Cxcr1 and cxcr2 chemokine antagonists

Abstract

The present invention is directed to a compound having the general structure of formula (1): useful for the treatment, prevention or amelioration of a CXCR1 or CXCR2 chemokine-mediated disease.

1 . A compound of the formula:  
     
       
         
         
             
             
         
       
     
     and the pharmaceutically acceptable salts and solvates thereof, wherein: 
 Y is selected from the group consisting of: unsubstituted phenyl, substituted phenyl, unsubstituted pyridinyl, substituted pyridinyl, unsubstituted pyrazinyl, substituted pyrazinyl, unsubstituted pyrimidinyl substituted pyrimidinyl, unsubstituted thiophene-yl, substituted thiophene-yl, unsubstituted thiazolyl, substituted thiazolyl, unsubstituted furanyl, substituted furanyl, unsubstituted isoxazolyl, substituted isoxazolyl, unsubstituted oxazolyl, substituted oxazolyl, unsubstituted naphthyl, substituted naphthyl, unsubstituted indolyl, substituted indolyl, unsubstituted benzoimidazolyl, substituted benzoimidazoyl, unsubstituted benzodioxolyl, substituted benzodioxolyl, unsubstituted quinolinyl, substituted quinolinyl, unsubstituted benzofuranyl, substituted benzofuranyl, substituted benzothiophene-yl, unsubstituted benzothiophene-yl, unsubstituted pyrrolyl, substituted pyrrolyl, unsubstituted isothiazolyl, substituted isothiazolyl, unsubstituted pyrazolyl, substituted pyrazolyl, unsubstituted pyridazinyl, substituted pyridazinyl, unsubstituted isoquinolinyl, substituted isoquinolinyl, unsubstituted pyridopyrazinyl, substituted pyridopyrazinyl, unsubstituted napthyridinyl, substituted napthyridinyl, unsubstituted triazolyl, substituted triazolyl, unsubstituted tetrazolyl, substituted tetrazolyl, unsubstituted triazinyl, substituted triazinyl, unsubstituted chromenyl, substituted chromenyl, unsubstituted pteridinyl, substituted pteridinyl, unsubstituted purinyl, and substituted purinyl; said substituted Y groups being substituted with 1 to 5 substituents independently selected from the group consisting of: —OH, halogen, cyano, —CF 3 , —OCF 3 , —NR 11 R 12 , —NR 11 —(CO)NR 11 R 12 , —C(O)NR 11 R 12 , —CO 2 R 11 , —OR 11 , —SO (t) NR 11 R 12 , —NR 11 SO (t) R 12 , —COR 11 , substituted aryl, unsubstituted aryl, substituted alkyl, unsubstituted alkyl, substituted alkoxy, unsubstituted alkoxy, substituted arylalkyl, unsubstituted arylalkyl, substituted heteroaryl, unsubstituted heteroaryl, substituted aryloxy, unsubstituted aryloxy, substituted heteroarylalkyl, unsubstituted heteroarylalkyl, substituted heteroarylalkoxy, unsubstituted heteroarylalkoxy, substituted heterocycloalkyl, unsubstituted heterocycloalkyl, substituted hydroxyalkyl, unsubstituted hydroxyalkyl; wherein the substituted substituent groups bound to Ar are substituted with 1 to 6 substituents independently selected from the group consisting of halogen, —CF 3 , —COR 11 , —OR 11 , —NR 11 R 12 , —NO 2 , —CN, —SO 2 R 11 , —SO 2 NR 11 R 12 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —NR 11 CO 2 R 12  and —CO 2 R 11 ;  
 Q is selected from the group consisting of:  
                     
