Naphthyridine Integrase Inhibitors

Abstract

The present invention features compounds that are HIV integrase inhibitors and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is hydrogen, halogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 1-8 haloalkyl, C 6-14 aralkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 3-6 alkynyl, C 1-8 alkoxy, —CN, —R 3 OR 4 , —R 3 C(O)R 4 , —C(O)R 4 , —R 3 C(O)OR 4 , —R 3 COR 4 , —C(O)OR 4 , —R 3 SR 4 , —SR 4 , —N(R 4 ) 2 , —R 3 N(R 4 ) 2 , —R 3 C(O)N(R 4 ) 2 , —NC(O)N(R 4 ) 2 , —C(O)N(R 4 ) 2 , —R 3 N(R 4 )C(R 4 )(O), —N(R 4 )C(O)R 4 , —N(R 4 )C(O)OR 4 , —N(R 4 )C(O)C(O)N(R 4 ) 2 , —N(R 4 )C(R 4 )(O), —N(R 4 )C(R 4 )(O), —R 3 S(O) 2 R 4 , —NS(O) 2 NR 4 , —S(O) 2 R 4 , —S(O) 2 N(R 4 ) 2 , —R 3 N(R 4 )S(O) 2 R 4 , —N(R 4 )S(O) 2 R 4 , —R 3 S(O) 2 NR 4 , —N(R 4 )R 3 SR 4 , —N(R 4 )R 3 OR 4 , —N(R 4 )R 3 N(R 4 ) 2 , —N(R 4 )R 3 N(R 4 )C(R 4 )(O), C 6-14 aryl wherein said C 6-14 aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-8 alkyl, C 1-8 haloalkyl, —OR 3 , —SR 3 , —CN, hydroxy, —R 3 C(O)N(R 4 ) 2 , —C(O)N(R 4 ) 2 , —R 3 C(O)R 4 , —R 3 OR 3 OH, —C(O)R 4 , —N(R 4 )C(O)R 4 , —N(R 4 )C(O)R 4 , —N(R 4 )C(O)OR 4 , —S(O) 2 N(R 4 ) 2 , —S(O) 2 R 4 , —R 3 N(R 4 )C(O)OR 4 , —R 3 N(R 4 )C(O)R 4 , —N(R 4 ) 2 , —R 3 N(R 4 ) 2 , C 6-14 aryl, C 6-14 aryloxy, and R 3  optionally substituted with C 6-14 aryl, Y wherein said Y is optionally substituted with one or more substituents independently selected from the group consisting of —OR 5 , —NR 5 R 6 , —N(R 5 )YNR 6 , —C(O) m R 5 , —C(O)NR 5 R 6 , —N(R 5 )C(O) m R R 5 , —N(R 5 )Y p C(O)NR 5 R 6 , —O(Y)C(O)NR 5 R 6 , —S(O) n Y p C(O)NR 5 R 6 , —S(O) n R 5 R 6 , —S(O) n NR 5 , —N(R 5 )Y p S(O) n NR 5 R 6 , —C(O)C(O)NR 5 R 6 , —N(R 5 )C(O)C(O)NR 5 R 6 , —N(R 5 )Y p C(O)C(O)NR 5 R 6 , —C(O)NR 5 Y p C(O)NR 5 R 6 , —OY p NR 5 R 6 , —O(Y) p C(O)NR 5 R 6 , —O(Y) p N(R 5 )C(O) n R 5 , —O(Y) p C(O) m R 5 , —C 6-14 aryl, —N(C═NR 5 )NR 5 R 6 , —C(R 5 )(C═NR 5 )NR 5 R 6 , and —(C═NR 5 )NR 5 R 6 ; 
         R 2  is C 3-6 cycloalkyl, C 6-14 aryl optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 alkyl, —OR 5 , and NR 5 R 6 ; 
         R 3  is C 1-8 alkyl, C 3-6 cycloalkyl, haloC 1-8 alkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, or C 3-6 alkenyl; 
         R 4  is hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 1-8 haloalkyl, C 6-14 aryl, C 6-14 aralkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, or C 3-6 alkynyl; 
         R 5  and R 6  are independently selected from the group consisting of hydrogen, C 1-8 haloalkyl, C 1-8 alkylC 3-6 cycloalkyl, C 6-14 aryl, C 6-14 aralkyl, —C(O) m R 7 , —C(O)C(O) m R 7 , and Y optionally substituted with one or more —OR 7 , —C(O) m R 7 , —S(O) n R 7 , —S(O) n R 7 , and —C(O)C(O) m R 7 ; 
         R 7  is hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, —Ycycloalkyl, —YOH, or —Y(OY) w  where w is 1-10; 
         m is 1 or 2; 
         n is 0, 1, or 2; 
         p is 0, or 1; 
         A is 1,2,4,-triazole; 
         Q is C 1-3 alkyl, —NR 4 , —O—, —C(O), —C(OR 4 )—, S(O) 2 , or —CF 2 ; 
         Y is a C 1-5  alkylene chain, wherein said C 1-5  alkylene chain is optionally subsituted by one or more groups independently selected from ═O, ═S, and halo, and wherein said C 1-5  alkylene chain optionally contains 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is halogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 1-8 haloalkyl, C 6-14 aralkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 3-6 alkynyl, C 1-8 alkoxy, —CN, —R 3 OR 4 , —R 3 C(O)R 4 , —C(O)R 4 , —R 3 C(O)OR 4 , —R 3 COR 4 , —C(O)OR 4 , —R 3 SR 4 , —SR 4 , —N(R 4 ) 2 , —R 3 N(R 4 ) 2  , —R 3 C(O)N(R 4 ) 2 , —NC(O)N(R 4 ) 2 , —C(O)N(R 4 ) 2 , —R 3 N(R 4 )C(R 