CN102807607B - Fused ring heterocycle compound for restraining hepatitis c virus, midbody and application of fused ring heterocycle compound - Google Patents
Fused ring heterocycle compound for restraining hepatitis c virus, midbody and application of fused ring heterocycle compound Download PDFInfo
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- CN102807607B CN102807607B CN 201210266174 CN201210266174A CN102807607B CN 102807607 B CN102807607 B CN 102807607B CN 201210266174 CN201210266174 CN 201210266174 CN 201210266174 A CN201210266174 A CN 201210266174A CN 102807607 B CN102807607 B CN 102807607B
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- 0 C=*([C@@](C1CCCCC1)*=O)C(C(C=*)=*)=O Chemical compound C=*([C@@](C1CCCCC1)*=O)C(C(C=*)=*)=O 0.000 description 5
- VGHBWKACJXNKAF-RCOVLWMOSA-N C=C[C@@H](C1)[C@@]1(C(NS(C1CC1)(=O)=O)=O)N Chemical compound C=C[C@@H](C1)[C@@]1(C(NS(C1CC1)(=O)=O)=O)N VGHBWKACJXNKAF-RCOVLWMOSA-N 0.000 description 1
- FTXZHTIVOPMXBI-ZETCQYMHSA-N CCC[C@@H](C(C(NC1CC1)=O)=O)N Chemical compound CCC[C@@H](C(C(NC1CC1)=O)=O)N FTXZHTIVOPMXBI-ZETCQYMHSA-N 0.000 description 1
- QAZQSHREYPZYJS-CBAPKCEASA-N CC[C@@H](C1)[C@@]1(C(NS(C(C)C)(=O)=O)=O)N Chemical compound CC[C@@H](C1)[C@@]1(C(NS(C(C)C)(=O)=O)=O)N QAZQSHREYPZYJS-CBAPKCEASA-N 0.000 description 1
- ILRFPAGMZBGIFU-RUDKPGORSA-N CC[C@@H](C1)[C@@]1(C(NS(C1CC1)(=O)=O)=O)NC(C(C[C@H](C1)OC(N(Cc2c3)Cc2cc2c3OCO2)=O)N1C([C@H](C(C)C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CC[C@@H](C1)[C@@]1(C(NS(C1CC1)(=O)=O)=O)NC(C(C[C@H](C1)OC(N(Cc2c3)Cc2cc2c3OCO2)=O)N1C([C@H](C(C)C)NC(OC(C)(C)C)=O)=O)=O ILRFPAGMZBGIFU-RUDKPGORSA-N 0.000 description 1
- HUNUGCBBNSQCSY-CABZTGNLSA-N CC[C@@H](C1)[C@@]1(C(NS(c1ccccc1)(=O)=O)=O)N Chemical compound CC[C@@H](C1)[C@@]1(C(NS(c1ccccc1)(=O)=O)=O)N HUNUGCBBNSQCSY-CABZTGNLSA-N 0.000 description 1
- SMGWWXHSLIIVSH-VGXSVCTOSA-N CC[C@@H](C1)[C@@]1(C(NS(c1ccccc1)(=O)=O)=O)NC(C(C[C@H](C1)OC(N(Cc2c3)Cc2cc2c3OCO2)=O)N1C([C@H](C(C)(C)C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CC[C@@H](C1)[C@@]1(C(NS(c1ccccc1)(=O)=O)=O)NC(C(C[C@H](C1)OC(N(Cc2c3)Cc2cc2c3OCO2)=O)N1C([C@H](C(C)(C)C)NC(OC(C)(C)C)=O)=O)=O SMGWWXHSLIIVSH-VGXSVCTOSA-N 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a fused ring heterocycle compound shown in a formula Ia or Ib, or a stereoisomer, a tautomer, an esterifiable or amidate pro-drug, pharmaceutically acceptable salt or a mixture of the stereoisomer, the tautomer, the esterifiable or amidate pro-drug and the pharmaceutically acceptable salt of the fused ring heterocycle compound shown in the formula Ia or Ib. The invention also discloses a drug composition containing the formula Ia or Ib, and application of the drug composition and a midbody compound. The fused ring heterocycle compound disclosed by the invention can effectively restrain hepatitis c virus protease, and treat hepatitis c virus (HCV) infection.
Description
Technical field
The present invention is specifically related to a kind of fused ring heterocycle compounds and application thereof that suppresses hepatitis C virus.
Background technology
Hepatitis C virus (HCV) is to cause most of non-A non-B hepatitis main pathogens.Infection with hepatitis C virus causes chronic hepatopathy, such as liver cirrhosis and liver cancer.Because the number of the infected of hepatitis C virus estimates to have reached the world population of 3-5%, therefore infection with hepatitis C virus can be regarded as a kind of urgent human health problems.With reference to WO 89/04669; Lavanchy, J. Viral Hepatitis, 1999,6,35-47; Alter, J.Hepatology, 3l (Suppl.1), 1999,88-91; With Alberti et al, J.Hepatology, 3l (Suppl.1), 1999,17-24.
