KLK5 tricyclic heteroaromatic inhibitor

JP2026530611APending Publication Date: 2026-09-09BIOCRYST PHARMACEUTICALS INC
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Patent Information

Application Number
JP2026512273
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2023-08-25
Filing Date
2024-08-23
Publication Date
2026-09-09

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Abstract

Disclosed are tricyclic heteroaromatic compounds of formulas (I) and (II) that are inhibitors of kallikrein-related peptidase 5 (KLK5), as well as pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions comprising such compounds, and methods of using the compounds and compositions for the treatment or prevention of diseases or conditions characterized by abnormal KLK5 activity, such as Netherton syndrome. Formulas (I) and (II) [Formula 1] TIFF2026530611000772.tif86115
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Claims

1. A compound of formula (I), 【Chemistry 1】 During the ceremony, ring 【Chemistry 2】 However, it is a tricyclic ring system containing at least one aromatic ring or heteroaromatic ring, ring 【Transformation 3】 However, it is an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, J and ring 【Chemistry 4】 However, 【Transformation 5】 It is bonded to the same ring within the aforementioned tricyclic ring system, ring 【Transformation 6】 However, it is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, J is -NH-, -CH ２ -, -C(O)-, -O-, -S-, -S(O)-, -SO ２ -, -N (alkyl)-, -CH (alkyl)-, -CH (CF ３ )-,-CH (aryl)-,-C (alkyl) ２ -, -CH (cycloalkyl)-, 【Transformation 7】 It represents, or is absent. K is -C(O)-, -O-, -NH-, -CH ２ -, -S-, -S(O)-, -SO ２ -, -N (alkyl)-, -NHCH ２ -, -CH(alkyl)-, -CH(cycloalkyl)-, or absent, At least one of J and K is absent, or -C(O)-, -CH ２ -, -CH(alkyl)-, or -CH(aryl)-, Y is -H, -CH ２ NH ２ , -C(=NH)(NH ２ ), -C(O)NH ２ , -NH ２ , -CN, halo, -CH ２ C(O)OH, -C(O)OH, -S(O) ２ NH ２ , -CH ２ CN, -NHBoc, -CH ２ NHCH ３ , -CH(CH ３ )NH ２ , -CH ２ NHCH=NOH, -CH ２ OH, amino-substituted cycloalkyl, or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl, V is -C(O)R Ｅ or H, R Ｅ However, -OH, -NH-OH, -O (alkyl), -C(O) (haloalkyl), or 【Transformation 8】 And, T is either a bond, or -C(O)-, -C(O)NH-, -C(O)N(alkyl)-, -C(O)O-, -CH ２ NH-, -CH ２ O-, -CH(CF ３ )-NH-, -NH-CH(CF ３ ) - or -NHC(O)-, R Ｔ However, H, Halo, -CH ２ C(O)NH ２ ien-CH ２ C(O)OH represents an optionally substituted alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, spirocycloalkyl, heterospirocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. R Ａ However, each occurrence independently represents alkyl, halo, -NHBoc, tosyl, hydroxyalkyl, aminoalkyl, or alkoxyalkyl, R Ｂ However, independently of each occurrence, halo, -C(O)OH, -C(O)NH ２ , represents -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 However, independently of each occurrence, hydroxy, halo, -CN, -C(O)OH, -C(O)NH(alkyl), -C(O)NH(cycloalkyl), and -CH are present. ２ C(O)(alkyl), -CH ２ C(O)OR Ｄ１ ien-CH ２ C(O)NHR Ｄ１ , -O[(CH ２ ) ｘ O] ｙ (Alkyl), -O(CH ２ ) ｘ COOH, (hydroxy)alkoxy, (halo)alkoxy, (alkoxy)alkoxy, arylalkoxy, (cycloalkyl)alkoxy, or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, alkoxy, hydroxyalkyl, or haloalkyl, R Ｄ１ However, each occurrence independently represents H, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. m, n, and q are integers independently selected from 0 to 3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, where x and y are each integers independently selected from 1 to 10.

