CXCR3 antagonists
View Patent ↗Compounds, compositions and methods that are useful in the treatment of inflammatory and immune conditions and diseases are provided herein. In particular, the invention provides compounds which modulate the expression and/or function of a chemokine receptor. The subject methods are useful for the treatment of inflammatory and immunoregulatory disorders and diseases, such as multiple sclerosis, rheumatoid arthritis and type I diabetes.
1. A compound having the formula:
wherein
{circle around (A)} is
optionally independently substituted with one to four R a groups, where each R a is independently selected from the group consisting of halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO 2 , —CO 2 R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O) 2 R′, —NR′—C(O)NR″R′″, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —S(O)R′, —S(O) 2 R′, S(O) 2 NR′R″, —N 3 , —CH(Ph) 2 , perfluoro(C 1 –C 4 )alkoxy, and perfluoro(C 1 –C 4 )alkyl, wherein R′, R″ and R′″ are each independently selected from the group consisting of hydrogen, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl, (unsubstituted aryl)-(C 1 –C 4 )alkyl, and (unsubstituted aryl)oxy-(C 1 –C 4 )alkyl;
L is a member selected from the group consisting of a bond, C(O)—(C 1 –C 8 )alkylene, (C 1 –C 8 )alkylene and (C 2 –C 8 )heteroalkylene;
Q is a member selected from the group consisting of a bond, (C 1 –C 8 )alkylene, (C 2 –C 8 )heteroalkylene, —C(O)—, —OC(O)—, —N(R 8 )C(O)—, —CH 2 CO—, —CH 2 SO— and —CH 2 SO 2 —;
optionally L and Q can be linked together to form a 5- or 6-membered heterocyclic group having from 1 to 3 heteroatoms;
R 1 and R 2 are members independently selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, aryl and heteroaryl, or optionally are combined to form a 3 to 8-membered ring having from 0 to 2 heteroatoms as ring vertices;
R 3 is a member selected from the group consisting of hydroxy, (C 1 –C 8 )alkoxy, amino, (C 1 –C 8 )alkylamino, di(C 1 –C 8 )alkylamino, (C 2 –C 8 )heteroalkyl, (C 3 –C 9 )heterocyclyl, (C 1 –C 8 )acylamino, amidino, guanidino, ureido, cyano, heteroaryl, —CONR 9 R 10 and —CO 2 R 11 ;
R 4 is a member selected from the group consisting of (C 1 –C 20 )alkyl, (C 2 –C 20 )heteroalkyl, heteroaryl, aryl, heteroaryl(C 1 –C 6 )alkyl, heteroaryl(C 2 –C 6 )heteroalkyl, aryl(C 1 –C 6 )alkyl and aryl(C 2 –C 6 )heteroalkyl;
R 8 is selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, heteroaryl and aryl;
each R 9 , R 10 and R 11 is independently selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, heteroaryl, aryl, heteroaryl(C 1 –C 6 )alkyl, heteroaryl(C 2 –C 8 )heteroalkyl, aryl(C 1 –C 8 )alkyl and aryl(C 2 –C 8 )heteroalkyl; and
R 14 is a member selected from the group consisting of(C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, aryl(C 1 –C 8 )alkyl, aryl(C 2 –C 8 )heteroalkyl, heteroaryl(C 1 –C 8 )alkyl, heteroaryl(C 2 –C 8 )heteroalkyl, heteroaryl and aryl.
2. The compound of claim 1 , wherein R 14 is selected from the group consisting of aryl and heteroaryl.
3. The compound of claim 1 , wherein L is (C 1 –C 8 )alkylene.
4. The compound of claim 1 , wherein Q is —C(O)—.
5. The compound of claim 1 , wherein R 4 is selected from the group consisting of (C 5 –C 15 )alkyl, substituted or unsubstituted phenyl and biphenyl.
6. The compound of claim 1 , wherein R 3 is selected from the group consisting of (C 1 –C 8 )alkoxy, (C 1 –C 8 )alkylamino, di(C 1 –C 8 )alkylamino, (C 2 –C 8 )heteroalkyl, (C 3 –C 9 )heterocyclyl, C 1 –C 8 )acylamino, cyano, heteroaryl, —CONR 9 R 10 and —CO 2 R 11 .
7. The compound of claim 6 , wherein R 3 is (C 2 –C 8 )heteroalkyl or (C 3 –C 9 )heterocyclyl.
8. The compound of claim 6 , wherein R 3 is heteroaryl.
9. The compound of claim 8 , wherein R 3 is selected from the group consisting of substituted or unsubstituted pyridyl, and substituted or unsubstituted imidazolyl.
10. The compound of claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of H and (C 1 –C 4 )alkyl.
11. The compound of claim 1 , wherein R 1 is H.
12. The compound of claim 1 , wherein R 4 is selected from the group consisting of substituted or unsubstituted benzyl, wherein said substituents are selected from the group consisting of halogen, halo(C 1 –C 4 )alkyl, halo(C 1 –C 4 )alkoxy, cyano, nitro, and phenyl.
13. The compound of claim 1 , wherein R 14 is selected from the group consisting of substituted phenyl, substituted pyridyl, substituted thiazolyl and substituted thienyl, wherein the substituents are selected from the group consisting of cyano, halogen, (C 1 –C 8 )alkoxy, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, CONH 2 , methylenedioxy and ethylenedioxy.
14. The compound of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl and propyl, and R 2 is hydrogen.
15. The compound of claim 1 , wherein R 1 and R 2 are each methyl.
16. The compound of claim 14 , wherein R 3 is selected from the group consisting of substituted or unsubstituted pyridyl and substituted or unsubstituted imidazolyl.
17. The compound of claim 1 , wherein
R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl and ethyl;
R 14 is selected from the group consisting of substituted or unsubstituted phenyl;
Q is —CO; L is methylene, ethylene or propylene;
R 3 is selected from the group consisting of (C 2 –C 8 )heteroalkyl, (C 3 –C 9 )heterocyclyl, substituted or unsubstituted pyridyl, and substituted or unsubstituted imidazolyl;
R 4 is selected from the group consisting of substituted or unsubstituted benzyl, wherein said substituents are selected from the group consisting of halogen, halo(C 1 –C 4 )alkyl, halo(C 1 –C 4 )alkoxy, cyano, nitro, and phenyl; and
each R a is selected from the group consisting of halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO 2 , —CO 2 R′, —CONR′R″, —C(O)R′, —NR″C(O)R′, —NR′—C(O)NR″R′″, perfluoro(C 1 –C 4 )alkoxy, and perfluoro(C 1 –C 4 )alkyl, wherein R′, R″ and R′″ are each independently selected from the group consisting of hydrogen, (C 1 C 8 )alkyl, (C 2 –C 8 )heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl, (unsubstituted aryl)-(C 1 –C 4 )alkyl, and (unsubstituted aryl)oxy-(C 1 –C 4 )alkyl.
18. The compound of claim 17 wherein R 3 is (C 2 –C 8 )heteroalkyl, or (C 3 –C 9 )heterocyclyl.
19. The compound of claim 17 wherein R 3 is selected from the group consisting of substituted or unsubstituted pyridyl, and substituted or unsubstituted imidazolyl.
20. A composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1 .