Compositions and methods of modulating short-chain dehydrogenase activity
Compounds and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating disease, diseases disorders, or conditions in which it is desired to modulate 15-PGDH activity and/or prostaglandin levels include 15-PGDH inhibitors described herein.
1. A compound of Formula (IA):
or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl;
R 2 is —NH 2 , CN, or —NHC(O)alkyl;
R 6 is a fused bicyclic heterocyclyl or a fused bicyclic heteroaryl, each of which is optionally substituted with one or more R 3 ;
R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)-alkyl, —C(O)O-alkyl, or —C(O)NR 5 -alkyl, each of which is optionally substituted with one or more R 4 ;
R 3 is oxo, —OH, —O-alkylene-OH, —O-alkylene-N(R 5 ) 2 , —N(R 5 ) 2 , —N(R 5 ) (alkylene-OH), —N(R 5 )(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R 5 ) 2 , —C(O)N(R 5 )(alkylene-OH), —C(O)-alkyl, —C(O)O-alkyl, or —S(O) m -alkyl, wherein each of the cycloalkyl and the heterocyclyl is optionally substituted with R 10 ;
R 4 is oxo, halogen, —CN, —N(R 5 ) 2 , —OH, —O-alkylene-OH, —S(O) m -alkyl, —C(O)-alkyl, —C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R 8 ;
each R 5 is independently; H, alkyl, -alkylene-OH optionally substituted with —OH, -alkylene-NH 2 , -alkylene-N(R 9 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , —C(O)-alkyl, —C(O)O-alkyl, -alkylene-COOH, or —S(O) m -alkyl;
or alternatively, two R 5 together with the N atom to which they are attached can form a 4- to 7-membered heterocyclyl, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocyclyl is optionally substituted with R 8 ;
R 8 is halogen, alkyl, or alkoxy;
R 9 is H or alkyl, or two R 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocyclyl, optionally containing an additional heteroatom selected from O, S(O) t ,
or N;
R 10 is —OH, halogen, alkyl, or alkoxy;
X is N or CH;
m is 0, 1, or 2;
n is 0, 1, or 2; and
t is 0, 1, or 2.
2. The compound, salt, or solvate of claim 1 , wherein R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, —(C 1 -C 6 alkylene)-(3-to 6-membered cycloalkyl), —(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), 3- to 6-membered heterocyclyl, or —(C 1 -C 6 alkylene)-(3-to 6-membered heterocyclyl).
3. The compound, salt, or solvate of claim 1 , wherein R 2 is —NH 2 .
4. The compound, salt, or solvate of claim 1 , wherein R 6 is 8- to 10-membered heteroaryl optionally substituted with one or more R 3 .
5. The compound, salt, or solvate of claim 1 , wherein R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —C(O)(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 alkyl), or —C(O)NR 5 (C 1 -C 6 alkyl), each of which is optionally substituted with one or more R 4 .
6. The compound, salt, or solvate of claim 1 , wherein R 3 is —O—(C 1 -C 6 alkylene)-N(R 5 ) 2 , —N(R 5 ) 2 , —N(R 5 )(C 1 -C 6 alkylene-OH), C 1 -C 6 alkyl, —C(O) N(R 5 ) 2 , —C(O) N(R 5 )(C 1 -C 6 alkylene-OH), —C(O)(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 alkyl), —S(O) m (C 1 -C 6 alkyl), or —(C 1 -C 3 alkylene)-OH.
7. The compound, salt, or solvate of claim 1 , wherein R 4 is halogen, —CN, —N(R 5 ) 2 , —OH, —O—(C 1 -C 6 alkylene)-OH, —S(O) m (C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), —C(O)-(3-to 6-membered cycloalkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.
8. The compound, salt, or solvate of claim 1 , wherein n is 1.
9. The compound, salt, or solvate of claim 1 , wherein the compound is:
10. A pharmaceutical composition comprising the compound, salt, or solvate of claim 1 and a pharmaceutically acceptable excipient or a carrier.