4 )(O), —N(R 4 )C(O)R 4 , —N(R 4 )C(O)OR 4 , —N(R 4 )C(O)C(O)N(R 4 ) 2 , —N(R 4 )C(R 4 )(O), —N(R 4 )C(R 4 )(O), —R 3 S(O) 2 R 4 , —NS(O) 2 NR 4 , —S(O) 2 R 4 , —S(O) 2 N(R 4 ) 2 , —R 3 N(R 4 )S(O) 2 R 4 , —N(R 4 )S(O) 2 R 4 , —R 3 S(O) 2 NR 4 , —N(R 4 )R 3 SR 4 , —N(R 4 )R 3 OR 4 , —N(R 4 )R 3 N(R 4 ) 2 , —N(R 4 )R 3 N(R 4 )C(R 4 )(O), C 6-14 aryl wherein said C 6-14 aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-8 alkyl, C 1-8 haloalkyl, —OR 3 , —SR 3 , —CN, hydroxy, —R 3 C(O)N(R 4 ) 2 , —C(O)N(R 4 ) 2 , —R 3 C(O)R 4 , —R 3 OR 3 OH, —C(O)R 4 , —N(R 4 )C(O)R 4 , —N(R 4 )C(O)R 4 , —N(R 4 )C(O)OR 4 , —S(O) 2 N(R 4 ) 2 , —S(O) 2 R 4 , —R 3 N(R 4 )C(O)OR 4 , —R 3 N(R 4 )C(O)R 4 , —N(R 4 ) 2 , —R 3 N(R 4 ) 2 , C 6-14 aryl, C 6-14 aryloxy, Y wherein said Y is optionally substituted with one or more substituents independently selected from the group consisting of —OR 5 , —NR 5 R 6 , —N(R 5 )YNR 6 , —C(O) m R 5 , —C(O)NR 5 R 6 , —N(R 5 )C(O) m R 5 , —N(R 5 )Y p C(O)NR 5 R 6 , —O(Y)C(O)NR 5 R 6 , —S(O) n Y p C(O)NR 5 R 6 , —S(O) n R 5 R 6 , —N(R 5 )Y p S(O) n NR 5 R 6 , —C(O)C(O)NR 5 R 6 , —N(R 5 )C(O)C(O)NR 5 R 6 , —N(R 5 )Y p C(O)C(O)NR 5 R 6 , —C(O)NR 5 Y p C(O)NR 5 R 6 , —OY p NR 5 R 6 , —O(Y) p C(O)NR 5 R 6 , —O(Y) p N(R 5 )C(O) m R 5 , —O(Y) p C(O) m R 5 , —C 6-14 aryl, —N(C═NR 5 )NR 5 R 6 , —C(R 5 )(C═NR 5 )NR 5 R 6 , and —(C═NR 5 )NR 5 R 6 ; 
         R 2  is C 3-6 cycloalkyl, C 6-14 aryl optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 alkyl, —OR 5 , and NR 5 R 6 ; 
         R 3  is C 1-8 alkyl, C 3-6 cycloalkyl, haloC 1-8 alkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, or C 3-6 alkenyl; 
         R 4  is hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 1-8 haloalkyl, C 6-14 aryl, C 6-14 aralkyl, C 2-6 alkenyl, r C 3-6 cycloalkenyl, or C 3-6 alkynyl; 
         R 5  and R 6  are independently selected from the group consisting of hydrogen, C 1-8 haloalkyl, C 1-8 alkylC 3-6 cycloalkyl, C 6-14 aryl, C 6-14 aralkyl, —C(O) m R 7 , —C(O)C(O) m R 7 , and Y optionally substituted with one or more —OR 7 , —C(O) m R 7 , —S(O) n R 7 , —S(O) n R 7 , and —C(O)C(O) m R 7 ; 
         R 7  is hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, —Ycycloalkyl, —YOH, or —Y(OY) w  where w is 1-10; 
         m is 1 or 2; 
         n is 0, 1, or 2; 
         p is 0, or 1; 
         A is 1, 2, 4-triazole; 
         Q is C 1-8 alkyl, —NR 4 , —O—, —C(O), —C(OR 4 )—, S(O) 2 , or —CF 2 ; 
         Y is a C 1-5  alkylene chain, wherein said C 1-5  alkylene chain is optionally subsituted by one or more groups independently selected from ═O, ═S, and halo, and wherein said C 1-5  alkylene chain optionally contains 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . A compound of Formula (I) according to  claim 1  wherein R 1  is C 6-14 aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-8 alkyl, C 1-8 haloalkyl, —OR 3 , —SR 3 , —CN, hydroxy, —R 3 C(O)N(R 4 ) 2 , —C(O)N(R 4 ) 2 , —R 3 C(O)R 4 , —R 3 OR 3 OH, —C(O)R 4 , —N(R 4 )C(O)R 4 , —N(R 4 )C(O)R 4 ; R 2  is C 3-6 cycloalkyl, C 6-14 aryl optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 alkyl, —OR 5 , and NR 5 R 6 , or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A compound of Formula (I) according to  claim 1  wherein R 1  is —N(R 4 ) 2 , —NC(O)N(R 4 ) 2 , —N(R 4 )C(O)R 4 , —N(R 4 )C(O)OR 4 , —N(R 4 )C(O)C(O)N(R 4 ) 2 , —N(R 4 )C(R 4 )(O), —N(R 4 )C(R 4 )(O—NS(O) 2 NR 4 , —N(R 4 )S(O) 2 R 4 , —N(R 4 )R 3 SR 4 , —N(R 4 )R 3 OR 4 , —N(R 4 )R 3 N(R 4 ) 2 , —N(R 4 )R 3 N(R 4 )C(R 4 )(O); or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A compound of Formula (I) according to  claim 1  wherein R 1  is —C(O)R 4 , —C(O)OR 4 , —C(O)N(R 4 ) 2 , or a pharmaceutically acceptable salt thereof. 
     
