Resistance-repellent retroviral protease inhibitors

Abstract

Resistance-repellent and multidrug resistant retroviral protease inhibitors are provided. Pharmaceutical composition comprising such compounds, and methods of using such compounds to treat HIV infections in mammals, are also provided.

1 . 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) 2 NH, ZP(O)(V)NH, CONH, COCONH, S(O) 2 NH, P(O)(V)NH, wherein Z is NR2, O, S, or C(R2) 2 , and V is OR2 or NR2;   B is   
     
       
         
         
             
             
         
       
     
     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, CF 3 , 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, CF 3 , O-alkyl, or S-alkyl, and E′ is —CO— or —SO 2 —; 
 X′ is 
 
     
       
         
         
             
             
         
       
       wherein G1 is NH or 0; 
       wherein G2 is CZ″ or N; 
       wherein Z″ is selected from the group consisting of halogen, R2, R3, or R6; 
       wherein Z′″ is selected from the group consisting of H or R2, R3, R6, halo, haloalkyl, C(R2) 2 OR, C(R2) 2 COR, C(R2) 2 OCOR, C(R2) 2 CO 2 R, C(R2) 2 N(R) 2 , C(R2) 2 SR, C(R2) 2 SOR, C(R2) 2 SO 2 R, optionally substituted with one or more substituents selected from the group consisting of halo, OR, ROH, R-halo, NO 2 , CN, CO n R, CON(R) 2 , C(S)R, C(S)N(R) 2 , SO n N(R) 2 , SR, SO n R, N(R) 2 , N(R)CO n R, NRS(O) n R, NRC[═N(R)]N(R) 2 , N(R)N(R)CO n R, NRPO n N(R) 2 , NRPO n OR; 
       wherein X′ is optionally substituted with one or more substituents, each independently selected from (a)-(h) as follows: 
       (a) OR3, OR6, OR7, OR2; 
       (b) alkyl substituted by R3, R5, R6; 
       (c) C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, and heterocyclyl, which groups may be optionally substituted with one or more substituents selected from R5; 
       (d) 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; 
       (e) C3-C7 cycloalkyl substituted by R2, R3, R5 or R6; 
       (f) CO 2 H or R7; 
       (g) NR8R8, NR7R8, NR7R7; and 
       (h) SO n N(R8) 2 , SO n NR7R8, SR8, S(O) n R8; and n is 1 or 2; 
       R is H or is selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo and 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, NO 2 , CN, CO n R, CON(R) 2 , C(S)R, C(S)N(R) 2 , SO n N(R) 2 , SR, SO n R, N(R) 2 , N(R)CO n R, NRS(O) n R, NRC[═N(R)]N(R) 2 , N(R)N(R)CO n R, NRPO n N(R) 2 , NRPO n OR, oxo, ═N—OR, ═N—N(R) 2 , ═NR, ═NNRC(O)N(R) 2 , ═NNRCO n R, ═NNRS(O) n N(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, NO 2 , CN, CO n R, CON(R) 2 , C(S)R, C(S)N(R) 2 , SO n N(R) 2 , SR, SO n R, N(R) 2 , N(R)CO n R, NRS(O) n R, NRC[═N(R)]N(R) 2 , N(R)N(R)CO n R, NRPO n N(R) 2  NRPO n OR; 