Hepatitis C virus is the positive single strand RNA virus of a kind of flaviviridae (Flaviviridae), and its genome contains about 10000 Nucleotide and the approximately polymeric protein of 3000 amino acid of encoding.It comprises a nucleocapsid protein (C) and envelope protein (E1 and E2), and some Nonstructural Proteins (NS1, NS2, NS3, NS4a, NS5a and NS5b).The NS3 protease has serine protease, and [with reference to Chamber et al, Proc.Natl.Acad.Sci.USA 1990,87,8898-8902 to be considered to the essential key element of virus replication and infection mechanism; Rice et al, J.Virol.2000,74 (4) 2046-51].Therefore, HCV NS3 serine protease has become the most attractive target target spot for the treatment of infection with hepatitis C virus.
Since nineteen ninety-nine, American-European many institutes and drugmaker have researched and developed the small molecules hepatitis C virus inhibitors of various line styles and ring-type extensively and profoundly, and relevant patent and the document of representative HCV NS3 serpin aspect are as follows: WO2010033466, WO2010075127, US20100003214, US20100022578, US20100029715, US20100041889, WO2009134624, WO2009010804, US20090269305, WO2008057209, WO2008057208, WO2007015787, WO2005037214, WO200218369, WO200009558, WO200009543, WO199964442, WO199907733, WO199907734, WO199950230, WO199846630, WO199817679, US5,990,276, Dunsdon et al, Biorg.Med.Chem.Lett.2000,10,1571-1579; Llinas-Brunet et al, Biorg.Med.Chem.Lett.2000,10,2267-2270; And S.LaPlante et al., Biorg.Med.Chem.Lett.2000,10,2271-2274.
In addition, other HCV NS3 serpins, such as Tibotec company and the WO2007/014920 of Medivir house journal that on February 8th, 2007 announced, disclose about quinoline and the derivative large cyclic polypeptide compound of N-zygonema propylhomoserin class carbamate of isoquinoline 99.9; The WO2008/074035 of Abbott house journal discloses the derivative straight-chain polypeptide compound of a kind of special cycloalkanes on June 19th, 2008; The WO2008/106130 of Achillion house journal (announcing on September 4th, 2008) is disclosed by straight chain that special piperidines derive and large cyclic polypeptide compound; The patent WO2008/057209 (Merck company) that on May 15th, 2008 announced then discloses the large cyclic polypeptide compound that is formed by connecting from the locational aromatic nucleus of HCV NS3 serine protease P2; And the WO2007/016476 of Phenomix house journal that on February 8th, 2007 announced disclosed be to be bonded on the straight-chain polypeptide heterocyclic compounds that forms on HCV NS3 serine protease P 1 position with special boric acid ester; The WO2008/134397 of Enanta house journal (announcing on November 6th, 2008) is disclosed then to be to be connected in the straight-chain polypeptide compound that is derived on the HCV NS3 serine protease P3 position with diazanyl; In addition, the large cyclic polypeptide compound that the dicyclo condensed ring of a kind of locational aromatic nucleus of HCV NS3 serine protease P2 and saturated heterocyclic formation is derived is disclosed among the US2005/0267018 of InterMune house journal (announcing on December 1st, 2005).
Summary of the invention
Technical problem to be solved by this invention has provided a kind of and the diverse fused ring heterocycle compounds of prior art, or its stereoisomers, compounds tautomeric, esterification or amidated prodrug, pharmacy acceptable salt or their mixture, with and use.But fused ring heterocycle compounds establishment hcv protease of the present invention, treatment hepatitis C virus (HCV) infects.
For solve do not have at present active drug suppression therapy hepatitis C virus predicament, the inventor is through a large amount of research and development, a class fused ring heterocycle compounds has been synthesized in design, it is novel HCV-NS3 serpin, can be used for the establishment hcv protease, treatment hepatitis C virus (HCV) infects.The present invention is by at the straight-chain polypeptide compounds being the main different novel tricyclic condensed ring functional group substituting group of structure introduction, and the structure of optimizing novel straight-chain polypeptide polycyclic compounds, improved the biological activity of straight-chain polypeptide heterocyclic compounds inhibition hepatitis C virus, further optimization and clinical application for the straight-chain polypeptide polycyclic compounds of establishment hepatitis C virus provide how better selection.