     
         6 . A compound of Formula (I) according to  claim 1  wherein R 1  is Y optionally substituted with one or more substituents independently selected from the group consisting of —OR 5 , —NR 5 R 6 , —N(R 5 )YNR 6 , —C(O) m R 5 , —C(O)NR 5 R 6 , —N(R 5 )C(O) m R 5 , —N(R 5 )Y p C(O)NR 5 R 6 , —O(Y)C(O)NR 5 R 6 , —S(O) n Y p C(O)NR 5 R 6 , —S(O) n R 5 R 6 , —S(O) n NR 5 ; N(R 5 )Y p S(O) n NR 5 R 6 , —C(O)C(O)NR 5 R 6 , —N(R 5 )C(O)C(O)NR 5 R 6 , —N(R 5 )Y p C(O)C(O)NR 5 R 6 , —C(O)NR 5 Y p C(O)NR 5 R 6 , —OY p NR 5 R 6 , —O(Y) p C(O)NR 5 R 6 , —O(Y) p N(R 5 )C(O) m R 5 , —O(Y) p C(O) m R 5 , —C 6-14 aryl, —N(C═NR 5 )NR 5 R 6 , —C(R 5 )(C═NR 5 )NR 5 R 6 , and —(C═NR 5 )NR 5 R 6 ; or a pharmaceutically acceptable salt thereof. 
     
