IP Library › Patent Application 12498633
Patent Application
App. No. 12/498,633

ARYL SULFONAMIDES

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Patent No.
US None
App. No.
12/498,633
Abstract

Compounds are provided that act as potent antagonists of the CCR9 receptor, and which have been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR9. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR9-mediated diseases, and as controls in assays for the identification of CCR9 antagonists.

Claims (29)

1 . A compound of the formula (I), or a salt thereof:

where

X represents from 1 to 4 substituents independently selected from the group consisting of halogen, —CN, —NO 2 , —OH, —OR 1 , —C(O)R 1 , —CO 2 R 1 , —O(CO)R 1 , —C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —SR 1 , —SOR 1 , —SO 2 R 1 , —SO 2 NR 1 R 2 , NR 1 R 2 , —NR 1 C(O)R 2 , —NR 1 C(O) 2 R 2 , —NR 1 SO 2 R 2 , —NR 1 (CO)NR 2 R 3 , unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 2-8 alkenyl, unsubstituted or substituted C 2-8 alkynyl, unsubstituted or substituted C 3-8 cycloalkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, and unsubstituted or substituted 3- to 10-membered heterocyclyl;

R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C 1-6 haloalkyl, unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted C 2-6 alkenyl, unsubstituted or substituted C 2-6 alkynyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, unsubstituted or substituted aryl-C 1-4 alkyl, unsubstituted or substituted aryl-C 1-4 alkyl, and unsubstituted or substituted aryloxy-C 1-4 alkyl; or

two of R 1 , R 2 and R 3 together with the atom(s) to which they are attached, may form an unsubstituted or substituted 5-, 6- or 7-membered ring;

Y represents from 1 to 3 substituents, each independently selected from the group consisting of halogen, —CN, —NO 2 , —OH, —OR 4 , —C(O)R 4 , —CO 2 R 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , and unsubstituted or substituted C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, unsubstituted or substituted C 1-6 haloalkyl, unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted C 2-6 alkenyl, and unsubstituted or substituted C 2-6 alkynyl;

L is —C(O)—, —S—, —SO— or —S(O) 2 —; and

Z represents either unsubstituted or substituted monocyclic or bicyclic C 5-10 heteroaryl or unsubstituted or substituted monocyclic or bicyclic C 3-10 heterocyclyl, with the proviso that when X is methyl, then Z is not 2-thiophene, 2-(3-hydroxy-1H-indole) or 3-(1-methylpyridinium).

2 . The compound of claim 1 , where L is —CO—.

3 . The compound of claim 2 , where X represents from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —NO 2 , —OH, —OR 1 , —C(O)R 1 , —CO 2 R 1 , —O(CO)R 1 , —OC(O)NR 1 R 2 , —SR 1 , —SOR 1 , —SO 2 R 1 , —NR 1 R 2 , —NR 1 C(O)R 2 , —NR 1 C(O) 2 R 2 , —NR 1 (CO)NR 1 R 2 , unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 2-8 alkenyl, unsubstituted or substituted C 2-8 alkynyl, unsubstituted or substituted C 3-8 cycloalkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, or unsubstituted or substituted 4- to 7-membered heterocyclyl.

4 . The compound of claim 3 , where X represents 1 to 3 substituents independently selected from the group consisting of —NO 2 , —OR 1 , —C(O)R 1 , —SO 2 R 1 , —NR 1 R 2 , unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, or unsubstituted or substituted 5- or 6-membered heterocyclyl.

5 . The compound of claim 2 , where at least one X substituent is situated para to the sulfonamido bond as defined in formula (I).

6 . The compound of claim 2 , where X is unsubstituted C 1-8 alkyl, unsubstituted C 3-8 cycloalkyl, unsubstituted C 2-8 alkenyl, or unsubstituted C 2-8 alkynyl.

7 . The compound of claim 2 , where X is substituted C 1-8 alkyl, substituted C 3-8 cycloalkyl, substituted C 2-8 alkenyl, or substituted C 2-8 alkynyl, each having from 1 to 5 substituents independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , ═O, —OC(O)R 1 , —OR 1 , —C(O)R 1 , —CONR 1 R 2 , —OC(O)NR 1 R 2 , —NR 2 C(O)R 1 , —NR 1 C(O)NR 2 R 3 , —CO 2 R 1 , —NR 1 R 2 , —NR 2 CO 2 R 1 , —SR 1 , —SOR 1 , —SO 2 R 1 , —SO 2 NR 1 R 2 , —NR 1 SO 2 R 2 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocyclyl.