2. Equation (Ia): 【Chemistry 9】 Having a structure, During the ceremony, ring 【Chemistry 10】 and ring 【Chemistry 11】 Each of these is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, partially unsaturated cycloalkyl, or partially unsaturated heterocycloalkyl. m1 and m2 are integers selected from 0 to 3, The compound according to claim 1, wherein the sum of m1 and m2 is 3 or less.

3. Equation (Ia-1): 【Chemistry 12】 The compound according to claim 2, having the structure. 【Request Item 4】 【Chemistry 13】 However, the structure is as follows: 【Chemistry 14】 The compound according to claim 3, having the following characteristics. 【Request Item 5】 【Chemistry 15】 but, 【Chemistry 16】 A compound according to claim 4, selected from the group consisting of the following. 【Request Item 6】 【Chemistry 17】 However, the structure is as follows: [Chemistry 18] It has, During the ceremony, Z １ Z ２ , and Z ３ Each of them independently represents S, CH, and CR Ａ Selected from, Z １ Z ２ , and Z ３ The compound according to claim 3, wherein only one of them is S. 【Request Item 7】 【Chemistry 19】 but, 【Chemistry 20】 A compound according to claim 6, selected from the group consisting of the following. 【Request Item 8】 【Chemistry 21】 However, the structure is as follows: 【Chemistry 22】 The compound according to claim 6, having the following characteristics. 【Request Item 9】 【Chemistry 23】 but, 【Chemistry 24】 A compound according to claim 6, selected from the group consisting of the following. 【Request Item 10】 【Chemistry 25】 However, the structure is as follows: 【Chemistry 26】 The compound according to claim 6, having the following characteristics. 【Request Item 11】 【Chemistry 27】 but, 【Chemistry 28】 A compound according to claim 6, selected from the group consisting of the following. 【Request Item 12】 【Chemistry 29】 but, 【Transformation 30】 The compound according to claim 3. 【Request Item 13】 【Chemistry 31】 but, 【Chemistry 32】 The compound according to claim 3. 【Request Item 14】 【Chemistry 33】 but, 【Transformation 34】 The compound according to claim 3.

15. R Ａ The compound according to any one of claims 1 to 14, wherein each occurrence independently represents an alkyl group.

16. The compound according to any one of claims 2 to 15, wherein the occurrence of m1 and m2 is 0.

17. ring 【Chemistry 35】 The compound according to any one of claims 1 to 16, wherein the ring is a bicyclic ring.

18. ring 【Transformation 36】 The compound according to any one of claims 1 to 16, wherein the ring is a monocyclic ring. 【Request Item 19】 【Chemistry 37】 but, 【Chemistry 38】 And, The compound according to any one of claims 1 to 16, wherein W is 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. 【Request Item 22】 【Chemistry 39】 but, 【Chemistry 40】 The compound according to any one of claims 1 to 16.

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

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

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

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

27. -T-R Ｔ The compound according to any one of claims 1 to 26, wherein H is present.

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

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. T is -C(O)-, and R Ｔ The compound according to any one of claims 1 to 26, wherein the compound is an optionally substituted heterocycloalkyl, preferably an optionally substituted N-bonded heterocycloalkyl.

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

32. R Ｔ The compound according to claim 31, wherein the alkyl, hydroxyalkyl, haloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl), arylalkyl, or heteroarylalkyl is optionally substituted.

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

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

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

36. -JK- is -C(O)-NH-, -C(O)-N(CH ３ )-, -C(O)-NHCH ２ -ien-CH ２ -O- and -CH ２ A compound according to any one of claims 1 to 35, selected from the group consisting of -NH-.

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

38. ring 【Chemistry 41】 The compound according to any one of claims 1 to 37, wherein the ring is bicyclic.

