CXCR3 antagonists

Abstract

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 (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 X is a member selected from the group consisting of a bond, —C(O)—, —C(R 5 )(R 6 )—, —C(R 5 )═, —S(O)—, —S(O) 2 — and —N═;  
 Z is a member selected from the group consisting of a bond, —N═, —O—, —S—, —N(R 17 )— and —C(R 7 )═, with the proviso that X and Z are not both a bond;  
 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;  
 optionally R 2  and L can be linked together to form a 5- or 6-membered heterocyclic group having from 1 to 4 heteroatoms;  
 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 5  and R 6  are each members independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, heteroaryl and aryl, or optionally R 5  and R 6  are combined to form a 3- to 7-membered ring;  
 R 7  and R 8  are each members independently 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;  
 Y 1  and Y 2  are each members independently selected from the group consisting of —C(R 12 )=, —N═, —O—, —S— and —N(R 13 )—;  
 Y 3  is a member selected from the group consisting of N and C wherein the carbon atom shares a double bond with either Z or Y 4 ; and  
 Y 4  is a member selected from the group consisting of —N(R 14 )—, —C(R 14 )═, —N═ and —N(R 14 )—C(R 15 )(R 16 )—, wherein  
 each R 12  is a member independently selected from the group consisting of H, halogen, hydroxy, amino, alkylamino, dialkylamino, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, heteroaryl and aryl, or optionally when Y 1  and Y 2  are both —C(R 12 )═ the two R 12  groups can be combined to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; or optionally when Y 1  is —C(R 12 )═ and X is —C(R 5 )═ or —C(R 5 )(R 6 )—, R 12  and R 5  can be combined to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;  
 R 13  is a member 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;  
 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;  
 R 15  and R 16  are each members independently selected from the group consisting of H, (C 1 -C 8 )alkyl and (C 2 -C 8 )heteroalkyl; and  
 R 17  is a member 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, or optionally when Y 2  is —C(R 12 )═ or —N(R 13 )—, R 17  can be combined with R 12  or R 13  to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;  
 with the proviso that when the Y 3 -containing ring system is a quinazolinone or quinolinone ring system, and R 4 -Q- is substituted or unsubstituted (C 5 -C 15 )alkyl, then R 3 -L- is other than substituted or unsubstituted (C 2 -C 8 )alkylene or a substituted or unsubstituted (C 2 -C 8 )heteroalkylene attached to —NR′R″, wherein R′ and R″ are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or optionally are combined with the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered ring.  
 
     
     
         2 .- 65 . (canceled)  
     
     
         66 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound having the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 X is a member selected from the group consisting of a bond, —C(O)—, —C(R 5 )(R 6 )—, —C(R 5 )═, —S(O)—, —S(O) 2 — and —N═;  
 Z is a member selected from the group consisting of a bond, —N═, —O—, —S—, —N(R 17 )— and —C(R 7 )═, with the proviso that X and Z are not both a bond;  
 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;  
 optionally R 2  and L can be linked together to form a 5- or 6-membered heterocyclic group having from 1 to 4 heteroatoms;  
 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 5  and R 6  are each members independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, heteroaryl and aryl, or optionally R 5  and R 6  are combined to form a 3- to 7-membered ring;  
 R 7  and R 8  are each members independently 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;  
 Y 1  and Y 2  are each members independently selected from the group consisting of —C(R 12 )═, —N═, —O—, —S— and —N(R 13 )—;  
 Y 3  is a member selected from the group consisting of N and C wherein the carbon atom shares a double bond with either Z or Y 4 ; and  
 Y 4  is a member selected from the group consisting of —N(R 14 )—, —C(R 14 )═, —N═ and —N(R 14 )—C(R 15 )(R 16 )—, wherein  
 each R 12  is a member independently selected from the group consisting of H, halogen, hydroxy, amino, alkylamino, dialkylamino, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, heteroaryl and aryl, or optionally when Y 1  and Y 2  are both —C(R 12 )═ the two R 12  groups can be combined to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; or optionally when Y 1  is —C(R 12 )═ and X is —C(R 5 )═ or —C(R 5 )(R 6 )—, R 12  and R 5  can be combined to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;  
 R 13  is a member 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;  
 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;  
 R 15  and R 16  are each members independently selected from the group consisting of H, (C 1 -C 8 )alkyl and (C 2 -C 8 )heteroalkyl; and  
 R 17  is a member 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, or optionally when Y 2  is —C(R 12 )═ or —N(R 13 )—, R 17  can be combined with R 12  or R 13  to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;  
 with the proviso that when the Y 3 -containing ring system is a quinazolinone or quinolinone ring system, and R 4 -Q- is substituted or unsubstituted (C 5 -C 15 )alkyl, then R 3 -L- is other than substituted or unsubstituted (C 2 -C 8 )alkylene or a substituted or unsubstituted (C 2 -C 8 )heteroalkylene attached to —NR′R″, wherein R′ and R″ are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or optionally are combined with the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered ring.  
 