 the ring of the 5-het moiety is a heteroaryl selected from the group consisting of: thiophene-yl, isothiazolyl, pyrrolyl and pyrazolyl;  
 R 1  is bonded to a carbon atom of said 5-het and R 1  is selected from the group consisting of: hydrogen, halogen, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy, —OH, —OCF 3 , —CF 3 , —CN, —NO 2 , —C(O)R 11 , —C(O)OR 11 , —C(O)NR 11 R 12 , —SO (t) NR 11 R 12 , —SO (t) R 11 , —C(O)NR 11 OR 12 , unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl;  
 R 2  is bound to a carbon atom of said 5-het and R 2  is selected from the group consisting of: —OH, —OC(O)NHR 16 , —NHC(O)R 16  and —NHS(O) 2 R 16 ;  
 n=0 or 1;  
 n′=0 or 1;  
 R 3 , when n is 1, is bonded to a carbon atom in said 5-het, and R 3  is selected from the group consisting of: halogen, cyano, —CF 3 , substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl and unsubstituted heteroaryl;  
 R 4 , when n′ is 1, is bonded to a nitrogen atom in said 5-het and R 4  is selected from the group consisting of: substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, —COOR 17  and —OR 17 ;  
 R 5  is selected from the group consisting of: hydrogen, cyano, substituted alkyl, unsubstituted alkyl, substituted alkoxy, unsubstituted alkoxy, substituted aryl or unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted arylalkyl, unsubstituted arylalkyl, —S(O) t NR 13 R 14 , —S(O) t R 13 , —SO 2 fluoroalkyl, —C(O) 2 R 13 , —C(O)NR 13 R 14  and —C(O)R 13 ;  
 R 11  and R 12  are independently selected from the group consisting of: hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, unsubstituted alkylaryl, substituted alkylaryl, unsubstituted arylalkyl, substituted arylalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, carboxyalkyl, aminoalkyl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heteroarylalkyl, substituted heteroarylalkyl, unsubstituted heterocycloalkylalkyl, substituted heterocycloalkylalkyl, unsubstituted cycloalkylalkyl, substituted cycloalkylalkyl, unsubstituted heterocyclic, substituted heterocyclic, unsubstituted fluoroalkyl, and substituted fluoroalkyl; or  
 R 11  and R 12 , together with the nitrogen atom to which they are bound to in the groups —C(O)NR 11 R 12  and —SO (t) NR 11 R 12 , form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing 1 to 3 additional heteroatoms wherein said optional heteroatoms are selected from the group consisting of O, S and —N(R 15 ), wherein there are optionally 1 to 3 substituents on the substituted cyclized R 11  and R 12  groups and each substituent is independently selected from the group consisting of alkyl, aryl, hydroxy, cyano, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, aminoalkyl, —C(O)OR 13 , —C(O)NR 13 R 14 , —S(O) t NR 13 R 14 , —C(O)R 13 , —SO 2 R 13 , —NHC(O)NR 13 R 14 , —NHC(O)OR 13 , halogen, and —N(R 15 ) 2  wherein each R 15  is independently selected;  
 R 13  and R 14  independently selected from the group consisting of: H, unsubstituted alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, substituted arylalkyl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heteroarylalkyl, and substituted heteroarylalkyl;  
 R 15  is selected from the group consisting of: H, unsubstituted alkyl, substituted alkyl, unsubstituted fluoroalkyl, substituted fluoroalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted arylalkyl, substituted arylalkyl —C(O) 2 R 13 , —C(O)NR 13 R 14 , —S(O) t NR 13 R 14 , —C(O)R 13  and —SO 2 R 13 ;  
 R 16  is selected from the group consisting of: substituted alkyl, unsubstituted alkyl, substituted fluoroalkyl, unsubstituted fluoroalkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl and unsubstituted heteroaryl;  
 R 17  is selected from the group consisting of: alkyl, substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, unsubstituted fluoroalkyl, substituted fluoroalkyl, unsubstituted arylalkyl, substituted arylalkyl, unsubstituted heteroarylalkyl, substituted heteroarylalkyl, substituted cycloalkyl and unsubstituted cycloalkyl;  
 wherein when said substituted R 1 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  groups are other than substituted alkyl, then the substituents for said substituted R 1 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  groups are independently selected from the group consisting of: alkyl, —CF 3 , —OH, alkoxy, hydroxyalkyl, aryl, arylalkyl, aminoalkyl, fluoroalkyl, fluoroalkoxy, cycloalkyl, cycloalkylaryl, heteroaryl, heteroarylalkyl, halogen, —C(O) 2 R 13a , —C(O)NR 13a R 14a , —S(O) t NR 13a R 14a , —C(O)R 13a , —SO 2 R 13a , and —N(R 15a ) 2 , wherein each R 13a , R 14a , and R 15a  is independently selected from the group consisting of unsubstituted alkyl, unsubstituted aryl, halo substituted aryl, unsubstituted arylalkyl, halo substituted arylalkyl, and unsubstituted cycloalkyl, except that the cyclized R 11  and R 12  are optionally substituted as provided above;  
 wherein when said substituted R 1 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  groups are substituted alkyl, then the substituents for said substituted R 1 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  groups are independently selected from the group consisting of: —CF 3 , —OH, alkoxy, hydroxyalkyl, aryl, arylalkyl, aminoalkyl, fluoroalkyl, fluoroalkoxy, cycloalkyl, cycloalkylaryl, heteroaryl, heteroarylalkyl, halogen, —C(O) 2 R 13a , —C(O)NR 13a R 14a , —S(O) t NR 13a R 14a , —C(O)R 13a , —SO 2 R 13a , and —N(R 15a ) 2 , wherein each R 13a , R 14a , and R 15a  is independently selected from the group consisting of unsubstituted alkyl, unsubstituted aryl, halo substituted aryl, unsubstituted arylalkyl, halo substituted arylalkyl, and unsubstituted cycloalkyl, except that the cyclized R 11  and R 12  are optionally substituted as provided above; and  
 t is 1 or 2.  
 
