Novel compounds and compositions as cathepsin inhibitors

A compound having a structure of formula (I):

• wherein
• A is
• X1 is methylene, ethylene or a bond;
• X2is CN, CHO, C(O)R6, C(O)C(O)NR7R7, C(O)C(O)NR7R8, C(O)C(O)R13, C(O)C(O)OR13, C(O)CH2X3R13;
• X3 is selected from the group consisting of O, S(O)n, CO, CONH, NHCO, NHSO2 and SO2NH;
• X4 is CH(R12) or CH(R12)—CH2;
• X5 is methylene, ethylene, propylene or a bond;
• X6 is a bond or (C1-2)alkylene;
• R1 is R13C(O)—, R13S(O)2—, R13OC(O)—, R8R7NC(O)—, R8R7NS(O)2—;
• R13S(O)2NC(O)— or R13C(O)NS(O)2—;
• R2 is selected from the group consisting of hydrogen, (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl or hetero(C5-12)aryl(C0-6)alkyl;
• R3 is selected from the group consisting of H, (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl or hetero(C5-13)aryl(C0-6)alkyl optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, —X6NR9R9, —X6OR9, —X6SR9, —X6C(O)NR9R9, —X6OC(O)NR9R9, —X6C(O)OR9, —X6NC(O)OR9, —X6S(O)R10, —X6S(O)2R10 and —X6C(O)R10;
• R4 is H or (C1-6)alkyl;
• or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached to form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene;
• R5 is H, F, or R5 is (C1-9)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C513)aryl(C0-6)alkyl each optionally substituted by 1 to 5 radicals independently selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, —X6NR9R9, —X6OR9, —X6SR9, —X6C(O)NR9R9, —X6OC(O)NR9R9, —X6C(O)OR9, —X6NC(O)OR9, —X6S(O)R10, —X6S(O)2R10 and —X6C(O)R10;
• R6 is (C6-12)aryl, hetero(C5-13)aryl and halo substituted (C1-6)alkyl;
• wherein R6 is optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C1-9)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-13)aryl(C0-6)alkyl, cyano, halo, halo-substituted (C1-6)alkyl, —X6NR9R9, —X6OR9, —X6SR9, —X6C(O)NR9R9, —X6OC(O)NR9R9, —X6C(O)OR9, —X6NC(O)OR9, —X6S(O)R10, —X6S(O)2R10 and —X6C(O)R10;
• R7 is H, (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-13)aryl(C0-6)alkyl, and halo substituted (C1-6)alkyl;
• wherein R7 is optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, —X6NR9R9, —X6OR9, —X6SR9, —X6C(O)NR9R9, —X6OC(O)NR9R9, —X6C(O)OR9, —X6NC(O)OR9, —X6S(O)R10, —XS(O)2R10 and —X6C(O)R10;
• R8 is selected from the group consisting of H, (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, and hetero(C5-13)aryl(C0-6)alkyl, or R7 and R8 together with the atom attached to form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene;
• R9 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-6)alkyl;
• R10 is (C1-6)alkyl or halo-substituted (C1-6)alkyl;
• R11 is selected from the group consisting of hydrogen, (C1-9)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-13)aryl(C0-6)alkyl, (C9-12)bicycloaryl(C0-3)alkyl, hetero(C8-12)-bicycloaryl(C0-3)alkyl, —C(O)R13, —C(S)R13, —S(O)R2R13, —C(O)OR13, —C(O)N(R7)R8, —C(S)N(R7)R8 and —S(O)2N(R7)R8;
• R12 is H or C1-6alkyl optionally substituted by amido, (C6-12)aryl, hetero(C5-12)aryl, hetero(C5-12)cycloalkyl or hydroxy;
• R13 is (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-13)aryl(C0-6)alkyl, and halo substituted (C1-6) alkyl;
• wherein R13 is optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, —X6NR9R9, —X6OR9, —X6SR9, —X6C(O)NR9R9, —X6OC(O)NR9R9, —X6C(O)OR9, —X6NC(O)OR9, —X6S(O)R10, —X6S(O)2R10 and —X6C(O)R10;
• and
• n is zero or an integer 1 or 2;
• and their corresponding N-oxides, and their prodrugs, and their protected derivatives, individual isomers and mixtures of isomers thereof;
• and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds of Formula (Ia) and their N-oxides and their prodrugs, and their protected derivatives, individual isomers and mixtures of isomers thereof.