IP Library › Granted Patent US 9,416,139

Granted Patent B2

US 9,416,139 · App. 14/647,445 · Granted Aug 16, 2016

Spiro ring compound as hepatitis C virus (HCV) inhibitor and uses thereof

Inventors: Jiancun Zhang (San Mateo, CA); Yingjun Zhang (Dongguan, CN); Hongming Xie (Dongguan, CN); Qingyun Ren (Dongguan, CN); Bailin Hu (Dongguan, CN); Changping Fu (Dongguan, CN); Xiwei Wu (Dongguan, CN); Shifeng Li (Dongguan, CN); Chenglin Wang (Dongguan, CN); Zhikeng Zhang (Dongguan, CN)

Assignee: SUNSHINE LAKE PHARMA CO., LTD.

C07D491/113 A61K31/4184 A61K31/423 A61K31/435 A61K31/4709 A61K31/517 A61K31/527 A61K31/549 A61K38/204 A61K38/208 A61K38/2013 A61K38/21 A61K45/06 C07D401/14 C07D403/14 C07D405/14 C07D409/14 C07D413/14 C07D417/14 C07D491/107

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Quick Facts

Patent No.: US 9,416,139
App. No.: 14/647,445
Granted: Aug 16, 2016
Kind: B2

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Abstract

A compound of formula (I) or a stereoisomer, a geometric isomer. a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof is provided, which can be used for treating HCV infection or a HCV disorder. Also a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof are provided, which can also be used for treating HCV infection or a HCV disorder.

Claims (224)

1. A compound having Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

A is a single bond, alkylene, alkenylene, cycloalkylene, heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, or —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, or A is

A′ is

wherein each X 1 and X 2 is independently O, S, NR 6 , or CR 7 R 7a ;

X 4 is (CR 7 R 7a ) n , —Y 1 ═Y 2 —, O, S or NR 6 ;

W is a C 3-8 carbocyclyl or C 2-10 heterocyclyl ring;

each Y 1 and Y 2 is independently N or CR 7 ;

Z is —(CH 2 ) a —, —CH═CH—, —N═CH—, —(CH 2 ) a —N(R 5 )—(CH 2 ) b — or —(CH 2 ) a —O—(CH 2 ) b ;

each c and d is independently 1 or 2;

each a, b, n and p is independently 0, 1, 2 or 3;

each r is independently 0, 1 or 2;

each of Q 1 and Q 2 is independently NR 6 , O, S, C(═O) or (CR 7 R 7a ) e ;

each e and f is independently 0, 1, 2, 3 or 4;

each of X and X′ is independently N or CR 7 ;

each of Y and Y′ is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, a monovalent group derived from α-amino acid or an optically isomer thereof, or —[U—(CR 9 R 9a ) r —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 , —U—(CR 9 R 9a ) t —R 12 or —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 ;

each Q 4 and U is independently —C(═O)—, —C(═S)—, —S(═O)— or —S(═O) 2 —;

each t is independently 0, 1, 2, 3 or 4;

each k is independently 0, 1 or 2;

each of R 1 , R 2 , R 3 and R 4 is independently H, deuterium, alkyl, heteroalkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl; or R 1 and R 2 , together with X—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12 fused bicycle, C 5-12 fused heterobicycle, C 5-12 spiro bicycle or C 5-12 spiro heterobicycle; or R 3 and R 4 , together with X′—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12 fused bicycle, C 5-12 fused heterobicycle, C 5-12 spiro bicycle or C 5-12 spiro heterobicycle;

each R 5 is independently H, deuterium, hydroxy, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(═O)—, alkyl-C(═O)—, carbamoyl, alkyl-OS(═O) r —, alkyl-S(═O) r O—, alkyl-S(═O) r — or aminosulfonyl;

each R 5a is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13a R 13 N-alkyl, R 13 S(═O)-alkyl, R 13 R 13a N—C(═O)-alkyl, R 13a R 13 N-alkoxy, R 13 S(═O)-alkoxy, R 13 R 13a N—C(═O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalky, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkylacyl, alkylacyloxy, alkoxyacyl, alkyl sulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino or aryloxy;

each R 6 is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;