   
   
       2 . The compound according to  claim 1  wherein Y is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein: 
 k=0 to 5;  
 m=0 to 4;  
 q=0 to 3;  
 p=0 to 2;  
 R 6  and R 7  are independently selected from the group consisting of: —OH, halogen, cyano, —CF 3 , —OCF 3 , —NR 11 R 12 , —NR 11 (CO)NR 11 R 12 , —C(O)NR 11 R 12 , —COR 11 , —OR 11 , —SO (t) NR 11 R 12 , —NR 11 SO (t) R 12 , —COR 11 , substituted aryl, unsubstituted aryl, substituted alkyl, unsubstituted alkyl, substituted alkoxy, unsubstituted alkoxy, substituted arylalkyl, unsubstituted arylalkyl, substituted heteroaryl, unsubstituted heteroaryl, substituted aryloxy, unsubstituted aryloxy, substituted heteroarylalkyl, unsubstituted heteroarylalkyl, substituted heteroarylalkoxy, unsubstituted heteroarylalkoxy, substituted heterocycloalkyl, unsubstituted heterocycloalkyl, substituted hydroxyalkyl, and unsubstituted hydroxyalkyl;  
 wherein the R 6  groups are substituted with 1-6 substituents, and the substituted R 7  groups are optionally substituted with 1 to 6 substituents, and each substituent on said substituted R 6  group and each substituent on said substituted R 7  group is independently selected from the group consisting of: R 11 , halogen, —CF 3 , —COR 11 , —OR 11 , —NR 11 R 12 , —NO 2 , —CN, —SO 2 R 11 , —SO 2 NR 11 R 12 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —NR 11 CO 2 R 12  and —CO 2 R 11 .  
 
