Compounds and compositions as cathepsin inhibitors

A compound of Formula I:

• in which:
• X1 is —C(R1)(R2)X2;
• X2 is cyano, —CHO, —C(R7)(R8)R5, —C(R7)(R8)CF3, —C(R7)(R8)CF2CF2R9—CH═CHS(O)2R5, —C(R7)(R8)CF2C(O)NR5R6, —C(R7)(R8)C(R7)(R8)NR5R6, —C(R7)(R8)C(R7)(R8)OR5, —C(R7)(R8)CH2OR5, —C(R7)(R8)CH2N(R6)SO2R5, —C(R7)(R8)C(R7)(R8)N(R6)(CH2)2OR6, —C(R7)(R8)C(R7)(R8)N(R6)CH2)2NR6 or —C(R7)(R8)C(R7)(R8)R5;
• wherein R5 is (C1-4)alkyl, (C6-10)aryl(C0-6)alkyl, hetero(C4-10)aryl(C0-6)alkyl, (C4-10)cycloalkyl(C0-6)alkyl or hetero(C4-10)cycloalkyl(C0-6)alkyl wherein hetero(C4-10)aryl or hetero(C4-10)cycloalkyl is pyran, thiopyran, pyrimidine, thiazole, isothiazole, pyridine, furan, imidazole, isoxazole, oxadiazole, oxazole or triazole;
• R6 is hydrogen or (C1-6)alkyl;
• R7 is hydrogen or (C1-4)alkyl and R8 is hydroxy or R7 and R8 together form oxo;
• R9 is hydrogen, halo, (C1-4)alkyl, or (C5-10)aryl(C0-6)alkyl;
• wherein within X1 any cycloalkyl, is substituted or unsubstituted;
• R1 and R2 are both fluoro;
• or
• R1 is hydrogen or (C1-6)alkyl and R2 is selected from the group consisting of hydrogen, (C1-6)alkyl, cyano, —X4NR12R12, —X4NR12C(O)R12, —X4NR12C(O)OR12, —X4NR12C(O)NR12R12, —X4NR12C(NR12)NR12R12, —X4OR13, —X4SR13, —X4C(O)OR12, —X4C(O)R13, —X4OC(O)R13, —X4C(O)NR12R12, —X4S(O)2NR12R12, —X4NR12S(O)2R13, —X4P(O)(OR12)OR12, —X4OP(O)(OR12)OR12, —X4S(O)R14, —X4S(O)2R14, —R15, —X4OR15, —X4SR15, —X4S(O)R15, —X4S(O)2R15, —X4C(O)R15, —X4C(O)OR15, —X4OC(O)R15, —X4NR15R12, —X4NR12C(O)R15, —X4NR12C(O)OR15, —X4C(O)NR15R12, —X4S(O)2NR15R12, —X4NR12S(O)2R15, —X4NR12C(O)NR15R12 and —X4NR12C(NR12)NR15R12, wherein X4 is a bond or (C1-6)alkylene, R12 at each occurrence independently is hydrogen or (C1-6)alkyl, R13 is hydrogen, (C1-6)alkyl or halo-substituted(C1-6)alkyl, R14 is (C1-6)alkyl or halo-substituted(C1-6)alkyl, and R15 is (C3-10)cycloalkyl(C0-6)alkyl, (C6-10)aryl(C0-6)alkyl, or (C9-12)bicycloaryl(C0-6)alkyl;
• or R1 and R2 taken together with the carbon atom to which both R1 and R2 are attached form (C3-8)cycloalkylene;
• wherein R2, and said cycloalkylene may be substituted further with 1 to 3 radicals independently selected from (C1-6)alkyl, cyano, halo, halo-substituted(C1-4)alkyl, nitro, —X4NR12R12, —X4NR12C(O)R12, —X4NR12C(O)OR12, —X4NR12C(O)NR12R12, —X4NR12C(NR12)N12R12, —X4OR13, —X4SR13, —X4C(O)OR12, —C(O)R13, —X4OC(O)R13, —X4C(O)NR12R12, —X4S(O)2NR12R12, —X4NR12S(O)2R13, —X4P(O)(OR12)OR12, —X4OP(O)(OR12)OR12, —X4S(O)R14 and —X4S(O)2R14, wherein —X4, R12, R13 and R14 are as defined above;
• R3 is —C(R16)(R17)X7, wherein R16 and R17 are hydrogen, (C1-6)alkyl or fluoro, or R16 is hydrogen and R17 is hydroxyl;
• and X7 is selected from —X4NR12R12, —X4NR12C(O)R12, —X4NR12C(O)OR12, —X4NR12C(O)NR12R12, —X4NR12C(NR12)NR12R12, —X4OR13, —X4SR13, —X4C(O)OR12, —X4C(O)R13, —X4OC(O)R13, —X4C(O)NR12R12, —X4S(O)2NR12R12, —X4NR12S(O)2R13, —X4P(O)(OR12)OR12, —X4OP(O)(OR12)OR12, —X4S(O)R14, —X4S(O)2R14, —R15, —X4OR15, —X4SR15, —X4S(O)R15, —X4S(O)2R15, —X4C(O)R15, —X4C(O)OR15, —X4OC(O)R15, —X4NR15R12, —X4NR12C(O)R15, —X4NR12C(O)OR15, —X4C(O)NR15R12, —X4S(O)2NR15R12, —X4NR12S(O)2R15, —X4NR12C(O)NR15R12 and —X4NR12C(NR12)NR15R12, wherein X4, R12, R13, R14 and R15 are as defined above;
• R4 is —C(R16)(R17)X7, wherein R16 and R17 are hydrogen, (C1-6)alkyl or fluoro, or R16 is hydrogen and R17 is hydroxy and X7 is selected from —R15, —X4OR15, —X4SR15, —X4S(O)R15, —X4NR12C(O)OR15, —X4C(O)NR15R12, —X4S(O)2NR15R12, —X4NR12S(O)2R15, —X4NR12C(O)NR15R12 and —X4NR12C(NR12)NR15R12, wherein X4, R12, R13 and R14 are as defined above for R3 and R15 is hetero(C3-10)cycloalkyl(C0-3) alkyl wherein said hetero(C3-10)cycloalkyl(C0-3)alkyl is morpholinyl,
• wherein within one of R3 or R4 any cycloalkyl or aryl is substituted or unsubstituted and provided that when X2 is cyano and X7 within one of R3 or R4 is —X4C(O)R13 or —X4C(O)R15, wherein X4 is a bond, then X7 within the other of R3 or R4 is limited to —X4SR15, —X4S(O)R15 and —X4S(O)2R15, wherein R15 is as defined above for each of R3 and R4, respectively;
• or the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof;
• or the pharmaceutically acceptable salts and solvates of such compounds or the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.