Azaindazole compounds and methods of use

Abstract

Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are generally aryl piperazine derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.

1 .- 54 . (canceled) 
     
     
         55 . A method of treating CCR1-mediated diseases or conditions comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or N-oxide thereof, wherein 
         the subscript m is 0 or 1; 
         R 1  is methyl; 
         R 2a  is hydrogen or fluoro; 
         R 2c  is chloro; 
         R 2d  is selected from the group consisting of methyl, methoxy, ethoxy and 2-fluoroethoxy; 
         ring vertex a is N; 
         ring vertex b is C(R 3a ); 
         ring vertex c is N or C(R 3a ); 
         ring vertex d is C(R 3a ); 
         each R 3a  is independently selected from the group consisting of hydrogen, halogen, —OR f , —NR f R g , —R h , —CN, —NO 2 , —NR g C(O)R f , —S(O) 2 R h , —N 3 , —Y, and —X 3 N 3 , wherein Y is selected from the group consisting of morpholinyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl and pyridyl, each of which is optionally substituted with methyl and wherein each X 3  is independently C 1-4  alkylene, each R f  and R g  is independently selected from the group consisting of hydrogen, C 1-8  alkyl and C 1-8  haloalkyl, and each R h  is independently selected from the group consisting of C 1-8  alkyl and C 1-8  haloalkyl. 
       
     
     
         56 . A method in accordance with  claim 55 , wherein said CCR1-mediated disease or condition is an inflammatory condition. 
     
     
         57 . A method in accordance with  claim 55 , wherein said CCR1-mediated disease or condition is an immunoregulatory disorder. 
     
     
         58 . A method in accordance with  claim 55 , wherein said CCR1-mediated disease or condition is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, transplant rejection, restenosis, dermatitis, eczema, urticaria, vasculitis, inflammatory bowel disease, food allergy, asthma, Alzheimer's disease, Parkinson's disease, psoriasis, lupus erythematosus, osteoarthritis, stroke, restenosis and encephalomyelitis. 
     
     
         59 . A method in accordance with  claim 55 , wherein said administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical. 
     
     
         60 . A method in accordance with  claim 55 , wherein said compound is administered in combination with an anti-inflammatory agent, analgesic agent, an anti-proliferative agent, a metabolic inhibitor, a leukocyte migration inhibitor or an immuno-modulator. 
     
     
         61 .- 75 . (canceled) 
     
     
         76 . A method in accordance with  claim 55 , wherein each R 3a  substituent is independently selected from the group consisting of hydrogen,
 halogen, —NH 2 , —CH 3 , —CN, —S(O) 2 CH 3 , —CH 2 N 3 , —OCH 3 , —N 3 , —NO 2 , —NHC(O)CH 3 , morpholinyl, pyridyl, thiazolyl, oxazolyl, imidazolyl and oxadiazolyl.   
     
     
         77 . A method in accordance with  claim 55 , wherein ring vertices b and d are each CH. 
     
     
         78 . A method in accordance with  claim 55 , wherein ring vertex c is CH. 
     
     
         79 . A method in accordance with  claim 55 , wherein ring vertex c is N. 
     
     
         80 . A method in accordance with  claim 55 , wherein m is 0. 
     
     
         81 . A method in accordance with  claim 55 , wherein each R 3a  is a member independently selected from the group consisting of hydrogen, fluoro, chloro, iodo, methyl, cyano, nitro, azido, azidomethyl, methylsulfonyl, methoxy, amino, acetylamino, pyrid-2-yl, oxadiazol-3-yl, imidazol-2-yl, morpholin-4-yl, oxazol-2-yl and thiazol-2-yl. 
     
     
         82 . A method in accordance with  claim 55 , wherein m is 0, and R 2a  is H. 
     
     
         83 . A method in accordance with  claim 55 , wherein m is 0, and R 2a  is F. 
     
     
         84 . A method in accordance with  claim 55 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         85 . A method of treating CCR1-mediated diseases or conditions comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         86 . A method in accordance with  claim 55 , wherein m is 1, R 2a  is F, said compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         87 . A method in accordance with  claim 55 , wherein an R 3a  group attached to the six-membered ring is selected from the group consisting of methyl, iodo, chloro, methylsulfonyl, methoxy, azido, amino, nitro and acetamido. 
     
     
         88 . A method in accordance with  claim 87 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         89 . A method in accordance with  claim 55 , wherein the R 3a  group attached to the five-membered ring is H. 
     
     
         90 . A method in accordance with  claim 89 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         91 . A method in accordance with  claim 55 , wherein an R 3a  group attached to the five-membered ring is selected from the group consisting of thiazolyl, oxazolyl, imidazolyl and oxadiazolyl, each of which is optionally substituted with methyl 
     
     
         92 . A method in accordance with  claim 91 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         93 . A method in accordance with  claim 58 , wherein said CCR1-mediated disease or condition is rheumatoid arthritis.