   
   
       3 . The compound according to  claim 1 , wherein 5-het is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       4 . The compound according to  claim 1 , wherein 5-het is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       Q is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       Y is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       k=0 to 5;  
       q=0 to 3;  
       p=0 to 2;  
       R 6  and R 7  are independently selected from the group consisting of: —OH, halogen, cyano, —CF 3 , —OCF 3 , —NR 11 R 12 , —NR 11 (CO)NR 11 R 12 , —C(O)NR 11 R 12 , —CO 2 R 11 , —OR 11 , —SO (t) NR 11 R 12 , —NR 11 SO (t) R 12 , —COR 11 , substituted aryl, unsubstituted aryl, substituted alkyl, unsubstituted alkyl, substituted alkoxy, unsubstituted alkoxy, substituted arylalkyl, unsubstituted arylalkyl, substituted heteroaryl, unsubstituted heteroaryl, substituted aryloxy, unsubstituted aryloxy, substituted heteroarylalkyl, unsubstituted heteroarylalkyl, substituted heteroarylalkoxy, unsubstituted heteroarylalkoxy, substituted heterocycloalkyl, unsubstituted heterocycloalkyl, substituted hydroxyalkyl, and unsubstituted hydroxyalkyl;  
       wherein the R 6  groups are substituted with 1-6 substituents, and the substituted R 7  groups are optionally substituted with 1 to 6 substituents, and each substituent on said substituted R 6  group and each substituent on said substituted R 7  group is independently selected from the group consisting of: R 11 , halogen, —CF 3 , —COR 11 , —OR 11 —NR 11 R 12 , —NO 2 , —CN, —SO 2 R 11 , —SO 2 NR 11 R 12 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —NR 11 CO 2 R 12  and —CO 2 R 11 .  
     
   
   
       5 . The compound according to  claim 4  wherein 5-het is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       Q is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       Y is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
   
   
       6 . The compound according to  claim 5  wherein 5-het is:  
     
       
         
         
             
             
         
       
       Q is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       Y is:  
       
         
           
           
               
               
           
         
       
       R 1  is selected from the group consisting of —SO (t) NR 11 R 12  and —SO (t) R 11 ;  
       R 2  is selected from the group consisting of: —OH and —OC(O)NHR 16 ;  
       R 3  is selected from the group consisting of: H, alkyl, halogen and —CF 3 ;  
       R 6  is selected from the group consisting of: halogen and alkyl; and  
       k is 2 and each R 6  is independently selected.  
     
   
   
       7 . The compound according to  claim 6  wherein: 
 R 1  is —SO 2 NR 11 R 12 ;    R 3  is selected from the group consisting of, H, Cl and —CF 3 ;    R 11  is selected from the group consisting of: H, unsubstituted alkyl, substituted alkyl unsubstituted cycloalkyl, and substituted cycloalkyl;    R 12  is selected from the group consisting of: H, unsubstituted alkyl, substituted alkyl, unsubstituted cycloalkyl, and substituted cycloalkyl;    R 2  is selected from the group consisting of: —OH and —OC(O)NHR 16 ;    R 16  is selected from the group consisting of: alkyl, aryl and heteroaryl; and    Y is                          wherein each R 6  is independently selected.    
   
   
       8 . The compound according to  claim 1  wherein 5-het is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       R 1  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       R 2  is selected from the group consisting of —OH, —OC(O)NHCH 2 CH 3 , —OC(O)NHCH(CH 3 ) 2 , and —NHCOCF 3 ;  
       R 3 , when n is 1, is selected from the group consisting of: H, Cl, and —CH 3 ;  
       R 4 , when n′ is 1, is CH 3 ;  
       Q is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       R 5  is selected from the group consisting of: H, —CN, —SO 2 Ph,  
       
         
           
           
               
               
           
         
       
       Y is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
   
   
       9 . The compound according to  claim 8  wherein 5-het is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       R 1  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       R 5  is —CN or  
       
         
           
           
               
               
           
         
       
       Y is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
   
   
       10 . The compound of  claim 1  in an isolated and pure form.  
   