each R 6a is independently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo(═O), R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13a R 13 N-alkyl, R 13 S(═O)-alkyl, R 13 R 13a N—C(═O)-alkyl, R 13a R 13 N-alkoxy, R 13 S(═O)-alkoxy, R 13 R 13a N—C(═O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, alkylacyl, alkylacyloxy, alkoxyacyl, alkyl sulfonyl, alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino or aryloxy;

each R 7 and R 7a is independently H, deuterium, F, Cl, Br, I, aliphatic, heteroalkyl, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;

each R 8 and R 8a is independently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(═O)—, alkyl-C(═O)—, carbamoyl, alkyl-OS(═O) r —, alkyl-S(═O) r O—, alkyl-S(═O) r — or aminosulfonyl;

each R 9 , R 9a , R 10 and R 11 is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyl;

each R 12 is independently R 13a R 13 N—, —C(═O)R 13 , —C(═S)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13 OS(═O) 2 —, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl;

or R 11 and R 12 are optionally joined to form a 4-7 membered ring; and

and each R 13 and R 13a is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl; with the proviso that where R 13 and R 13a are bonded to the same nitrogen atom, R 13 and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring;

wherein each of alkylene, alkenylene, cycloalkylene, heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, —[U—(CR 9 R 9a ) t —NR 10 —(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —NR 11 —(CR 9 R 9a ) t —R 12 , —U—(CR 9 R 9a ) t —R 12 , —[U—(CR 9 R 9a ) t —NR 10 —(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 , NR 6 , CR 7 R 7a , CR 7 , —(CH 2 ) a —, —CH═CH—, —N═CH—, —(CH 2 ) a —N(R 5 )—(CH 2 ) b —, —(CH 2 ) a —O—(CH 2 ) b —, R 13a R 13 N—, —C(═O)R 13 , —C(═S)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13 OS(═O) 2 —, alkyl-OC(═O)—, alkyl-C(═O)—, alkyl-OS(═O) r —, alkyl-S(═O) r O—, alkyl-S(═O) r —, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13a R 13 N-alkyl, R 13 S(═O)-alkyl, R 13 R 13a N—C(═O)-alkyl, R 13a R 13 N-alkoxy, R 13 S(═O)-alkoxy, R 13 R 13a N—C(═O)-alkylamino, alkyl, heteroalkyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, α-amino acid, C 5-12 fused bicycle, C 5-12 fused heterobicycle, C 5-12 spiro bicycle, C 5-12 spiro heterobicycle, alkoxy, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, haloalkyl, alkenyl, alkynyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylamino, heterocyclylalkylamino and aryloxy is optionally substituted with one or more substituents independently selected from hydroxy, deuterium, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo(═O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O) 2 —, hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O) 2 — or carboxyl-substituted alkoxy.

2. The compound according to claim 1 , wherein

wherein each X 3 and X 5 is independently O, S, NR 6 , C(═O) or CR 7 R 7a ;

each X 6 is independently CR 7 R 7a , O, S or NR 6 ;

each Y 1 and Y 2 is independently N or CR 7 ;

each Q 1 and Q 2 is independently NR 6 , O, S, C(═O) or (CR 7 R 7a ) e ;

each e and f is independently 0, 1, 2, 3 or 4;

each R 6 is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 alkylamino-C 1-6 -alkyl, C 1-6 alkylthio-C 1-6 -alkyl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl-C 1-6 -alkyl, C 2-10 heterocyclyl-C 1-6 -alkyl, C 3-10 cycloalkyl-C 1-6 -alkyl, C 6-10 aryloxy-C 1-6 -alkyl, C 2-10 heterocyclyloxy-C 1-6 -alkyl, C 3-10 cycloalkyloxy-C 1-6 -alkyl, C 6-10 arylamino-C 1-6 -alkyl, C 2-10 heterocyclylamino-C 1-6 -alkyl, C 3-10 cycloalkylamino-C 1-6 -alkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl;

