Broadspectrum substituted benzimidazole sulfonamide hiv protease inhibitors

Abstract

The present invention concerns the compounds having the formula N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein R 1 and R 8 each are H, optionally substituted C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, aryl, Het 1 , Het 2 ; R 1 may also be a radical of formula (R 11a R 11b )NC(R 10a R 10b )CR 9 —; t is 0, 1 or 2; R 2 is H or C 1-6 alkyl; L is —C(═O)—, —O—C(═O)—, —NR 8 —C(═O)—, —O—C 1-6 alkanediyl-C(═O)—, —NR 8 —C 1-6 alkanediyl-C(═O)—, —S(═O) 2 —, —O—S(═O) 2 —, —NR 8 —S(═O) 2 ; R 3 is C 1-6 alkyl, aryl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, or arylC 1-4 alkyl; R 4 is H, C 1-4 alkylOC(═O), carboxyl, aminoC(═O), mono- or di(C 1-4 alkyl)aminoC(═O), C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or optionally substituted C 1-6 alkyl; A is C 1-6 alkanediyl, —C(═O)—, —C(═S)—, —S(═O) 2 —, C 1-6 alkanediyl-C(═O)—, C 1-6 alkanediyl-C(═S)— or C 1-6 alkanediyl-S(═O) 2 —; R 5 is H, OH, C 1-6 alkyl, Het 1 C 1-6 alkyl, Het 2 C 1-6 alkyl, optionally substituted aminoC 1-6 alkyl; R 6 is C 1-6 alkylO, Het 1 , Het 1 O, Het 2 , Het 2 O, aryl, arylO, C 1-6 alkyloxy-carbonylamino or amino; and in case -A- is other than C 1-6 alkanediyl then R 6 may also be C 1-6 alkyl, Het 1 C 1-4 alkyl, Het 1 OC 1-4 alkyl, Het 2 C 1-4 alkyl, Het 2 OC 1-4 alkyl, arylC 1-4 alkyl, arylOC 1-4 alkyl or aminoC 1-4 alkyl; whereby each of the amino groups in the definition of R 6 may optionally be substituted; R 5 and -A-R 6 taken together with the nitrogen atom to which they are attached may also form Het 1 or Het 2 ′R 12 is H, —NH 2 , —NR 5 AR 6 , —C 1-6 alkyl or alkyl-W—R 14 , wherein said alkyl is optionally substituted with halogen, hydroxy, aryl, heteroaryl, Het 1 , Het 2 , or amino wherein said amino is optionally mono- or di-substituted with C 1-4 alkyl and R 13 is H, C 1-6 -alkyl, optionally substituted by aryl, Het 1 , Het 2 , hydroxy, halogen, amino whereby the amino group may be optionally be mono- or di-substituted with C 1-4 alkyl.

1 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       or N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, wherein 
 R 1  is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, arylC 1-6 alkyl, arylC 2-6 alkenyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-6 alkyl, aryl, Het 1 , Het 1 C 1-6 alkyl, Het 2 , or Het 2 C 1-6 alkyl;  
 R 1  may also be a radical of formula  
                     
