Inhibiting human integrin α4β7

HK40137840APending Publication Date: 2026-09-18MORPHIC THERAPEUTIC INC
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Patent Information

Application Number
HK62026126547
Authority / Receiving Office
HK · HK
Patent Type
Applications
Current Assignee / Owner
Priority Date
2024-08-26
Filing Date
2026-07-23
Publication Date
2026-09-18
Estimated Expiration
2044-09-12

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Abstract

Disclosed are compounds for and methods of treating or preventing a disease or condition responsive to inhibition human α4β7 integrin by administering to a patient in need thereof a compound disclosed herein, such as a compound of Formula (I) or Formula (VI), or a pharmaceutically acceptable salt thereof. Many diseases and conditions can be treated by administration of the compounds disclosed herein such as compounds of Formula (I), including, for example, inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease.
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Description

Abstract This invention discloses compounds and methods for treating or preventing diseases or conditions that respond to inhibition of human α4β7 integrin. Specifically, such diseases or conditions can be treated or prevented by administering the compounds disclosed herein (e.g., compounds of formula (I) or (VI), or pharmaceutically acceptable salts thereof) to a patient in need. Many diseases and conditions can be treated by administering the compounds disclosed herein (e.g., compounds of formula (I), such as inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease.

Claims

CLAIMS1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein:a 3 to 12 member heterocyclyl ring structure optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen; a is 0, 1, 2 or 3;Xi is N or CRa;Rais H, halogen or C1-4 alkyl optionally substituted with one or more halogen;X2 is NRb or CRb'Rb ;Rb is H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, C3- ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Rb' and Rb'' are each independently H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl- OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3- ecycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Ri is H or -COORib;Rib is H or C 1-4 alkyl;R2 is H or C 1-4 alkyl;R3 is H, C1-4 alkyl, or halogen; n is 0, 1, 2, 3, or 4;RHs H, Ci-4 alkyl optionally substituted with one or more halogen, or halogen; p is 0, 1, 2, 3, 4 or 5;Rs is H, Ci-4alkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 R7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each R7 is independently halogen.

2. The compound of claim 1, wherein Ri is COOH.

3. The compound of any one of claims 1-2, wherein R2 is methyl.

4. The compound of any one of claims 1-3, wherein Rb'' is H.

5. The compound of any one of claims 1-4, wherein Xi is CRa.

6. The compound of claim 5, wherein Rais H.

7. The compound of any one of claims 1-6, wherein X2 is NRb.

8. The compound of claim 7, wherein Rb is Ci-4alkyl optionally substituted with one or more halogen.

9. The compound of claim 8, wherein Rb is Ci-4alkyl optionally substituted with one or more flouro.

10. The compound of claim 9, wherein Rb is -CH2CF3.

11. The compound of any one of claims 1-6, wherein X2 is CRb'Rb ' .

12. The compound of claim 11, wherein Rb'' is H.

13. The compound of any one of claims 11-12, wherein Rb' is -O-C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted with one or more halogen.

14. The compound of claim 13, wherein Rb' is -O-C1-4 alkyl or -O-C3-6 cycloalkyl, wherein the C1-4 alkyl is optionally substituted with one or more fluoro.

15. The compound of claim 14, wherein Rb' is -O-CF3.

16. The compound of claim 14, wherein Rb' is -O-CH3.

17. The compound of claim 14, wherein Rb' is -O-C3 cycloalkyl optionally substituted with C1-4 alkyl.

18. The compound of claim 14, wherein Rb' is -O-C3 cycloalkyl optionally substituted with methyl.

19. The compound of claim 13, wherein Rb' is -O-C1-4 alkyl optionally substituted with one or more fluoro.

20. The compound of any one of claims 1-4, wherein Xi is CH and X2 is CHRb' and Rb' is21. The compound of any one of claims 1-20, wherein m is 0.

22. The compound of any one of claims 1-21, wherein R3 and R4 are each independently halogen or C1-4 alkyl optionally substituted with one or more halogen.

23. The compound of any one of claims 1-21, wherein R3 and R4 are each independently fluoro, chloro or methyl optionally substituted with one or more fluoro.

24. The compound of any one of claims 1-23, wherein n and p are each independently 1 or 2.

25. The compound of claim 24, wherein n is 1.

26. The compound of any one of claims 1-25, wherein m is 1.

27. The compound of any one of claims 1-25, wherein m is 2.

28. The compound of any one of claims 1-27, wherein the compound is a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof,whereinRcis H, halogen or C1-4 alkyl optionally substituted with one or more halogen;Y2 is NRa or CRa'Rd ;Rd is H, halogen, C1-4 alkyl or 3-6 member heterocycloalkyl, wherein the C1-4 alkyl or 3-6 member heterocycloalkyl is optionally substituted with one or more halogen;Rd' and Rd'' are each independently H, halogen, or C1-4 alkyl, and each C1-4 alkyl is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Re is H, Ci-salkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 Rs; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each Rs is independently halogen.