each R 7 and R 7a is independently H, deuterium, F, Cl, Br, I, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 alkylamino-C 1-6 -alkyl, C 1-6 alkylthio-C 1-6 -alkyl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl-C 1-6 -alkyl, C 2-10 heterocyclyl-C 1-6 -alkyl, C 3-10 cycloalkyl-C 1-6 -alkyl, C 6-10 aryloxy-C 1-6 -alkyl, C 2-10 heterocyclyloxy-C 1-6 -alkyl, C 3-10 cycloalkyloxy-C 1-6 -alkyl, C 6-10 arylamino-C 1-6 -alkyl, C 2-10 heterocyclylamino-C 1-6 -alkyl, C 3-10 cycloalkylamino-C 1-6 -alkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl; and

each R 13 and R 13a is independently H, deuterium, C 1-6 alkyl, C 2-6 heteroalkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl or C 6-10 aryl-C 1-6 -alkyl; with the proviso that where R 13 and R 13a are bonded to the same nitrogen atom, R 13 and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclic ring; or

wherein

wherein each Y 1 and Y 2 is independently N or CH;

each X 6 is independently CR 7 R 7a , O, S, or NR 6 ;

R 6 is H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 alkylamino-C 1-6 -alkyl, C 1-6 alkylthio-C 1-6 -alkyl, C 6-10 aryl-C 1-6 -alkyl, C 1-6 heteroaryl-C 1-6 -alkyl, C 2-10 heterocyclyl-C 1-6 -alkyl, C 3-8 cycloalkyl-C 1-6 -alkyl, C 6-10 aryloxy-C 1-6 -alkyl, C 2-10 heterocyclyloxy-C 1-6 -alkyl, C 3-10 cycloalkyloxy-C 1-6 -alkyl, C 6-10 arylamino-C 1-6 -alkyl, C 2-10 heterocyclylamino-C 1-6 -alkyl, C 3-10 cycloalkylamino-C 1-6 -alkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-8 carbocyclyl; and

each of R 7 and R 7a is independently H, deuterium, F, Cl, Br, I, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 alkylamino-C 1-6 -alkyl, C 1-6 alkylthio-C 1-6 -alkyl, C 6-10 aryl-C 1-6 -alkyl, C 2-10 heterocyclyl-C 1-6 -alkyl, C 1-6 heteroaryl-C 1-6 -alkyl, C 3-10 cycloalkyl-C 1-6 -alkyl, C 6-10 aryloxy-C 1-6 -alkyl, C 2-10 heterocyclyloxy-C 1-6 -alkyl, C 3-10 cycloalkyloxy-C 1-6 -alkyl, C 6-10 arylamino-C 1-6 -alkyl, C 2-10 heterocyclylamino-C 1-6 -alkyl, C 3-10 cycloalkylamino-C 1-6 -alkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-8 carbocyclyl;

3. The compound according to claim 1 , wherein A is a single bond, C 1-6 alkylene, C 2-6 alkenylene, C 3-8 cycloalkylene, C 2-10 heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, or —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, or A is

A′ is

wherein each X 1 and X 2 is independently O, S, NR 6 or CR 7 R 7a ;

Q 4 is —C(═O)—, —S(═O)— or —S(═O) 2 —;

each e is independently 0, 1, 2, 3 or 4;

each Y 1 and Y 2 is independently N or CR 7 ;

Z is —(CH 2 ) a —, —CH═CH—, —(CH 2 ) a —N(R 5 )—(CH 2 ) b — or —(CH 2 ) a —O—(CH 2 ) b —;

each c and d is independently 1 or 2;

each a b n and p is independently 0, 1, 2 or 3;

each r is independently 0, 1 or 2;

each R 5 is independently H, deuterium, hydroxy, C 1-6 alkyl, C 2-6 heteroalkyl, C 3-8 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 6-10 aryl-C 1-6 -alkyl, C 1-6 alkoxy, C 1-6 alkyl-OC(═O)—, C 1-6 alkyl-C(═O)—, carbamoyl, C 1-6 alkyl-OS(═O) r —, C 1-6 alkyl-S(═O) r O—, C 1-6 alkyl-S(═O) r — or aminosulfonyl;