Therefore, it is a kind of suc as formula the fused ring heterocycle compounds shown in Ia or the Ib that a first aspect of the present invention provides, or its stereoisomers, compounds tautomeric, esterification or amidated prodrug, pharmacy acceptable salt or their mixture;
Wherein,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
Ra is hydrogen, C
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl amino sulfonyl, C
2-C
20Heterocyclic amino group alkylsulfonyl or C
6-C
20The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
1-C
20Alkoxyl group, C
1-C
20Alkylthio, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkylamino, C
2-C
20Heterocyclic amino group, C
6-C
20Arylamino, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl-carbonylamino, C
1-C
20Alkylsulfonamido, C
2-C
20Heterocyclic sulfonamide base, C
6-C
20Aryl-sulfonyl amino or C
1-C
20The alkyl sulfonyl amino amido;
During r=0, E does not exist, D and E
1Directly connect;
U be carbonyl ,-SO-,-SO
2-,-P (O) (ORd)-or-B (ORe)-; Wherein, Rd and Re are hydrogen (H), C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
2-C
20Heterocyclic radical, C
6-C
20Aryl, C
3-C
20Heterocyclic aryl;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen (N) or CH;
Z is hydrogen (H), hydroxyl (OH), amino (NH
2), C
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
1-C
20Alkoxyl group, C
3-C
20Cycloalkyloxy, C
1-C
20Alkylamino, C
3-C
20Cycloalkyl amino, C
2-C
20Heterocyclic amino group, C
1-C
20Alkoxyl group-carbonyl, C
3-C
20Cycloalkyloxy-carbonyl, C
1-C
20Alkylamino-carbonyl, C
3-C
20Cycloalkyl amino-carbonyl, C
2-C
20Heterocyclic amino group-carbonyl, C
6-C
20Aryl, C
6-C
20Virtue is amino, C
3-C
20The heterocycle virtue is amino, C
1-C
20Alkylsulfonamido, C
3-C
20Naphthene sulfamide amido, C
6-C
20Aryl-sulfonyl amino, C
1-C
20Alkoxyl group sulfoamido, C
3-C
20Cycloalkyloxy sulfoamido, C
6-C
20Aryloxy sulfoamido, C
1-C
20Alkylamino sulfoamido, C
3-C
20Naphthene amino sulfoamido, C
6-C
20Virtue aminosulfonyl amido, urea groups, C
1-C
20Alkyl-urea groups or C
1-C
20Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
1-C
20Alkoxyl group, C
1-C
20Alkylamino, C
2-C
20Heterocyclic amino group, C
6-C
20Aryl, C
6-C
20Arylamino, C
1-C
20Alkylsulfonamido, C
2-C
20Heterocyclic sulfonamide base, C
6-C
20Aryl-sulfonyl amino or C
1-C
20The alkyl sulfonyl amino amido;
R
5And R
6Be hydrogen, halogen, hydroxyl, itrile group, nitro, amino, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
1-C
20Alkoxyl group, C
1-C
20Alkylamino, C
2-C
20Heterocyclic amino group, C
6-C
20Aryl, C
6-C
20Arylamino, C
1-C
20Alkoxyl group-carbonylamino, C
1-C
20Alkyl-amino carbonyl amino, C
1-C
20Alkylsulfonamido, C
2-C
20Heterocyclic sulfonamide base, C
6-C
20Aryl-sulfonyl amino or C
1-C
20The alkyl sulfonyl amino amido; Wherein, R
5With R
6Between can be interconnected to ring texture;
R
7, R
8And R
9Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
20Alkyl, C
1-C
20Alkoxyl group, C
1-C
20Alkylthio, C
1-C
20Alkoxyl group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl-carbonylamino, C
2-C
20Heterocyclyloxy base-carbonyl, C
6-C
20Aryl, C
6-C
20Aryloxy, C
6-C
20Aryloxy-carbonyl or C
2-C
20Heterocyclic radical.
R
11, R
12And R
13Be hydrogen, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl amino sulfonyl, C
2-C
20Heterocyclic amino group alkylsulfonyl or C
6-C
20The virtue amino-sulfonyl.
Among the present invention, better, in formula Ia or Ib,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
R
10Be hydrogen, halogen, oxygen, hydroxyl, itrile group, trifluoromethyl, C
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylthio, C
1-C
15Alkoxyl group-carbonyl, C
1-C
15Alkylamino-carbonyl, C
1-C
15Alkyl-carbonylamino, C
6-C
15Aryl, C
6-C
15Aryloxy, C
6-C
15Aryloxy-carbonyl or C
2-C
15Heterocyclic radical;
Ra is hydrogen, C
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl amino sulfonyl, C
2-C
15Heterocyclic amino group alkylsulfonyl, C
6-C
15The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
1-C
15Alkoxyl group, C
1-C
15Alkylthio, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkylamino, C
2-C
15Heterocyclic amino group, C
6-C
15Arylamino, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl-carbonylamino, C
1-C
15Alkylsulfonamido, C
2-C
15Heterocyclic sulfonamide base, C
6-C
15Aryl-sulfonyl amino or C
1-C
15The aminosulfonyl amido;
During r=0, E does not exist, D and E
1Directly connect.
