Cathepsin k inhibitor, and preparation method therefor and use thereof

A compound of formula I or formula II or a pharmaceutically acceptable salt thereof or an optical isomer thereof, wherein the general structure thereof is as follows:

• wherein in formula I, X is C or N;
• R1 is selected from H, substituted or unsubstituted C1-10 alkyl, and substituted or unsubstituted C3-C10 cycloalkyl;
• wherein the substituent is selected from halogen, amino, cyano, hydroxyl, an aldehyde group, carboxyl and sulfonyl;
• Y is a ring group, located at any position of an attached aromatic ring, and optionally C3-10 cycloalkyl, a C6-12 aromatic ring or a C5-12 heterocyclic ring,
• wherein the C6-12 aromatic ring contains a C6-12 aromatic ring or a C6-12 heteroaromatic ring;
• wherein the C6-12 heteroaromatic ring contains at least one heteroatom;
• wherein the C5-12 heterocyclic ring is a saturated heterocyclic ring or an unsaturated heterocyclic ring, and the heterocyclic ring contains 1-3 heteroatoms;
• wherein the heteroatom is optionally O, N or S;
• R5 is selected from H, halogen, amino, cyano, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl, —S(O) 2R2, —C(O)R2, —NR3R4, —SR6 and —OR6;
• wherein R2 is selected from H, amino, halogen, C1-6 alkyl, C1-6 alkoxy and C3-8 cycloalkyl;
• wherein R3 and R4 together with N to which they are attached form a 4-8 membered ring containing at least one N;
• wherein R6 is selected from C1-6 alkyl;
• and
• wherein the halogen is mono-substituted or poly-substituted and selected from F, Cl, Br and I;
• and
• in formula II, R1 and R2 are each independently selected from H, halogen, cyano, amino, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, and the substituted C1-6 alkyl or C1-6 alkoxy is further substituted by at least one halogen or hydroxyl;
• and t in formula II is a chemical bond, optionally at least one of , or .

A compound of formula 0 or formula II or a pharmaceutically acceptable salt thereof or an optical isomer thereof, specifically selected from the following compounds:

• 1) 2-[(2,2-dimethylpropyl){[4-(4-methylpiperazin-1-yl)phenyl]methyl}amino]pyrimidine-4-carbonitrile
• 2) 2-[(2,2-dimethylpropyl)[(4-phenylphenyl)methyl]amino]pyrimidine-4-carbonitrile
• 3) 2-[(2,2-dimethylpropyl) ({4-[4-(methylthio)phenyl]phenyl}methyl)amino]pyrimidine-4-carbonitrile
• 4) 2-[(2,2-dimethylpropyl){[4-(4-fluorophenyl)phenyl]methyl}amino]pyrimidine-4-carbonitrile
• 5) 2-[(2,2-dimethylpropyl){[4-(4-methoxyphenyl)phenyl]methyl}amino]pyrimidine-4-carbonitrile
• 6) 2-[(2,2-dimethylpropyl) ({4-[4-(methylsulfonyl)phenyl]phenyl}methyl)amino]pyrimidine-4-carbonitrile
• 7) 2-({[4-(5-cyanothiophen-2-yl)phenyl]methyl}(2,2-dimethylpropyl)amino)pyrimidine-4-carbonitrile
• 8) 2-({[4-(6-chloropyridin-3-yl)phenyl]methyl}(2,2-dimethylpropyl)amino)pyrimidine-4-carbonitrile
• 9) 2-({[4-(3,4-dichlorophenyl)phenyl]methyl}(2,2-dimethylpropyl)amino)pyrimidine-4-carbonitrile
• 10) 2-[(2,2-dimethylpropyl){[4-(5-methylthiophen-2-yl)phenyl]methyl}amino]pyrimidine-4-carbonitrile
• 11) 4-(4-{[(4-cyanopyrimidin-2-yl) (2,2-dimethylpropyl)amino]methyl}phenyl)methyl benzoate
• 12) 2-({[4-(4-chloro-3-fluorophenyl)phenyl]methyl}(2,2-dimethylpropyl)amino)pyrimidine-4-carbonitrile
• 13) 2-[(2,2-dimethylpropyl) ({4-[4-(4-methylpiperazin-1-yl)phenyl]phenyl}methyl)amino]pyrimidine-4-carbonitrile
• 14) 2-[(cyclohexylmethyl)[(4-phenylphenyl)methyl]amino]pyrimidine-4-carbonitrile
• 15) 2-[(cyclohexylmethyl) ({4-[4-(4-methylpiperazin-1-yl)phenyl]phenyl}methyl)amino]pyrimidine-4-carbonitrile
• 16) 2-[(cyclohexylmethyl) ({4-[4-(methylsulfonyl)phenyl]phenyl}methyl)amino]pyrimidine-4-carbonitrile
• 17) 2-(neopentyl(4-(thiazol-4-yl)benzyl)amino)pyrimidine-4-carbonitrile
• 18) 2-((4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzyl) (neopentyl)amino)pyrimidine-4-carbonitrile
• 19) (1R,2R)-2-(8-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbonyl)-N-(4-oxotetrahydrofuran-3-yl)cyclohexane-1-carboxamide;
• 20) (1R,2R)-2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)-N-(4-oxotetrahydrofuran-3-yl)-cyclohexane-1-carboxamide;
• 21) (1R,2R)-2-(8-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbonyl)-N—((S)-4-oxotetrahydrofuran-3-yl)cyclohexane-1-carboxamide;
• 22) (1R,2R)-2-(6,8-difluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbonyl)-N—((S)-4-oxotetrahydrofuran-3-yl)cyclohexane-1-carboxamide;
• 23) (1R,2R)-2-(8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)-N—((S)-4-oxotetrahydrofuran-3-yl)cyclohexane-1-carboxamide;
• 24) (1R,2R)-2-(8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)-N—((S)-4-oxotetrahydrofuran-3-yl)cyclohexane-1-carboxamide;
• 25) (1R,2R)-2-(6-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)-N-(4-oxotetrahydrofuran-3-yl)-cyclohexane-1-carboxamide;
• 26) (1R,2R)-2-(6-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)-N—(S)-(4-oxotetrahydrofuran-3-yl)-cyclohexane-1-carboxamide;
• 27) (1R,2R)-2-(6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)-N—(S)-(4-oxotetrahydrofuran-3-yl)-cyclohexane-1-carboxamide;
• 28) (1R,2R)-2-(6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)-N—(S)-(4-oxotetrahydrofuran-3-yl)-cyclohexane-1-carboxamide;
• 29) (1R,2R)-2-(6-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)-N—(S)-(4-oxotetrahydrofuran-3-yl)-cyclohexane-1-carboxamide;
• 30) (1R,2R)-2-(6-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)-N-(4-oxotetrahydrofuran-3-yl)-cyclohexane-1-carboxamide;
• 31) (1R,2R)-2-(8-fluoro-6-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)-N—(S)-(4-oxotetrahydrofuran-3-yl)-cyclohexane-1-carboxamide;
• 32) (1R,2R)-2-(8-fluoro-6-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)-N-(4-oxotetrahydrofuran-3-yl)-cyclohexane-1-carboxamide;
• 33) 2-((4-chlorobenzyl) (neopentyl)amino)pyrimidine-4-carbonitrile;
• 34) 2-((4-bromobenzyl) (neopentyl)amino)pyrimidine-4-carbonitrile;
• 35) 2-((naphthalen-2-ylmethyl) (neopentyl)amino)pyrimidine-4-carbonitrile;
• 36) 2-(neopentyl(quinolin-2-ylmethyl)amino)pyrimidine-4-carbonitrile;
• 37) 2-(((4′-(4-(2-hydroxyethyl)piperazin-1-yl)-[1,1′-biphenyl]-4-yl)methyl) (neopentyl)amino)pyrimidine-4-carbonitrile;
• 38) 2-(((4′-(4-hydroxypiperidin-1-yl)-[1,1′-biphenyl]-4-yl)methyl) (neopentyl)amino)pyrimidine-4-carbonitrile;
• 39) 2-(((2-methyl-4′-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methyl) (neopentyl)amino)pyrimidine-4-carbonitrile;
• 40) 2-(((2-chloro-4′-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methyl) (neopentyl)amino)pyrimidine-4-carbonitrile;
• 41) 2-(neopentyl(4-(4-(2-oxopropyl)piperazin-1-yl)benzyl)amino)pyrimidine-4-carbonitrile;
• 42) 2-(isobutyl((4′-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)pyrimidine-4-carbonitrile;
• 43) N-(4-((4-cyanopyrimidin-2-yl) (neopentyl)amino)methyl)phenyl)-2-(4-methylpiperazin-1-yl)acetamide;
• 44) 2-((4-(4-methylpiperazin-1-carbonyl)benzyl) (neopentyl)amino)pyrimidine-4-carbonitrile;
• and
• 45) 4-(((4-cyanopyrimidin-2-yl) (neopentyl)amino)methyl)-N-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)benzamide.