IP Library › Granted Patent US 8,642,808

Granted Patent B2

US 8,642,808 · App. 13/092,615 · Granted Feb 4, 2014

Bis-aryl sulfonamides

Inventors: Solomon Ungashe (Fremont, CA); Zheng Wei (Redwood City, CA); John J. Wright (Sandringham, CA); Andrew Pennell (San Francisco, CA); Brett Permack (San Francisco, CA); Thomas Schall (Palo Alto, CA)

Assignee: ChemoCentryx, Inc.

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Quick Facts

Patent No.: US 8,642,808
App. No.: 13/092,615
Granted: Feb 4, 2014
Kind: B2

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Abstract

Compounds are provided that act as potent antagonists of chemokine receptors. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of chemokine receptor-mediated diseases, and as controls in assays for the identification of chemokine antagonists.

Claims (49)

1. A modulator of the formula (I) or a salt or N-oxide thereof:

L is —C(O)—, —S—, —S(O)— or —S(O)2—;

X represents from 1 to 5 substituents independently selected from the group consisting of halogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, —CN, —NO 2 , —C(O)R 1 , —CO 2 R 1 , —C(O)NR 1 R 2 , —OR 1 , —OC(O)R 1 , —OC(O)NR 1 R 2 , —NO 2 , —NR 3 C(O)R 1 , —NR 3 C(O)NR 1 R 2 , —NR 1 R 2 , —NR 3 CO 2 R 1 , —NR 3 S(O) 2 R 1 , —SR 1 , —S(O)R 1 , —S(O) 2 R 1 , —S(O) 2 NR 1 R 2 , substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;

substituted C 1-8 alkyl, substituted C 2-8 alkenyl, or substituted C 2-8 alkynyl may have from 1-5 substituents independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , ═O, —OC(O)R 1 , —OR 1 , —C(O)R 1 , —C(O)NR 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 , —S(O)R 1 , —S(O) 2 R 1 , —S(O) 2 NR 1 R 2 , —NR 1 S(O) 2 R 2 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocyclyl;

substituted C 6-10 aryl, substituted 5- to 10-membered heteroaryl, or substituted 3- to 10-membered heterocyclyl, may have from 1-4 substituents independently selected from the group consisting of halogen, unsubstituted C 1-8 alkyl, unsubstituted C 1-8 haloalkyl, unsubstituted 4- to 7-membered heterocycle, —CN, —NO 2 , —OR 1 , ═O, —OC(O)R 1 , —CO 2 R 1 , —C(O)R 1 , —C(O)NR 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 , —S(O)R 1 , —S(O) 2 R 1 , —S(O) 2 NR 1 R 2 , and —NR 1 S(O) 2 R, with the proviso that if X represents a heterocycle, suitable substituents preferably do not include another heterocycle;

R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl-C 1-4 alkyl, aryloxy-C 1-4 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycle, or where R 1 and R 2 , or R 3 and R 2 , or R 1 and R 3 , may together with the atom(s) to which they are attached, form an substituted or unsubstituted 5-, 6-, or 7-membered ring;

and where the aliphatic and aromatic portions of R 1 , R 2 and R 3 are optionally further substituted with from 1 to 3 substituents selected from the group consisting of

halogen, —OH, —OR m , —OC(O)NHR m , —OC(O)NR m R n , —SH, —SR m , —S(O)R m , —S(O) 2 R m , —S(O) 2 NH 2 , —S(O) 2 NHR m , —S(O) 2 NR m R n , —NHS(O) 2 R m , —NR m S(O) 2 R n , —C(O)NH 2 , —C(O)NHR m , —C(O)N(R m ) 2 , —C(O)R m , —NHC(O)R m , —NR m C(O)R n , —NHC(O)NH 2 , —NR m C(O)NH 2 , —NR m C(O)NHR n , —NHC(O)NHR m , —NR o C(O)NR m R n , —NHC(O)N(R m ) 2 , —CO 2 H, —CO 2 R m , —NHCO 2 R m , —NR m CO 2 R n , —CN, —NO 2 , —NH 2 , —NHR n , —NR m R n , —NR m S(O)NH 2 and —NR m S(O) 2 NHR n , where R m , R n , and R o are each independently unsubstituted C 1-6 alkyl;

Y represents from 1 to 4 substituents, each independently selected from the group consisting of fluoro, —CN, —OR 4 , —C(O)R 4 , —CO 2 R 4 , —SR 4 , —S(O)R 4 , —S(O) 2 R 4 , substituted C 1 alkyl, and unsubstituted or substituted C 2-4 alkyl;

substituted C 1-4 alkyl may have from 1 to 3 substituents independently selected from the group consisting of chloro, bromo, iodo, —OR 4 , —CN, —NO 2 , ═O, —OC(O)R 4 , —CO 2 R 4 , —C(O)R 4 , —CONR 4 R 5 , —OC(O)NR 4 R 5 , —NR 4 C(O)R 5 , —NR 4 C(O)NR 5 R 6 , —NR4R 5 , —NR 4 CO 2 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , and —NR 4 SO 2 R 5 ;

