CCR9 ANTAGONIST COMPOUNDS
Provided herein are compounds that inhibit CCR9 receptor function. Also provided herein are methods of treating inflammatory disease in a subject, comprising administering to the subject a compound of the invention. Accordingly, in one aspect, provided herein is a compound of Formula (1) or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a pharmaceutical composition, comprising a compound of Formula (1), and a pharmaceutically acceptable carrier.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R 2 is H, C 1-6 alkyl, C 1-6 alkoxy optionally substituted one or more times with OH, C 1-6 haloalkyl, C 1-6 di-haloalkyl, C 1-6 tri-haloalkyl, NH 2 , N(H)(C 1-3 alkyl), N(C 1-3 alkyl) 2 , (CH 2 ) 1-4 —NH 2 , (CH 2 ) 1-4 —N(H)(C 1-3 alkyl), (CH 2 ) 1-4 —N(C 1-3 alkyl) 2 , (CH 2 ) 1-4 —C 1-6 alkoxy, C(O)NH 2 , C(O)N(H)(C 1-3 alkyl), C(O)N(C 1-3 alkyl) 2 , OH, (CH 2 ) 1-4 —OH, or a C 3-5 heterocycle optionally substituted one or more times with OH;
R 5 is OH, C 2-6 alkyl, C 1-6 alkoxy, (CH 2 ) 1-4 —C 1-6 alkoxy, C 3-7 cycloalkyl, N(C 1-3 alkyl) 2 , or heterocycle;
R 6 is (CH 2 ) 1-4 -aryl, wherein aryl can be optionally independently substituted one or more times with C 1-6 alkyl, C 1-6 alkoxy, halo, or heterocycle, wherein the C 1-6 alkyl or heterocycle groups can be optionally independently substituted one or more times with C 1-6 alkyl, CN, or C 1-6 alkoxy; and
R 7 is OH, C 1-3 alkyl, or C 1-3 alkoxy.
2 . The compound of claim 1 , wherein R 2 is H, CF 3 , or (CH 2 ) 1-4 —C 1-6 alkoxy.
3 . The compound of claim 1 or 2 , wherein R 2 is CF 3 or (CH 2 ) 1-4 —C 1-6 alkoxy.
4 . The compound of any of the above claims, wherein R 5 is C 2-6 alkyl, (CH 2 ) 1-4 —C 1-6 alkoxy, C 3-7 cycloalkyl, heterocycle, OH, NH 2 , N(H)(C 1-3 alkyl), or N(C 1-3 alkyl) 2 .
5 . The compound of any of the above claims, wherein R 5 is C 2-6 alkyl.
6 . The compound of any of the above claims, wherein R 7 is CH 3 or OH.
7 . The compound of any of the above claims, wherein R 6 is (CH 2 ) 1-4 -phenyl, wherein phenyl can be optionally independently substituted one or more times with C 1-6 alkyl, C 1-6 alkoxy, halo, or heterocycle, wherein the C 1-6 alkyl or heterocycle groups can be optionally independently substituted one or more times with C 1-6 alkyl, CN, or C 1-6 alkoxy.
8 . The compound of any of the above claims, wherein R 6 is (CH 2 )-phenyl, wherein phenyl can be optionally independently substituted one or more times with C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl group is optionally substituted with CN.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is H, C 1-6 alkyl, CF 3 , NH 2 , N(H)(C 1-3 alkyl), N(C 1-3 alkyl) 2 , (CH 2 ) 1-4 —NH 2 , (CH 2 ) 1-4 —N(H)(C 1-3 alkyl), (CH 2 ) 14 —N(C 1-3 alkyl) 2 , (CH 2 ) 1-4 —C 1-6 alkoxy, C(O)N(C 1-3 alkyl) 2 , or (CH 2 ) 1-4 —OH;
R 5 is OH, C 2-6 alkyl, C 1-6 alkoxy, (CH 2 ) 1-4 —C 1-6 alkoxy, C 3-7 cycloalkyl, or heterocycle;
R 6 is (CH 2 ) 1-4 -phenyl, wherein phenyl can be optionally independently substituted one or more times with C 1-6 alkyl, C 1-6 alkoxy, halo, or heterocycle, wherein the C 1-6 alkyl or heterocycle groups can be optionally independently substituted one or more times with C 1-6 alkyl, CN, or C 1-6 alkoxy; and
R 7 is OH.
10 . A compound of claim 1 , selected from compounds 3, 8, 10, and 40 of Table 1, or pharmaceutically acceptable salts thereof.
11 . A compound of claim 1 , selected from compounds 13, 14, 15, 16, 17, 18, 19 and 20 of Table 2, or pharmaceutically acceptable salts thereof.
12 . A compound of claim 1 , selected from compounds 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and 32 of Table 3, or pharmaceutically acceptable salts thereof.
13 . A compound of claim 1 , selected from compounds 35, 36, 37 and 38 of Table 4, or pharmaceutically acceptable salts thereof.
14 . A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
15 . A method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 .
16 . The method of claim 15 , wherein the inflammatory disease is inflammatory bowel disease.
17 . The method of claim 15 , wherein the inflammatory disease is Crohn's disease or ulcerative colitis.
18 . A method of inhibiting CCR9 receptor function in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound of claim 1 .
19 . The method of claim 15 , wherein the compound inhibits the binding of a ligand to CCR9.
20 . The method of claim 19 , wherein the ligand is TECK.
21 . (canceled)