   
       11 . A compound of formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, or solvate thereof wherein: 
 Y is selected from the group consisting of: unsubstituted phenyl, substituted phenyl, unsubstituted pyridinyl, substituted pyridinyl, unsubstituted pyrazinyl, substitute pyrazinyl, unsubstituted pyrimidinyl substituted pyrimidinyl, unsubstituted thiophene-yl, substituted thiophene-yl, unsubstituted thiazolyl, substituted thiazolyl, unsubstituted furanyl, substituted furanyl, unsubstituted isoxazolyl, substituted isoxazolyl, unsubstituted oxazolyl, substituted oxazolyl, unsubstituted naphthyl, substituted napthyl unsubstituted indolyl, substituted indolyl, unsubstituted benzoimidazolyl, substituted benzoimidazolyl, unsubstituted benzodioxolyl, substituted benzodioxolyl, unsubstituted quinolinyl, substituted quinolinyl, unsubstituted benzofuranyl, substituted benzofuranyl, substituted benzothiophene-yl, unsubstituted benzothiophene-yl, unsubstituted pyrrolyl, substituted pyrrolyl, unsubstituted isothiazolyl, substituted isothiazolyl, unsubstituted pyrazolyl, substituted pyrazolyl, unsubstituted pyridazinyl, substituted pyridazinyl, unsubstituted isoquinolinyl, substituted isoquinolinyl, unsubstituted pyridopyrazinyl, substituted pyridopyrazinyl, unsubstituted napthyridinyl, substituted napthyridinyl, unsubstituted triazolyl, substituted triazolyl, unsubstituted tetrazolyl, substituted tetrazolyl, unsubstituted triazinyl, substituted triazinyl, unsubstituted chromenyl, substituted chromenyl, unsubstituted pteridinyl, substituted pteridinyl, unsubstituted purinyl, and substituted purinyl; said substituted Y groups being substituted with 1 to 5 substituents independently selected from the group consisting of: —OH, halogen, cyano, —CF 3 , —OCF 3 , —NR 11 R 12 , —NR 11 —(CO)NR 11 R 12 , —C(O)NR 11 R 12 , —CO 2 R 11 , —OR 11 , —SO (t) NR 11 R 12 , —NR 11 SO (t) R 12 , —COR 11 , substituted aryl, unsubstituted aryl, substituted alkyl, unsubstituted alkyl, substituted alkoxy, unsubstituted alkoxy, substituted arylalkyl, unsubstituted arylalkyl, substituted heteroaryl, unsubstituted heteroaryl, substituted aryloxy, unsubstituted aryloxy, substituted heteroarylalkyl, unsubstituted heteroarylalkyl, substituted heteroarylalkoxy, unsubstituted heteroarylalkoxy, substituted heterocycloalkyl, unsubstituted heterocycloalkyl, substituted hydroxyalkyl, unsubstituted hydroxyalkyl; wherein the substituted substituent groups bound to Y are substituted with 1 to 6 substituents independently selected from the group consisting of halogen, —CF 3 , —COR 11 , —OR 11 , —NR 11 R 12 , —NO 2 , —CN, —SO 2 R 11 , —SO 2 NR 11 R 12 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —NR 11 CO 2 R 12  and —CO 2 R 11 ;  
 Q is selected from the group consisting of:  
                     