R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or where R 4 and R 5 , or R 6 and R 4 or R 5 and R 6 , together with the atom to which they are attached, form a substituted or unsubstituted 5-, 6- or 7-membered ring;

and the aliphatic and aromatic portions of R 4 , R 5 , and R 6 are optionally further substituted with from 1 to 3 substituents selected from the group consisting of

Z represents from 0 to 5 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 2-8 alkenyl, unsubstituted or substituted C 2-8 alkynyl, —CN, —NO 2 , —OW, —OC(O)R 7 , —CO 2 R 7 , —C(O)R 7 , —CONR 7 R 8 , —OC(O)NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O)NR 8 R 9 , —NR 7 R 8 , —NR 7 CO 2 R 8 , —SR 7 , —S(O)R 7 , —S(O) 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 SO 2 R 8 , unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl and unsubstituted or substituted 3- to 10-membered heterocyclyl;

substituted C 1-8 alkyl, C 2-8 alkenyl and C 2-8 alkynyl substituents on Z may have from 1 to 5 substituents independently selected from the group consisting of halogen, —OR 7 , —CN, —NO 2 , ═O, —CN, —NO 2 , —OC(O)R 7 , —CO 2 R 7 , —C(O)R 7 , —CONR 7 R 8 , —OC(O)NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O)NR 8 R 9 , —NR 7 R 8 , —NR 7 CO 2 R 8 , —SR 7 , —S(O)R 7 , —S(O) 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 SO 2 R 8 , unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, or unsubstituted or substituted 4- to 7-membered heterocyclyl;

substituted aryl, heteroaryl and heterocyclyl substituents on Z may have from 1 to 5 substituents independently selected from the group consisting of halogen, —OR 7 , —CN, —NO 2 , ═O, —OC(O)R 7 , —OC(O)R 7 , —CO 2 R 7 , —C(O)R 7 , —CONR 7 R 8 , —OC(O)NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O)NR 8 R 9 , —NR 7 R 8 , —NR 7 CO 2 R 8 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 SO 2 R 8 ,unsubstituted 4- to 7-membered heterocyclyl, unsubstituted C 1-8 alkyl and unsubstituted C 1-8 haloalkyl;

R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-10 aryl, 5 to 10 membered heteroaryl and 3- to 10-membered heterocycle, or R 7 and R 8 , or R 8 and R 9 , or R 7 and R 9 , may together with the atom(s) to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring; and

the aliphatic and aromatic portions of R 7 , R 8 and R 9 are optionally further substituted with 1 to 3 substituents selected from the group consisting of halogen, —OH, —OR m , —OC(O)NHR m , —OC(O)NR m R n , —SH, —SR m , —S(O)R m , —S(O) 2 R m , —S(O) 2 NH 2 , —S(O) 2 NHR m , —S(O) 2 NR m R n , —NHS(O) 2 R m , —NR m S(O) 2 R n , —C(O)NH 2 , —C(O)NHR m , —C(O)N(R m ) 2 , —C(O)R m , —NHC(O)R m , —NR m C(O)R n , —NHC(O)NH 2 , —NR m C(O)NH 2 , —NR m C(O)NHR n , —NHC(O)NHR m , —NR o C(O)NR m R n , —NHC(O)N(R m ) 2 , —CO 2 H, —CO 2 R m , —NHCO 2 R m , —NR m CO 2 R n , —CN, —NO 2 , —NH 2 , —NHR n , —NR m R n , —NR m S(O)NH 2 and —NR m S(O) 2 NHR n , where R m , R n , and R o are each independently unsubstituted C 1-6 alkyl.

2. A composition comprising a pharmaceutically acceptable carrier and a compound according to any of claim 1 .

3. A method for treating a CCR9-mediated condition or disease comprising administering to a subject a safe and effective amount of the compound according to any of claim 1 .

4. A method of modulating CCR9 function in a cell, comprising contacting the cell with a CCR9 modulating amount of the compound according to any of claim 1 .