29. The compound of claim 28, wherein Yi is N and Y2 is NRd.

30. The compound of claim 29, wherein Rd is C1-4 alkyl, C3-6 cycloalkyl or 3-6 member heterocycloalkyl.

31. The compound of claim 30, wherein Rd is methyl.

32. The compound of claim 30, wherein Rd is isopropyl.

33. The compound of claim 30, wherein Rd is cyclopropyl.

34. The compound of claim 30, wherein Rd is tetrahydrofuran.

35. The compound of claim 28, wherein Y2 is CRd'Rd ".

36. The compound of claim 35, wherein Rd'' is H.

37. The compound of claim 36, wherein Rd' is fluoro.

38. The compound of claim 36, wherein Rd' is methoxy.

39. The compound of claim 36, wherein Rd' is methyl.

40. The compound of claim 35, wherein Rd'' is methyl.

41. The compound of claim 28, wherein the compound is a compound of Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof,whereinR3', R3 , R4 , and R4'' are each independently H, halogen or C1-4 alkyl optionally substituted with one or more halogen.

42. The compound of claim 41, wherein Xi is N.

43. The compound of any one of claims 41-42, wherein X2 is NRb.

44. The compound of claim 43, wherein Rb is Ci-4alkyl optionally substituted with one or more halogen.

45. The compound of claim 43, wherein Rb is Ci-4alkyl optionally substituted with one or more flouro.

46. The compound of claim 43, wherein Rb is -CH2CF3.

47. The compound of any one of claims 41-42, wherein X2 is CRb'Rb '.

48. The compound of claim 47, wherein Rb'' is H.

49. The compound of any one of claims 47-48, wherein Rb is -O-Ci-4 alkyl, wherein the Ci-4 alkyl is optionally substituted with one or more halogen.

50. The compound of claim 49, wherein Rb' is -O-Ci-4 alkyl or -O-C3-6 cycloalkyl, wherein the C1-4 alkyl is optionally substituted with one or more fluoro.

51. The compound of claim 50, wherein Rb' is -O-CF3.

52. The compound of claim 50, wherein Rb' is -O-CH3.

53. The compound of claim 50, wherein Rb' is -O-C3 cycloalkyl optionally substituted with C1-4 alkyl.

54. The compound of claim 50, wherein Rb' is -O-C3 cycloalkyl optionally substituted with methyl.

55. The compound of claim 50, wherein Rb' is -O-C1-4 alkyl optionally substituted with one or more fluoro.

56. The compound of any one of claims 41-55, wherein Yi is N.

57. The compound of claim 56, wherein Y2 is NRd.

58. The compound of claim 57, wherein Rd is C1-4 alkyl, C3-6 cycloalkyl or 3-6 member heterocycloalkyl.

59. The compound of claim 58, wherein Rd is methyl.

60. The compound of claim 58, wherein Rd is isopropyl.

61. The compound of claim 58, wherein Rd is cyclopropyl.

62. The compound of claim 58, wherein Rd is tetrahydrofuran.

63. The compound of claim 56, wherein Y2 is CRd'Rd ".

64. The compound of claim 63, wherein Rd'' is H.

65. The compound of claim 63, wherein Rd' is fluoro.

66. The compound of claim 63, wherein Rd' is methoxy.

67. The compound of claim 63, wherein Rd' is methyl.

68. The compound of claim 63, wherein Rd'' is methyl.

69. The compound of claim 1, wherein the compound is a compound of Formula (V)(V), wherein, a is 1 or 2;R3', R3 ", R4', and R4" are each independently H, halogen or C1-4 alkyl optionally substituted with one or more halogen;Rs is H, Ci-4alkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 R7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each R7 is independently halogen.

70. The compound of claim 69, whereina 5- to 10-membered heterocyclyl ring structure, whose ring structures include one to four heteroatoms, optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen.

71. The compound of claim 70, whereina 5- to 10-membered heterocyclyl ring structure, whose ring structures include one or two heteroatoms, optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen.(A)72. The compound of claim 71, wherein ' is a 5- to 6-membered monocyclic heterocyclyl ring structure, whose ring structures include one or two heteroatoms, optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen.

73. The compound of claim 71, whereinis a 7- to 8-membered bicyclic bridged heterocyclyl ring structure, whose ring structures include one or two heteroatoms, optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen.

74. The compound of claim 71, whereina 7- to 8-membered spirocyclic heterocyclyl ring structure, whose ring structures include one or two heteroatoms, optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen.