U be carbonyl ,-SO-,-SO
2-,-P (O) (ORd)-or-B (ORe)-; Wherein, Rd and Re are hydrogen (H), C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
2-C
15Heterocyclic radical, C
6-C
15Aryl, C
3-C
15Heterocyclic aryl;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen (N) or CH;
Z is hydrogen (H), hydroxyl (OH), amino (NH
2), C
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
3-C
15Cycloalkyloxy, C
1-C
15Alkylamino, C
3-C
15Cycloalkyl amino, C
2-C
15Heterocyclic amino group, C
1-C
15Alkoxyl group-carbonyl, C
3-C
15Cycloalkyloxy-carbonyl, C
1-C
15Alkylamino-carbonyl, C
3-C
15Cycloalkyl amino-carbonyl, C
2-C
15Heterocyclic amino group-carbonyl, C
6-C
15Aryl, C
6-C
15Virtue is amino, C
3-C
15The heterocycle virtue is amino, C
1-C
15Alkylsulfonamido, C
3-C
15Naphthene sulfamide amido, C
6-C
15Aryl-sulfonyl amino, C
1-C
15Alkoxyl group sulfoamido, C
3-C
15Cycloalkyloxy sulfoamido, C
6-C
15Aryloxy sulfoamido, C
1-C
15Alkylamino sulfoamido, C
3-C
15Naphthene amino sulfoamido, C
6-C
15Virtue aminosulfonyl amido, urea groups, C
1-C
15Alkyl-urea groups or C
1-C
15Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylamino, C
2-C
15Heterocyclic amino group, C
6-C
15Aryl, C
6-C
15Arylamino, C
1-C
15Alkylsulfonamido, C
2-C
15Heterocyclic sulfonamide base, C
6-C
15Aryl-sulfonyl amino or C
1-C
15Alkyl-aminosulfonyl amido;
R
5And R
6Be hydrogen, halogen, hydroxyl, itrile group, nitro, amino, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylamino, C
2-C
15Heterocyclic amino group, C
6-C
1Aryl, C
6-C
15Arylamino, C
1-C
15Alkoxyl group-carbonylamino, C
1-C
15Alkyl-amino carbonyl amino, C
1-C
15Alkylsulfonamido, C
2-C
15Heterocyclic sulfonamide base, C
6-C
15Aryl-sulfonyl amino or C
1-C
15The alkyl sulfonyl amino amido; Wherein, R
5With R
6Between can be interconnected to ring texture;
R
7, R
8And R
9Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
15Alkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylthio, C
1-C
15Alkoxyl group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl-carbonylamino, C
2-C
15Heterocyclyloxy base-carbonyl, C
6-C
15Aryl, C
6-C
15Aryloxy, C
6-C
15Aryloxy-carbonyl or C
2-C
15Heterocyclic radical.
R
11, R
12And R
13Be hydrogen, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl-amino-sulfonyl, C
2-C
15Heterocyclic amino group alkylsulfonyl or C
6-C
15The virtue amino-sulfonyl.
Among the present invention, better, in formula Ia or Ib,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
Ra is hydrogen, C
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
6-C
12Aryl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl amino sulfonyl, C
2-C
8Heterocyclic amino group alkylsulfonyl or C
6-C
12The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently of one another
1-C
8Alkyl, C
2-C
8Cycloalkyl, C
6-C
12Aryl, C
1-C
8Alkoxyl group, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkylamino, C
2-C
8Heterocyclic amino group, C
6-C
12Arylamino, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl-carbonylamino, C
1-C
8Alkylsulfonamido, C
2-C
8Heterocyclic sulfonamide base, C
6-C
12Aryl-sulfonyl amino or C
1-C
8The aminosulfonyl amido;
During r=0, E does not exist, D and E
1Directly connect;
U be carbonyl ,-SO-,-SO
2-,-P (O) (ORd)-or-B (ORe)-; Wherein, Rd and Re are hydrogen (H), C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