11. The compound, salt, or solvate of claim 1 , wherein
R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 10-membered cycloalkyl, —(C 1 -C 12 alkylene)-(3-to 10-membered membered cycloalkyl), —(C 1 -C 12 alkylene)-(C 1 -C 12 alkoxy), 3- to 20-membered heterocyclyl, or —(C 1 -C 12 alkylene)-(3-to 20-membered heterocyclyl);
R 2 is —NH 2 , CN, or —NHC(O)(C 1 -C 6 alkyl);
R 6 is 8- to 10-membered fused bicyclic heteroaryl optionally substituted with one or more R 3 ;
R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 10-membered cycloalkyl, 6- to 18-membered aryl, 3- to 20-membered heterocyclyl, 5- to 20-membered heteroaryl, —C(O)—(C 1 -C 6 alkyl), —C(O)O—(C 1 -C 6 alkyl), or —C(O)NR 5 —(C 1 -C 6 alkyl), each of which is optionally substituted with one or more R 4 ;
R 3 is oxo, —OH, —O—(C 1 -C 12 alkylene)-OH, —O—(C 1 -C 12 alkylene)-N(R 5 ) 2 , —N(R 5 ) 2 , —N(R 5 ) (C 1 -C 12 alkylene-OH),—N(R 5 ) (C 1 -C 12 alkylene)-O—(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —(C 1 -C 12 alkylene)-OH, C 1 -C 6 haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, —C(O) N(R 5 ) 2 , —C(O) N(R 5 ) (C 1 -C 12 alkylene-OH), —C(O)—(C 1 -C 6 alkyl), —C(O)O—(C 1 -C 6 alkyl), or —S(O) m —(C 1 -C 6 alkyl), wherein each of the 3- to 10-membered cycloalkyl and the 3- to 20-membered heterocyclyl is optionally substituted with R 10 ;
R 4 is oxo, halogen, —CN, —N(R 5 ) 2 , —OH, —O—(C 1 -C 12 alkylene)-OH, —S(O) m —(C 1 -C 6 alkyl), —C(O)—(C 1 -C 6 alkyl), —C(O)-(3-to 10-membered cycloalkyl), C 1 -C 6 alkyl, —(C 1 -C 12 alkylene)-O—(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, or —(C 1 -C 12 alkylene)-(C 6 -C 18 aryl), wherein the —(C 1 -C 12 alkylene)-(C 6 -C 18 aryl) is optionally substituted with R 8 each R 5 is independently H, C 1 -C 6 alkyl, —(C 1 -C 12 alkylene)-OH optionally substituted with —OH, —(C 1 -C 12 alkylene)-NH 2 , —(C 1 -C 12 alkylene)-N(R 9 ) 2 , —(C 1 -C 12 alkylene)-O—(C 1 -C 12 alkylene)-OH, —(C 1 -C 12 alkylene)-O—(C 1 -C 12 alkylene)-NH 2 , —C(O)—(C 1 -C 6 alkyl), —C(O)O—(C 1 -C 6 alkyl), —(C 1 -C 12 alkylene)-COOH, or —S(O) m —(C 1 -C 6 alkyl);
or alternatively, two R 5 groups together with the N atom to which they are attached can form a 4- to 7-membered heterocyclyl, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycyl is optionally substituted with R 8 ;
R 8 is halogen, C 1 -C 6 alkyl, or C 1 -C 12 alkoxy;
R 9 is H or C 1 -C 6 alkyl, or two R 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocyclyl, optionally containing an additional heteroatom selected from O, S(O) t , or N;
R 10 is —OH, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
X is CH or N;
m is 0, 1, or 2;
n is 0, 1, or 2; and
t is 0, 1, or 2.
12. The compound, salt, or solvate of claim 11 , wherein
R 1 is 3- to 10-membered cycloalkyl or —(C 1 -C 12 alkylene)-(C 1 -C 12 alkoxy);
R 2 is —NH 2 or —NHC(O)(C 1 -C 6 alkyl);
R 6 is 8- to 10-membered fused bicyclic heteroaryl optionally substituted with one or more R 3 ;
R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 10-membered cycloalkyl, 6- to 18-membered aryl, or 5- to 20-membered heteroaryl, each of which is optionally substituted with one or more R 4 ;
R 3 is oxo, C 1 -C 6 alkyl, or —(C 1 -C 12 alkylene)-OH;
R 4 is —O—(C 1 -C 12 alkylene)-OH or C 1 -C 6 alkyl;
X is CH or N; and
n is 1.