       or R2 is C1-C6 alkyl; optionally substituted by halo, OR, ROH, R-halo, NO 2 , CN, CO n R, CON(R) 2 , C(S)R, C(S)N(R) 2 , SO n N(R) 2 , SR, SO n R, N(R) 2 , N(R)CO n R, NRS(O) n R, NRC[═N(R)]N(R) 2 , N(R)N(R)CO n R, NRPO n N(R) 2 , NRPO n OR, oxo, ═N—OR, ═N—N(R) 2 , ═NR, ═NNRC(O)N(R) 2 , ═NNRCO n R, ═NNRS(O) n N(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, NO 2 , CN, CO n R2, C(O)N(R2) 2 , C(O)N(R2)N(R2) 2 , C(S)R2, C(S)N(R2) 2 , S(O) n N(R2) 2 , SR2, SO n R2, N(R) 2 , N(R2)CO n R2, NR2S(O) n R2, NR2C[═N(R2)]N(R2) 2 , N(R2)N(R2)CO n R2, NR2PO n N(R2) 2 , NR2PO n OR2, oxo, ═N—OR2, ═N—N(R2) 2 , ═NR2, ═NNRC(O)N(R2) 2 , ═NNR2C(O) n R2, ═NNR2S(O) n N(R2) 2 , or ═NNR2S(O) n (R2); 
       R4 is selected from the group consisting of halo, OR8, R2-OH, R3-OH, R2-halo, R3-halo, NO 2 , CN, CO n R8, CO n R8, CON(R8) 2 , C(O)N(R8)N(R8) 2 , C(S)R8, C(S)N(R8) 2 , SO n N(R8) 2 , SR8, SO n R8, N(R8) 2 , N(R8)CO n R8, NR8S(O) n R8, NR8C[═N(R8)]N(R8) 2 , N(R8)N(R8)CO n R8, NR8PO n N(R8) 2  NR8PO n OR8, OC(O)R2, OC(S)R8, OC(O)N(R8) 2 , OC(S)N(R8) 2  and OPO n (R8) 2 ; 
       R5 is selected from the group consisting of OR8, N(R8) 2 , NHOH, N(R8)COR8, NR8S(O) n R8, NR8C[═N(R8)]N(R8) 2 , N(R8)N(R8)C(O)R8, NR8PO n N(R8) 2 , NR8PO n OR8, R2OH, R3-OH, R2-halo, R3-halo, CN, CO n R8; CON(R8) 2 , C(O)N(R8)N(R8) 2 , C(S) n R8, C(S)N(R8) 2 , S(O) n R8, SO n N(R8) 2 , halo, NO 2 , SR8, oxo, —N—OH, ═N—OR8, ═N—N(R8) 2 , —NR8, ═NNR8C(O)N(R8) 2 , ═NNR8C(O) n R8, ═NNR8S(O) n N(R8) 2 , or ═NNR8S(O) n (R8) and 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, NO 2 , CN, CO n R2, C(O)N(R2) 2 , C(O)N(R2)N(R2) 2 , C(S)R2, C(S)N(R2) 2 , S(O) n N(R2) 2 , SR2, SO n R2, N(R) 2 , N(R2)CO n R2, NR2S(O) n R2, NR2C[═N(R2)]N(R2) 2 , N(R2)N(R2)CO n R, NR2PO n N(R2) 2 , NR2PO n OR2, OC(O)R2, OC(S)R2, OC(O)N(R2) 2 , OC(S)N(R2) 2 , OPO n (R2) 2 ; 
       R7 is selected from the group consisting of C(O) n R8; C(S)R8, C(O)N(R8) 2 , C(S)N(R8) 2 , S(O) n R8 and S(O)nN(R8) 2 ; 
       R8 is R2, R3, or R6; 
       R9 is alkyl optionally substituted by R3, R5, R6; 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 the group consisting of —OR2, C(O)N(R2) 2 , S(O) n N(R2) 2 , CN, SR2, SO n R2, COR2, CO 2 R2 or NR2C(O)R2, R5, and R7; 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 optionally substituted by R2, R3, R5, R6; CO 2 H or R7; NR3R3, NR6R6, NR7R7, NR3R6, NR6R7, NR3R7, NR2R3, NR2R6, NR2R7, NR2R2; SO n N(R8) 2 , SO n NR7R8, SR8, S(O) n R8; and n is 1 or 2; SO n N(R2) 2 , SO n N(R3) 2 , SO n N(R6) 2 , SO n N(R7) 2 , SO n NR2R3, SO n NR2R6, SO n NR2R7, SO n NR3R6, SO n NR3R7, SO n NR6R7; S(O) m R2, S(O) m R3, S(O) m R6; and m is 0, 1 or 2; and each n is independently 1 or 2. 
     
