Chromene modulators of chemokine receptor activity

Abstract

The present application describes modulators of MCP-1 or CCR-2 of formula or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein W 1 , W 2 , W 3 , Y, Z, R 2 , R 3 , R 3′ and R 4 , are defined in the specification. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and transplant rejection using modulators of formula (I) are disclosed.

What is claimed is: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
 R 2  is H, or C 1-4  alkyl; 
 R 3  and R 3′  are independently H, C 1-4  alkyl, C 1-4  alkoxy, halo, or haloC 1-4  alkyl; 
 or R 3  and R 3′ , when attached to neighboring carbons, taken together form —CH═CH—CH═CH—; 
 R 4  is H or C 1-4  alkyl; 
 W 1  is N or C—Z′; 
 W 2  is N or C—Y′; 
 W 3  is N or C—X; 
 X is H, C 1-4  alkyl, C 1-4  alkoxy, halo or haloC 1-4  alkyl; 
 Y and Y′ are independently H, C 1-4  alkyl, C 1-4  alkoxy, halo, haloC 1-4  alkyl or NO 2 ; 
 Z and Z′ are independently H or halo; 
 or Y and Z, Y′ and Z′, Y and X, or Y′ and X are taken together to form —CH═CH—CH═CH—; 
 or Y and X or Y′ and X are taken together to form —O—CH 2 —O—; 
 
       provided that:
 (1) one and only one of W 1 , W 2  or W 3  is N; 
 (2) if W 2  is N, then X, Y, Z and Z′ are not all H; 
 (3) if W 3  is N, then W 1  and W 2  are both CH and Y and Z are H; 
 (4) if Y is C 1-4 alkoxy then X is not H; and 
 (5) if X is F then one of Y or Y′ is not H. 
 
     
     
         2 . The compound of  claim 1 , wherein:
 R 2  is H, or C 1-4  alkyl;   R 3  and R 3′  are independently H, C 1-4  alkyl, C 1-4  alkoxy, halo, or haloC 1-4  alkyl;   R 4  is H or C 1-4  alkyl;   W 1  is N or C—Z′;   W 2  is N or C—Y′;   W 3  is N or C—X;   X is H, C 1-4  alkyl, C 1-4  alkoxy, halo or haloC 1-4  alkyl;   Y and Y′ are independently H, C 1-4  alkyl, C 1-4  alkoxy, halo, haloC 1-4  alkyl or NO 2 ;   Z and Z′ are independently H or halo;   or Y and Z, Y′ and Z′, Y and X, or Y′ and X are taken together to form —CH═CH—CH═CH—;   or Y and X or Y′ and X are taken together to form —O—CH 2 —O—.   
     
     
         3 . The compound of  claim 1 , wherein:
 R 2  is H, or C 1-4  alkyl;   R 3  and R 3′  are independently H, C 1-4  alkyl, C 1-4  alkoxy, halo, or haloC 1-4  alkyl;   R 4  is H or C 1-4  alkyl;   W 1  is N or C—Z′;   W 2  is N or C—Y′;   W 3  is N or C—X;   X is H, C 1-4  alkyl, C 1-4  alkoxy, halo or haloC 1-4  alkyl;   Y and Y′ are independently H, C 1-4  alkyl, C 1-4  alkoxy, halo, haloC 1-4  alkyl or NO 2 ;   Z and Z′ are independently H or halo;   or Y and Z, Y′ and Z′, Y and X, or Y′ and X are taken together to form —CH═CH—CH═CH—.   
     
     
         4 . The compound of  claim 1 , wherein:
 R 2  is H, or C 1-4  alkyl;   R 3  and R 3′  are independently H, C 1-4  alkyl, C 1-4  alkoxy, halo, or haloC 1-4  alkyl;   R 4  is H or C 1-4  alkyl;   W 1  is N or C—Z′;   W 2  is N or C—Y′;   W 3  is N or C—X;   X is H, C 1-4  alkyl, C 1-4  alkoxy, halo or haloC 1-4  alkyl;   Y and Y′ are independently H, C 1-4  alkyl, C 1-4  alkoxy, halo, haloC 1-4  alkyl or NO 2 ; and   Z and Z′ are independently H or halo.   
     
