Inhibitors of the hiv integrase enzyme

Abstract

The present invention is directed to compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, their synthesis, and their use as modulators or inhibitors of the human immunodeficiency virus (“HIV”) integrase enzyme.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, or C 1 -C 8  heteroalkyl, wherein said C 1 -C 8  alkyl, C 2 -C 8  alkenyl, or C 1 -C 8  heteroalkyl groups may be optionally substituted with at least one substituent independently selected from: 
 halo, —OR 12a , —N(R 12a R 12b ), CC(O)N(R 12a R 12b ), —NR 12a C(O)N(R 12a R 12b ), —NR 12a C(O)R 12a , —NR 12a C(NR 12a )N(R 12a R 12b ), —SR 12a , —S(O)R 12a , —S(O) 2 R 12a , —S(O) 2 N(R 12a R 12b ), C 1 -C 8  alkyl, C 8 -C 14  aryl, C 3 -C 8  cycloalkyl, and C 2 -C 9  heteroaryl, wherein said C 1 -C 8  alkyl, C 6 -C 14  aryl, C 3 -C 8  cycloalkyl, and C 2 -C 9  heteroaryl groups are optionally substituted with at least one substituent independently selected from halo, —C(R 12a R 12b R 12c ), —OH, and C 1 -C 8  alkoxy; 
 R 2  is hydrogen or C 1 -C 8  alkyl; 
 R 3  is hydrogen, C 1 -C 8  alkyl, —(CR 7 R 8 ) t NR 9 R 10 , —S(O) z NR 9 R 10 , —C(O)NR 9 R 10 , or C 1 -C 8  heteroalkyl, wherein said C 1 -C 8  heteroalkyl is optionally substituted with R 11 ; 
 Z is —(CR 4 R 4 ) n —, —C(R 4 )═C(R 4 )—, —C(R 4 )═C(R 4 )—(CR 4 R 4 ) n —, —(CR 4 R 4 ) n —C(R 4 )═C(R 4 )—, or —(CR 4 R 4 ) n —C(R 4 )═C(R 4 )—(CR 4 R 4 ) n —; 
 each R 4  is independently selected from hydrogen, halo, C 1 -C 8  heteroalkyl, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 14  aryl, C 2 -C 9  cycloheteroalkyl, and C 2 -C 9  heteroaryl, wherein said C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 14  aryl, C 2 -C 9  cycloheteroalkyl, and C 2 -C 9  heteroaryl are optionally substituted with at least one R 13 ; 
 R 5  is hydrogen, C 1 -C 8  heteroalkyl, C 6 -C 14  aryl, C 2 -C 8  alkenyl, or C 1 -C 8  alkyl, wherein said C 1 -C 8  alkyl is optionally substituted with at least one C 3 -C 8  cycloalkyl or C 6 -C 14  aryl group; 
 R 6  is hydrogen; 
 each R 7  and R 8 , which may be the same or different, are independently selected from hydrogen and C 1 -C 8  alkyl; 
 R 9  and R 10 , which may be the same or different, are independently selected from hydrogen, C 3 -C 8  cycloalkyl, C 2 -C 9  cycloheteroalkyl, and C 1 -C 8  alkyl, wherein said C 1 -C 6  alkyl may be optionally substituted by at least one C 2 -C 9  cycloheteroalkyl, C 2 -C 9  heteroaryl, halo, or C 6 -C 14  aryl group, and wherein said C 6 -C 14  aryl group may be optionally substituted by at least one C 1 -C 8  alkyl or halo group; or 
 R 9  and R 10 , together with the nitrogen atom to which they are attached, form a C 2 -C 9  cycloheteroalkyl or a C 2 -C 9  heteroaryl group, each of which is optionally substituted with at least one R 13  group; 
 R 11  is C 3 -C 8  cycloalkyl, C 1 -C 8  heteroalkyl, C 2 -C 9  cycloheteroalkyl, C 6 -C 14  aryl, or C 2 -C 8  heteroaryl, each of which is optionally substituted with at least one substituent independently selected from C 1 -C 8  alkyl, C 6 -C 14  aryl, C 2 -C 9  heteroaryl, —CF 3 , —COR 12a , —CO 2 R 12a , and —OR 12a ; 
 each R 12a , R 12b , and R 12c , which may be the same or different, is independently selected from hydrogen, C 1 -C 8  alkyl, and oxo; or 
 R 12a  and R 12b , together with the nitrogen atom to which they are attached, may form a C 2 -C 9  cycloheteroalkyl group; 
 each R 13  is independently selected from halo, C 1 -C 8  alkyl, —(CR 7 R 8 ) t OR 7 , —C(O)R 12a , —S(O) 2 R 7 , —(CR 7 R 8 ) z C(O)NR 12a R 12b , —NR 12a R 12b , and —CF 3 ; 
 t is an integer from 1 to 3; 
 each n, which may be the same or different, is independently selected and is an integer from 1 to 4; and 
 each z, which may be the same or different, is independently selected and is 0, 1, or 2; or a pharmaceutically acceptable salt or solvate thereof, with the proviso that R 5  is not hydrogen when Z is —(CH 2 )—, R 1  is 2,4-difluorobenzyl, and R 2 , R 3 , and R 6  are hydrogen. 
 
