3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors

Abstract

The present invention relates to 3-cycloalkylaminopyrrolidine derivatives of the formula I: (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Y and Z are as defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors and more specifically as modulators of the CCR2 and/or CCR5 receptor. The compounds and compositions of the invention may bind to chemokine receptors, e.g., the CCR2 and/or CCR5 chemokine receptors, and are useful for treating diseases associated with chemokine, e.g., CCR2 and/or CCR5, activity, such as atherosclerosis, restenosis, lupus, organ transplant rejection and rheumatoid arthritis.

1 - 38 . (canceled) 
     
     
         39 . A method of treating inflammation, rheumatoid arthritis, atherosclerosis, neuropathic pain, lupus, systemic lupus erythematosus, restenosis, immune disorders, and transplant rejection in a mammal in need thereof comprising administering to such mammal a therapeutically effective amount of a compound of the formula 1: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         X and Y together are selected from the group consisting of: 
         a) —CH 2 —NH—(C=O)—: 
         b) —CH 2 —O—CH 2 —: 
       
       
         
           
           
               
               
           
         
         Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF 3  group; 
         R 1  is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R 1  is substituted with 0-3 R 1a , wherein R 1a  is independently selected from the group consisting of: CH 2 —OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH 2 —NMe 2 , pyridyl, carboxylate, phenyl bearing a CH 2 —OH group, pyrimidine, thiazole, oxazole and pyrazine; 
         R 2  is OH; 
         R 3  and R 4  are H 
         R 5  is independently selected from the group consisting of hydrogen, alkyl, and formyl; 
         R 6  and R 7  are each independently selected from the group consisting of H, C 12 , C 10  alkyl, OH, CH 2 —OMe and hydroxyalkyl; and 
         r=1. 
       
     
     
         40 . A method of modulating chemokine receptor activity in a mammal comprising administering an effective amount of a compound of the formula  1 : 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         X and Y together are selected from the group consisting of: 
         a) —CH 2 —NH—(C═O)—; 
         b) —CH 2 —O—CH 2 —; 
       
       
         
           
           
               
               
           
         
         Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF 3  group; 
         R 1  is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R 1  is substituted with 0-3 R 1a , wherein R 1a  is independently selected from the group consisting of: CH 2 —OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH 2 —NMe 2 , pyridyl, carboxylate, phenyl bearing a CH 2 —OH group, pyrimidine, thiazole, oxazole and pyrazine; 
         R 2  is OH; 
         R 3  and R 4  are H 
         R 5  is independently selected from the group consisting of hydrogen, alkyl, and formyl; 
         R 6  and R 7  are each independently selected from the group consisting of H, C 12 , C 10  alkyl, OH, CH 2 —OMe and hydroxyalkyl; and 
         r=1. 
       
     
     
         41 . A method of treating a CCR2-mediated 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 of the formula I: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         X and Y together are selected from the group consisting of: 
         a) —CH 2 —NH—(C═O)—; 
         b) —CH 2 —O—CH 2 —; 
       
       
         
           
           
               
               
           
         
         Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF 3  group; 
         R 1  is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R 1  is substituted with 0-3 R 1a , wherein R 1a  is independently selected from the group consisting of: CH 2 —OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH 2 —NMe 2 , pyridyl, carboxylate, phenyl bearing a CH 2 —OH group, pyrimidine, thiazole, oxazole and pyrazine; 
         R 2  is OH; 
         R 3  and R 4  are H 
         R 5  is independently selected from the group consisting of hydrogen, alkyl, and formyl; 
         R 6  and R 7  are each independently selected from the group consisting of H, C 12 , C 10  alkyl, OH, CH 2 —OMe and hydroxyalkyl; and 
         r=1. 
       
     
     
         42 . A method of treating a CCR5-mediated 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 of the formula I: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         X and Y together are selected from the group consisting of: 
         a) —CH 2 —NH—(C═O)—; 
         b) —CH 2 —O—CH 2 —; 
       
       
         
           
           
               
               
           
         
         Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF 3  group; 
         R 1  is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R 1  is substituted with 0-3 R 1a , wherein R 1a  is independently selected from the group consisting of: CH 2 —OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH 2 —NMe 2 , pyridyl, carboxylate, phenyl bearing a CH 2 —OH group, pyrimidine, thiazole, oxazole and pyrazine; 
         R 2  is OH; 
         R 3  and R 4  are H 
         R 5  is independently selected from the group consisting of hydrogen, alkyl, and formyl; 
         R 6  and R 7  are each independently selected from the group consisting of H, C 12 , C 10  alkyl, OH, CH 2 —OMe and hydroxyalkyl; and 
         r=1. 
       
