 2026-05-19BIOCRYST PHARMACEUTICALS INC
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
BIOCRYST PHARMACEUTICALS INC
Filing Date
2024-08-23
Publication Date
2026-05-19

AI Technical Summary

Technical Problem

Skin diseases caused by excessive KLK5 activity, such as Netherton syndrome, lack effective inhibitors in current technology.

Method used

Develop tricyclic system compounds with specific structures, including compounds with aromatic or heteroaromatic rings, to inhibit KLK5 activity.

Benefits of technology

It effectively inhibits KLK5 activity, reduces skin disease symptoms, and provides therapeutic potential.

✦ Generated by Eureka AI based on patent content.

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Abstract

The present invention discloses tricyclic heteroaromatic compounds of Formula (I) and Formula (II) and pharmaceutically acceptable salts thereof as kallikrein-related peptidase 5 (KLK5) inhibitors. Also provided are pharmaceutical compositions comprising such compounds, as well as methods of using the compounds and compositions to treat or prevent diseases or conditions characterized by aberrant KLK5 activity, such as Internal Thiphon Syndrome.
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Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: ； in: ring It is a tricyclic system containing at least one aromatic ring or heteroaromatic ring; ring It is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; Among them, J and ring Bond to loop The same ring within the aforementioned three-ring system; ring It is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; J represents -NH-, -CH2-, -C(O)-, -O-, -S-, -S(O)-, -SO2-, -N(alkyl)-, -CH(alkyl)-, -CH(CF3)-, -CH(aryl)-, -C(alkyl)2-, -CH(cycloalkyl)-, Or it may not exist; K represents -C(O)-, -O-, -NH-, -CH2-, -S-, -S(O)-, -SO2-, -N(alkyl)-, -NHCH2-, -CH(alkyl)-, -CH(cycloalkyl)-, or is absent; At least one of J and K is absent, or it is -C(O)-, -CH2-, -CH(alkyl)- or -CH(aryl)-; Y represents -H, -CH2NH2, -C(=NH)(NH2), -C(O)NH2, -NH2, -CN, halogenated, -CH2C(O)OH, -C(O)OH, -S(O)2NH2, -CH2CN, -NHBoc, -CH2NHCH3, -CH(CH3)NH2, -CH2NHCH=NOH, -CH2OH, amino-substituted cycloalkyl or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalyl, heteroaryl or heteroarylalkyl; V is -C(O)R E Or H; R E It is -OH, -NH-OH, -O (alkyl), -C(O) (haloalkyl) or ; T is a bond, or represents -C(O)-, -C(O)NH-, -C(O)N(alkyl)-, -C(O)O-, -CH2NH-, -CH2O-, -CH(CF3)-NH-, -NH-CH(CF3)- or -NHC(O)-; R T It represents H, halogen, -CH2C(O)NH2, -CH2C(O)OH or optionally substituted alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, spirocycloalkyl, heterospirocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R A Each time it appears, it independently indicates alkyl, halogenated, -NHBoc, toluenesulfonyl, hydroxyalkyl, aminoalkyl, or alkoxyalkyl; R B Each time it appears, it independently represents halogen, -C(O)OH, -C(O)NH2, -C(O)NH (alkyl), -C(O)NH (aminoalkyl), oxo, cyano, hydroxy or optionally substituted alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. R D Each occurrence independently represents hydroxyl, halogen, -CN, -C(O)OH, -C(O)NH (alkyl), -C(O)NH (cycloalkyl), -CH2C(O) (alkyl), -CH2C(O)OR D1 -CH2C(O)NHR D1 -O[(CH2) x O] y (alkyl), -O(CH2) x COOH, (hydroxy)alkoxy, (halo)alkoxy, (alkoxy)alkoxy, arylalkoxy, (cycloalkyl)alkoxy or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalenyl, heteroaryl, heteroarylalkyl, alkoxy, hydroxyalkyl or haloalkyl. R D1 Each time it appears, it independently represents H, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; m, n, and q are each independent integers selected from 0 to 3; and x and y are each independent integers selected from 1 to 10.