39. ring 【Chemistry 42】 The compound according to any one of claims 1 to 37, wherein the ring is a monocyclic ring.

40. ring 【Chemistry 43】 The compound according to any one of claims 1 to 39, wherein the compound is selected from the group consisting of phenyl, pyrazinyl, pyridinyl, pyrimyl, thiophenyl, tetrahydroisoquinolinyl, benzimidazolyl, indolyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, cyclohexyl, isoindolinyl, isoquinolinyl, or naphthalenyl.

41. ring 【Chemistry 44】 The compound according to claim 40, wherein the compound is phenyl.

42. ring 【Chemistry 45】 The compound according to claim 40, wherein the compound is pyridinyl.

43. ring 【Chemistry 46】 The compound according to claim 40, wherein the compound is benzimidazolyl, indolyl, or isoquinolinyl.

44. ring 【Chemistry 47】 but, 【Chemistry 48】 The compound according to any one of claims 1 to 37, as represented by [the specified method].

45. Y is -NH ２ The compound according to claim 44.

46. ring 【Chemistry 49】 but, [Transformation 50] The compound according to any one of claims 1 to 37, as represented by [the specified method].

47. ring 【Chemistry 51】 but, 【Chemistry 52】 The compound according to any one of claims 1 to 37, as represented by [the specified method].

48. Y is -CH ２ NH ２ , -C(=NH)(NH ２ ), and -C(O)NH ２ A compound according to claim 46 or 47, selected from the group consisting of the following.

49. Y is -CH ２ NH ２ The compound according to claim 48.

50. ring 【Chemistry 53】 but, 【Chemistry 54】 The compound according to any one of claims 1 to 37, as represented by [the specified method].

51. Y is -CH ２ NH ２ The compound according to claim 50.

52. R Ｄ The compound according to any one of claims 1 to 51, wherein each occurrence independently represents a hydroxyl, halo, -C(O)NH(alkyl), or optionally substituted alkyl, alkoxy, hydroxyalkyl, or haloalkyl.

53. The following table: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

54. A compound of formula (II), 【Transformation 55】 During the ceremony, ring 【Transformation 56】 and ring 【Chemistry 57】 Each of these is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, partially unsaturated cycloalkyl, or partially unsaturated heterocycloalkyl. ring [Chem. 58] However, it is an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, ring 【Chemistry 59】 However, it is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, J is -NH-, -CH ２ -, -C(O)-, -O-, -S-, -S(O)-, -SO ２ -, -N (alkyl)-, -CH (alkyl)-, -CH (CF ３ )-,-CH (aryl)-,-C (alkyl) ２ -, -CH (cycloalkyl)-, 【Transformation 60】 It represents, or is absent. K is -C(O)-, -O-, -NH-, -CH ２ -, -S-, -S(O)-, -SO ２ -, -N (alkyl)-, -NHCH ２ -, -CH(alkyl)-, -CH(cycloalkyl)-, or absent, At least one of J and K is absent, or -C(O)-, -CH ２ -, -CH(alkyl)-, or -CH(aryl)-, Y is -H, -CH ２ NH ２ , -C(=NH)(NH ２ ), -C(O)NH ２ , -NH ２ , -CN, halo, -CH ２ C(O)OH, -C(O)OH, -S(O) ２ NH ２ , -CH ２ CN, -NHBoc, -CH ２ NHCH ３ , -CH(CH ３ )NH ２ , -CH ２ NHCH=NOH, -CH ２ OH, amino-substituted cycloalkyl, or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, or heteroarylalkyl, V is -C(O)R Ｅ or H, R Ｅ However, -OH, -NH-OH, -O (alkyl), -C(O) (haloalkyl), or 【Chemistry 61】 And, R Ａ However, H represents alkyl, alkoxy, halo, -NHBoc, tosyl, hydroxyalkyl, aminoalkyl, or alkoxyalkyl. R Ｂ２ and R Ｂ３ Each of these independently corresponds to halo, -C(O)OH, and -C(O)NH for each occurrence. ２ , represents -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 However, independently of each occurrence, hydroxy, halo, -CN, -C(O)OH, -C(O)NH(alkyl), -C(O)NH(cycloalkyl), and -CH are present. ２ C(O)(alkyl), -CH ２ C(O)OR Ｄ１ ien-CH ２ C(O)NHR Ｄ１ , -O[(CH ２ ) ｘ O] ｙ (Alkyl), -O(CH ２ ) ｘ COOH, (hydroxy)alkoxy, (halo)alkoxy, (alkoxy)alkoxy, arylalkoxy, (cycloalkyl)alkoxy, or optionally substituted alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, alkoxy, hydroxyalkyl, or haloalkyl, R Ｄ１ However, each occurrence independently represents H, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. q, m1, and m2 are integers independently selected from 0 to 3. The sum of m1 and m2 is 3 or less. A compound of formula (II), or a pharmaceutically acceptable salt thereof, where x and y are integers independently selected from 1 to 10. 【Request Item 55】 【Chemistry 62】 However, the structure is as follows: 【Transformation 63】 The compound according to claim 54, having the following characteristics. 【Request Item 56】 【Chemistry 64】 but, 【Transformation 65】 The compound according to claim 55, having a structure selected from the group consisting of the following. 【Request Item 57】 【Transformation 66】 However, the structure is as follows: 【Transformation 67】 The compound according to claim 54, having the following characteristics. [Request Item 58] [Transformation 68] but, 【Transformation 69】 The compound according to claim 57, having a structure selected from the group consisting of the following.