   
   
       2 . The compound of  claim 1 , wherein
 X is   
     
       
         
         
             
             
         
       
       Y is O, NH, or S; 
       Z is O, NH, or S; and 
       wherein any ring carbon is optionally substituted by R2, R3, R5, or R6. 
     
   
   
       3 . The compound of  claim 1 , wherein
 X is   
     
       
         
         
             
             
         
       
       wherein 
       G is C, O, NR2, or S; 
       n is an integer between 1-2; and 
       wherein any ring carbon is optionally substituted by R2, R3, R5, or R6. 
     
   
   
       4 . The compound of  claim 1 , wherein
 X is   
     
       
         
         
             
             
         
       
       wherein 
       J is independently CH 2 , or O, and 
       wherein any ring carbon is optionally substituted by R2, R3, R5, or R6. 
     
   
   
       5 . The compound of  claim 1 , wherein:
 X is   
     
       
         
         
             
             
         
       
       wherein any ring carbon is optionally substituted by R2, R3, R5, or R6. 
     
   
   
       6 . The compound of  claim 1 , wherein
 X is   
     
       
         
         
             
             
         
       
       wherein 
       each L is independently H, lower alkyl, oxo, or L forms a carbocyclic or heterocyclic ring with M; 
       each M is independently H, OH, chloro, fluoro, or M forms a carbocyclic or heterocyclic ring with Q, provided that if one M is OH, the other M is not OH; 
       Q is H, OH, amino, lower alkyl, alkylamino, alkoxy, halo, or forms a 3-7-membered carbocyclic or heterocyclic ring together with T; 
       each F is independently H, OH, lower alkyl, halo, or spirocylopropyl, provided that if one R is OH, the other R is not OH; 
       T is H or F, or T forms a carbocyclic or heterocyclic ring together with F. 
     
   
   
       7 . The HIV protease inhibitor according to  claim 1 , wherein
 X is tetrahydrofurodihydrofuranyl, tetrahydrofurotetrahydrofuranyl, tetrahydropyranotetrahydrofuranyl or tetrahydropyranodihydrofuranyl;   A is OCONH;   B is   
     
       
         
         
             
             
         
       
     
     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, CF 3 , C3-C7 cycloalkyl, C5-C7 cycloalkenyl, R6, OR2, SR2, NHR2, OR3, SR3, NHR3, OR6, SR6, or NHR6; and
 A′ is N(D′)E′, wherein D′ is alkyl, alkenyl, alkynyl aryl, cycloalkyl, or aralkyl optionally substituted by alkyl, halo, or CF 3 , and E′ is —SO 2 —. 
 
   
   
       8 . The HIV protease inhibitor of  claim 1 , wherein:
 X is tetrahydrofurotetrahydrofuranyl;   A is OCONH;   B is   
     
       
         
         
             
             
         
       
     
     wherein D′ is benzyl; and
 A′ is N(D′)E′, wherein D′ is isobutyl and E′ is —SO 2 —; 
 
   
   
       9 . The HIV protease inhibitor of  claim 1 , wherein
 X is   
     
       
         
         
             
             
         
       
       wherein A2, B2, and C′ are each independently O, NR2, or S; 
       D2 is CH or N; and 
       n is an integer between 1 and 2. 
     
   
   
       10 . The HIV protease inhibitor of  claim 1 , wherein:
 X is   
     
       
         
         
             
             
         
       
       wherein 
       A3 is H, F or alkoxy; 
       B3 is F, alkoxy, lower alkyl, or A3 and B3 can form a 3-7 membered heterocyclic ring; 
       Z′ is O, NR2, or S; and 
       n is an integer between 1-3. 
     
   
   
       11 . The HIV protease inhibitor of  claim 1 , wherein X′ is selected from 
     
       
         
         
             
             
         
       
       wherein said groups are optionally substituted with one or more of the following groups: 
       oxo, halo, OR3, OR6, OR7, OR2 provided R2 is not H or unsubstituted alkyl; 
       alkyl optionally 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; 
       CO 2 H or R7; provided R8 is not H or unsubstituted alkyl; 
       NR8R8, NR7R8, NR7R7; provided R8 is not H or unsubstituted alkyl; and 
       SO n N(R8) 2 , SO n NR7R8, SR8, S(O) n R8, provided R8 is not H or methyl; and n is 1 or 2. 
     