2. The compound according to claim 1, wherein the compound has the structure of formula (Ia): ； in: ring and ring Each is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, partially unsaturated cycloalkyl, or partially unsaturated heterocycloalkyl; m1 and m2 are each integers selected from 0 to 3; and The sum of m1 and m2 is 3 or less.

3. The compound according to claim 2, wherein the compound has the structure of formula (Ia-1): 。 4. The compound according to claim 3, wherein... It has the following structure: .

5. The compound according to claim 4, wherein... Choose from the following groups: , , , , and .

6. The compound according to claim 3, wherein... It has the following structure: ; in: Z 1 Z 2 and Z 3 Each was independently selected from S, CH and CR A ;and Z 1 Z 2 and Z 3 One and only one of them is S.

7. The compound according to claim 6, wherein... Choose from the following groups: , , , , , , , , , , and .

8. The compound according to claim 6, wherein It has the following structure: .

9. The compound according to claim 6, wherein... Choose from the following groups: , and .

10. The compound according to claim 6, wherein... It has the following structure: .

11. The compound according to claim 6, wherein... Choose from the following groups: , and .

12. The compound according to claim 3, wherein... yes .

13. The compound according to claim 3, wherein... yes .

14. The compound according to claim 3, wherein yes .

15. The compound according to any one of claims 1 to 14, wherein R A Each time it appears, it independently indicates an alkyl group.

16. The compound according to any one of claims 2 to 15, wherein m1 and m2 are 0 each time they occur.

17. The compound according to any one of claims 1 to 16, wherein the ring... It is a double ring.

18. The compound according to any one of claims 1 to 16, wherein the ring It is a single ring.

19. The compound according to any one of claims 1 to 16, wherein yes ;and W is either N or CH.

20. The compound according to claim 19, wherein W is N.

21. The compound according to claim 19, wherein W is CH.

22. The compound according to any one of claims 1 to 16, wherein yes .

23. The compound according to any one of claims 1 to 22, wherein V is -C(O)R E .

24. The compound according to claim 23, wherein R E It is -OH or -O (methyl).

25. The compound according to claim 23, wherein R E It is -OH.

26. The compound according to any one of claims 1 to 25, wherein n is 0.

27. The compound according to any one of claims 1 to 26, wherein -TR T It's H.

28. The compound according to any one of claims 1 to 26, wherein T is a bond, and R T It is an aryl, heteroaryl, heterocycloalkyl, or cycloalkyl group that is optionally substituted.

29. The compound according to any one of claims 1 to 26, wherein T is -C(O)-, -C(O)NH- or -C(O)N(alkyl)-.

30. The compound according to any one of claims 1 to 26, wherein T is -C(O)-, and R T It is an optionally substituted heterocyclic alkyl group, preferably an optionally substituted N-linked heterocyclic alkyl group.

31. The compound according to any one of claims 1 to 26, wherein T is -C(O)NH-.

32. The compound according to claim 31, wherein R T It is an alkyl, hydroxyalkyl, haloalkyl, (cycloalkyl)alkyl, (heterocyclic alkyl), arylalkyl or heteroarylalkyl that may be optionally substituted.

33. The compound according to claim 32, wherein R T It is an alkyl group that is optionally substituted.

34. The compound according to claim 31, wherein R T It is optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

35. The compound according to claim 34, wherein R T It is a cycloalkyl group that is optionally substituted.

36. The compound according to any one of claims 1 to 35, wherein -JK- is selected from the group consisting of: -C(O)-NH-, -C(O)-N(CH3)-, -C(O)-NHCH2-, -CH2-O- and -CH2-NH-.