R 6 is H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 alkylamino-C 1-6 -alkyl, C 1-6 alkylthio-C 1-6 -alkyl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl-C 1-6 -alkyl, C 2-10 heterocyclyl-C 1-6 -alkyl, C 3-10 cycloalkyl-C 1-6 -alkyl, C 6-10 aryloxy-C 1-6 -alkyl, C 2-10 heterocyclyloxy-C 1-6 -alkyl, C 3-10 cycloalkyloxy-C 1-6 -alkyl, C 6-10 arylamino-C 1-6 -alkyl, C 2-10 heterocyclylamino-C 1-6 -alkyl, C 3-10 cycloalkylamino-C 1-6 -alkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl;

each R 6a is independently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo(═O), R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13a R 13 N—C 1-6 -alkyl, R 13 S(═O)—C 1-6 -alkyl, R 13 R 13a N—C(═O)—C 1-6 -alkyl, R 13a R 13 N—C 1-6 -alkoxy, R 13 S(═O)—C 1-6 -alkoxy, R 13 R 13a N—C(═O)—C 1-6 -alkoxy, C 6-10 aryl, C 1-9 heteroaryl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-10 heterocyclyl, C 3-8 cycloalkyl, mercapto, nitro, C 6-10 aryl-C 1-6 -alkyl, C 6-10 arylamino, C 1-9 heteroarylamino or C 6-10 aryloxy;

each R 7 and R 7a is independently H, deuterium, F, Cl, Br, I, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 alkylamino-C 1-6 -alkyl, C 1-6 C 6-10 aryl-C 1-6 -alkyl, C 2-10 heterocyclyl-C 1-6 -alkyl, C 1-9 heteroaryl-C 1-6 -alkyl, C 3-10 cycloalkyl-C 1-6 -alkyl, C 6-10 aryloxy-C 1-6 -alkyl, C 2-10 heterocyclyloxy-C 1-6 -alkyl, C 3-10 cycloalkyloxy-C 1-6 -alkyl, C 6-10 arylamino-C 1-6 -alkyl, C 2-10 heterocyclylamino-C 1-6 -alkyl, C 3-10 cycloalkylamino-C 1-6 -alkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-8 carbocyclyl;

each R 8 and R 8a is independently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, C 1-6 alkyl, C 2-6 heteroalkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 6-10 aryl-C 1-6 -alkyl, C 1-6 alkoxy, C 1-6 alkyl-OC(═O)—, C 1-6 alkyl-C(═O)—, carbamoyl, C 1-6 alkyl-OS(═O) r —, C 1-6 alkyl-S(═O) r O—, C 1-6 alkyl-S(═O) r — or aminosulfonyl; or

wherein A is a single bond, —CH 2 —, —(CH 2 ) 2 —, —CH═CH—, —CH═CH—CH 2 —, —N(R 5 )—, —C(═O)—, —C(═S)—, —C(═O)—O—, —C(═O)N(R 5 )—, —OC(═O)N(R 5 )—, —OC(═O)O—, —N(R 5 )C(═O)N(R 5 )—, —(R 5 )N—S(═O) 2 —, —S(═O) 2 —, —OS(═O) 2 —, —(R 5 )N—S(═O)—, —S(═O)—, —OS(═O)—, or A is

A′ is

wherein, X 1 is O or S;

Y 1 is N or CH;

each e is independently 0, 1, 2 or 3;

each R 6 is independently H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 alkylamino-C 1-6 -alkyl, C 1-6 alkylthio-C 1-6 -alkyl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl, C 6-10 aryl, C 2-10 heterocyclyl or C 3-8 carbocyclyl;

each R 6a is independently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo(═O), R 13a R 13 N—, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, mercapto or nitro; and

each R 13 and R 13a is independently H, deuterium, C 1-6 alkyl, C 2-6 heteroalkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl or C 6-10 aryl-C 1-6 -alkyl; with the proviso that where R 13 and R 13a are bonded to the same nitrogen atom, R 13 and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 emembered ring, spiro bicyclic ring or fused bicyclic ring.