 wherein  
 R 9 , R 10a  and R 10b  are, each independently, hydrogen, C 1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-4 alkyl optionally substituted with aryl, Het 1 , Het 2 , C 3-7 cycloalkyl, C 1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, aminosulfonyl, C 1-4 alkylS(O) t , hydroxy, cyano, halogen or optionally mono- or disubstituted amino where the substituents are selected from C 1-4 alkyl, aryl, arylC 1-4 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, Het 1 , Het 1 , Het 1 C 1-4 alkyl and Het 2 C 1-4 alkyl; wherein R 9 , R 10a  and the carbon atoms to which they are attached optionally form a C 3-7 cycloalkyl radical;  
 R 11a  is hydrogen, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, aryl, optionally mono- or disubstituted aminocarbonyl, optionally mono- or disubstituted aminoC 1-4 alkylcarbonyloxy, C 1-4 alkyloxycarbonyl, aryloxycarbonyl, Het 1 oxycarbonyl, Het 2 oxycarbonyl, aryloxycarbonylC 1-4 alkyl, arylC 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, C 3-7 cycloalkylcarbonyl, C 3-7 cycloalkylC 1-4 alkyloxycarbonyl, C 3-7 cycloalkylcarbonyloxy, carboxylC 1-4 alkylcarbonyloxy, C 1-4 alkylcarbonyloxy, arylC 1-4 alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, Het 1  carbonyl, Het 1 carbonyloxy, Het 1 C 1-4 alkyloxycarbonyl, Het 2 carbonyl oxy, Het 2 C 1-4 alkylcarbonyloxy, Het 2 C 1-4 alkyloxycarbonyloxy or C 1-4 alkyl optionally substituted with aryl, aryloxy, Het 2  or hydroxy; wherein the optional substituents on the amino groups are each independently selected from C 1-4 alkyl, aryl, arylC 1-4 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, Het 1 , Het 2 , Het 1 C 1-4 alkyl and Het 2 C 1-4 alkyl;  
 wherein R 11a  may be optionally linked to the remainder of the molecule via a sulfonyl group;  
 R 11b  is hydrogen, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, Het 1 , Het 2  or C 1-4 alkyl optionally substituted with halogen, hydroxy, C 1-4 alkylS(═O) t , aryl, C 3-7 cycloalkyl, Het 1 , Het 2 , optionally mono- or disubstituted amino where the substituents are selected from C 1-4 alkyl, aryl, arylC 1-4 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, Het 1 , Het 2 , Het 1 C 1-4 alkyl and Het 2 C 1-4 alkyl;  
 each t independently is zero, 1 or 2;  
 R 2  is hydrogen or C 1-6 alkyl;  
 L is —C(═O)—, —O—C(═O)—, —NR 8 —C(═O)—, —O—C 1-6 alkanediyl-C(═O)—, —NR 8 —C 1-6 alkanediyl-C(═O)—, —S(═O) 2 —, —O—S(═O) 2 —, —NR 8 —S(═O) 2 , or —NR 8 —C 1-6 alkanediyl-S(═O) 2 , wherein either the C(═O) group or the S(═O) 2  group is attached to the NR 2  moiety; whreein the C 1-6 alkanediyl moiety is optionally substituted with hydroxy, aryl, Het 1  or Het 2 ;  
 R 3  is C 1-6 alkyl, aryl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, or arylC 1-4 alkyl optionally substituted with C 1-4 alkyl, halogen, nitro, cyano, polyhaloC 1-4 alkyl, hydroxy, C 1-4 alkyloxy, mercapto or C 1-4 alkylthio;  
 R 4  is hydrogen, C 1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-4 alkyl optionally substituted with aryl, Het 1 , Het 2 , C 3-7 cycloalkyl, C 1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, aminosulfonyl, C 1-4 alkylS(═O) t , hydroxy, cyano, halogen or optionally mono- or disubstituted amino where the substituents are selected from C 1-4 alkyl, aryl, arylC 1-4 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, Het 1 , Het 2 , Het 1 C 1-4 alkyl and Het 2 C 1-4 alkyl; or  
 R 4  may also be —X—R 7  wherein  
 X is —O— or —N(R 7 )—Y—;  
 Y is —C(═O)—, —S(═O) 2 —, —O—C(═O)—, —NR 8 —C(═O)—, —C(═O)—C(═O)—, —O—S(═O) 2 — or —NR 8 —S(═O) 2 —;  
 R 5  is hydrogen, hydroxy, C 1-6 alkyl, Het 1 C 1-6 alkyl, Het 2 C 1-6 alkyl, or aminoC 1-6 alkyl wherein the amino group may optionally be mono- or di-substituted with C 1-4 alkyl;  
 R 6  is hydrogen, C 1-6 alkyloxy, Het 1 , Het 1 oxy, Het 2 , Het 2  oxy, aryl, aryloxy, aryloxyC 1-4 alkyl, C 1-4 alkyloxyaryl, C 1-4  alkyloxyHet 1 , C 1-4  alkyloxyHet 2 , C 1-4 alkyloxycarbonylamino, aminoC 1-4 alkylamino, amino or aminoC 1-4 alkyloxy and in case A is other than C 1-6 alkanediyl, then R may also be C 1-6 alkyl, Het 1 C 1-4 alkyl, Het 1 oxyC 1-4 alkyl, Het 2 C 1-4 alkyl, Het 2 oxyC 1-4 alkyl, arylC 1-4 alkyl, aryloxyC 1-4 alkyl or aminoC 1-4 alkyl; whereby wherein each amino group may optionally be mono- or where possible disubstituted with C 1-4 alkyl;  
 R 5  and -A-R taken together with the nitrogen atom to which they are attached may also form Het 1  or Het 2 ;  
 R 7  is hydrogen, aryl, C 3-7 cycloalkyl, Het 1 , Het 2 , C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkyl optionally substituted with aryl, Het 1 , Het 2 , C 3-7 cycloalkyl, C 1-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, aminosulfonyl, C 1-4 alkylS(═O) t , hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from C 1-4 alkyl, aryl, arylC 1-4 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, Het 1 , Het 2 , Het 1 C 1-4 alkyl and Het 2 C 1-4 alkyl;  
 R 8  is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, arylC 1-4 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-6 alkyl, aryl, Het 1 , Het 1 C 1-6 alkyl, Het 2 , or Het 2 C 1-6 alkyl;  
 R 12  is hydrogen, —NH 2 , —C 1-6 alkyl or C 1-6 alkyl-W—R 14 , wherein said C 1-6 alkyl is optionally substituted with halogen, hydroxy, aryl, heteroaryl, Het 1 , Het 2 , or amino wherein said amino is optionally mono- or di-substituted with C 1-4  alkyl; or  
 R 12  may also be —N(R 5 )(AR 6 ), wherein  
 A is C 1-6 alkanediyl, —C(═O)—, —C(═S)—, —S(═O) 2 —, C 1-6 alkanediyl —C(═O)—, C 1-6 alkanediyl —C(═S)— or C 1-6 alkanediyl —S(═O) 2 —; wherein if A is C 1-6 alkanediyl —C(═O)—, C 1-6 alkanediyl —C(═S)— or C 1-6 alkanediyl —S(═O) 2 —, the NR5 moiety is attached to the C 1 alkanediyl moiety;  
 W is oxy, carbonyl, oxycarbonyl, carbonyloxy, oxycarbonyloxy, amino, aminocarbonyl, carbonylamino or sulphur;  
 R 13  is hydrogen, C 1-6 -alkyl, optionally substituted by aryl, Het 1 , Het 2 , hydroxy, halogen, amino wherein the amino group may optionally be mono- or di-substituted with C 1-4 alkyl; and  
 R 14  is C 1-6 alkyl, aryl, Het 1  or Het 2 .  
 