2-C
8Heterocyclic radical, C
6-C
12Aryl, C
3-C
12Heterocyclic aryl;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen (N) or CH;
Z is hydrogen (H), hydroxyl (OH), amino (NH
2), C
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
3-C
8Cycloalkyloxy, C
1-C
8Alkylamino, C
3-C
8Cycloalkyl amino, C
2-C
8Heterocyclic amino group, C
1-C
8Alkoxyl group-carbonyl, C
3-C
8Cycloalkyloxy-carbonyl, C
1-C
8Alkylamino-carbonyl, C
3-C
8Cycloalkyl amino-carbonyl, C
2-C
8Heterocyclic amino group-carbonyl, C
6-C
12Aryl, C
6-C
12Virtue is amino, C
3-C
12The heterocycle virtue is amino, C
1-C
8Alkylsulfonamido, C
3-C
8Naphthene sulfamide amido, C
6-C
12Aryl-sulfonyl amino, C
1-C
8Alkoxyl group sulfoamido, C
3-C
8Cycloalkyloxy sulfoamido, C
6-C
12Aryloxy sulfoamido, C
1-C
8Alkylamino sulfoamido, C
3-C
8Naphthene amino sulfoamido, C
6-C
12Virtue aminosulfonyl amido, urea groups, C
1-C
8Alkyl-urea groups or C
1-C
8Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylamino, C
2-C
8Heterocyclic amino group, C
6-C
12Aryl, C
6-C
12Arylamino, C
1-C
8Alkylsulfonamido, C
2-C
8Heterocyclic sulfonamide base, C
6-C
12Aryl-sulfonyl amino or C
1-C
8The alkyl sulfonyl amino amido;
R
5And R
6Be hydrogen, halogen, hydroxyl, itrile group, nitro, amino, C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylamino, C
2-C
8Heterocyclic amino group, C
6-C
12Aryl, C
6-C
12Arylamino, C
1-C
8Alkoxycarbonyl amino, C
1-C
8Alkyl-amino carbonyl amino, C
1-C
8Alkylsulfonamido, C
2-C
8Heterocyclic sulfonamide base, C
6-C
12Aryl-sulfonyl amino or C
1-C
8The alkyl sulfonyl amino amido; Wherein, R
5With R
6Between can be interconnected to ring texture;
R
7, R
8And R
4Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
8Alkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl-carbonylamino, C
2-C
8Heterocyclyloxy base-carbonyl, C
6-C
12Aryl, C
6-C
12Aryloxy, C
6-C
12Aryloxy-carbonyl or C
2-C
8Heterocyclic radical;
R
11, R
12And R
13Be hydrogen, C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
6-C
12Aryl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl amino sulfonyl, C
2-C
8Heterocyclic amino group alkylsulfonyl or C
6-C
12The virtue amino-sulfonyl.
Among the present invention, further preferred, among formula Ia or the Ib,
N=1; P=1; Q=1; R=0,1 or 2;
At D, E, E
1Be singly-bound in the heterocycle at G place; E and E
1Be independently of one another-CH
2-, D and G are oxygen independently of one another; R
10Be hydrogen;
During r=0, E does not exist, D and E
1Directly connect;
U is carbonyl;
V is carbonyl;
W is oxygen;
X is oxygen;
Y is nitrogen (N) or CH;
Z is hydroxyl, C
1-C
6Alkoxyl group, C
3-C
6Cycloalkyl amino-carbonyl, C
1-C
6Alkylsulfonamido, C
3-C
6Naphthene sulfamide amido or C
6-C
10Aryl-sulfonyl amino;
R
1, R
2, R
3And R
4Be hydrogen independently of one another;
R
5And R
6Be hydrogen, C independently of one another
1-C
6Alkyl, C
3-C
6Cycloalkyl or R
5With R
6Between be interconnected to C
1-C
6Alkyl replaces or unsubstituted C
3-C
6Cycloalkyl;
R
7, R
8And R
9Be hydrogen independently;
R
11Be C
1-C
6Alkyl, C
1-C
6Cycloalkyl or C
6-C
12Aryl;
R
12Be hydrogen;
R
13Be C
1-C
8Alkyl, C
1-C
8Alkoxyl group or C
2-C
8Heterocyclic aryl, the heteroatoms in the described heterocyclic aryl are N, and number of heteroatoms is 1～2.
