Aza-aryl 1H-pyrazol-1-YL benzene sulfonamides
Compounds are provided that act as potent antagonists of the CCR(9) receptor. Animal testing demonstrates that these compounds are useful for treating inflammation, a hallmark disease for CCR(9). The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR(9)-mediated diseases, and as controls in assays for the identification of CCR(9) antagonists.
1. A compound or salt thereof, of formula (IIIa) or (IIIb):
where
R 1 is selected from the group consisting of substituted or unsubstituted C 2-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylamino, and substituted or unsubstituted C 3-10 heterocyclyl;
R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy; or
R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring;
R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halo;
R 4 is H or F;
R 5 is H, F, Cl, or —CH 3 ;
R 6 is H, halo, —CN, —CO 2 R a , —CONH 2 , —NH 2 , substituted or unsubstituted C 1-8 aminoalkyl, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted C 1-8 alkoxy;
R a is H or substituted or unsubstituted C 1-8 alkyl;
or where R 5 and R 6 together with the carbon atoms to which they are attached form a carbocyclic ring;
each R 8 is independently selected from the group consisting of H, halo, —CN, —OH, oxo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, and —NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
R 20 and R 21 are each independently H, or substituted or unsubstituted C 1-8 alkyl; and
n is 0, 1, 2 or 3.
2. The compound of claim 1 or salt thereof, where
R 1 is selected from the group consisting of: —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —C(CH 3 ) 2 CH 2 CH 3 , —C(CH 2 CH 2 )CN, —C(OH)(CH 3 ) 2 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OC(CH 3 ) 3 , —OCH 2 CH(CH 3 ) 2 , —OCF 3 , and morpholino;
R 2 is H, F, or Cl; or
R 1 and R 2 may together form —OC(CH 3 ) 2 CH 2 — or —C(CH 3 ) 2 CH 2 CH 2 —;
R 3 is H, —CH 3 , or —OCH 3 ;
R 4 is H or F;
R 5 is H;
R 6 is H, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C 3 H 7 , —CH 2 F, —CHF 2 , —CF 2 CH 3 , —CF 3 , —CH 2 OCH 3 , —CH 2 OH, —CH 2 CN, —CN, or —CONH 2 ; and
each R 8 is independently selected from the group consisting of H, F, Cl, Br, —CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —NH 2 , —N(CH 3 ) 2 , and —CN.
3. The compound of claim 2 or salt thereof, where R 1 is —C(CH 3 ) 3 .
4. The compound of claim 3 or salt thereof, where
R 2 is H or F;
R 3 is H;
R 4 is H; and
R 6 is —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 .
5. The compound of claim 4 or salt thereof, selected from the group consisting of:
6. A compound or salt, selected from the group consisting of
and N-oxides thereof.
7. A composition comprising a pharmaceutically acceptable carrier and a compound or salt of claim 1 .
8. A method of modulating CCR(9) function in a cell, comprising contacting the cell with a CCR(9) modulating amount of the compound of claim 1 .
9. A method for treating a CCR(9)-mediated condition or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , wherein the CCR(9)-mediated disease or condition is selected from an inflammatory bowel disease, an inflammatory hepatic disease, and post-operative ileus.
10. The method of claim 9 , wherein the subject is a human.
11. The method of claim 9 , where the administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.
12. The method of claim 9 , where the CCR(9)-mediated disease or condition is an inflammatory bowel disease selected from Crohn's disease and ulcerative colitis.
13. The method of claim 9 , wherein the CCR(9)-mediated condition or disease is selected from primary sclerosing cholangitis and post-operative ileus.
14. The method of claim 13 , wherein the primary sclerosing cholangitis is subsequent to or associated with an inflammatory bowel disease.
15. A method for treating a CCR(9)-mediated condition or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 2 , wherein the CCR(9)-mediated disease or condition is selected from an inflammatory bowel disease, an inflammatory hepatic disease, primary sclerosing cholangitis, and post-operative ileus.
16. A method for treating a CCR(9)-mediated condition or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 5 , wherein the CCR(9)-mediated disease or condition is selected from an inflammatory bowel disease, an inflammatory hepatic disease, primary sclerosing cholangitis, and post-operative ileus.
17. A method for treating a CCR(9)-mediated condition or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 6 , wherein the CCR(9)-mediated disease or condition is selected from an inflammatory bowel disease, an inflammatory hepatic disease, primary sclerosing cholangitis, and post-operative ileus.
18. A method for treating a CCR(9)-mediated condition or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 15 , wherein the CCR(9)-mediated disease or condition is selected from an inflammatory bowel disease, primary sclerosing cholangitis, and post-operative ileus.
19. A method for treating a CCR(9)-mediated condition or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 16 , wherein the CCR(9)-mediated disease or condition is selected from an inflammatory bowel disease, primary sclerosing cholangitis, and post-operative ileus.
20. A method for treating a CCR(9)-mediated condition or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 17 , wherein the CCR(9)-mediated disease or condition is selected from an inflammatory bowel disease, primary sclerosing cholangitis, and post-operative ileus.