37. The compound according to claim 36, wherein -JK- is -C(O)-NH-.

38. The compound according to any one of claims 1 to 37, wherein the ring It is a double ring.

39. The compound according to any one of claims 1 to 37, wherein the ring... It is a single ring.

40. The compound according to any one of claims 1 to 39, wherein the ring Choose from the group consisting of: phenyl, pyrazinyl, pyridinyl, pyrimidinyl, thiophene, tetrahydroisoquinolinyl, benzimidazolyl, indolyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, cyclohexyl, isoindololinyl, isoquinolinyl, or naphthyl.

41. The compound according to claim 40, wherein the ring... It is phenyl.

42. The compound according to claim 40, wherein the ring... It is pyridyl.

43. The compound according to claim 40, wherein the ring... It is benzimidazolyl, indolyl, or isoquinolinyl.

44. The compound according to any one of claims 1 to 37, wherein the ring It is represented by the following: , , , , , or .

45. The compound according to claim 44, wherein Y is -NH2.

46. ​​The compound according to any one of claims 1 to 37, wherein the ring Depend on express.

47. The compound according to any one of claims 1 to 37, wherein the ring Depend on express.

48. The compound according to claim 46 or 47, wherein Y is selected from the group consisting of -CH2NH2, -C(=NH)(NH2) and -C(O)NH2.

49. The compound according to claim 48, wherein Y is -CH2NH2.

50. The compound according to any one of claims 1 to 37, wherein the ring Depend on express.

51. The compound according to claim 50, wherein Y is -CH2NH2.

52. The compound according to any one of claims 1 to 51, wherein R D Each time it appears, it independently represents hydroxyl, halogen, -C(O)NH(alkyl) or optionally substituted alkyl, alkoxy, hydroxyalkyl or haloalkyl.

53. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following table: 。 54. A compound of formula (II), or a pharmaceutically acceptable salt thereof: ； in: ring and ring Each is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, partially unsaturated cycloalkyl, or partially unsaturated heterocycloalkyl; ring It is optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; ring It is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; J represents -NH-, -CH2-, -C(O)-, -O-, -S-, -S(O)-, -SO2-, -N(alkyl)-, -CH(alkyl)-, -CH(CF3)-, -CH(aryl)-, -C(alkyl)2-, -CH(cycloalkyl)-, Or it may not exist; K represents -C(O)-, -O-, -NH-, -CH2-, -S-, -S(O)-, -SO2-, -N(alkyl)-, -NHCH2-, -CH(alkyl)-, -CH(cycloalkyl)-, or is absent; At least one of J and K is absent, or it is -C(O)-, -CH2-, -CH(alkyl)- or -CH(aryl)-; Y represents -H, -CH2NH2, -C(=NH)(NH2), -C(O)NH2, -NH2, -CN, halogenated, -CH2C(O)OH, -C(O)OH, -S(O)2NH2, -CH2CN, -NHBoc, -CH2NHCH3, -CH(CH3)NH2, -CH2NHCH=NOH, -CH2OH, amino-substituted cycloalkyl or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalyl, heteroaryl or heteroarylalkyl; V is -C(O)R E Or H; R E It is -OH, -NH-OH, -O (alkyl), -C(O) (haloalkyl) or ; R A It represents H, alkyl, alkoxy, halogen, -NHBoc, toluenesulfonyl, hydroxyalkyl, aminoalkyl, or alkoxyalkyl; R B2 and R B3 Each time it appears, it independently represents halogen, -C(O)OH, -C(O)NH2, -C(O)NH (alkyl), -C(O)NH (aminoalkyl), oxo, cyano, hydroxy or optionally substituted alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. R D Each occurrence independently represents hydroxyl, halogen, -CN, -C(O)OH, -C(O)NH (alkyl), -C(O)NH (cycloalkyl), -CH2C(O) (alkyl), -CH2C(O)OR D1 -CH2C(O)NHR D1 -O[(CH2) x O] y (alkyl), -O(CH2) x COOH, (hydroxy)alkoxy, (halo)alkoxy, (alkoxy)alkoxy, arylalkoxy, (cycloalkyl)alkoxy or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalyl, heteroaryl, heteroarylalkyl, alkoxy, hydroxyalkyl or haloalkyl. R D1 Each time it appears, it independently represents H, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; q, m1, and m2 are each independent integers selected from 0 to 3; The sum of m1 and m2 is 3 or less; and x and y are each independent integers selected from 1 to 10.

