Peptide inhibitors of NS3 serine protease of hepatitis C virus, Pharmaceutical composition that comprises a method for their preparation, their use for the manufacture of a Medicament and a method of modulating the activity of the protease of hepatitis C virus

摘要

Hepatitis C virus serine-NS3 protease inhibitor peptides, comprising a compound including enantiomers, stereoisomers, rotamers, tautomers, racemates and a prodrug, said compound possesses the structure shown in formula (1) in which : Y is selected from the group consisting of the following functional groups: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino,with the proviso that Y can be optionally substituted with X11 or X12; X11 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with the proviso that X11 can optionally be substituted with X12; X12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, arylureido, arylureido, that said alkyl, alkoxy,and aryl can be optionally substituted with functional groups independently selected from X12; R1 is COR5 or B (OR) 2, in which R5 is H, OH, OR8, NR9R10, CF3, C2F5, C3F2R6, R6 or COR7 in which R7 is H, OH, OR8, CHR9R10, or NR9R10, in which R6, R8, R9 and R10 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH (R1 ')] pCOOR11, [CH (R1')] pCONR12R13, [CH (R1 ')] pSO2R11, [CH (R1')] pCOR11, [CH (R1 ')] pCH (OH) R11, CH (R1') CONHCH (R2 ') COOR11, CH (R1') CONHCH- (R2 ') COOR11, CH (R1') CONHCH (R2 ') CONR12R13, CH (R1) CONHCH (R2') R ',CH (R1 ') CONHCH- (R2') CONHCH (R3 ') COOR11, CH (R1') CONHCH (R2 ') CONHCH (R3') CONR12R13, CH (R1 ') CONHCH- (R2') CONHCH (R3 ' ) CONHCH (R4 ') COOR11, CH (R1') CONHCH (R2 ') CONHCH (R3') CONHCH (R4 ') - CONR12R13, CH (R1') CONHCH (R2 ') CONHCH (R3') CONHCH (R4 ' ) CONHCH (R5 ') COOR11 and CH (R1') CONHCH (R2 ') CONHCH (R3') CONHCH (R4 ') CONHCH (R5') CONR12R13, in which R1 ',R2',R3',R4',R5',R11, R12, R13 and R ',they are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; Z is selected from O, N, CH, or CR; W can be present or absent, and if W is present, W is selected from C = O, C = S, C (= N-CN),or SO2; Q may be present or absent, and when Q is present, Q is CH, N, P, (CH2) p, (CHR) p, (CRR ') p, O, NR, S, or SO2; and when Q is absent, M can be present or absent, when Q and M are absent, A is directly linked to L; A is O, CH2, (CHR) p, (CHR-CHR ') p, (CRR') p, NR, S, SO2 or a bond, E is CH, N, CR, or a double bond to A, L or G; G can be present or absent, and when G is present, G is (CH2) p, (CHR) p, or (CRR ') p; and when G is absent, J is present and E directly connected to the carbon atom in formula (1) as G is bonded to; J can be present or absent, and when J is present, J is (CH2) p, (CHR) p, or (CRR ') p, SO2, NH,NR u; in the absence of J, G is present, e is directly linked to N in Formula 1, linked to j; L is present or absent; L is present, l is present, l is present, l is present, CH, Cr, or s, or NR; in the absence of L, M may be present or absent; in the absence of M, M is present, Then M directly and independently contacts e, J directly and independently contacts E; m may be present or absent, M may be present, M may not be present, M may be present, M may be o, NR, s, SO2, (CH2) P, (CHr) P, O (CRR) P, P is 0-6, R ',R2, R3 and R4 were selected separately from group H; tar C1-10, alquenilo C2-10, calcium cyclophosphate C3-8; propylisocyclohexane C3-4 alcoxi, ariloxi, asphalt, ariltio, amino, amido, ester, carboxyl acid, carbamato, urea, acetaldehyde, cyanogen, nitric acid, halogen; (silicon) asphalt and (isocyclohexane) tar, Among them, cyclopentanediol is composed of three to eight carbon atoms, from zero to six oxygen, nitrogen, sulfur or phosphorus atoms, and tar is composed of one to six carbon atoms; arilo; heteromorphic; tar; tar; tar heterogeneous; tar; tar heterogeneous; tar heterogeneous; halogen; isohalogen; arilo.It can replace heteromorphic, cyclopentanediol and non cyclopentanediol for chemical purposes, where "substitution" refers to the optional and appropriate chemical substitution of one or more functional groups selected from the coagulation reservoir, tonsil, tar, arilo, aralquilo and cyclopentanediol, Heterocyclic, halogen, hydroxyl, uncle, alcoxi, ariloxi, pitch, ariltio, amido, ester, carboxyl acid, carbamato, urea, cetona, aldehy, ciao 1. Nitrate, sulfur amide, sulfur, sulfur, sulfuryl urea, hydrazine and hydrogenate;In addition, n-c-g-e-l-j-n represents a cyclic ring structure of 5 or 6 components, provided that n-c-g-e-l-j-n represents a cyclic ring structure of 5 components, or the double cyclic ring structure of formula (1) includes N, C, G, e, l, J, N, a, Q and m. A periodic ring structure composed of five elements, then the periodic ring structure of five elements does not have a carbon group as a part of the periodic ring; the pharmaceutical composition containing these elements, a preparation method,3. Use hepatitis C vaccine in the production of hepatitis C virus protein active drugs and modulation methods.