Resistance-repellent retroviral protease inhibitors

An HIV protease inhibitor represented by a formula:

• X-A-B-A′-X′
• wherein
• X is a 5-7 membered non-aromatic monocyclic heterocycle, wherein said heterocycle is optionally fused or bridged with one or more 3-7 membered non-aromatic monocyclic heterocycle to form a polycyclic system, wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, or P;
• wherein any nitrogen forming part of the heterocycles may optionally be substituted by R2, R3, R6, R7 or O;
• wherein any sulfur may be optionally be substituted by one or two oxygen atoms;
• wherein any P may be optionally be substituted by one or more of O NR2, or S, and any of said ring systems optionally contains 1 to 6 substituents selected from the group consisting of R2, R3, R5, and R6;
• A is ZCZNH, ZCOCONH, ZS(O)2NH, ZP(O)(V)NH, CONH, COCONH, S(O)2NH, P(O)(V)NH, wherein Z is NR2, O, S, or C(R2)2, and V is OR2 or NR2;
• B is
• 30
• wherein D is selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or aralkyl optionally substituted with one or more groups selected from alkyl , halo, nitro, cyano, CF3, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, R6, OR2, SR2, NHR2, OR3, SR3, NHR3, OR6, SR6, or NHR6;
• A′ is N(D′)E′, wherein D′ is selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or aralkyl optionally substituted by alkyl, halo, nitro, cyano, CF3, O-alkyl, or S-alkyl, and E′ is —CO— or —SO2—;
• X′ is selected from the group consisting of aryl and heteroaryl, which are substituted with one or more of the following groups:
• OR3, OR6, OR7, OR2 provided R2 is not H or unsubstituted alkyl;
• alkyl substituted by R3, R5, R6 provided R5 is not halo;
• C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, and heterocyclo, which groups may be optionally substituted with one or more substituents selected from R5;
• aryl or heteroaryl, wherein said aryl or heteroaryl may be optionally substituted with one or more groups selected from the group consisting of aryl, heteroaryl, R2, R3, R4, and R6;
• C3-C7 cycloalkyl substituted by R2, R3, R5, R6;
• provided R2 is not H;
• CO2H or R7;
• provided R8 is not H or unsubstituted alkyl;
• NR8R8, NR7R8, NR7R7;
• provided R8 is not H or unsubstituted alkyl;
• SOnN(R8)2, SOnNR7R8, SR8, S(O)nR8, provided R8 is not H or methyl;
• and n is 1 or 2;
• R is H or alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, heteroaryl;
• optionally substituted by halo, hydroxy, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, cyano, nitro, alkylthio, arylthio, cycloalkylthio, amino, or mono- or dialkylamino, mono- or diarylamino, mono- or di-cycloalkylamino, mono- or di-heteroarylamino, alkanoyl, cycloalkanoyl, aroyl, heteroaroyl, carboxamido, mono- or dialkylcarboxamido, mono- or diarylcarboxamido, sulfonamido, mono- or dialkylsulfonamido, mono- or diarylsulfonamido, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl;
• R2 is H or C1-C6 alkyl;
• optionally substituted by C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo;
• which groups may be optionally substituted with one or more substituents selected from the group consisting of halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR, oxo, ═N—OR, ═N—N(R)2, ═NR, ═NNRC(O)N(R)2, ═NNRCOnR, ═NNRS(O)nN(R)2, or ═NNRS(O)n(R);
• or R2 is C1-C6 alkyl;
• substituted by aryl or heteroaryl;
• which groups may be optionally substituted with one or more substituents selected from the group consisting of halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR;
• or R2 is C1-C6 alkyl;
• optionally substituted by halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)CO1R, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR, oxo, ═N—OR, ═N—N(R)2, ═NR, ═NNRC(O)N(R)2, ═NNRCOnR, ═NNRS(O)nN(R)2, or ═NNRS(O)n(R);
• R3 is C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, or heterocyclo;
• which groups may be optionally substituted with one or more substituents selected from the group consisting of halo, OR2, R2-OH, R2-halo, NO2, CN, COnR2, C(O)N(R2)2, C(O)N(R2)N(R2)2, C(S)R2, C(S)N(R2)2, S(O)nN(R2)2, SR2, SOnR2, N(R)2, N(R2)COnR, NR2S(O)nR2, NR2C[═N(R2)]N(R2)2, N(R2)N(R2)COnR2, NR2POnN(R2)2, NR2POnOR2, oxo, ═N—OR2, ═N—N(R2)2, ═N2, ═NNRC(O)N(R)2, ═NNR2C(O)nR2, ═NNR2S(O)nN(R2)2, or ═NNR2S(O)n(R2);
• R4 is halo, OR8, R2-OH, R3-OH, R2-halo, R3-halo, NO2, CN, COnR8, COnR8, CON(R8)2, C(O)N(R8)N(R8)2, C(S)R8, C(S)N(R8)2, SOnN(R8)2, SR8, SOnR8, N(R8)2, N(R8)COnR8, NR8S(O)nR8, NR8C[═N(R8)]N(R8)2, N(R8)N(R8)COnR8, NR8POnN(R8)2, NR8POnOR8, OC(O)R2, OC(S)R8, OC(O)N(R8)2, OC(S)N(R8)2, OPOn(R8)2;
• R5 is OR8, N(R8)2, NHOH, N(R8)COR8, NR8S(O)nR8, NR8C[═N(R8)]N(R8)2, N(R8)N(R8)C(O)R8, NR8POnN(R8)2, NR8POnOR8, R2OH, R3-OH, R2-halo, R3-halo, CN, CO1R8;
• provided that when n=2, R8 is not H;
• CON(R8)2, C(O)N(R8)N(R8)2, C(S)nR8, C(S)N(R8)2, S(O)nR8, SOnN(R8)2, halo, NO2, SR8, oxo, ═N—OH , ═N—OR8, ═N—N(R8)2, ═NR8, ═NNR8C(O)N(R8)2, ═NNR8C(O)nR8, ═NNR8S(O)nN(R8)2, or ═NNR8S(O)n(R8), or R3
• R6 is aryl or heteroaryl, wherein said aryl or heteroaryl may be optionally substituted with one or more groups selected from aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO2, CN, COnR2, C(O)N(R2)2, C(O)N(R2)N(R2)2, C(S)R2, C(S)N(R2)2, S(O)nN(R2)2, SR2, SOnR2, N(R)2, N(R2)COnR2, NR2S(O)nR2, NR2C[═N(R2)]N(R2)2, N(R2)N(R2)COnR2, NR2POnN(R2)2, NR2POnOR2, OC(O)R2, OC(S)R2, OC(O)N(R2)2, OC(S)N(R2)2, OPOn(R2)2
• R7 is C(O)nR8;
• provided that when n=2;
• R8 is not H;
• C(S)R8, C(O)N(R8)2, C(S)N(R8)2, S(O)nR8, S(O)nN(R8)2;
• R8 is R2, R3, or R6;
• each n is independently 1 or 2;
• its stereoisomeric forms;
• and its pharmacologically acceptable salts.