55. The compound according to claim 54, wherein... It has the following structure: .

56. The compound according to claim 55, wherein... It has a structure that selects groups from the following: , and .

57. The compound according to claim 54, wherein... It has the following structure: .

58. The compound according to claim 57, wherein... It has a structure that selects groups from the following: , and .

59. The compound according to any one of claims 54 to 58, wherein R B2 and R B3 Each of these terms independently indicates either a halogenated or alkyl group.

60. The compound according to any one of claims 54 to 59, wherein V is -C(O)R E .

61. The compound according to claim 60, wherein R E It is -OH or -O (methyl).

62. The compound according to claim 60, wherein R E It is -OH.

63. The compound according to any one of claims 54 to 62, wherein R A It represents H, alkyl, alkoxy, or halogen.

64. The compound according to claim 63, wherein R A It represents an alkoxy group.

65. The compound according to any one of claims 54 to 64, wherein -JK- is selected from the group consisting of: -C(O)-NH-, -C(O)-N(CH3)-, -C(O)-NHCH2-, -CH2-O- and -CH2-NH-.

66. The compound according to claim 65, wherein -JK- is -C(O)-NH-.

67. The compound according to any one of claims 54 to 66, wherein the ring It is a thiophene group that is optionally substituted.

68. The compound according to any one of claims 54 to 67, wherein the ring It is phenyl.

69. The compound according to any one of claims 54 to 67, wherein the ring It is benzimidazolyl, indolyl, or isoquinolinyl.

70. The compound according to any one of claims 54 to 69, wherein the ring It is represented by the following: , or .

71. The compound according to claim 70, wherein Y is -NH2.

72. The compound according to any one of claims 54 to 69, wherein the ring... Depend on express.

73. The compound according to claim 72, wherein Y is selected from the group consisting of -CH2NH2, -C(=NH)(NH2) and -C(O)NH2.

74. The compound according to claim 73, wherein Y is -CH2NH2.

75. The compound according to claim 73, wherein Y is -C(=NH)(NH2).

76. The compound according to any one of claims 54 to 75, wherein q is 0.

77. The compound of claim 54 or a pharmaceutically acceptable salt thereof, selected from the following table: 。 78. A pharmaceutical composition comprising a compound according to any one of claims 1 to 77 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

79. A method for treating or preventing a disease or disorder characterized by abnormal kallikrein activity, the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1 to 77, or a pharmaceutically acceptable salt thereof.

80. The method of claim 79, wherein the disease or ailment is characterized by abnormal kallikrein-associated peptidase 5 (KLK5) activity.

81. The method according to claim 79 or 80, wherein the disease or ailment is a skin disease.

82. The method according to any one of claims 79 to 81, wherein the disease or ailment is Netherton syndrome.

83. The method of claim 81, wherein the skin disease is eczema, atopic eczema, atopic dermatitis, ichthyoid (squamous) erythroderma (IE), rosacea, or a skin infection.

84. The method according to claim 79 or 80, wherein the disease or ailment is selected from the group consisting of: rhinitis, conjunctivitis, angioedema, eosinophilia, eosinophilic esophagitis, growth retardation, developmental disorders, intussusception (TI), respiratory tract infection, systemic infection, and gastrointestinal disorders.

85. The method according to claim 79 or 80, wherein the disease or ailment is selected from the group consisting of: immune system hypersensitivity (atopic anaphylaxis), hyperIgE syndrome, allergies (including allergies to food and airborne substances), asthma, allergic asthma, and chronic inflammation.

86. The method according to claim 79 or 80, wherein the disease or ailment is cancer.

87. The method of claim 86, wherein the cancer is selected from the group consisting of: ovarian cancer, breast cancer, prostate cancer, bladder cancer, cervical cancer, glioblastoma multiforme, and neuroblastoma.