Papain Family Cysteine Protease Inhibitors for the Treatment of Parasitic Diseases

A pharmaceutical composition comprising a papain family cysteine protease inhibitor of formula I:

• wherein R1 is hydrogen, C1-6 alkyl or C2-6 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with one to six halo, C3-6 cycloalkyl, —SR9, —SR12, —SOR9, —SOR12, —SO2R9, —SO2R12, —SO2CH(R12)(R11), —OR12, —OR9, —N(R12)2, aryl, heteroaryl or heterocyclyl wherein said aryl, heteroaryl and heterocyclyl groups are optionally substituted with one or two substitutents independently selected from C1-6 alkyl, halo, hydroxyalkyl, hydroxy, alkoxy or keto;
• R2 is hydrogen, C1-6 alkyl or C2-6 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with one to six halo, C3-6 cycloalkyl, —SR9, —SR12, —SOR9, —SOR12, —SO2R9, —SO2R12, —SO2CH(R12)(R11), —OR12, —OR9, —N(R12)2, aryl, heteroaryl or heterocyclyl wherein said aryl, heteroaryl and heterocyclyl groups are optionally substituted with one or two substitutents independently selected from C1-6 alkyl, C3-6 cycloalkyl, halo, hydroxyalkyl, hydroxy, alkoxy or keto;
• or R1 and R2 can be taken together with the carbon atom to which they are attached to form a C3-8 cycloalkyl ring or heterocyclyl ring wherein said cycloalkyl and heterocycl rings are optionally substituted with one or two substituents independently selected from C1-6 alkyl, hydroxyalkyl, haloalkyl, aryl, heteroaryl, heterocyclyl or halo;
• R3 is hydrogen, C1-6 alkyl or C2-6 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with C3-6 cycloalkyl, aryl or halo;
• R4 is hydrogen, C1-6 alkyl or C2-6 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with C3-6 cycloalkyl, aryl or halo;
• or R3 and R4 can be taken together with the carbon atom to which they are attached to form a C3-8 cycloalkyl ring, C5-8 cycloalkenyl ring, or five to seven membered heterocyclyl ring wherein said cycloalkyl, cycloalkenyl and heterocyclyl rings are optionally substituted with C1-6 alkyl, halo, hydroxyalkyl, hydroxy, alkoxy or keto;
• R5 is hydrogen or C1-6 haloalkyl;
• R6 is aryl, heteroaryl, C1-6 haloalkyl, arylalkyl or heteroarylalkyl, wherein said aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are optionally substituted with halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, —SR9, —SR12, —SOR9, —SOR12, —SO2R9, —SO2R12, —SO2CH(R12)(R11), —OR12, —N(R10)(R11), or cyano;
• D is C1-3 alkyl, C2-3 alkenyl, C2-3 alkenyl, aryl, heteroaryl, C3-8 cycloalkyl or heterocyclyl wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups, which may be monocyclic or bicyclic, are optionally substituted on either the carbon or the heteroatom with one to five substituents selected from C1-6 alkyl, halo or keto;