 the ring for the 5-het moiety is a heteroaryl ring selected from the group consisting of: thiophene-yl, isothiazolyl, pyrrolyl and pyrazolyl;  
 R 1  is bonded to a carbon atom of said 5-het and R 1  is selected from the group consisting of: hydrogen, halogen, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy, —OH, —OCF 3 , —CF 3 , —CN, —NO 2 , —C(O)R 11 , —C(O)OR 11 , —C(O)NR 11 R 12 , —SO (t) NR 11 R 12 , —SO (t) R 11 , —C(O)NR 11 R 12 , unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl;  
 n=0 or 1;  
 n′=0 or 1;  
 R 3 , when n is 1, is bonded to a carbon atom in said 5-het, and R 3  is selected from the group consisting of: halogen, cyano, —CF 3 , substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl and unsubstituted heteroaryl;  
 R 4 , when n′ is 1, is bonded to a nitrogen atom in said 5-het and R 4  is selected from the group consisting of: substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, —COOR 17  and —OR 17 ;  
 R 5  is selected from the group consisting of: hydrogen, cyano, substituted alkyl, unsubstituted alkyl, substituted alkoxy, unsubstituted alkoxy, substituted aryl or unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted arylalkyl, unsubstituted arylalkyl, —S(O) t NR 13 R 14 , —S(O) t R 13 , —SO 2 fluoroalkyl, —C(O) 2 R 13 , —C(O)NR 13 R 14  and —C(O)R 13 ;  
 R 11  and R 12  are independently selected from the group consisting of: hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, unsubstituted alkylaryl, substituted alkylaryl, unsubstituted arylalkyl, substituted arylalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, carboxyalkyl, aminoalkyl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heteroarylalkyl, substituted heteroarylalkyl, unsubstituted heterocycloalkylalkyl, substituted heterocycloalkylalkyl, unsubstituted cycloalkylalkyl, substituted cycloalkylalkyl, unsubstituted heterocyclic, substituted heterocyclic, unsubstituted fluoroalkyl, and substituted fluoroalkyl; or  
 R 11  and R 12 , together with the nitrogen atom to which they are bound to in the groups —C(O)NR 11 R 12  and —SO (t) NR 11 R 12 , form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing 1 to 3 additional heteroatoms wherein said optional heteroatoms are selected from the group consisting of O, S and —N(R 15 ), wherein there are optionally 1 to 3 substituents on the substituted cyclized R 11  and R 12  groups and each substituent is independently selected from the group consisting of alkyl, aryl, hydroxy, cyano, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, aminoalkyl, —C(O)OR 13 , —C(O)NR 13 R 14 , —S(O) t NR 13 R 14 , —C(O)R 13 , —SO 2 R 13 , —NHC(O)NR 13 R 14 , —NHC(O)OR 13 , halogen, and —N(R 15 ) 2  wherein each R 15  is independently selected;  
 R 13  and R 14  independently selected from the group consisting of: H, unsubstituted alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, substituted arylalkyl, Unsubstituted heteroaryl, substituted heteroaryl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heteroarylalkyl, and substituted heteroarylalkyl;  
 R 15  is selected from the group consisting of H, unsubstituted alkyl, substituted alkyl, unsubstituted fluoroalkyl, substituted fluoroalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted arylalkyl, substituted arylalkyl —C(O) 2 R 13 , —C(O)NR 13 R 14 , —S(O) t NR 13 R 14 , —C(O)R 13  and —SO 2 R 13 ;  
 R 17  is selected from the group consisting of: alkyl, substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, unsubstituted fluoroalkyl, substituted fluoroalkyl, unsubstituted arylalkyl, substituted arylalkyl, unsubstituted heteroarylalkyl, substituted heteroarylalkyl, substituted cycloalkyl and unsubstituted cycloalkyl;  
 wherein when said substituted R 1 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 17  groups are other than substituted alkyl, then the substituents for said substituted R 1 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  groups are independently selected from the group consisting of: alkyl, —CF 3 , —OH, alkoxy, hydroxyalkyl, aryl, arylalkyl, aminoalkyl, fluoroalkyl, fluoroalkoxy, cycloalkyl, cycloalkylaryl, heteroaryl, heteroarylalkyl, halogen, —C(O) 2 R 13a , —C(O)NR 13a R 14a , —S(O) t NR 13a R 14a , —C(O)R 13a , —SO 2 R 13a , and —N(R 15a ) 2 , wherein each R 13a , R 14a , and R 15a  is independently selected from the group consisting of unsubstituted alkyl, unsubstituted aryl, halo substituted aryl, unsubstituted arylalkyl, halo substituted arylalkyl, and unsubstituted cycloalkyl, except that the cyclized R 11  and R 12  are optionally substituted as provided above;  
 wherein when said substituted R 1 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 17  groups are substituted alkyl, then the substituents for said substituted R 1 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17  groups are independently selected from the group consisting of: —CF 3 , —OH, alkoxy, hydroxyalkyl, aryl, arylalkyl, aminoalkyl, fluoroalkyl, fluoroalkoxy, cycloalkyl, cycloalkylaryl, heteroaryl, heteroarylalkyl, halogen, —C(O) 2 R 13a , —C(O)NR 13a R 14a , —S(O) t NR 13a R 14a , —C(O)R 13a , —SO 2 R 13a  and —N(R 15a ) 2 , wherein each R 13a , R 14a , and R 15a  is independently selected from the group consisting of unsubstituted alkyl, unsubstituted aryl, halo substituted aryl, unsubstituted arylalkyl, halo substituted arylalkyl, and unsubstituted cycloalkyl, except that the cyclized R 11  and R 12  are optionally substituted as provided above; and  
 t is 1 or 2.  
 