     
         7 . A compound of Formula (I) according to  claim 1  wherein R 1  is C 6-14 aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-8 alkyl, C 1-8 haloalkyl, —OR 3 , —SR 3 , —CN, hydroxy, —R 3 C(O)N(R 4 ) 2 , —C(O)N(R 4 ) 2 , —R 3 C(O)R 4 , —R 3 OR 3 OH, —C(O)R 4 , —N(R 4 )C(O)R 4 , —N(R 4 )C(O)R 4 ; R 2  is C 6-14 aryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 alkyl, —OR 5 , and NR 5 R 6 ; Q is C 1-3 alkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A compound of Formula (I) according to  claim 1  wherein R 1  is —N(R 4 ) 2 , —NC(O)N(R 4 ) 2 , —N(R 4 )C(O)R 4 , —N(R 4 )C(O)OR 4 , —N(R 4 )C(O)C(O)N(R 4 ) 2 , —N(R 4 )C(R 4 )(O), —N(R 4 )C(R 4 )(O—NS(O) 2 NR 4 , —N(R 4 )S(O) 2 R 4 , —N(R 4 )R 3 SR 4 , —N(R 4 )R 3 OR 4 , —N(R 4 )R 3 N(R 4 ) 2 , —N(R 4 )R 3 N(R 4 )C(R 4 )(O); R 2  is C 6-14 aryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 alkyl, —OR 5 , and NR 5 R 6 ; Q is C 1-3 alkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A compound of Formula (I) according to  claim 1  wherein R 1  is —C(O)R 4 , —C(O)OR 4 , —C(O)N(R 4 ) 2 ; R 2  is C 6-14 aryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 alkyl, —OR 5 , and NR 5 R 6 ; Q is C 1-3 alkyl; or pharmaceutically acceptable salt thereof. 
     
     
         10 . A compound of Formula (I) according to  claim 1  wherein R 1  is Y optionally substituted with one or more substituents independently selected from the group consisting of —OR 5 , —NR 5 R 6 , —N(R 5 )YNR 6 , —C(O) m R 5 , —C(O)NR 5 R 6 , —N(R 5 )C(O) m R 5 , —N(R 5 )Y p C(O)NR 5 R 6 ; —O(Y)C(O)NR 5 R 6 , —S(O)Y p C(O)NR 5 R 6 , —S(O) n R 5 R 6 , —S(O) n NR 5 ; —N(R 5 )Y p S(O) n NR 5 R 6 ; —C(O)C(O)NR 5 R 6 , —N(R 5 )C(O)C(O)NR 5 R 6 , —N(R 5 )Y p C(O)C(O)NR 5 R 6 ; —C(O)NR 5 Y p C(O)NR 5 R 6 ; —OY p NR 5 R 6 , —O(Y) p C(O)NR 5 R 6 , —O(Y) p N(R 5 )C(O) m R 5 , —O(Y) p C(O) m R 5 , —C 6-14 aryl, —N(C═NR 5 )NR 5 R 6 , —C(R 5 )(C═NR 5 )NR 5 R 6 , and —(C═NR 5 )NR 5 R 6 ; R 2  is C 6-14 aryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 alkyl, —OR 5 , and NR 5 R 6 ; Q is C 1-3 alkyl; or pharmaceutically acceptable salt thereof. 
     
     
         11 . A compound selected from the group consisting of
 7-(5-benzyl-4H-1,2,4-triazol-3-yl)-1,6-naphthyridin-8-ol;   7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol;   7-[5-(3-chlorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol;   7-[5-(3-methoxybenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol;   7-[5-(3,4-dimethoxybenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol;   7-(5-benzyl-4H-1,2,4-triazol-3-yl)-5-bromo-1,6-naphthyridin-8-ol;   5-bromo-7-[5-(4-fluorobenzyl)-4H-1,2,4,-triazol-3-yl]-1,6-naphthyridin-8-ol;   7-[5-(4-fluorobenzyl)-4H-1,2,4,-triazol-3-yl]-5-(methylsulfonyl)-1,6-naphthyridin-8-ol;   7-[5-(4-chlorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol;   7-[5-(2-phenylethyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol;   7-[5-(1-naphthylmethyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol;   7-[3-(4-fluorobenzyl)-1-methyl-1H-1,2,4,-triazol-5-yl]-1,6-naphthyridin-8-ol;   7-[5-(4-fluorobenzyl)-1-methyl-1H-1,2,4,-triazol-5-yl]-1,6-naphthyridin-8-ol;   and pharmaceutically acceptable salts thereof.   
     
     
         12 . A method of treatment or prevention of a viral infection in a human comprising administering to said human an antiviral effective amount of a compound according to  claim 1 . 
     
     
         13 . A method according to  claim 12  wherein the viral infection is a HIV infection. 
     
     
         14 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
         15 . A pharmaceutical composition according to  claim 14  in the form of a tablet or capsule. 
     
     
         16 . A pharmaceutical composition according to  claim 14  in the form of a liquid or suspension. 
     
     
         17 . A method of treatment or prevention of a viral infection in a human comprising administering to said human a composition comprising a compound according to  claim 1  and another therapeutic agent. 
     
     
         18 . The method according to  claim 17  wherein the viral infection is an HIV infection.