8 . The compound of claim 7 , where X is substituted C 1-8 alkyl or substituted C 3-8 cycloalkyl, each having from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —CN, ═O, —OC(O)R 1 , —OR 1 , —C(O)R 1 , —CONR 1 R 2 , —NR 2 C(O)R 1 , —CO 2 R 1 , —NR 1 R 2 , —SR 1 , —SOR 1 , —SO 2 R 1 , —NR 1 SO 2 R 2 , unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

9 . The compound of claim 8 , where X is substituted C 1-8 alkyl, having from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —CN, ═O, —OC(O)R 1 , —OR 1 , —C(O)R 1 , —CONR 1 R 2 , —NR 2 C(O)R 1 , —CO 2 R 1 , —NR 1 R 2 , —SO 2 R 1 , unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

10 . The compound of claim 2 , where X is unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5- to 1 0-membered heteroaryl, or unsubstituted or substituted 3- to 1 0-membered heterocyclyl, where when X is substituted is has from 1 to 4 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 1-8 haloalkyl, —CN, —NO 2 , —OH, —OR 1 , ═O, —OC(O)R 1 , —CO 2 R 1 , —C(O)R 1 , —CONR 1 R 2 , —OC(O)NR 1 R 2 , —NR 2 C(O)R 1 , —NR 1 C(O)NR 2 R 3 , —NR 1 R 2 , —NR 2 CO 2 R 1 , —SR 1 , —SOR 1 , —SO 2 R 1 , —SO 2 NR 1 R 2 , and —NR 1 SO 2 R 2 .

11 . The compound of claim 10 , where X is substituted C 6-10 aryl or unsubstituted or substituted 5- to 1 0-membered heteroaryl, where when X is substituted it has from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —OH, —OR 1 , ═O, —OC(O)R 1 , —CO 2 R 1 , —C(O)R 1 , —CONR 1 R 2 , —NR 2 C(O)R 1 , —NR 1 R 2 , —SR 1 , —SOR 1 , —SO 2 R 1 , —NR 1 SO 2 R 2 , unsubstituted or substituted C 1-8 alkyl, and C 1-8 unsubstituted or substituted haloalkyl.

12 . The compound of claim 11 , where X is unsubstituted or substituted phenyl or unsubstituted or substituted 5- or 6-membered heteroaryl, where when X is substituted it has from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR 1 , —C(O)R 1 , —CONR 1 R 2 , —NR 2 C(O)R 1 , —NR 1 R 2 , —SO 2 R 1 , unsubstituted or substituted C 1-8 alkyl, and unsubstituted or substituted C 1-8 haloalkyl.

13 . The compound of claim 10 , where X is unsubstituted or substituted 4- to 7-membered heterocyclyl, where when X is substituted it has from 1 to 3 substituents independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, —OR 1 , —OH, —OC(O)R 1 , —CO 2 R 1 , —C(O)R 1 , —CONR 1 R 2 , —NR 1 R 2 , —SO 2 R 1 , and —NR 1 SO 2 R 2 .

14 . The compound of claim 13 , where X is a unsubstituted or substituted 5- or 6-membered heterocyclyl, where when X is substituted it has 1 to 2 substituents independently selected from the group consisting of unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 1-8 haloalkyl, —OR 1 , —OH, —C(O)R 1 , —CONR 1 R 2 , —NR 1 R 2 , and —SO 2 R 1 .

15 . The compound of claim 2 , where R 1 , R 2 and R 3 are unsubstituted.

16 . The compound of claim 2 , where R 1 , R 2 and R 3 , when substituted, can have from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR 1 , —OCOHNR 1 , —OCONR′ 2 , —SH, —SR′, —SO 2 NH 2 , —CONH 2 , —NHC(O)NH 2 , NR′C(O)NH 2 , —CO 2 H, —CN, —NO 2 , —NH 2 , —NHR′ and —NR′ 2 , —S(O)R′, —S(O) 2 R′, —CO 2 R′, —CONR′ 2 , —CONHR′, —C(O)R′, —NR′COR′, —NHCOR′, —NR′CO 2 R′, —NHCO 2 R′, —CO 2 R′, —NR′C(O)NR′ 2 , —NHC(O)NR′ 2 , —NR′C(O)NHR′, —NHC(O)NHR′, —NR′SO 2 R′, —NHSO 2 R′, —SO 2 NR′ 2 , and —SO 2 NHR′, where R′ is C 1-6 alkyl.

17 . The compound of claim 2 , where Y represents from 1 to 2 substituents, each independently selected from the group consisting of halogen, —CN, —NO 2 , —OH, —OR 4 , —C(O)R 4 , —CO 2 R 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , and unsubstituted or substituted C 1-4 alkyl.

18 . The compound of claim 2 , where Y represents from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —NO 2 , —OR 4 , —C(O)R 4 , —SR 4 , —CF 3 , —SOR 4 , and —SO 2 R 4 .

19 . The compound of claim 18 , where Y represents from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —NO 2 , —CF 3 , and —SO 2 R 4 .

20 . The compound of claim 18 , where Y represents 1 or 2 substituents where at least halogen is present and optionally another substituent selected from the group consisting of halogen, —CN, —NO 2 , —OH, —OR 4 , —C(O)R 4 , —CO 2 R 4 , —SR 4 , —SOR 4 , —SO 2 R 4 and unsubstituted or substituted C 1-4 alkyl.

21 - 85 . (canceled)