4. The compound according to claim 1 , wherein each of R 1 , R 2 , R 3 and R 4 is independently H, C 1-8 alkyl, C 1-8 heteroalkyl, C 6-10 aryl-C 1-6 -alkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 1-9 heteroaryl or C 6-10 aryl; or R 1 and R 2 , together with X—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12 fused bicycle, C 5-12 fused heterobicycle, C 5-12 spiro bicycle or C 5-12 spiro heterobicycle; or R 3 and R 4 , together with X′—CH they are attached to, optionally form a 3-8 membered heterocycle or carbocycle, C 5-12 fused bicycle, C 5-12 fused heterobicycle, C 5-12 spiro bicycle or C 5-12 spiro heterobicycle; or

wherein R 1 and R 2 , together with X—CH they are attached to, or R 3 and R 4 , together with X′—CH they are attached to, optionally form a 3-8 membered heterocycle, C 5-12 fused bicycle, C 5-12 fused heterobicycle, C 5-12 spiro bicycle or C 5-12 spiro heterobicycle; or

wherein R 1 , R 2 and Y—X—CH together form one of the following monovalent groups:

wherein R 3 , R 4 and Y′—X′—CH together form one of the following monovalent groups:

wherein each R 15 is independently H, deuterium, oxo(═O), F, Cl, Br, I, cyano, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio, C 6-10 arylamino, C 6-10 aryloxy, C 1-9 heteroaryl, C 1-9 heteroaryloxy, C 1-9 heteroaryl-C 1-3 -alkyl or C 2-10 heterocyclyl;

each R 6 is independently H, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 alkoxy-C 1-3 -alkyl, C 1-3 alkylamino-C 1-3 -alkyl, C 1-3 alkylthio-C 1-3 -alkyl, C 6-10 aryl-C 1-3 -alkyl, C 1-9 heteroaryl, C 6-10 aryl, C 2-10 heterocyclyl or C 3-8 carbocyclyl; and

each n 1 and n 2 is independently 1, 2, 3 or 4.

5. The compound according to claim 1 having formula (II):

wherein,

wherein each Q 1 and Q 2 is independently NR 6 , O, S, C(═O) or (CH 2 ) e ;

each e and f is independently 0, 1, 2, 3 or 4;

each X 3 and X 5 is independently O, S, NR 6 , C(═O) or CR 7 R 7a ;

each Y 1 and Y 2 is independently N or CR 7 ;

A is a single bond, C 1-6 alkylene, C 2-6 alkenylene, C 3-8 cycloalkylene, C 2-10 heterocycloalkylene, —(CR 8 R 8a ) n —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—S(═O) r —N(R 5 )—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —S(═O) r —O—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═O)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —C(═S)—(CR 8 R 8a ) p —, —(CR 8 R 8a ) n —N(R 5 )—C(═O)—O—(CR 8 R 8a ) p —, or A is

A′ is

X 1 is O, S, NR 6 or CR 7 R 7a ;

each R 5 is independently H, deuterium, hydroxy, C 1-6 alkyl, C 2-6 heteroalkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 6-10 aryl-C 1-6 -alkyl, C 1-6 alkoxy, C 1-6 alkyl-OC(═O)—, C 1-6 alkyl-C(═O)—, carbamoyl, C 1-6 alkyl-OS(═O) r —, C 1-6 alkyl-S(═O) r O—, C 1-6 alkyl-S(═O) r — or aminosulfonyl;

each R 5a and R 6a is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R 13a R 13 N—, —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, C 1-6 alkylacyl, C 1-6 alkylacyloxy, C 1-6 alkoxyacyl, C 1-6 alkylsulfonyl, C 1-6 alkoxysulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyloxy, C 1-6 alkylsulfinyloxy, C 1-6 alkoxy, C 1-6 alkyl, C 6-10 aryl, —CF 3 , —OCF 3 , mercapto, nitro, C 1-6 alkylamino, C 3-10 cycloalkyl or C 6-10 aryloxy;

each R 6 is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6 aliphatic, C 1-6 alkoxy-C 1-6 -aliphatic, C 1-6 alkylamino-C 1-6 -aliphatic, C 6-10 aryl-C 1-6 -aliphatic, C 1-9 heteroaryl-C 1-6 -aliphatic, C 2-10 heterocyclyl-C 1-6 -aliphatic, C 3-10 cycloalkyl-C 1-6 -aliphatic, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl;

each of R 7 and R 7a is independently H, deuterium, F, Cl, Br, I, C 1-6 aliphatic, C 2-6 heteroalkyl, C 1-6 alkoxy-C 1-6 -aliphatic, C 1-6 alkylamino-C 1-6 -aliphatic, C 6-10 aryl-C 1-6 -aliphatic, C 2-10 heterocyclyl-C 1-6 -aliphatic, C 3-10 cycloalkyl-C 1-6 -aliphatic, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl;