59. R Ｂ２ and R Ｂ３ The compound according to any one of claims 54 to 58, wherein each of the elements independently represents a halo or alkyl group for each occurrence.

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

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

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

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

64. R Ａ However, the compound according to claim 63, which represents an alkoxy.

65. -JK- is -C(O)-NH-, -C(O)-N(CH ３ )-, -C(O)-NHCH ２ -ien-CH ２ -O- and -CH ２ A compound according to any one of claims 54 to 64, selected from the group consisting of -NH-.

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

67. ring 【Transformation 70】 The compound according to any one of claims 54 to 66, wherein the thiophenyl is optionally substituted.

68. ring 【Chemistry 71】 The compound according to any one of claims 54 to 67, wherein the compound is phenyl.

69. ring 【Chemistry 72】 The compound according to any one of claims 54 to 67, wherein the compound is benzimidazolyl, indolyl, or isoquinolinyl.

70. ring 【Transformation 73】 but, 【Chemistry 74】 The compound according to any one of claims 54 to 69, as represented by [the specified method].

71. Y is -NH ２ The compound according to claim 70.

72. ring 【Chemistry 75】 but, 【Transformation 76】 The compound according to any one of claims 54 to 69, as represented by [the specified method].

73. Y is -CH ２ NH ２ , -C(=NH)(NH ２ ), and -C(O)NH ２ A compound according to claim 72, selected from the group consisting of the following.

74. Y is -CH ２ NH ２ The compound according to claim 73.

75. Y is -C(=NH)(NH ２ The compound according to claim 73, which is the compound described in claim 73.

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

77. The following table: Table 2-1 Table 2-2 Table 2-3 A compound according to claim 54, or a pharmaceutically acceptable salt thereof, selected from the above.

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 condition characterized by abnormal kallikrein activity, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 77, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

80. The method according to claim 79, wherein the disease or condition is characterized by abnormal kallikrein-related peptidase 5 (KLK5) activity.

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

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

83. The method according to claim 81, wherein the skin disease is eczema, atopic eczema, atopic dermatitis, ichthyosis-like (scaly) erythroderma (IE), rosacea, or a skin infection.

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

85. The method according to claim 79 or 80, wherein the disease or condition is selected from the group consisting of hypersensitivity of the immune system (atopy), hyper IgE 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 condition is cancer.

87. The method according to 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.