75. The compound of anyone of claim 70-74, wherein the heterocyclyl ring structure is saturated.

76. The compound of claim 69, whereinis tetrahydrofuran.

77. The compound of claim 69, wherein78. The compound of claim 69, wherein79. The compound of claim 69, wherein80. The compound of claim 69, wherein81. The compound of claim 69, wherein82. The compound of claim 69, wherein83. The compound of claim 69, wherein84. The compound of claim 69, wherein OisO85. The compound of claim 69, wherein86. The compound of claim 69, wherein87. The compound of claim 69, wherein88. The compound of claim 69, wherein89. The compound of claim 69, wherein90. The compound of claim 69, wherein91. The compound of claim 69, wherein92. The compound of claim 69, wherein93. The compound of claim 69, wherein94. The compound of claim 69, wherein95. The compound of claim 69, wherein96. The compound of claim 69, wherein97. The compound of any one of claim 28-40, wherein the compound is a compound of Formula (IV-A), or a pharmaceutically acceptable salt thereof,98. The compound of any one of claim 41-68, wherein the compound is a compound of Formula (II-A), Formula (III), or a pharmaceutically acceptable salt thereof,(in-A) whereinR3', R3 , R4 , and R4'' are each independently H, halogen or C1-4 alkyl optionally substituted with one or more halogen.

99. The compound of any one of claim 69-96, wherein the compound is a compound of Formula (V-A), or a pharmaceutically acceptable salt thereof100. A compound Formula (VI) or a pharmaceutically acceptable salt thereof,whereinYi, Y2, Y3, Y4, Y5 and Zi, Z2 and Z3 are each CH or N, provided that at least three of Yi, Y2, Y3, Y4, and Y5 are CH and at least one of Zi, Z2 and Z3 is CH;a 3 to 12 member heterocyclyl ring structure (including monocyclic heterocyclic, bicyclic bridged, and bicyclic spirocyclic ring structures) optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl (e.g., methyl) and Ci-4alkyloxy (e.g., methoxy) are optionally substituted with one or more halogen (e.g., one or more fluoro); a is 0, 1, 2 or 3;Xi is N or CRa;Rais H, halogen or C1-4 alkyl optionally substituted with one or more halogen;X2 is NRb or CRb'Rb ;Rb is H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, C3-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Rb' and Rk' are each independently H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl- OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3- ecycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Ri is H or -COORib;Rib is H or C 1-4 alkyl;R2 is H or C 1-4 alkyl;R3 is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen; n is 0, 1, 2, 3, or 4;R4is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen; p is 0, 1, 2, 3, 4 or 5;Rs is H, Ci-4alkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 R7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each R7 is independently halogen.

101. The compound of claim 97, whereinYi is N or CRc;Rcis H, halogen or C1-4 alkyl optionally substituted with one or more halogen;Y2 is NRa or CRd'Ra ;Rd is H, halogen, C1-4 alkyl or 3-6 member heterocycloalkyl, wherein the C1-4 alkyl or 3-6 member heterocycloalkyl is optionally substituted with one or more halogen;Rd' and Rd'' are each independently H, halogen, or C1-4 alkyl, and each C1-4 alkyl is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy; q is O, 1, 2, 3, 4, 5, 6, 7 or 8;Re is H, Ci-salkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Cnalkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 Rs; and each Rs is independently halogen.

102. The compound of claim 98, wherein Yi is N and Y2 is CH2 or C(CH3)2.A compound of the chemical formulapharmaceutically acceptable salt thereof.

104. A compound of the chemical formulapharmaceutically acceptable salt thereof.

105. A compound of the chemical formulapharmaceutically acceptable salt thereof.

106. A compound of the chemical formulapharmaceutically acceptable salt thereof.

107. A compound of the chemical formulapharmaceutically acceptable salt thereof.

108. A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.

109. A compound of the chemical formulapharmaceutically acceptable salt thereof.

110. A compound of the chemical formulaa pharmaceutically acceptable salt thereof.

111. A compound of the chemical formulapharmaceutically acceptable salt thereof.

112. A compound of the chemical formulapharmaceutically acceptable salt thereof.

113. A compound of the chemical formulapharmaceutically acceptable salt thereof.

114. A compound of the chemical formulapharmaceutically acceptable salt thereof.

115. A compound of the chemical formulapharmaceutically acceptable salt thereof.

116. A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.

117. A compound selected from the group consisting of the compounds in Figure 1, or a pharmaceutically acceptable salt thereof.

118. A compound selected from the group consisting of the compounds in Table 2, or a pharmaceutically acceptable salt thereof.

119. A compound selected from the group consisting of the compounds in Table 3, or a pharmaceutically acceptable salt thereof.

120. A compound selected from the group consisting of the compounds in Table 4, or a pharmaceutically acceptable salt thereof.

121. A pharmaceutical composition comprising the compound of any one of claims 1- 120, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

122. A method of treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 121.