each n and p is independently 0, 1, 2 or 3;

each r is independently 0, 1 or 2; and

each of Y 4 and Y 4 ′ is independently a single bond, O, S, —(CH 2 ) n —, —CH═CH—, —S(═O) r —, —CH 2 O—, —CH 2 S—, —CF 2 —, —CHR 5a —, —CR 5a R 6a —, —CH 2 S(═O) r , or —CH 2 N(R 6 )—.

6. The compound according to claim 1 having formula (II′):

wherein

wherein each Q 1 and Q 2 is independently NR 6 , O, S, C(═O) or (CH 2 ) e ;

each e and f is independently 0, 1, 2, 3 or 4;

each X 3 and X 5 is independently O, S, NR 6 , C(═O) or CR 7 R 7a ;

each X 6 is independently CH 2 , O, S or NR 6 ;

A′ is

each R 5 is independently H, deuterium, hydroxy, C 1-6 alkyl, C 2-6 heteroalkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 6-10 aryl-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 alkyl-OC(═O)—, C 1-6 alkyl-C(═O)—, carbamoyl, C 1-6 alkyl-OS(═O) r —, C 1-6 alkyl-S(═O) r O—, C 1-6 alkyl-S(═O) r — or aminosulfonyl;

each R 6 is independently H, deuterium, R 13 R 13a NC(═O)—, R 13 OC(═O)—, R 13 C(═O)—, R 13 R 13a NS(═O)—, R 13 OS(═O)—, R 13 S(═O)—, R 13 R 13a NS(═O) 2 —, R 13 OS(═O) 2 —, R 13 S(═O) 2 —, C 1-6 aliphatic, C 1-6 alkoxy-C 1-6 -aliphatic, C 1-6 alkylamino-C 1-6 -aliphatic, C 6-10 aryl-C 1-6 -aliphatic, C 1-9 heteroaryl-C 1-6 -aliphatic, C 2-10 heterocyclyl-C 1-6 -aliphatic, C 3-10 cycloalkyl-C 1-6 -aliphatic, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-10 carbocyclyl;

each n and p is independently 0, 1, 2 or 3;

each r is independently 0, 1 or 2; and

each of Y 4 and Y 4 ′ is independently a single bond, O, S, —(CH 2 ) n —, —CH═CH—, —S(═O) r —, —CH 2 O—, —CH 2 S—, —CF 2 —, —CR 5a R 6a —, CHR 5a —, —CH 2 S(═O) r , or —CH 2 N(R 6 )—.

7. The compound according to claim 5 having formula (III), or Formula (IV), or Formula (V):

wherein each of Q 2 and Q 3 is independently O, S, C(═O), NR 6 , or CH 2 ; and

wherein e is 1, 2, 3 or 4.

8. The compound according to claim 6 having formula (III′), or Formula (IV′), or Formula (V′):

wherein each of Q 2 and Q 3 is independently O, S, C(═O), NR 6 , or CH 2 ; and

wherein e is 1, 2, 3 or 4.

9. The compound according to claim 1 , wherein, each of Y and Y′ is independently a monovalent group derived from an α-amino acid which is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, I, hydroxy or cyano; or

wherein the α-amino acid is isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophane, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline, serine, p-tyrosine, arginine, histidine, cysteine, glycine, sarcosine, N,N-dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, homophenylalanine, phenylglycine, o-tyrosine, m-tyrosine or hydroxyproline; or

wherein the α-amino acid is in the D configuration; or

wherein the α-amino acid is in the L configuration.

10. The compound according to claim 1 wherein each of Y and Y′ is independently —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 , —U—(CR 9 R 9a ) t —R 12 or —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —[C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —U—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —[C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —C(═O)—R 13 ; or

wherein each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—C(═O)—R 13 ; or

wherein each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—(CR 9 R 9a ) t —C(═O)—R 13 ; or

wherein each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—C(═O)—O—R 13 ; or

wherein each of Y and Y′ is independently —U—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —[U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t ] k —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —U—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 10 )—(CR 9 R 9a ) t —C(═O)—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —U—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —O—(CR 9 R 9a ) t —R 12 ; or

wherein each of Y and Y′ is independently —C(═O)—(CR 9 R 9a ) t —N(R 11 )—R 12 , wherein R 11 and R 12 , together with the atom they are attached to, form a 4-7 membered ring.