5. A modulator of the formula (I) or a salt or N-oxide thereof:

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

X represents from 1 to 5 substituents independently selected from the group consisting of halogen, substituted or unsubstituted C 2-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, —CN, —C(O)R 1 , —CO 2 R 1 , —C(O)NR 1 R 2 , —OR 1 , —OC(O)R 1 , —OC(O)NR 1 R 2 , —NO 2 , —NR 3 C(O)R 1 , —NR 3 C(O)NR 1 R 2 , —NR 3 CO 2 R 1 , —NR 3 S(O) 2 R 1 , —SR 1 , —S(O)R 1 , —S(O) 2 R 1 , —S(O) 2 NR 1 R 2 , substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;

substituted C 1-8 alkyl, substituted C 2-8 alkenyl, or substituted C 2-8 alkynyl may have from 1-5 substituents independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , ═O, —OC(O)R 1 , —OR 1 , —C(O)R 1 , —(O)NR 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 , —S(O)R 1 , —S(O) 2 R 1 , —S(O) 2 NR 1 R 2 , —NR 1 S(O) 2 R 2 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocyclyl;

substituted C 6-10 aryl, substituted 5- to 10-membered heteroaryl, or substituted 3- to 10-membered heterocyclyl, may have from 1-4 substituents independently selected from the group consisting of halogen, unsubstituted C 1-8 alkyl, unsubstituted C 1-8 haloalkyl, unsubstituted 4- to 7-membered heterocycle, —CN, —NO 2 , —OR 1 , ═O, —OC(O)R 1 , —CO 2 R 1 , —C(O)R 1 , —C(O)NR 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 , —S(O)R 1 , —S(O) 2 R 1 , —S(O) 2 NR 1 R 2 , and —NR 1 S(O) 2 R, with the proviso that if X represents a heterocycle, suitable substituents preferably do not include another heterocycle;

and where the aliphatic and aromatic portions of R 1 , R 2 and R 3 are optionally further substituted with from 1 to 3 substituents selected from the group consisting of

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

and the aliphatic and aromatic portions of R 4 , R 5 , and R 6 are optionally further substituted with from 1 to 3 substituents selected from the group consisting of

Z represents from 0 to 5 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 2-8 alkenyl, unsubstituted or substituted C 2-8 alkynyl, —CN, —NO 2 , —OR 7 , —OC(O)R 7 , —CO 2 R 7 , —C(O)R 7 , —CONR 7 R 8 , —OC(O)NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O)NR 8 R 9 , —NR 7 R 8 , —NR 7 CO 2 R 8 , —SR 7 , —S(O)R 7 , —S(O) 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 SO 2 R 8 , unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl and unsubstituted or substituted 3- to 10-membered heterocyclyl;

6. The modulator of claim 5 , where Y represents from 1 to 4 substituents, each independently selected from the group consisting of —CN, —NO 2 , —OR 4 , —C(O)R 4 , —CO 2 R 4 , —SR 4 , —S(O)R 4 , —S(O) 2 R 4 , substituted C 1 alkyl, and unsubstituted or substituted C 2-4 alkyl;

substituted C 1-4 alkyl may have from 1 to 3 substituents independently selected from the group consisting of chloro, bromo, and iodo, —OR 4 , —CN, —NO 2 , ═O, —OC(O)R 4 , —CO 2 R 4 , —C(O)R 4 , —CONR 4 R 5 , —OC(O)NR 4 R 5 , —NR 4 C(O)R 5 , —NR 4 C(O)NR 5 R 6 , —NR4R 5 , —NR 4 CO 2 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , and —NR 4 SO 2 R 5 ;

and the aliphatic and aromatic portions of R 4 , R 5 , and R 6 are optionally further substituted with from 1 to 3 substituents selected from the group consisting of

7. The modulator of claim 5 , where Z represents from 1 to 5 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 2-8 alkenyl, unsubstituted or substituted C 2-8 alkynyl, —CN, —NO 2 , —OR 7 , —OC(O)R 7 , —CO 2 R 7 , —C(O)R 7 , —CONR 7 R 8 , —OC(O)NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O)NR 8 R 9 , —NR 7 R 8 , —NR 7 CO 2 R 8 , —SR 7 , —S(O)R 7 , —S(O) 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 SO 2 R 8 , unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl and unsubstituted or substituted 3- to 10-membered heterocyclyl;

substituted aryl, heteroaryl and heterocyclyl substituents on Z may have from 1 to 5 substituents independently selected from the group consisting of halogen, —OR 7 , —CN, —NO 2 , ═O, —OC(O)R 7 , —OC(O)R 7 , —CO 2 R 7 , —C(O)R 7 , —CONR 7 R 8 , —OC(O)NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O)NR 8 R 9 , —NR 7 R 8 , —NR 7 CO 2 R 8 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 7 R 8 , —NR 7 SO 2 R 8 , unsubstituted 4- to 7-membered heterocyclyl, unsubstituted C 1-8 alkyl and unsubstituted C 1-8 haloalkyl;

Continuity (7)

Continuation 12780390 · May 14, 2010

Continuation 12024860 · Feb 1, 2008

Continuation 11789304 · Apr 23, 2007

Continuation 10848836 · May 19, 2004

Continuation In Part 10716183 · Nov 18, 2003

Provisional Application 60427670 · Nov 18, 2002

Related Publication 20110257183A1 · Oct 20, 2011