     
     
         2 . A compound according to  claim 1 , wherein R 13  is selected from C 1 -C 8  alkyl, —(CR 7 R 6 ) t OR 7 , —C(O)R 12a , —S(O) 2 R 7 , —(CR 7 R 8 ) z C(O)NR 12a R 12b , and —NR 12a R 12b . 
     
     
         3 . A compound according to  claim 2 , wherein R 13  is selected from C 1 -C 8  alkyl, —(CR 7 R 8 ) t OR 7 , —C(O)R 12a , —S(O) 2 R 7 , —C(O)NR 12a R 12b , and —NR 12a R 12b . 
     
     
         4 . A compound according to  claim 3 , wherein R 13  is selected from C 1 -C 8  alkyl and —C(O)NR 12a R 12b . 
     
     
         5 . A compound according to  claim 1 , wherein:
 R 1  is C 1 -C 8  alkyl substituted with C 8 -C 14  aryl, wherein said C 6 -C 14  aryl group is optionally substituted with at least one substituent independently selected from halo, —C(R 12a R 12b R 12c ), —OH, and C 1 -C 8  alkoxy;   R 2  is hydrogen;   R 3  is hydrogen, —(CR 7 R 8 ) t NR 9 R 10  or C 1 -C 8  heteroalkyl, wherein said C 1 -C 8  heteroalkyl is optionally substituted with R 11 ;   R 9  and R 10 , together with the nitrogen atom to which they are attached, form a C 2 -C 8  cycloheteroalkyl group optionally substituted with at least one C 1 -C 8  alkyl;   each R 12a , R 12b , and R 12c , which may be the same or different, is independently selected from hydrogen and C 1 -C 8  alkyl; and   each R 13  is independently selected from halo, C 1 -C 8  alkyl, —(CR 7 R 8 ) t R 7 , —NR 12a R 12b , and —CF 3 .   
     
     
         6 . A compound according to  claim 1 , wherein R 1  is C 1 -C 8  alkyl substituted with C 6 -C 14  aryl, wherein said C 6 -C 14  aryl group is optionally substituted with at least one halo. 
     
     
         7 . A compound according to  claim 6 , wherein R 3  is hydrogen. 
     
     
         8 . A compound according to  claim 6 , wherein R 3  is —(CR 7 R 8 ) t NR 9 R 10 . 
     
     
         9 . A compound according to  claim 8 , wherein R 9  and R 10 , together with the nitrogen atom to which they are attached, form a C 2 -C 9  cycloheteroalkyl or a C 2 -C 9  heteroaryl group, each of which is optionally substituted with at least one R 13  group. 
     
     
         10 . A compound according to  claim 9 , wherein R 13  is selected from C 1 -C 8  alkyl, —(CR 7 R 8 ) t OR 7 , —C(O)R 12a , —S(O) 2 R 7 , —C(O)NR 12a R 12b , and —NR 12a R 12b . 
     
     
         11 . A compound according to  claim 10 , wherein R 13  is selected from C 1 -C 8  alkyl and —C(O)NR 12a R 12b . 
     
     
         12 . A compound according to  claim 6 , wherein R 3  is C 1 -C 8  heteroalkyl optionally substituted with R 11 . 
     
     
         13 . A compound according to  claim 1 , wherein Z is —C(H)═C(H)—. 
     
     
         14 . A compound according to  claim 13 , wherein R 3  is —(CR 7 R 8 ) t NR 9 R 10 . 
     