11. The compound according to claim 10 , wherein each R 9 , R 9a , R 10 and R 11 is independently H, deuterium, C 1-6 alkyl, C 2-6 heteroalkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 6-10 aryl-C 1-6 -alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-9 heteroaryl-C 1-6 -alkyl, C 2-10 heterocyclyl-C 1-6 -alkyl or C 3-8 cycloalkyl-C 1-6 -alkyl;

each R 12 is independently R 13a R 13 N—, —C(═O)R 13 , —C(═S)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , —OC(═O)NR 13 R 13a , —OC(═O)OR 13 , —N(R 13 )C(═O)NR 13 R 13a , —N(R 13 )C(═O)OR 13a , —N(R 13 )C(═O)—R 13a , R 13 R 13a N—S(═O) 2 —, R 13 S(═O) 2 —, R 13 S(═O) 2 N(R 13a )—, R 13 OS(═O) 2 —, C 1-6 alkyl, C 2-6 heteroalkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl or C 6-10 aryl-C 1-6 -alkyl;

or R 11 and R 12 , together with the atom they are attached to, form a 4-7 membered ring;

each t is independently 0, 1, 2, 3 or 4; and

each k is independently 0, 1 or 2; or

wherein each R 9 , R 9a , R 10 and R 11 is independently H, deuterium, methyl, ethyl, isopropyl, cyclohexyl, isobutyl or phenyl;

each R 12 is independently —C(═O)R 13 , —C(═O)—O—R 13 , —C(═O)NR 13 R 13a , methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl;

or R 11 and R 12 , together with the atom they are attached to, form a 4-7 membered ring; and

each R 13 and R 13a is independently H, deuterium, methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl.

12. The compound according to claim 5 having formula (VI):

wherein each of R 14 and R 14a is independently H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 heteroalkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl-C 1-6 -alkyl, C 2-10 heterocyclyl-C 1-6 -alkyl or C 3-8 cycloalkyl-C 1-6 -alkyl;

wherein each of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 heteroalkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl-C 1-6 -alkyl, C 2-10 heterocyclyl-C 1-6 -alkyl and C 3-8 cycloalkyl-C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.

13. The compound according to claim 12 having formula (VII):

wherein each of R 14 and R 14a is independently H, deuterium, C 1-3 hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C 1-9 heteroaryl;

wherein each of C 1-3 hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl and C 1-9 heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.

14. The compound according to claim 1 having formula (VIII) or formula (IX):

each n 1 and n 2 is independently 1, 2, 3 or 4; and

15. The compound according to claim 1 having formula (X):

wherein R 5a is H, deuterium, methyl, ethyl, F, Cl, Br or I;

each of R 14 and R 14a is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl or tert-butyl;

each of R 16 and R 16a is independently hydroxy, methoxy, ethoxy, phenoxy,

or tert-butoxy;

wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, methoxy, ethoxy, benzyl, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano;

wherein

wherein Bn is benzyl;

A is

A′ is

wherein R 1 , R 2 and N—CH together form one of the following divalent groups:

wherein R 3 , R 4 and N—CH together form one of the following divalent groups:

16. The compound according to claim 1 having formula (XI):

wherein, each R 5a is independently H, deuterium, C 1-4 alkyl, F, Cl, Br or I;

i is 1, 2, 3 or 4;

each of Q 1 and Q 2 is independently NR 6 , O, S, C(═O) or (CR 7 R 7a ) e ;

each of e and f is independently 0, 1, 2, 3 or 4;

Q 4 is —C(═O)—, —S(═O)— or —S(═O) 2 ;