     
     
         2 . A compound according to  claim 1  wherein 
 L is —C(═O)—, —O—C(═O)—, —NR 8 —C(═O)—, —O—C 1-6 alkanediyl-C(═O)—,    —NR 8 —C 1-6 alkanediyl-C(═O)—, —S(═O) 2 —, —O—S(═O) 2 —, —NR 8 —S(═O) 2 , or    —NR 8 —C 1-6 alkanediyl-S(═O) 2 , wherein either the C(═O) group or the S(═O) 2  group is attached to the NR 2  moiety.    
     
     
         3 . A compound according to  claim 1  wherein R 1  is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, arylC 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-6 alkyl, aryl, Het 1 , Het 1 C 1-6 alkyl, Het 2  or Het 2 C 1-6 alkyl; wherein Het 1  is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen and sulfur and which is optionally substituted on one or more carbon atoms.  
     
     
         4 . A compound according to  claim 1  wherein L is —O—CH 2 —C(═O)—, —O—C(═O)—, —C(═O)— or —CH 2 —O—C(═O)—.  
     
     
         5 . A compound according to  claim 1  wherein 
 A is C 1-6 alkanediyl, —C(═O)— or C 1-6 alkanediyl-C(═O)—; wherein the point of attachment to the NR 5  moiety is the C 1-6 alkanediyl group in those moieties containing said group;    R 5  is hydrogen, C 1-6 alkyl, Het 1 C 1-6 alkyl, Het 2 C 1-6 alkyl, or aminoC 1-6 alkyl wherein the amino group may optionally be mono- or di-substituted with C 1-4 alkyl; and in case -A- is —C(═O)— then R 6  is C 1-6 alkyloxy, Het 1 , Het 1 oxy or Het 2 oxy, aryl, Het 1 C 1-4 alkyl, Het 1 oxyC 1-4 alkyl, Het 2 C 1-4 alkyl, Het 2 oxyC 1-4 alkyl, arylC 1-4 alkyl, aryloxyC 1-4 alkyl or aminoC 1-4 alkyl; and    in case -A- is C 1-6 alkanediyl then R 6  is amino, C 1-6 alkyloxy, Het 1 , Het 1 oxy or Het 2 oxy; and    in case -A- is C 1-6 alkanediyl-C(═O)— then R 6  is C 1-6 alkyloxy, Het 1 , Het 1 oxy or Het 2 oxy, aryl, C 1-6 alkyl, Het 1 C 1-4 alkyl, Het 1 oxyC 1-4 alkyl, Het 2 C 1-4 alkyl, Het 2 oxyC 1-4 alkyl, arylC 1-4 alkyl, aryloxyC 1-4 alkyl or aminoC 1-4 alkyl;    wherein each of the amino groups in the definition of R 6  may optionally be substituted with one or more substituents selected from C 1-4 alkyl, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het 1 , Het 2 , arylC 1-4 alkyl, Het 1 C 1-4 alkyl and Het 2 C 1-4 alkyl; and    R 5  and -A-R 6  taken together with the nitrogen atom to which they are attached may also form Het 1  wherein Het 1  is substituted by at least an oxo group.    
     