   
   
       12 . The compound according to  claim 11 , wherein R 1  is selected from the group consisting of heteroaryl and aminosulfonyl.  
   
   
       13 . The compound according to  claim 12 , wherein 
 R 1  is —SO (2) NR 11 R 12 ; and    R 11  and R 12  are independently selected from the group consisting of: H, unsubstituted alkyl, substituted alkyl, unsubstituted cycloalkyl, substituted cycloalkyl, and the unsubstituted or substituted saturated heterocyclic ring formed when R 11  and R 12  are taken together with the nitrogen atom to which they are bound.    
   
   
       14 . The compound of  claim 1  selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, or solvate thereof.  
   
   
       15 . The compound of  claim 1  selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, or solvate thereof.  
     
   
   
       16 . The compound of  claim 1  selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, or solvate thereof.  
   
   
       17 . The compound of  claim 1  selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, or solvate thereof.  
   
   
       18 . The compound of  claim 1  selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, or solvate thereof.  
   
   
       19 . The compound of  claim 1  having the formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, or solvate thereof.  
   
   
       20 . A compound of the formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, or solvate thereof.  
   
   
       21 . A pharmaceutical composition comprising at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier.  
   
   
       22 . A method of treating CXCR1 or CXCR2 chemokine mediated disease in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       23 . The method according to  claim 22  further comprising administering said compound concurrently or sequentially with at least one additional agent, drug, medicament, antibody and/or inhibitor for treating a chemokine mediated disease, in combination with a pharmaceutically acceptable carrier.  
   
   
       24 . The method according to  claim 22  wherein the compound binds to a CXCR1 receptor.  
   
   
       25 . The method according to  claim 22  wherein the compound binds to a CXCR2 receptor.  
   
   
       26 . The method according to  claim 22  comprising administering: said compound concurrently or sequentially with at least one medicament selected from the group consisting of: disease modifying antirheumatic drugs; nonsteroidal antiinflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors; immunosuppressives; steroids, biological response modifiers; and other anti-inflammatory agents or therapeutics useful for the treatment of chemokine mediated diseases.  
   
   
       27 . The method according to  claim 26  wherein said disease is an inflammatory disease.  
   
   
       28 . A method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       29 . A method according to  claim 28  further comprising administering said compound concurrently or sequentially with at least one antineoplastic agent selected from the group consisting of: (1) gemcitabine, (2) paclitaxel, (3) 5-Fluorouracil, (4) cyclophosphamide, (5) temozolomide and (6) Vincristine.  
   
   
       30 . The method according to  claim 28  further comprising administering said compound and at least one agent selected from the group consisting of microtubule affecting agents, antineoplastic agents, anti-angiogenesis agents, VEGF receptor kinase inhibitors, antibodies against the VEGF receptor, interferon, and radiation.  
   