X 1 is O, NR 6 or CR 7 R 7a ;

each of Y 1 and Y 2 is independently N or CR 7 ;

each R 6 , R 7 and R 7a is independently H, deuterium, C 1-4 alkyl, C 6-10 aryl, C 2-10 heterocyclyl or C 3-8 cycloalkyl;

each of R 14 and R 14a is independently H, deuterium, C 1-4 alkyl, C 6-10 aryl, C 2-10 heterocyclyl or C 3-8 cycloalkyl;

each of R 16 and R 16a is independently hydroxy, C 1-4 alkoxy, C 6-10 aryloxy, C 2-10 heterocyclyl or C 3-8 cycloalkyl;

wherein each of C 1-4 alkyl, C 6-10 aryl, C 2-10 heterocyclyl, C 3-8 cycloalkyl and C 6-10 aryloxy is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano;

A is

wherein R 1 , R 2 and N—CH together form one of the following divalent groups:

wherein R 3 , R 4 and N—CH together form one of the following divalent groups:

each R 5a is independently H, deuterium, methyl, ethyl, F, Cl, Br or I;

each R 7 is independently H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;

each of R 14 and R 14a is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, isobutyl or tert-butyl;

each of R 16 and R 16a is independently hydroxy, methoxy, ethoxy, phenoxy,

or tert-butoxy;

wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy, tert-butoxy and tert-butyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, hydroxy or cyano.

17. The compound according to claim 1 having formula (X′):

wherein R 5a is independently H, deuterium, methyl, ethyl, F, Cl, Br or I;

each of Q 1 and Q 2 is independently CH 2 , C(═O), CF 2 , O, NR 6 or S;

X 6 is O, S, NH or CH 2 ;

R 6 is H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;

each of R 14 and R 14a is independently methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl, isobutyl, isopropyl or tert-butyl;

each of R 16 and R 16a is independently hydroxy, methoxy, ethoxy, phenoxy,

or tert-butoxy;

A is

A′ is

wherein

wherein R 1 , R 2 and N—CH together form one of the following divalent groups:

wherein R 3 , R 4 and N—CH together form one of the following divalent groups:

18. The compound of claim 1 having one of the following structures:

or a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound according to claim 1 ; a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof; an anti-HCV agent; and at least one HCV inhibitor;

wherein the anti-HCV agent is an interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine-5′-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, human hepatitis C immune globulin (CIVACIR™), boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, G1-59728, GL-60667, AZD-2795, TMC647055 or a combination thereof;

wherein the interferon is interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, consensus interferon-α, interferon γ or a combination thereof; and

wherein the at least one HCV inhibitor inhibits at least one of HCV replication process and HCV viral protein function, wherein the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress; and wherein the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B; or an internal ribosome entry site (IRES) and inosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.

20. A method of inhibiting at least one of HCV replication process and HCV viral protein function with the compound according to claim 1 , wherein the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress; and wherein the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B; or an internal ribosome entry site (IRES) and inosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.

21. A method of preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of the compound according to claim 1 , wherein the HCV encodes NS5A.

22. A method of inhibiting at least one of HCV replication process and HCV viral protein function with the pharmaceutical composition according to claim 19 , wherein the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress; and wherein the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B; or an internal ribosome entry site (IRES) and inosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.

23. A method of preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition according to claim 19 , wherein the HCV encodes NS5A.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 12, 2020

From: NORTH & SOUTH BROTHER PHARMACY INVESTMENT COMPANY LIMITED

To: SUNSHINE LAKE PHARMA CO., LTD.

Reel/Frame 052921/0778 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 21, 2019

From: SUNSHINE LAKE PHARMA CO., LTD.

To: NORTH & SOUTH BROTHER PHARMACY INVESTMENT COMPANY LIMITED

Reel/Frame 050781/0929 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 29, 2015

From: ZHANG, JIANCUN; ZHANG, YINGJUN; XIE, HONGMING; REN, QINGYUN; HU, BAILIN; FU, CHANGPING; WU, XIWEI; LI, SHIFENG; WANG, CHENGLIN; ZHANG, ZHIKENG

To: SUNSHINE LAKE PHARMA CO., LTD.

Reel/Frame 035738/0576 →

Priority Claims (2)

CN 2012 1 0495665 · Nov 29, 2012 · national

CN 2013 1 0116312 · Apr 4, 2013 · national

Continuity (1)

Related Publication 20150299215A1 · Oct 22, 2015