Cathepsin K inhibitors and application thereof

A compound having Formula (I) or a stereoisomer, a tautomer, a geometric isomer, an N-oxide, or a pharmaceutically acceptable salt thereof,

• wherein,
• R4a is H, C1-6 alkyl or C2-6 alkenyl, wherein each of the C1-6 alkyl and C2-6 alkenyl is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, C3-6 cycloalkyl, cyano, C6-10 aryl, C1-9 heteroaryl and C2-9 heterocyclyl;
• R4 is C1-6 alkyl, —C(R7)(R7a)—R8, C3-9 heterocyclyl or C2-6 alkenyl, wherein each of the C1-6 alkyl and C2-6 alkenyl is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, C3-6 cycloalkyl, cyano, C6-10 aryl, C1-9 heteroaryl or C3-9 heterocyclyl;
• or, R4 and R4a, together with the nitrogen atom to which they are attached, form a C3-9 heterocyclyl group containing nitrogen, wherein the C3-9 heterocyclyl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from C1-6 alkyl, C1-6 hydroxyalkyl, cyano, —C(R10)(R10a)—C(═O)—N(R12)(R12a), —C(═O)—OR8a, oxo (═O), C1-6 haloalkyl and halogen;
• each of R7 and R7a is independently H, C1-6 alkyl, —C(R10)(R10a)—C(═O)—N(R12)(R12a), —C(═O)—OR8a, C2-9 heterocyclyl or C2-6 alkenyl;
• or, R7 and R7a, together with the carbon atom to which they are attached, form a C3-6 carbocyclic ring or C2-6 heterocyclic ring, wherein each of the C3-6 carbocyclic ring and C2-6 heterocyclic ring is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, oxo (═O), cyano, —C(═O)—OR8a and halogen;
• R8 is H, C1-6 alkyl, cyano, —N(R12)(R12a), —C(═O)—C(═O)—N(R12)(R12a), —C(═O)—N(R12)(R12a), —C(═O)—OR8a, C3-6 heterocyclyl or C2-6 alkenyl;
• each R3, R3a, R2, R2a, R8a, R10, R10a, R12 and R12a is independently H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, hydroxy, amino, carboxy, cyano, C3-6 cycloalkyl, C6-10 aryl, C1-9 heteroaryl and C2-9 heterocyclyl;
• or, R2 and R2a, together with the carbon atom to which they are attached, form a C3-9 carbocyclic ring or C2-9 heterocyclic ring, wherein each of the C3-9 carbocyclic ring and C2-9 heterocyclic ring is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from C1-6 alkyl, C2-6 alkenyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, hydroxy, amino, carboxy, cyano and halogen;
• or, R3 and R3a, together with the carbon atom to which they are attached, form a >C(═O), C3-9 carbocyclic ring or C2-9 heterocyclic ring, wherein each of the C3-9 carbocyclic ring and C2-9 heterocyclic ring is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from C1-6 alkyl, C2-6 alkenyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, hydroxy, amino, carboxy, cyano and halogen;
• X is —O—, —S—, or —NH—;
• each of V, Z and Y is independently C(R9) or N;
• each R9 is independently H, halogen, hydroxy, C1-4 alkoxy, C1-4 haloalkyl or C1-4 alkyl, wherein each of the C1-4 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, C3-6 cycloalkyl, C6-10 aryl, C1-9 heteroaryl and C2-9 heterocyclyl;
• R5 is H, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, nitro, or C1-4 haloalkyl;
• R1 is C6-10 aryl, C1-9 heteroaryl, C3-12 cycloalkyl or C2-12 heterocyclyl, wherein of the R1 is independently and optionally substituted with 1, 2, 3, 4 or 5 R1a which are the same or different;
• each R1a is independently H, C1-6 alkyl, C1-6 haloalkyl, halogen, cyano, oxo (═O), C1-6 alkoxy, C6-10 aryl, C1-9 heteroaryl, C3-12 cycloalkyl, C2-12 heterocyclyl, —OR14, —SO2—N(R13)(R13a), —N(R13a)—SO2—R11, —N(R13)(R13a), —C(═O)—C(═O)—N(R13)(R13a), —C(═O)—N(R13)(R13a), —C(═N—OH)(R14a), —N(R13)—C(═O)R14a, —C(═O)—OR14, —C(═O)—R14a or —SO2R14, wherein each of the R1a is independently and optionally substituted with 1, 2, 3, 4 or 5 R1b which are the same or different;
• each R1b is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen, nitro, cyano, hydroxy, oxo (═O), —OR15, —SO2R15, —N(R16)(R16a), —C(═O)—N(R16)(R16a), C6-10 aryl, C1-9 heteroaryl, C3-12 cycloalkyl or C2-12 heterocyclyl, wherein each of the R1b is independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from hydroxy, nitro, cyano, C1-6 alkyl, C1-6 haloalkyl, halogen, oxo (═O), C1-6 alkoxy, C6-10 aryl, C1-9 heteroaryl, C3-12 cycloalkyl, C2-12 heterocyclyl and amino;
• each R16 and R16a is independently H, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C1-9 heteroaryl, C3-6 cycloalkyl, —SO2R17, —N(R18)(R18a), C1-4 haloalkyl or C2-9 heterocyclyl;
• each R15, R13, R14, R14a, R17, R18 and R18a is independently H, C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, 5- to 6-membered heteroaryl, C3-6 cycloalkyl or 4- to 7-membered heterocyclyl, wherein each of the phenyl, 5- to 6-membered heteroaryl, C3-6 cycloalkyl and 4- to 7-membered heterocyclyl is independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, cyano, hydroxy, trifluoromethyl, C1-4 alkyl, C1-4 alkoxy and 2,2-difluoroethyl.