• R7 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyloxy, halo, nitro, cyano, aryl, heteroaryl, C3-8 cycloalkyl, heterocyclyl, —C(O)OR10, —C(O)OSi[CH(CH3)2]3, —OR10, —C(O)R10, —R10C(O)R9, —C(O)R9, —C(O)N(R12)(R12), —C(O)N(R10)(R11), —C(R10)(R11)OH, —SR12, —SR9, —R10SR9, —R9, —C(R9)3, —C(R10)(R11)N(R9)2, —NR10C(O)NR10S(O)2R9, —SO2R12, —SO(R12), —SO2R9, —SO2N(Rc)(Rd), —SO2CH(R10)(R11), —SO2N(R10)C(O)(R12), —SO2(R10)C(O)N(R12)2, —OSO2R10, —N(R10)(R11), —N(R10)C(O)N(R10)(R9), —N(R10)C(O)R10, —N(R10)C(O)OR10, —N(R10)SO2(R10), —C(R10)(R11)NR10C(R10)(R11)R9, —C(R10)(R11)N(R10)R9, —C(R10)(R11)N(R10)(R11), —C(R10)(R11)SC(R10)(R11)(R9), R10S—, —C(Ra)(Rb)NRaC(Ra)(Rb)(R9), —C(Ra)(Rb)N(Ra)(Rb), —C(Ra)(Rb)C(Ra)(Rb)N(Ra)(Rb), —C(O)C(Ra)(Rb)N(Ra)(Rb), —C(Ra)(Rb)N(Ra)C(O)R9, —C(O)C(Ra)(Rb)S(Ra) or C(Ra)(Rb)C(O)N(Ra)(Rb);
• wherein said alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted on either the carbon or the heteroatom with one to five substituents independently selected from C1-6 alkyl, halo, keto, cyano, haloalkyl, hydroxyalkyl, —OR9, —NO2, —NH2, —NHS(O)2R8, —R9SO2R12, —SO2R12, —SO(R12), —SO2N(Rc)(Rd), —SO2N(R10)C(O)(R12), —C(R10)(R11)N(R10)(R11), —C(R10)(R11)OH, —COOH, —C(Ra)(Rb)C(O)N(Ra)(Rb), —N(R10)C(R10)(R11)(R9), —NH(CH2)2OH, —NHC(O)OR10, —Si(CH3)3, heterocycyl, aryl or heteroaryl;
• R8 is hydrogen or C1-6 alkyl;
• or R4 and R8 or can be taken together with any of the atoms to which they may be attached or are between them to form a 410 membered heterocyclyl ring system wherein said ring system, which may be monocyclic or bicyclic, is optionally substituted with C1-6 alkyl, halo, hydroxyalkyl, hydroxy, keto, —OR10, —SR10 or —N(R10)2;
• R9 is hydrogen, aryl, aryl(C114) alkyl, heteroaryl, heteroaryl(C1-4)alkyl, C3-8cycloalkyl, C3-8cycloalkyl(C1-4)alkyl, and heterocyclyl(C1-4)alkyl wherein said groups can be optionally substituted with halo or alkoxy;
• R10 is hydrogen or C1-6 alkyl;
• R11 is hydrogen or C1-6 alkyl;
• R12 is hydrogen or C1-6 alkyl which is optionally substituted with halo, alkoxy, cyano, —NR10 or —SR10;
• Ra is hydrogen, C1-6 alkyl, (C1-6 alkyl)aryl, (C1-6 alkyl)hydroxyl, —O(C1-6 alkyl), hydroxyl, halo, aryl, heteroaryl, C3-8 cycloalkyl or heterocyclyl, wherein said alkyl, aryl, heteroaryl, C3-8 cycloalkyl and heterocyclyl are optionally substituted on either the carbon or the heteroatom with C1-6 alkyl or halo;
• Rb is hydrogen, C1-6 alkyl, (C1-6 alkyl)aryl, (C1-6 alkyl)hydroxyl, alkoxyl, hydroxyl, halo, aryl, heteroaryl, C3-8 cycloalkyl or heterocyclyl, wherein said alkyl, aryl, heteroaryl, C3-8 cycloalkyl and heterocyclyl are optionally substituted on either the carbon or the heteroatom with C1-6 alkyl or halo;
• or Ra and Rb can be taken together with the carbon atom to which they are attached or are between them to form a C3-8 cycloalkyl ring or C3-8 heterocyclyl ring wherein said 3-8 membered ring system may be optionally substituted with C1-6 alkyl and halo;
• n is an integer from zero to three;
• and another agent selected from the group consisting of nifurtimox, benznidazole, allopurinol, terbinafine, lovastatin, ketoconazole, itraconazole, posaconazole, miltefosine, ilmofosine, pamidronate, alendronate, risedronate, chloroquine, proguanil, mefloquine, quinine, pyrimethamine-sulphadoxine, doxocycline, berberine, halofantrine, primaquine, atovaquone, pyrimethamine-dapsone, artemisinin, quinhaosu. meglumine antimonite, sodium stibogluconate, amphotericin B, praziquantel, oxamniquine, pentamidine, melarsoprol, suramin and eflornithine.