13. The compound, salt, or solvate of claim 12 , wherein R 2 is —NH 2 .
14. The compound, salt, or solvate of claim 12 , wherein R 3 is C 1 -C 6 alkyl.
15. The compound, salt, or solvate of claim 12 , wherein R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or 3- to 10-membered cycloalkyl, each of which is unsubstituted.
16. The compound, salt, or solvate of claim 12 , wherein R 4 is C 1 -C 3 alkyl.
17. The compound, salt, or solvate of claim 12 , wherein X is CH.
18. The compound, salt, or solvate of claim 1 , where the compound has the structure of Formula (II):
wherein:
R 1 is cyclobutyl or —(C 1 -C 4 alkylene)-(C 1 -C 3 alkoxy);
R 2 is —NH 2 ;
R 6 is
each of which is optionally substituted with one or more R 3 ;
R 7 is
—CF 3 , isopropyl, cyclopropyl, cyclobutyl,
each of which is optionally substituted with one or more R 4 ;
R 3 is —NH 2 ,—NH(C 1 -C 3 alkyl),—NH(C 1 -C 4 alkylene)-OH, or C 1 -C 3 alkyl;
R 4 is C 1 -C 3 alkyl; and
X is CH or N.
19. The compound of claim 1 , wherein the compound is:
20. The compound of claim 1 , wherein the compound is:
21. The compound of claim 1 , wherein the compound is:
22. The compound of claim 1 , wherein the compound is:
23. The compound of claim 1 , wherein the compound is:
24. The compound of claim 1 , wherein the compound is:
25. The compound of claim 1 , wherein the compound is:
26. The compound of claim 1 , wherein the compound is:
27. The compound of claim 1 , wherein the compound is:
28. The pharmaceutical composition of claim 10 , wherein the compound is:
29. The pharmaceutical composition of claim 10 , wherein the compound is:
30. The pharmaceutical composition of claim 10 , wherein the compound is:
31. The pharmaceutical composition of claim 10 , wherein the compound is:
32. The pharmaceutical composition of claim 10 , wherein the compound is:
33. The pharmaceutical composition of claim 10 , wherein the compound is:
34. The pharmaceutical composition of claim 10 , wherein the compound is:
35. The pharmaceutical composition of claim 10 , wherein the compound is:
36. The pharmaceutical composition of claim 10 , wherein the compound is:
37. The salt of claim 1 , wherein the compound is:
38. The salt of claim 1 , wherein the compound is:
39. The salt of claim 1 , wherein the compound is:
40. The salt of claim 1 , wherein the compound is:
41. The salt of claim 1 , wherein the compound is:
42. The salt of claim 1 , wherein the compound is:
43. The salt of claim 1 , wherein the compound is:
44. The salt of claim 1 , wherein the compound is:
45. The salt of claim 1 , wherein the compound is:
46. The solvate of claim 1 , wherein the compound is:
47. The solvate of claim 1 , wherein the compound is:
48. The solvate of claim 1 , wherein the compound is:
49. The solvate of claim 1 , wherein the compound is:
50. The solvate of claim 1 , wherein the compound is:
51. The solvate of claim 1 , wherein the compound is:
52. The solvate of claim 1 , wherein the compound is:
53. The solvate of claim 1 , wherein the compound is:
54. The solvate of claim 1 , wherein the compound is:
55. A method of treating inflammatory bowel disease, the method comprising administering to a human subject in need of treatment a therapeutic amount of compound of Formula (IA):