Among the present invention, best, described Ia is following arbitrary compound:
Described Ib is following arbitrary compound:
A second aspect of the present invention provides a kind of fused ring heterocycle compounds IIa or IIb;
In formula IIa or IIb,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
Ra is hydrogen, C
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl amino sulfonyl, C
2-C
20Heterocyclic amino group alkylsulfonyl or C
6-C
20The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
1-C
20Alkoxyl group, C
1-C
20Alkylthio, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkylamino, C
2-C
20Heterocyclic amino group, C
6-C
20Arylamino, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl-carbonylamino, C
1-C
20Alkylsulfonamido, C
2-C
20Heterocyclic sulfonamide base, C
6-C
20Aryl-sulfonyl amino or C
1-C
20The alkyl sulfonyl amino amido;
During r=0, E does not exist, D and E
1Directly connect;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen (N) or CH;
Z
1Be hydrogen (H), hydroxyl (OH), amino (NH
2), C
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
1-C
20Alkoxyl group, C
3-C
20Cycloalkyloxy, C
1-C
20Alkylamino, C
3-C
20Cycloalkyl amino, C
2-C
20Heterocyclic amino group, C
6-C
20Aryl, C
6-C
20Virtue is amino, C
3-C
20The heterocycle virtue is amino, C
1-C
20Alkylsulfonamido, C
3-C
20Naphthene sulfamide amido, C
6-C
20Aryl-sulfonyl amino, C
1-C
20Alkoxyl group sulfoamido, C
3-C
20Cycloalkyloxy sulfoamido, C
6-C
20Aryloxy sulfoamido, C
1-C
20Alkylamino sulfoamido, C
3-C
20Naphthene amino sulfoamido, C
6-C
20Virtue aminosulfonyl amido, urea groups, C
1-C
20Alkyl-urea groups or C
1-C
20Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
1-C
20Alkoxyl group, C
1-C
20Alkylamino, C
2-C
20Heterocyclic amino group, C
6-C
20Aryl, C
6-C
20Arylamino, C
1-C
20Alkylsulfonamido, C
2-C
20Heterocyclic sulfonamide base, C
6-C
20Aryl-sulfonyl amino or C
1-C
20The alkyl sulfonyl amino amido;
R
7, R
8And R
9Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
20Alkyl, C
1-C
20Alkoxyl group, C
1-C
20Alkylthio, C
1-C
20Alkoxyl group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl-carbonylamino, C
2-C
20Heterocyclyloxy base-carbonyl, C
6-C
20Aryl, C
6-C
20Aryloxy or C
6-C
20Aryloxy-carbonyl or C
2-C
20Heterocyclic radical;
R
11, R
12And R
13Be C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl amino sulfonyl, C
2-C
20Heterocyclic amino group alkylsulfonyl or C
6-C
20The virtue amino-sulfonyl.
Among the present invention, better, in formula IIa or IIb,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
R
10Be hydrogen, halogen, oxygen, hydroxyl, itrile group, trifluoromethyl, C
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylthio, C
1-C
15Alkoxyl group-carbonyl, C
1-C
15Alkylamino-carbonyl, C
1-C
15Alkyl-carbonylamino, C
6-C
15Aryl, C
6-C
15Aryloxy, C
6-C
15Aryloxycarbonyl or C
2-C
15Heterocyclic radical;
Ra is hydrogen, C
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl amino sulfonyl, C
2-C
15Heterocyclic amino group alkylsulfonyl or C
6-C
15The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
1-C
15Alkoxyl group, C
1-C
15Alkylthio, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkyl-amino, C
2-C
15Heterocyclic amino group, C
6-C
15Arylamino, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl-carbonylamino, C
1-C
15Alkylsulfonamido, C
2-C
15Heterocyclic sulfonamide base, C
6-C
15Aryl-sulfonyl amino or C
1-C
15The alkyl sulfonyl amino amido;
During r=0, E does not exist, D and E
1Directly connect;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen (N) or CH;
Z
1Be hydrogen (H), hydroxyl (OH), amino (NH
2), C
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
3-C
15Cycloalkyloxy, C
1-C
15Alkylamino, C
3-C
15Cycloalkyl amino, C
2-C
15Heterocyclic amino group, C
6-C
15Aryl, C
6-C
15Virtue is amino, C
3-C
15The heterocycle virtue is amino, C
1-C
15Alkylsulfonamido, C
3-C
15Naphthene sulfamide amido, C
6-C
15Aryl-sulfonyl amino, C
1-C
15Alkoxyl group sulfoamido, C
3-C
15Cycloalkyloxy sulfoamido, C
6-C
15Aryloxy sulfoamido, C
1-C
15Alkylamino sulfoamido, C
3-C
15Naphthene amino sulfoamido, C
6-C
15Virtue aminosulfonyl amido, urea groups, C
1-C
15Alkyl-urea groups or C
1-C
15Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylamino, C
2-C
15Heterocyclic amino group, C
6-C
15Aryl, C
6-C
15Arylamino, C
1-C
15Alkylsulfonamido, C
2-C
15Heterocyclic sulfonamide base, C
6-C
15Aryl-sulfonyl amino or C
1-C
15Alkyl-aminosulfonyl amido;
R
7, R
8And R
9Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
15Alkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylthio, C
1-C
15Alkoxyl group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl-carbonylamino, C
2-C
15Heterocyclyloxy base-carbonyl, C
6-C
15Aryl, C
6-C
15Aryloxy, C
6-C
15Aryloxy-carbonyl or C
2-C
15Heterocyclic radical;
R
11, R
12And R
13Be hydrogen, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl amino sulfonyl, C
2-C
15Heterocyclic amino group alkylsulfonyl or C
6-C
15The virtue amino-sulfonyl.