     
         15 . A compound according to  claim 14 , wherein R 9  and R 10 , together with the nitrogen atom to which they are attached, form a C 2 -C 9  cycloheteroalkyl or a C 2 -C 8  heteroaryl group, each of which is optionally substituted with at least one R 13  group. 
     
     
         16 . A compound according to  claim 15 , wherein R 13  is selected from C 1 -C 8  alkyl and —C(O)NR 12a R 12b . 
     
     
         17 . A compound according to  claim 1 , selected from 3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-3,7,8,9-tetrahydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-7,8,9,10-tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3-c]azepin-6(3H)-one; 1-[(dimethylamino)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methyl}-L-prolinamide; 3-(4-fluorobenzyl)-7-hydroxy-1-[(3-oxopiperazin-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(4-methylpiperazin-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(2-methoxyethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-(3,4-dihydroisoquinolin-2(1H)-ylmethyl)-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[methyl(pentyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methyl}-D-prolinamide; 3-(4-fluorobenzyl)-7-hydroxy-1-[(1-oxo-2,8-diazaspiro[4.5]dec-8-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[cyclohexyl(ethyl)amino]methyl}-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[methyl(2-pyridin-2-ylethyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; (3R)-1-{[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methyl}-N,N-dimethylpyrrolidine-3-carboxamide; 3-(4-fluorobenzyl)-7-hydroxy-1-({4-hydroxy-4-[(2-oxopyrrolidin-1-yl}methyl]piperidin-1-yl}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(5-oxo-1,4-diazepan-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-([3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]sulfonyl)-L-prolinamide; 3-(4-fluorobenzyl)-7-hydroxy-N-[2-(1H-indol-3-yl)ethyl]-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide; 3-(4-fluorobenzyl)-7-hydroxy-1-[(3-oxopiperazin-1-yl)sulfonyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-N,N-dimethyl-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide; 3-(4-fluorobenzyl)-7-hydroxy-6-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide; N,3-bis(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide; 3-(4-fluorobenzyl)-7-hydroxy-1-(pyrrolidin-1-ylcarbonyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-[(4-acetylpiperazin-1-yl)carbonyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-6-oxo-N-(2-pyrazin-2-ylethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-carboxamide; 3-(4-fluorobenzyl)-7-hydroxy-6-oxo-N-(pyridin-2-ylmethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-carboxamide; 3-(4-fluorobenzyl)-7-hydroxy-6-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-carboxamide; 1-[(4-ethylpiperazin-1-yl)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-({[(2S)-2,3-dihydroxypropyl]oxy}methyl)-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; tert-butyl 4-({[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methoxy}methyl)piperidine-1-carboxylate; 3-(4-fluorobenzyl)-7-hydroxy-1-[(2-pyridin-2-ylethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[2-(cyclohexyloxy)ethoxy]methyl}-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-[({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}amino)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(2-methoxyethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(tetrahydro-2H-pyran-4-yloxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[(1R)-1-phenylethoxy]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[1-(hydroxymethyl)cyclopentyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(propylamino)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[(3-methylbenzyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-({[(5-methylpyrazin-2-yl)methyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-({[4-(trifluoromethyl)benzyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[(pyridin-2-ylmethyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-7,8,9,10-tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3-c]azepin-6(3H)-one; 8-butyl-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-8-methyl-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one, 3-(4-fluorobenzyl)-7-hydroxy-1-{[(2-hydroxyethyl)(propyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[2-(hydroxymethyl)piperidin-1-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[[2-(diethylamino)ethyl](ethyl)amino]methyl}-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[ethyl(4-methylbenzyl)amino]methyl}-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[4-(ethylsulfonyl)piperazin-1-yl]methyl}-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(4-hydroxypiperidin-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[benzyl(methyl)amino]methyl}-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[(7R)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[(3aR,7aR)-3-oxooctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-(morpholin-4-ylmethyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[4-(2-morpholin-4-ylethyl)piperazin-1-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; and 3-(4-fluorobenzyl)-7-hydroxy-1-({methyl[(1-phenyl-1H -pyrazol-4-yl)methyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         18 . A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound according to  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         19 . A method of inhibiting HIV integrase enzyme activity, comprising contacting said integrase enzyme with an HIV integrase-inhibiting amount of at least one compound according to  claim 1 . 
     
     
         20 . A method of treating HIV infection in an HIV-infected mammal, comprising administering to said mammal a therapeutically effective amount of at least one compound according to  claim 1 .