or a pharmaceutically acceptable salt or solvate thereof;
wherein:
R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 10-membered cycloalkyl, —(C 1 -C 12 alkylene)-(3-to 10-membered membered cycloalkyl), —(C 1 -C 12 alkylene)-(C 1 -C 12 alkoxy), 3- to 20-membered heterocyclyl, or —(C 1 -C 12 alkylene)-(3-to 20-membered heterocyclyl);
R 2 is —NH 2 , CN, or —NHC(O)(C 1 -C 6 alkyl);
R 6 is 8- to 10-membered fused bicyclic heteroaryl optionally substituted with one or more R 3 ;
R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 10-membered cycloalkyl, 6- to 18-membered aryl, 3- to 20-membered heterocyclyl, 5- to 20-membered heteroaryl, —C(O)—(C 1 -C 6 alkyl), —C(O)O—(C 1 -C 6 alkyl), or —C(O)NR 5 —(C 1 -C 6 alkyl), each of which is optionally substituted with one or more R 4 ;
R 3 is oxo, —OH, —O—(C 1 -C 12 alkylene)-OH, —O—(C 1 -C 12 alkylene)-N(R 5 ) 2 , —N(R 5 ) 2 , —N(R 5 ) (C 1 -C 12 alkylene-OH),—N(R 5 ) (C 1 -C 12 alkylene)-O—(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —(C 1 -C 12 alkylene)-OH, C 1 -C 6 haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, —C(O) N(R 5 ) 2 , —C(O) N(R 5 ) (C 1 -C 12 alkylene-OH), —C(O)—(C 1 -C 6 alkyl), —C(O)O—(C 1 -C 6 alkyl), or —S(O) m —(C 1 -C 6 alkyl), wherein each of the 3- to 10-membered cycloalkyl and the 3- to 20-membered heterocyclyl is optionally substituted with R 10 ;
R 4 is oxo, halogen, —CN, —N(R 5 ) 2 , —OH, —O—(C 1 -C 12 alkylene)-OH, —S(O) m —(C 1 -C 6 alkyl), —C(O)—(C 1 -C 6 alkyl), —C(O)-(3-to 10-membered cycloalkyl), C 1 -C 6 alkyl, —(C 1 -C 12 alkylene)-O—(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, 3- to 10-membered cycloalkyl, 3- to 20-membered heterocyclyl, or —(C 1 -C 12 alkylene)-(C 6 -C 18 aryl), wherein the —(C 1 -C 12 alkylene)-(C 6 -C 18 aryl) is optionally substituted with R 8 ;
each R 5 is independently H, C 1 -C 6 alkyl, —(C 1 -C 12 alkylene)-OH optionally substituted with —OH, —(C 1 -C 12 alkylene)-NH 2 , —(C 1 -C 12 alkylene)-N(R 9 ) 2 , —(C 1 -C 12 alkylene)-O—(C 1 -C 12 alkylene)-OH, —(C 1 -C 12 alkylene)-O—(C 1 -C 12 alkylene)-NH 2 , —C(O)—(C 1 -C 6 alkyl), —C(O)O—(C 1 -C 6 alkyl), —(C 1 -C 12 alkylene)-COOH, or —S(O) m —(C 1 -C 6 alkyl);
or alternatively, two R 5 groups together with the N atom to which they are attached can form a 4- to 7-membered heterocyclyl, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocyclyl is optionally substituted with R 8 ;
R 8 is halogen, C 1 -C 6 alkyl, or C 1 -C 12 alkoxy;
R 9 is H or C 1 -C 6 alkyl, or two R 9 together with the N atom to which they are attached can form a 4- to 7-membered heterocyclyl, optionally containing an additional heteroatom selected from O, S(O) t , or N;
R 10 is —OH, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
X is CH or N;
m is 0, 1, or 2;
n is 0, 1, or 2; and
t is 0, 1, or 2.
56. The method of claim 55 , wherein the compound has the structure of Formula (II):
wherein:
R 1 is cyclobutyl or —(C 1 -C 4 alkylene)-(C 1 -C 3 alkoxy);
R 2 is —NH 2 ;
R 6 is
each of which is optionally substituted with one or more R 3 ;
R 7 is
—CF 3 , isopropyl, cyclopropyl, cyclobutyl,
each of which is optionally substituted with one or more R 4 ;
R 3 is —NH 2 ,—NH(C 1 -C 3 alkyl),—NH(C 1 -C 4 alkylene)-OH, or C 1 -C 3 alkyl;
R 4 is C 1 -C 3 alkyl; and
X is CH or N.