     
         6 . A compound according to  claim 1 , wherein 
 R 12  is H, —NH 2 , —N(R 5 )(AR 6 ), —C 1-6 alkyl or C 1 alkyl —W—R 14 , wherein said C 1-6 alkyl is optionally substituted with halogen, hydroxy, aryl, heteroaryl, Het 1 , Het 2 , or amino optionally mono- or di-substituted with C 1-4 alkyl; 
 A is C 1-6 alkanediyl or —C(═O)—; R 5  is hydrogen, methyl, Het 1 C 1-6 alkyl, or aminoC 1-6 alkyl wherein the amino group may optionally be mono- or di-substituted with C 1-4 alkyl; R 6  is C 1-6 alkyloxy, Het 1  or amino; and in case -A- is other than C 1-6 alkanediyl then R 6  may also be C 1-6 alkyl, Het 1 C 1-4 alkyl or aminoC 1-4 alkyl;  
 wherein each of the amino groups may optionally be substituted;  
 W is oxycarbonyloxy; and  
 R 14  is Het 1 .  
   
     
     
         7 . A compound according to  claim 1 , wherein 
 R 12  is —N(R 5 )(AR 6 );    A is C 1-6 alkanediyl or —C(═O)—; R 5  is hydrogen; R 6  is C 1-6 alkyloxy, Het 1 , C 1-4 alkyloxyaryl, amino, aminoC 1-4 alkylamino, or aminoC 1-4 alkyloxy; and in case -A- is —C(═O)— then R 6  may also be C 1-6 alkyl, Het 1 C 1-4 alkyl, or aminoC 1-4 alkyl; wherein each of the amino groups may optionally be substituted with C 1-4 alkyl.    
     
     
         8 . A compound according to  claim 1 , wherein R 13  is C 1-4 alkyl, methyl, ethyl or isobutyl; optionally substituted with aryl phenyl, Het 1 , pyrrolidinyl, Het 2 , imidazolyl, pyridinyl, or amino; wherein the amino group is optionally substituted with C 1-4 alkyl.  
     
     
         9 . A compound according to claim, wherein 
 R 12  is H, —NH 2 , —N(R 5 )(AR 6 ), —C 1-6 alkyl or C 1-6 alkyl-W—R 14 , wherein said C 1-6 alkyl is optionally substituted with hydroxy or amino wherein said amino is optionally mono- or di-substituted with C 1-4  alkyl;    A is C 1-6 alkanediyl or —C(═O)—; R 5  is hydrogen, methyl, Het 1 C 1-6 alkyl, or aminoC 1-6 alkyl whereby the amino group may optionally be mono- or di-substituted with C 1-4 alkyl; R 6  is C 1-6 alkyloxy, Het 1 , or amino; and in case -A- is other than C 1-6 alkanediyl then R 6  may also be C 1-6 alkyl, Het 1 C 1-4 alkyl or aminoC 1-4 alkyl; whereby wherein each of the amino groups may optionally be substituted;    R 13  is H, C 1-6 -alkyl, optionally substituted by aryl, Het 1 , Het 2 , hydroxy, halogen, or amino wherein the amino group may optionally be mono- or di-substituted with C 1-4 alkyl, and    R 14  is alkyl, aryl, Het 1 , or Het 2 .    
     
     
         10 . A pharmaceutical composition, comprising an effective amount of at least one compound as claimed in  claim 1 , and a pharmaceutically tolerable excipient.  
     
     
         11 . A method of inhibiting a protease of a multi-drug resistant retrovirus in a mammal infected with said retrovirus, comprising administering a protease inhibiting amount of a compound according to  claim 1  to said mammal in need thereof.  
     
     
         12 . A method of treating or combating infection or disease associated with multi-drug resistant retrovirus infection in a mammal, comprising administering an effective amount of at least one compound according to  claim 1  to said mammal.  
     
     
         13 . A method of inhibiting multi-drug resistant retroviral replication, comprising contacting a retrovirus with an effective amount of at least one compound according to  claim 1 .  
     
     
         14 . (canceled)  
     
     
         15 . A composition comprising at least (a) a compound of formula (I) as claimed in  claim 1  and, (b) a second antiretroviral agent for the simultaneous, separate or sequential use.