   
   
       12 . The HIV protease inhibitor of  claim 1 , wherein Z′″ is H and Z″ is CH 2 Cl, CH 2 Br, CH 2 I, CH 2 OR, CH 2 NH 2 , CH 2 N(R) 2 , CH 2 N(R)COR or CH 2 N(R)CO 2 R. 
   
   
       13 . The inhibitor according to  claim 12  wherein R is H or C 1 -C 6  alkyl. 
   
   
       14 . The HIV protease inhibitor of  claim 1 , wherein Z″ is H and Z′″ is selected from the group consisting of H, C(R2) 2 -halo, C(R2) 2 R, C(R2) 2 OR, C(R2) 2 COR, C(R2) 2 OCOR, C(R2) 2 CO 2 R, C(R2) 2 N(R) 2 , C(R2) 2 SR, C(R2) 2 SOR, C(R2) 2 SO 2 R, C(R2) 2 N(R)CO n R, C(R2) 2 NRS(O) n R, C(R2) 2 NRC[═N(R)]N(R) 2 , C(R2) 2 N(R)N(R)CO n R, C(R2) 2 C(S)R, C(R2) 2 C(S)N(R) 2 , and C(R2) 2 SO n N(R) 2 . 
   
   
       15 . The HIV protease inhibitor of  claim 8 , wherein Z″ is H and Z′″ is selected from the group consisting of H, C(R2) 2 -halo, C(R2) 2 R, C(R2) 2 OR, C(R2) 2 COR, C(R2) 2 OCOR, C(R2) 2 CO 2 R, C(R2) 2 N(R) 2 , C(R2) 2 SR, C(R2) 2 SOR, C(R2) 2 SO 2 R, C(R2) 2 N(R)CO n R, C(R2) 2 NRS(O) n R, C(R2) 2 NRC[═N(R)]N(R) 2 , C(R2) 2 N(R)N(R)CO n R, C(R2) 2 C(S)R, C(R2) 2 C(S)N(R) 2 , and C(R2) 2 SO n N(R) 2 . 
   
   
       16 . The HIV protease inhibitor of  claim 15 , wherein Z′″ is selected from the group consisting of H, Me, CH2OH, CH2OAc, CH2OMe, CH2NHiPr, CH2NH2, CH2S(O)Bu, CH2S-iPr, CH2OCOtBu, CH2NHCH2CH2OMe, CH2NHCOiPr, CH2NHCOPh, CH2NHCO2Pr, CH2NHCOMe, CH2-4-Morpholino, CH2-1-piperidino, CH2NHBoc, CH2NHCO2Et, CH2NHCOEt, CH2NHSO2iPr, CH2NHCbz, CH2NH(CH2)2-2-pyridyl, CH2NHCO-3-pyridyl, CH2NHCOCH2SCH2Ph, CH2NHCOCH2S(O)CH2Ph, CH2NHCO-2-furanyl, CH2N(CO2Et)CH2CH2OMe, NHCH(Me)CO2Et, CH2NHSO2Et, CH2NHSO2Me, CH2NMeSO2Me, CH2NMeTs, CH2NHCO2iPr, CH2OCOiPr, CH2-1-imidazole, CH2NHCH2CH2SEt, CH2N((CH2)2OMe)SO2Et, CH2NHCH2CF2CF3, CH2NHCH2CF3, CH2NHCH2CH2OPh, CH2NHBu, CH2NHCH2Ph, CH2SCH2CF3, CH2NHCOCF3, CH2NHcyclopentyl, CH2NHCH2CH2NHBoc, CH2NH(CH2)3-1-pyrrolidine-2-one, CH2NHCH2cyclohexyl, CH2NHCH2-2-pyridyl, CH2NHCH2-4-(2-methylthiazole), CH2SO2Me, CH2NHCOCF2CF3, CH2OCH2CF3, CH2N(Ac)CH2CF3, and CH2NHCH2-5-benzofuranyl. 
   