Among the present invention, better, in formula IIa or IIb,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
R
10Be hydrogen, halogen, oxygen, hydroxyl, itrile group, trifluoromethyl, C
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group-carbonyl, C
1-C
8Alkylamino-carbonyl, C
1-C
8Alkyl-carbonylamino, C
6-C
12Aryl, C
6-C
12Aryloxy, C
6-C
12Aryloxy-carbonyl or C
2-C
8Heterocyclic radical;
Ra is hydrogen, C
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
6-C
12Aryl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl-amino-sulfonyl, C
2-C
8Heterocyclic amino group alkylsulfonyl or C
6-C
12The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently of one another
1-C
8Alkyl, C
2-C
8Cycloalkyl, C
6-C
12Aryl, C
1-C
8Alkoxyl group, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkylamino, C
2-C
8Heterocyclic amino group, C
6-C
12Arylamino, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl-carbonylamino, C
1-C
8Alkylsulfonamido, C
2-C
8Heterocyclic sulfonamide base, C
6-C
12Aryl-sulfonyl amino or C
1-C
8The alkyl sulfonyl amino amido;
During r=0, E does not exist, D and E
1Directly connect;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen (N) or CH;
Z
1Be hydrogen (H), hydroxyl (OH), amino (NH
2), C
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
3-C
8Cycloalkyloxy, C
1-C
8Alkylamino, C
3-C
8Cycloalkyl amino, C
2-C
8Heterocyclic amino group, C
6-C
12Aryl, C
6-C
12Virtue is amino, C
3-C
12The heterocycle virtue is amino, C
1-C
8Alkylsulfonamido, C
3-C
8Naphthene sulfamide amido, C
6-C
12Aryl-sulfonyl amino, C
1-C
8Alkoxyl group sulfoamido, C
3-C
8Cycloalkyloxy sulfoamido, C
6-C
12Aryloxy sulfoamido, C
1-C
8Alkylamino sulfoamido, C
3-C
8Naphthene amino sulfoamido, C
6-C
12Virtue aminosulfonyl amido, urea groups, C
1-C
8Alkyl-urea groups or C
1-C
8Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylamino, C
2-C
8Heterocyclic amino group, C
6-C
12Aryl, C
6-C
12Arylamino, C
1-C
8Alkylsulfonamido, C
2-C
8Heterocyclic sulfonamide base, C
6-C
12Aryl-sulfonyl amino or C
1-C
8The alkyl sulfonyl amino amido;
R
7, R
8And R
9Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
8Alkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl-carbonylamino, C
2-C
8Heterocyclyloxy base-carbonyl, C
6-C
12Aryl, C
6-C
12Aryloxy, C
6-C
12Aryloxy-carbonyl or C
2-C
8Heterocyclic radical;
R
11, R
12And R
13Be hydrogen, C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
6-C
12Aryl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl amino sulfonyl, C
2-C
8Heterocyclic amino group alkylsulfonyl or C
6-C
12The virtue amino-sulfonyl.
Among the present invention, further preferred, among formula IIa or the IIb,
N=1; P=1; Q=1; R=0,1 or 2;
During r=0, E does not exist, D and E
1Directly link;
V is carbonyl;
W is oxygen;
X is oxygen;
Y is nitrogen (N) or CH;
Z
1Be hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylsulfonamido, C
3-C
6Naphthene sulfamide amido or C
6-C
10Aryl-sulfonyl amino;
R
1, R
2, R
3And R
4Be hydrogen independently of one another;
R
7, R
8And R
9Be hydrogen independently;
R
11Be C
1-C
6Alkyl, C
1-C
6Cycloalkyl or C
6-C
12Aryl;
R
12Be hydrogen;
R
13Be C
1-C
8Alkyl, C
1-C
8Alkoxyl group or C
2-C
8Heterocyclic aryl, in the described heterocyclic aryl, heteroatoms is N, number of heteroatoms is 1～2.
Among the present invention, best, described compound I Ia is following arbitrary compound:
Described compound I Ib is following arbitrary compound:
A third aspect of the present invention provides a kind of described compound I a or Ib, its stereoisomers, compounds tautomeric, esterification or amidated prodrug, pharmacy acceptable salt or its mixture for the preparation of the application in the medicine that suppresses HCV.
A fourth aspect of the present invention, a kind of pharmaceutical composition is provided, comprise: one or more formula Ia of the present invention or Ib compound or its stereoisomers, compounds tautomeric, esterification or amidated prodrug or its pharmacy acceptable salt, and pharmaceutically acceptable vehicle.
A fifth aspect of the present invention provides a kind of pharmaceutical composition, and it comprises: one or more are suc as formula Ia or Ib compound or its stereoisomers, compounds tautomeric, esterification or amidated prodrug or its pharmacy acceptable salt; And following in listed one or more: (1) immunomodulator; (2) hcv protease inhibitors, (3) hepatitis C virus AG14361, (4) do not belong to (2)-nucleosides and the nucleoside derivates of (3), (5) hepatitis B virus (HBV) inhibitor, (6) human immune deficiency virus (HIV) inhibitor, (7) cancer drug, (8) anti-inflammatory drug, or (9) do not belong to other compounds of above-mentioned (1)-(8).
