Cathepsin cysteine protease inhibitors

A compound of the following formula:

• wherein
• R1 is hydrogen, C1-6 alkyl or C2-6 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with C3-6 cycloalkyl, —SR6, —SR7, —SOR6, —SOR7, —SO2R6, —SO2R7, —SO2CH(R7)(R9), —OR7, —OR6, —N(R7)2, one to six halo, aryl, heteroaryl or heterocycyl wherein said aryl, heteroaryl and heterocycyl groups are optionally substituted with one or two substitutents independently selected from the group consisting of C1-6 alkyl, halo, hydroxyalkyl, hydroxy, alkoxy and keto;
• R2 is hydrogen, C1-6 alkyl or C2-6 alkenyl wherein said alkyl and alkenyl groups are optionally substituted with C3-6 cycloalkyl, —SR6, —SR7, —SOR6, —SOR7, —SO2R6, —SO2R7, —SO2CH(R7)(R9), —OR7, —OR6, —N(R7)2, one to six halo, aryl, heteroaryl or heterocycyl wherein said aryl, heteroaryl and heterocycyl groups are optionally substituted with one or two substitutents independently selected from the group consisting of C1-6 alkyl, halo, hydroxyakyl, 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 or heterocycyl ring wherein said ring system is optionally substituted with one or two substituents independently selected from the group consisting of C1-6 alkyl, hydroxyalkyl, haloalkyl and halo;
• each R3 is independently selected from the group consisting of hydrogen, halo and C1-2 allyl wherein said alkyl group is optionally substituted with halo;
• or
• two R3 groups can be taken together with the carbon atom to which they are attached to form a C3-4 cycloalkyl ring, wherein said group is optionally substituted with halo;
• D is C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, aryl, heteroaryl, C3-8 cycloalkyl or heterocycyl wherein each said aryl, heteroaryl, cycloalkyl and heterocycyl groups, which may be monocyclic or bicyclic, is optionally substituted on either the carbon or the heteroatom with one to five substituents independently selected from the group consisting of C1-6 alkyl, haloalkyl, halo, keto, alkoxy, —SR6, —SR7, —OR6, —OR7, N(R7)2, —SO2R6 and —SO2R8;
• E is C2-3 alkenyl, C2-3 alkynyl, aryl, heteroaryl, C3-8 cycloalkyl or heterocycyl wherein each said aryl, heteroaryl, cycloalkyl and heterocycyl groups, which may be monocyclic or bicyclic, is optionally substituted on either the carbon or the heteroatom with one to five substituents independently selected from the group consisting of C1-6 alkyl, haloalkyl, halo, keto, alkoxy, —SR6, —SR7, —OR6, —OR7, N(7)2, —SO2R6 and —SO2R8;
• R5 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)OR8, —C(O)OSi[CH(CH3)2]3, —OR6, —OR8, —C(O)R8, —R8C(O)R6, —C(O)R6, —C(O)N(Ra)(Rb), —C(O)N(R7)(R7), C(O)N(R8)(R9), —C(R8)(R9)OH, —SOmR7, —SOmR6, —R8SR6, —R6, —C(R6)3, —C(R8)(R9)N(R6)2, —NR8C(O)NR8S(O)2R6, —SOmN(Rc)(Rd), —SOmCH(R8)(R9), —SOm(C1-6alkyl)C(O)(C0-6alkyl)NR10, —SOm(C1-6akyl)N(R10)2, —SOm(C1-6alkyl)R10;
• —SOm(C3-8cycloalkyl)R10;
• —SO2N(R8)C(O)(R7), —SO2(R8)C(O)N(R7)2, —OSO2R8, —NR8)(R9), —N(R8)C(O)N(R8)(R6), —N(R8)C(O)R6, —N(R8)C(O)R8, —N(R8)C(O)OR8, —N(R8)SO2(R8), —C(R8)(R9)NR8C(R8)(R9)R6, —C(R8)(R9)N (R8)R6, —C(R8)(R9)N(R8)R9), —C(R8)(R9)SC(R8)(R9)(R6), R8S—, —C(Ra)(Rb)NraC(Ra)(Rb)(R6), —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)R6, —C(O)C(Ra)(Rb)S(Ra), C(Ra)(Rb)C(O)N(Ra)(Rb), —B(OH)2, —OCH2O— or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;
• wherein said groups are optionally substituted on either the carbon or the heteroatom with one to five substituents independently selected from the group consisting of C1-6 alkyl, halo, keto, cyano, haloalkyl, hydroxyalkyl, —OR6, —OR7, —NO2, —NH2, —NHS(O)2R8, —R6SO2R7, —SO2R7, —SO(R7), —SR7, —SR6, —SOmN(Rc)(Rd), —SOmN(R8)C(O)(R7), —C(R8)(R9)N(R8)(R9), —C(R8)(R9)OH, —COOH, —C(O)(O)(R7), —C(O)(O)C(R7)3, C(Ra)(Rb)C(O)N(Ra)(Rb), —C(O)(Ra), —N(R8)C(R8)(R9)(R6), —N(R8)CO(R6), —NH(CH2)2OH, —NHC(O)OR8, —Si(CH3)3, heterocyclyl, aryl, heteroaryl, (C1-4alkyl)heteroaryl and (C1-4alkyl)aryl;
• R6 is hydrogen, aryl, aryl(C1-4)alkyl, (C1-4alkyl)aryl, heteroaryl, heteroaryl(C1-4)alkyl, (C1-4alkyl)heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkyl(C1-4)alkyl, or heterocyclyl(C1-4)alkyl wherein said groups can be optionally substituted with one, two, or three substituents independendy selected from the group consisting of halo, alkoxy and —O2R7;
• R7 is hydrogen or C1-6 alkyl which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, alkoxy, cyano, —N(R8)(R9) and —SR8;
• R8 is hydrogen or C1-6 alkyl
• R9 is hydrogen or C1-6 alkyl;
• R10 is hydrogen, C1-6 alkyl, cyano, aryl, heteroaryl, heterocyclyl, SOmheteroaryl, (C═N)O(C1-6alkyl) or (C1-6alkyl)NH(SOm)heteroaryl;
• Ra is hydrogen, C1-6 alkyl, (C1-6 alkyl)aryl, (C1-6 alkyl)hydroxyl, —O(1-6 alkyl), hydroxyl, halo, aryl, heteroaryl, C3-8 cycloalkyl or heterocyclyl, wherein said alkyl, aryl, heteroaryl, C3-8 cycloalkyl and heterocycyl can be optionally substituted on either the carbon or the heteroatom with one, two, or three substituents independently selected from 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 heterocycyl, wherein said alkyl, aryl, heteroaryl, C3-8 cycloalkyl and heterocycyl can be optionally substituted on either the carbon or the heteroatom with one, two, or three substituents independently selected from group consisting of C1-6 alkyl and 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 heterocycyl ring wherein said 3-8 membered ring system may be optionally substituted with one or two substituents independently selected from C1-6 alkyl and halo;
• Rc is hydrogen or C1-6 alkyl which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo and —OR6;
• Rd is hydrogen or C1-6 alkyl which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo and —OR6;
• or
• Rc and Rd can be taken together with the nitrogen atom to which they are attached or are between them to form a C3-8 heterocycyl ring which is optionally substituted with one or two substituents independently selected from the group consisting of C1-6 alkyl, halo hydroxyalayl, hydroxy, alkoxy and keto;
• n is an integer from one to three;
• m is an integer from zero to two;
• p is an integer from one to three;
• or a pharnaceutically acceptable salts, stereoisomers or N-oxide derivatives thereof.