57. The method of claim 55 , wherein the compound is:
58. The method of claim 55 , wherein the compound is:
59. The method of claim 55 , wherein the compound is:
60. The method of claim 55 , wherein the compound is:
61. The method of claim 55 , wherein the compound is:
62. The method of claim 55 , wherein the compound is:
63. The method of claim 55 , wherein the compound is:
64. The method of claim 55 , wherein the compound is:
65. The method of claim 55 , wherein the compound is:
66. A method of treating a human subject in need of cell therapy comprising administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells and the compound, salt, or solvate of claim 11 .
67. A method of treating a human subject having at least one symptom associated with an ischemic tissue or a tissue damaged by ischemia comprising administering to the subject a therapeutically effective amount of the compound, salt, or solvate of claim 11 .
68. A method of increasing neutrophils in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, salt, or solvate of claim 11 .
69. A method of increasing numbers of or mobilizing peripheral blood hematopoietic stem cells in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, salt, or solvate of claim 11 .
70. A method of increasing numbers of hematopoietic stem cells in blood or bone marrow of a human subject, the method comprising administering to blood or bone marrow of the subject a therapeutically effective amount of the compound, salt, or solvate of claim 11 .
71. A method of treating or preventing a fibrotic disease, disorder or condition in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, salt, or solvate of claim 11 .
72. A method of treating inflammation or reducing the activity of the immune system in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, salt, or solvate of claim 11 and a corticosteroid.
73. A method of treatment of glucocorticoid insensitivity, restoring corticosteroid sensitivity, enhancing glucocorticoid sensitivity or reversing the glucocorticoid insensitivity in a human subject experiencing corticosteroid dependence or corticoid resistance or unresponsiveness or intolerance to corticosteroids, comprising administering a pharmaceutical composition comprising the compound, salt, or solvate of claim 11 in combination with a corticosteroid to the subject exhibiting one or more glucocorticoid insensitivity related conditions, wherein the glucocorticoid insensitivity related conditions comprise a range of immune-inflammatory disorders treated with steroids when the therapy fails to achieve disease control or is not effective or intolerant or dependent to corticosteroids, and combinations thereof.
74. The compound, salt, or solvate of claim 1 , wherein R 3 is —NH 2 , —N(C 1 -C 3 alkyl) 2 , —NHCH 2 CH 2 OH, —N(C 1 -C 3 alkyl) CH 2 CH 2 OH, —N(CH 2 CH 2 OH) 2 , —NHCH 2 CH 2 OCH 2 CH 2 OH, —NHCH 2 CH 2 OCH 2 CH 2 NH 2 , —NHCH 2 CH 2 NH 2 , —N(C 1 -C 3 alkyl) CH 2 CH 2 NH 2 , —NHCH 2 CH 2 NH(C 1 -C 3 alkyl), —NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 , —N(C 1 -C 3 alkyl) CH 2 CH 2 NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) CH 2 CH 2 N(C 1 -C 3 alkyl) 2 , —NHSO 2 CH 3 , —N(C 1 -C 3 alkyl) SO 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 NH(C 1 -C 3 alkyl), or —OCH 2 CH 2 N(C 1 -C 3 alkyl) 2 .
75. The method of claim 57 , wherein the inflammatory bowel disease is Crohn's Disease.
76. The method of claim 58 , wherein the inflammatory bowel disease is Crohn's Disease.
77. The method of claim 59 , wherein the inflammatory bowel disease is Crohn's Disease.
78. The method of claim 60 , wherein the inflammatory bowel disease is Crohn's Disease.
79. The method of claim 61 , wherein the inflammatory bowel disease is Crohn's Disease.
80. The method of claim 62 , wherein the inflammatory bowel disease is Crohn's Disease.
81. The method of claim 63 , wherein the inflammatory bowel disease is Crohn's Disease.
82. The method of claim 64 , wherein the inflammatory bowel disease is Crohn's Disease.
83. The method of claim 65 , wherein the inflammatory bowel disease is Crohn's Disease.