     
     
         67 .- 90 . (canceled)  
     
     
         91 . A method of treating an inflammatory or immune condition or disease in a subject, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound having the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 X is a member selected from the group consisting of a bond, —C(O)—, —C(R 5 )(R 6 )—, —C(R 5 )═, —S(O)—, —S(O) 2 — and —N═;  
 Z is a member selected from the group consisting of a bond, —N═, —O—, —S—, —N(R 17 )— and —C(R 7 )═, with the proviso that X and Z are not both a bond;  
 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;  
 optionally R 2  and L can be linked together to form a 5- or 6-membered heterocyclic group having from 1 to 4 heteroatoms;  
 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 5  and R 6  are each members independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, heteroaryl and aryl, or optionally R 5  and R 6  are combined to form a 3- to 7-membered ring;  
 R 7  and R 8  are each members independently 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 I—C 8 )alkyl and aryl(C 2 -C 8 )heteroalkyl;  
 Y 1  and Y 2  are each members independently selected from the group consisting of —C(R 12 )═, —N═, —O—, —S— and —N(R 13 )—;  
 Y 3  is a member selected from the group consisting of N and C wherein the carbon atom shares a double bond with either Z or Y 4 ; and  
 Y 4  is a member selected from the group consisting of —N(R 14 )—, —C(R 14 )═, —N═ and —N(R 14 )—C(R 15 )(R 16 )—, wherein  
 each R 12  is a member independently selected from the group consisting of H, halogen, hydroxy, amino, alkylamino, dialkylamino, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, heteroaryl and aryl, or optionally when Y 1  and Y 2  are both —C(R 12 )═ the two R 12  groups can be combined to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; or optionally when Y 1  is —C(R 12 )═ and X is —C(R 5 )═ or —C(R 5 )(R 6 )—, R 12  and R 5  can be combined to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;  
 R 13  is a member 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;  
 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;  
 R 15  and R 16  are each members independently selected from the group consisting of H, (C 1 -C 8 )alkyl and (C 2 -C 8 )heteroalkyl; and  
 R 17  is a member 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, or optionally when Y 2  is —C(R 12 )═ or —N(R 13 )—, R 17  can be combined with R 12  or R 13  to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;  
 with the proviso that when the Y 3 -containing ring system is a quinazolinone or quinolinone ring system, and R 4 -Q- is substituted or unsubstituted (C 5 -C 15 )alkyl, then R 3 -L- is other than substituted or unsubstituted (C 2 -C 8 )alkylene or a substituted or unsubstituted (C 2 -C 8 )heteroalkylene attached to —NR′R″ wherein R′ and R″ are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or optionally are combined with the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered ring.  
 
     
     
         91 - 133 . (canceled)  
     
     
         134 . A method for the modulation of CXCR3 function in a cell, comprising contacting said cell with a compound of  claim 1 .  
     
     
         135 . A method for the modulation of CXCR3 function, comprising contacting a CXCR3 protein with a compound of  claim 1.