     
     
         43 . A method of modulating activity of a chemokine receptor comprising contacting said chemokine receptor with a compound of the formula I: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         X and Y together are selected from the group consisting of: 
         a) —CH 2 —NH—(C═O)—; 
         b) —CH 2 —O—CH 2 —; 
       
       
         
           
           
               
               
           
         
         Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF 3  group; 
         R 1  is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R 1  is substituted with 0-3 R 1a , wherein R 1a  is independently selected from the group consisting of: CH 2 —OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH 2 —NMe 2 , pyridyl, carboxylate, phenyl bearing a CH 2 —OH group, pyrimidine, thiazole, oxazole and pyrazine; 
         R 2  is OH; 
         R 3  and R 4  are H 
         R 5  is independently selected from the group consisting of hydrogen, alkyl, and formyl; 
         R 6  and R 7  are each independently selected from the group consisting of H, C 12 , C 10  alkyl, OH, CH 2 —OMe and hydroxyalkyl; and 
         r=1. 
       
     
     
         44 . The method of  claim 43  wherein said chemokine receptor is CCR2 or CCR5. 
     
     
         45 . The method of  claim 43  wherein said modulating is inhibiting. 
     
     
         46 . A method of treating a disease associated with expression or activity of a chemokine receptor in a patient comprising administering to said patient a therapeutically effective amount of a compound of the formula I: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         X and Y together are selected from the group consisting of: 
         a) —CH 2 —NH—(C═O)—; 
         b) —CH 2 —O—CH 2 —; 
       
       
         
           
           
               
               
           
         
         Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF 3  group; 
         R 1  is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R 1  is substituted with 0-3 R 1a , wherein R 1a  is independently selected from the group consisting of: CH 2 —OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH 2 —NMe 2 , pyridyl, carboxylate, phenyl bearing a CH 2 —OH group, pyrimidine, thiazole, oxazole and pyrazine; 
         R 2  is OH; 
         R 3  and R 4  are H 
         R 5  is independently selected from the group consisting of hydrogen, alkyl, and formyl; 
         R 6  and R 7  are each independently selected from the group consisting of H, C 12 , C 10  alkyl, OH, CH 2 —OMe and hydroxyalkyl; and 
         r=1. 
       
     
     
         47 . The method of  claim 46  wherein said chemokine receptor is CCR2 or CCR5. 
     
     
         48 . The method of  claim 46  wherein said disease is an inflammatory disease. 
     
     
         49 . The method of  claim 46  wherein said disease is an immune disorder. 
     
     
         50 . The method of  claim 46  wherein said disease is rheumatoid arthritis, atherosclerosis, lupus, multiple sclerosis, neuropathic pain, transplant rejection, diabetes, or obesity. 
     
     
         51 . The method of  claim 46  wherein said disease is cancer. 
     
     
         52 . The method of  claim 51  wherein said cancer is characterized by tumor associated macrophages. ovarian cancer or multiple myeloma. 
     
     
         53 . The method of  claim 51  wherein said cancer is breast cancer, ovarian cancer or multiple myeloma. 
     
     
         54 . The method of  claim 46  wherein said disease or condition is a viral infection. 
     
     
         55 . The method of  claim 54  wherein said viral infection is HIV infection. 
     
     
         56 . A method of treating HIV infection in a patient comprising administering to said patient a therapeutically effective amount of a compound of the formula I: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         X and Y together are selected from the group consisting of: 
         a) —CH 2 —NH—(C═O)—; 
         b) —CH 2 —O—CH 2 —; 
       
       
         
           
           
               
               
           
         
         Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF 3  group; 
         R 1  is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R 1  is substituted with 0-3 R 1a , wherein R 1a  is independently selected from the group consisting of: CH 2 —OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH 2 —NMe 2 , pyridyl, carboxylate, phenyl bearing a CH 2 —OH group, pyrimidine, thiazole, oxazole and pyrazine; 
         R 2  is OH; 
         R 3  and R 4  are H 
         R 5  is independently selected from the group consisting of hydrogen, alkyl, and formyl; 
         R 6  and R 7  are each independently selected from the group consisting of H, C 12 , C 10  alkyl, OH, CH 2 —OMe and hydroxyalkyl; and 
         r=1. 
       
     
     
         57 . The method of  claim 56  further comprising simultaneously or sequentially administering at least one anti-viral agent. 
     
     
         58 . A method of treating cancer in a patient comprising administering to Said patient a therapeutically effective amount of a compound of the formula I: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein: 
         X and Y together are selected from the group consisting of: 
         a) —CH 2 —NH—(C═O)—; 
         b) —CH 2 —O—CH 2 —; 
       
       
         
           
           
               
               
           
         
         Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF 3  group; 
         R 1  is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R 1  is substituted with 0-3 R 1a , wherein R 1a  is independently selected from the group consisting of: CH 2 —OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH 2 —NMe 2 , pyridyl, carboxylate, phenyl bearing a CH 2 —OH group, pyrimidine, thiazole, oxazole and pyrazine; 
         R 2  is OH; 
         R 3  and R 4  are H 
         R 5  is independently selected from the group consisting of hydrogen, alkyl, and formyl; 
         R 6  and R 7  are each independently selected from the group consisting of H, C 12 , C 10  alkyl, OH, CH 2 —OMe and hydroxyalkyl; and 
         r=1. 
       
     
     
         59 . The method of  claim 58 , wherein the cancer is characterized by infiltration of macrophages into tumors or diseased tissue. 
     
     
         60 . The method of  claim 39 , wherein said compound is administered with a pharmaceutically acceptable carrier.