Macrocyclic NS3-serine protease inhibitors of hepatitis C virus comprising alkyl and aryl alanine P2 moieties

Macrocyclic NS3-serine protease inhibitors of hepatitis C virus comprising alkyl and aryl alanine P2 moieties

  • CN 1,432,022 A
  • Filed: 04/17/2001
  • Published: 07/23/2003
  • Est. Priority Date: 04/19/2000
  • Status: Active Application
First Claim
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1. macrocylc compound comprises enantiomer, steric isomer, rotational isomer and the tautomer of described compound and pharmacy acceptable salt or solvate with described compound of universal architecture shown in the formula I:

  • Formula I is wherein;

    E, X and Y can independently exist or not exist, if exist then independently be selected from;

    alkyl with the lower section, aryl, alkyl-aryl, assorted alkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyl oxide, alkyl-aryl ethers, aryl ethers, alkylamino, arylamino, alkyl-arylamino, alkyl thioether, alkyl-aryl thioethers, aryl thioethers, the alkyl sulfone, alkyl-aryl sulfone, aryl sulfone, alkyl-alkyl sulfoxide, alkyl-aryl sulfoxide, alkylamide, alkyl-arylamide, arylamide, alkyl sulfonamide, alkyl-aryl sulfonic acid amides, aryl sulfonic acid amides, alkyl urea, alkyl-aryl urea, the aryl urea, alkyl carbamate, carboxylamine alkyl-aryl ester, aryl carbamate, the alkyl hydrazides, alkyl-aryl hydrazide, alkyl hydroxyl acid amides, alkyl-aryl hydroxyl acid amides, alkyl sulphonyl, aryl sulfonyl, assorted alkyl sulphonyl, heteroarylsulfonyl, alkyl-carbonyl, aryl carbonyl, assorted alkyl-carbonyl, the heteroaryl carbonyl, carbalkoxy, aryloxy carbonyl, assorted aryloxy carbonyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, heteroaryl amino carbonyl or their combination, condition is E, X and Y can also choose wantonly by following part and replace;

    aromatics, alkyl, alkyl-aryl, assorted alkyl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyl oxide, alkyl-aryl ethers, alkyl thioether, alkyl-aryl thioethers, the alkyl sulfone, alkyl-aryl sulfone, alkylamide, alkyl-arylamide, alkyl sulfonamide, alkylamine, alkyl-arylamines, alkyl-aryl sulfonic acid amides, alkyl urea, alkyl-aryl urea, alkyl carbamate, carboxylamine alkyl-aryl ester, halogen, hydroxyl amino, the carbazic acid alkyl ester, the carbazic acid aryl ester;

    R 1=COR 5Or B (OR) 2, R wherein 5=H, OH, OR 8, NR 9N 10, CF 3, C 2F 5, C 3F 7, CF 2R 6, R 6, COR 7, R wherein 7=H, OH, OR 8, CHR 9R 10Or NR 9R 10, R wherein 6, R 8, R 9And R 10Independently be selected from;

    H, alkyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, CH (R 1 '"'"') COOR 11, CH (R 1 '"'"') CONR 12R 13, CH (R 1 '"'"') CONHCH (R 2 '"'"') COOR 11, CH (R 1 '"'"') CONHCH (R 2 '"'"') CONR 12R 13, CH (R 1 '"'"') CONHCH (R 2 '"'"') R '"'"', CH (R 1 '"'"') CONHCH (R 2 '"'"') CONHCH (R 3 '"'"') COOR 11, CH (R 1 '"'"') CONHCH (R 2 '"'"') CONHCH (R 3 '"'"') CONR 12R 13, CH (R 1 '"'"') CONHCH (R 2 '"'"') CONHCH (R 3 '"'"') CONHCH (R 4 '"'"') COOR 11, CH (R 1 '"'"') CONHCH (R 2 '"'"') CONHCH (R 3 '"'"') CONHCH (R 4 '"'"') CONR 12R 13, CH (R 1 '"'"') CONHCH (R 2 '"'"') CONHCH (R 3 '"'"') CONHCH (R 4 '"'"') CONHCH (R 5 '"'"') COOR 11, CH (R 1 '"'"') CONHCH (R 2 '"'"') CONHCH (R 3 '"'"') CONHCH (R 4 '"'"') CONHCH (R 5 '"'"') CONR 12R 13, R wherein 1 '"'"', R 2 '"'"', R 3 '"'"', R 4 '"'"', R 5 '"'"', R 11, R 12, R 13And R '"'"' independently is selected from;

    H, alkyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl;

    Z is selected from O, N or CH;

    W can exist or not exist, and if the W existence, then W is selected from C=O, C=S, SO 2Or C=NR;

    Q is (NR) P, O, S, CH 2, CHR, CRR '"'"' or towards two keys of V;

    A is O, CH 2, (CHR) P, (CHR-CHR '"'"') P, (CRR '"'"') P, NR, S, SO 2, C=O or key;

    G is (CH 2) P, (CHR) P, (CRR '"'"') P, NR, O, S, SO 2, S (O) 2NH, C=O or towards two keys of E or V;

    V is CH, CR or N;

    P is digital 0-6;

    WithR, R '"'"', R 2, R 3And R 4Independently be selected from;

    H;

    The C1-C10 alkyl;

    The C2-C10 alkenyl;

    The C3-C8 cycloalkyl;

    C3-C8 Heterocyclylalkyl, aryl, alkoxyl group, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano group, nitro;

    Heteroaryl;

    Alkyl-aryl;

    Miscellaneous alkyl aryl;

    (cycloalkyl) alkyl and (Heterocyclylalkyl) alkyl, wherein said cycloalkyl is made up of 3-8 carbon atom, a 0-6 Sauerstoffatom, nitrogen-atoms, sulphur atom or phosphorus atom, and described alkyl is made up of 1-6 carbon atom;

    Described alkyl, assorted alkyl, alkenyl, the heterochain thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl part can be chosen wantonly and be substituted, and described term " is substituted " and refers to be selected from the optional and suitable replacement of following part by one or more;

    alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocycle, halogen, hydroxyl, sulfo-, alkoxyl group, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano group, nitro, sulphonamide, sulfoxide, sulfone, sulfonylurea, hydrazides, hydroxamic acid ester and thiocarbamide.

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