     
         5 . The compound of  claim 1 , wherein:
 R 2  is H, or C 1-4  alkyl;   R 3  and R 3′  are independently H, C 1-4  alkyl, C 1-4  alkoxy, or halo;   R 4  is H or C 1-4  alkyl;   W 1  is N or C—Z′;   W 2  is N or C—Y′;   W 3  is N or C—X;   X is H, C 1-4  alkyl, C 1-4  alkoxy, halo or haloC 1-4  alkyl;   Y and Y′ are independently H, C 1-4  alkyl, C 1-4  alkoxy, halo, or haloC 1-4  alkyl; and   Z and Z′ are independently H or halo.   
     
     
         6 . The compound of  claim 1 , wherein:
 R 2  is H, or C 1-4  alkyl;   R 3  and R 3′  are independently H, C 1-4  alkoxy, or halo;   R 4  is H or C 1-4  alkyl;   W 1  is N or C—Z′;   W 2  is N or C—Y′;   W 3  is N or C—X;   X is H, C 1-4  alkyl, halo or haloC 1-4  alkyl;   Y and Y′ are independently H, C 1-4  alkyl, halo, or haloC 1-4  alkyl; and   Z and Z′ are independently H or halo.   
     
     
         7 . The compound of  claim 1 , wherein:
 R 2  is H, or C 1-4  alkyl;   R 3  and R 3′  are independently H or halo;   R 4  is H or C 1-4  alkyl;   W 1  is N or C—Z′;   W 2  is N or C—Y′;   W 3  is N or C—X;   X is H, halo or haloC 1-4  alkyl;   Y and Y′ are independently H, halo, or haloC 1-4  alkyl; and   Z and Z′ are independently H or halo.   
     
     
         8 . The compound of  claim 1 , wherein:
 R 2  is H, methyl or ethyl;   R 3  and R 3′  are H;   R 4  is H;   W 1  is N or C—Z′;   W 2  is N or C—Y′;   W 3  is N or C—X;   X is H, Br, Cl, F or CF 3 ;   Y and Y′ are independently H, Br, Cl, F or CF 3 ; and   Z and Z′ are independently H, Br, Cl or F.   
     
     
         9 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt from thereof, wherein the compound is selected from the compounds exemplified in the examples. 
     
     
         10 . A pharmaceutical composition comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 1 . 
     
     
         11 . A method for treating a disorder comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of  claim 1 ; wherein said disorder is selected from osteoarthritis, aneurysm, fever, cardiovascular effects, Crohn's disease, congestive heart failure, autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, inflammatory bowel disease, alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma, multiple sclerosis, atherosclerosis, rheumatoid arthritis, restinosis, organ transplantation, and cancer. 
     
     
         12 . A method for preparing a medicament for the treatment of osteoarthritis, aneurysm, fever, cardiovascular effects, Crohn's disease, congestive heart failure, autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, inflammatory bowel disease, alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma, multiple sclerosis, atherosclerosis, and rheumatoid arthritis comprising formulating at least one compound of  claim 1 . 
     
     
         13 . A method for treating a disorder comprising administering to a patient in need thereof a therapeutically effective amount of a composition of  claim 10 , wherein said disorder is selected from osteoarthritis, aneurysm, fever, cardiovascular effects, Crohn's disease, congestive heart failure, autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, inflammatory bowel disease, alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma, multiple sclerosis, atherosclerosis, rheumatoid arthritis, restinosis, organ transplantation, and cancer. 
     
     
         14 . A method for preparing a medicament for the treatment of osteoarthritis, aneurysm, fever, cardiovascular effects, Crohn's disease, congestive heart failure, autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, inflammatory bowel disease, alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma, multiple sclerosis, atherosclerosis, and rheumatoid arthritis comprising formulating a composition of  claim 10  into a useful pharmaceutical dosage-form. 
     
     
         15 . A method for treating a patient in need of therapy comprising administering to said patient in need thereof a therapeutically effective amount of a composition of  claim 10 .