   
       17 . A compound according to  claim 1 , wherein said compound is selected from the group of compounds in  FIGS. 1-3 . 
   
   
       18 . A compound according to  claim 1 , wherein said compound is bound in a complex with wild type or drug resistant mutant forms of HIV-1 protease. 
   
   
       19 . A pharmaceutical composition comprising an effective amount of an inhibitor according to  claim 1  and a pharmaceutically acceptable additive, excipient, or diluent. 
   
   
       20 . A pharmaceutical composition comprising an effective amount inhibitor according to  claim 1  and another antiretroviral agent. 
   
   
       21 . A pharmaceutical composition comprising an effective amount of an inhibitor according to  claim 1  and a second HIV inhibitor. 
   
   
       22 . The composition according to  claim 21  wherein said second HIV inhibitor is an HIV protease inhibitor. 
   
   
       23 . The composition according to  claim 21  wherein said second HIV inhibitor is an HIV reverse transcriptase inhibitor. 
   
   
       24 . A method of treating a patient suffering from HIV infection, comprising administering to said patient a composition according to  claim 19 . 
   
   
       25 . A method of treatment according to  claim 24  wherein said patient is suffering from a multi-drug resistant HIV infection. 
   
   
       26 . A method of inhibiting metabolic degradation of a retroviral protease inhibitor in a subject being treated with said inhibitor, comprising administering to the subject a degradation-inhibiting amount of a compound of  claim 1 . 
   
   
       27 . The method of  claim 26 , wherein the compound is administered substantially contemporaneously with said inhibitor. 
   
   
       28 . The method of  claim 26 , wherein the compound is administered prior to administration of said inhibitor. 
   
   
       29 . An HIV protease inhibitor having the structure 
     
       
         
         
             
             
         
       
       wherein each R2 may be the same or different, and R2 is H or C1-C6 alkyl; optionally substituted by C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C 5 -C 8  cycloalkenyl, heterocyclo; which groups may be optionally substituted with one or more substituents selected from the group consisting of halo, OR, ROH, R-halo, NO 2 , CN, CO n R, CON(R) 2 , C(S)R, C(S)N(R) 2 , SO n N(R) 2 , SR, SO n R, N(R) 2 , N(R)CO n R, NRS(O) n R, NRC[═N(R)]N(R) 2 , N(R)N(R)CO n R, NRPO n N(R) 2 , NRPO n OR, oxo, ═N—OR, ═N—N(R) 2 , ═NR, ═NNRC(O)N(R) 2 , ═NNRCO n R, ═NNRS(O) n N(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, NO 2 , CN, CO n R, CON(R) 2 , C(S)R, C(S)N(R) 2 , SO n N(R) 2 , SR, SO n R, N(R) 2 , N(R)CO n R, NRS(O) n R, NRC[═N(R)]N(R) 2 , N(R)N(R)CO n R, NRPO n N(R) 2  NRPO n OR; 
       or R2 is C1-C6 alkyl; optionally substituted by halo, OR, ROH, R-halo, NO 2 , CN, CO n R, CON(R) 2 , C(S)R, C(S)N(R) 2 , SO n N(R) 2 , SR, SO n R, N(R) 2 , N(R)CO n R, NRS(O) n R, NRC[═N(R)]N(R) 2 , N(R)N(R)CO n R, NRPO n N(R) 2 , NRPO n OR, oxo, ═N—OR, ═N—N(R) 2 , ═NR, ═NNRC(O)N(R) 2 , ═NNRCO n R, ═NNRS(O) n N(R) 2 , or ═NNRS(O) n (R); 
       and wherein D′ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl and aralkyl, and is optionally substituted by alkyl, halo, nitro, cyano, CF 3 , halo-C1-C6 alkyl, O-alkyl, or S-alkyl.