AZA-ARYL 1H-PYRAZOL-1-YL BENZENE SULFONAMIDES
Compounds are provided that act as potent antagonists of the CCR(9) receptor for treating Sjogren's syndrome. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions.
1 . A method of treating Sjogren's syndrome, comprising administering to a subject an effective amount of the compound or salt of formula (I):
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;
where R 5 and R 6 may together form a carbocyclic ring;
L is a bond, —CH 2 —, or —CH(CH 3 )—; and
each of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected from the group consisting of N, N—O, and —CR 8 —; where at least one and not more than two of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are N or N—O;
R 8 is each 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; and
R 20 and R 21 are each independently H, or substituted or unsubstituted C 1-8 alkyl.
2 . The method according to claim 1 , wherein the compound or salt thereof of formula (II):
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;
where R 5 and R 6 may together form a carbocyclic ring;
L is a bond, —CH 2 —, or —CH(CH 3 )—; and
Z is selected from the group consisting of
and N-oxides thereof,
where the Z group may be unsubstituted or substituted with 1 to 3 independently selected R 8 substituents;
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; and
R 20 and R 21 are each independently H, substituted or unsubstituted C 1-8 alkyl.
3 . The method according to claim 1 , wherein the compound of claim 2 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.
4 . The compound of claim 3 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.
5 . The compound of claim 4 or salt thereof, where R 1 is —C(CH 3 ) 3 .
6 . The compound of claim 7 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 .
7 . The method according to claim 6 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
8 . The method of claim 1 , wherein the subject is human.
9 . The method of claim 1 , wherein the administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.
10 . The method of claim 1 , further comprising administering an anti-inflammatory or analgesic agent.
11 . The method according to claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.