   
       31 . A method of inhibiting angiogenesis in a patient in need of such inhibition said method comprising administering to said patient an effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       32 . A method of treating an angiogenic ocular disease in a patient in need of such treatment said method comprising administering to said patient an effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       33 . A method of treating asthma in a patient in need of such treatment said method comprising administering to said patient a therapeutically effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       34 . A method of treating a pulmonary disease in a patient in need of such treatment said method comprising administering to said patient a therapeutically effective amount of: (a) at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: glucocorticoids, 5-lipoxygenase inhibitors, β-2 adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-b agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 anti-bodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones.  
   
   
       35 . A method of treating multiple sclerosis in a patient in need of such treatment said method comprising administering to said patient a therapeutically effective amount of; (a) at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, and CB2-selective agents.  
   
   
       36 . A method of treating multiple sclerosis in a patient in need of such treatment the method comprising administering to said patient a therapeutically effective amount of: a) at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: methotrexate, cyclosporin, leflunimide, sulfasalazine, β-methasone, β-interferon, glatiramer acetate, prednisone, etonercept, and infliximab.  
   
   
       37 . A method of treating rheumatoid arthritis in a patient in need of such treatment said method comprising administering to said patient a therapeutically effective amount of: (a) at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, steroids, PDE 4 inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, CB2-selective agents, and other classes of compounds indicated for the treatment of rheumatoid arthritis.  
   
   
       38 . A method of treating stroke and ischemia reperfusion injury in a patient in need of such treatment said method comprising administering to said patient a therapeutically effective amount of: (a) at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: thrombolitics, antiplatelet agents, antagonists, anticoagulants and other compounds indicated for the treatment of rheumatoid arthritis.  
   
   
       39 . A method of treating stroke and ischemia reperfusion injury in a patient in need of such treatment said method comprising administering to said patient a therapeutically effective amount of: (a) at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: tenecteplase, TPA, alteplase, abciximab, eftiibatide, and heparin.  
   
   
       40 . A method of treating psoriasis in a patient in need of such treatment said method comprising administering to said patient a therapeutically effective amount of: a) at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, concurrently or sequentially with (b) at least one compound selected from the group consisting of: immunosuppressives, steroids, and anti-TNF-α compounds.  
   
   
       41 . A method of treating a disease selected from the group consisting of: pain, acute inflammation, chronic inflammation, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury, renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimers disease, graft vs. host reaction, allograft rejections, malaria, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral ischemia, cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus, meningitis, cystic fibrosis, pre-term labor, cough, pruritis, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred, corneal neovascularization, polymyositis, vasculitis, acne, gastric ulcers, duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burn therapy, periodontitis, cancer, transplant reperfusion injury, and early transplantation rejection in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       42 . The method of  claim 41  wherein said 
 (a) Allograft rejections are selected from the group consisting of acute allograft rejections and chronic allograft rejections,    (b) Early transplantation rejection is an acute allograft rejection,    (c) Autoimmune deafness is Meniere's disease,    (d) Myocarditis is viral myocarditis,    (e) Neuropathies are selected from the group consisting of IgA neuropathy, membranous neuropathy and idiopathic neuropathy,    (f) Autoimmune diseases are anemias, and    (g) Vasculitis syndromes are selected from the group consisting of giant cell arteritis, Behcet's disease and Wegener's granulomatosis.    
   
   
       43 . A method of treating COPD in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       44 . A method of treating arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       45 . A method of treating osteoarthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       46 . A method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       47 . A method of treating pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof and administering a therapeutically effective amount of at least one medicament selected from the group consisting of: NSAIDs, COXIB inhibitors, anti-depressants, and anti-convulsants.  
   
   
       48 . A method of treating acute pain, acute inflammatory pain, chronic inflammatory pain, or neuropathic pain in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.