What wherein, described immunomodulator was better is Interferon, rabbit or interferon derivative.Wherein said Interferon, rabbit can be the polyoxyethylene glycol Interferon, rabbit.
Described hiv inhibitor is including but not limited to ritonavir medicine (Ritonavir).
Described hepatitis B virus (HBV) inhibitor comprises but is not limited to lamivudine (Lamivudine), Telbivudine (Telbivudine), adefovir ester (Adefovir, Adefovir or Dipivoxil), emtricitabine (Emtricitabine), Entecavir (Entecavir), tenofovir disoproxil (tynofovir, Tenofovir or Disoproxil) or L-FMAU (Clevudine).
In above-mentioned arbitrary pharmaceutical composition of the present invention, comprise formula Ia of the present invention or Ib compound or its stereoisomers, compounds tautomeric, esterification or amidated prodrug, pharmacy acceptable salt or their mixture.In the said composition, the significant quantity of described compound I a or Ib or its stereoisomers, compounds tautomeric, esterification or amidated prodrug, pharmacy acceptable salt or their mixture is 0.01-99.9%, and the gross weight of each component is as benchmark in the pharmaceutical composition.
A sixth aspect of the present invention provides the application of above-mentioned arbitrary pharmaceutical composition in preparation inhibition hepatitis C virus (HCV).
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but arbitrary combination namely get the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available getting all.
Positive progressive effect of the present invention is:
1) synthesized a kind of novel line style polypeptide compound that contains many ring functions group that can the establishment hepatitis C virus, novel compound and the dissimilar three ring small molecules intermediates thereof that contain many ring functions group that especially suppress hepatitis C virus.
2) the novel line style polypeptide compound that contains many ring functions group of the present invention has the advantages such as obvious inhibition hepatitis C virus cytotoxic activity, the present invention also further research and development optimized many looped cord of the various new compound that is effective to treat infection with hepatitis C virus.
3) the present invention has optimized the novel preparation method who contains line style polypeptide compound and the dissimilar three ring small molecules intermediates thereof of many ring functions group, reduced largely preparation cost, the novel method of an effective practicality is provided for the industrialization production of novel many looped cord hepatitis C virus inhibitors medicine.
4) the present invention preparation novel contains the main application of line style polypeptide compound of many ring functions group for suppressing hepatitis C virus, also can suppress the viruses such as HCV with other arbitrary or a plurality of medicine combination, can be the how better product innovation of providing of human society at the new drug development production field.
Next, the preparation method of the compound that the present invention relates to done further introduction:
The present invention not only designs and has synthesized for the fused ring heterocycle compounds that suppresses hepatitis C virus, also further by the fused ring heterocycle compounds being suppressed the research of hepatitis C virus cytotoxic activity, the novel condensed ring heterocyclic compound of deeply having probed into different structure and the relation that suppresses the hepatitis C virus cytotoxic activity, further research and development optimized the novel condensed ring heterocyclic compound that is effective to treat infection with hepatitis C virus, and preparation method thereof.
Chemical reagent in the synthetic fused ring heterocycle compounds thing process of the present invention and the whole summary column of english abbreviation note of solvent are instrument and raw material declaratives in an embodiment.
Crux innovative point of the present invention is at first to select the compound S M-1 (1a-1f) that contains three ring functions group in the following structural series 1 to be core monomer, synthesize IIa-IIb intermediate (seeing structural formula series 3 for details) by reactions such as amidation couplings thus, then synthesize novel formula Ia-Ib compound (seeing structural formula series 4 for details).Their preparation method is as described in the following reaction scheme 1-3.
Structural formula series 1:
Following reaction scheme 1 is the following particular compound reaction scheme of 4a-4f for example of preparation IIa-IIb, wherein adopt raw material SM-3 respectively with compound S M-1 (1a-1f) under the effect of reagent C DI and/or DCM, in organic solvent (methylene dichloride, tetrahydrofuran (THF) or DMF), obtain the key innovation polynuclear compound 4a-4f (IIIa-IIIb) shown in the following structural series 2 of the present invention by the coupling amidate action:
Reaction scheme 1:
The object lesson of the compound 4a-4f (IIIa-IIIb) of the key structure that following structural formula series 2 is synthesized for the present invention, it is as follows that they have structural formula:
Structural formula series 2:
Obtain novel multi-cyclic compounds 4a-4f (IIIa-IIIb) crucial the present invention from the method shown in the above-mentioned reaction scheme 1, then by the step in the following reaction scheme 2 of the present invention design, prepare respectively intermediate 6 (IIa-IIb) and novel line style polypeptide contains the compound 8 (Ia-Ib) that three ring functions are rolled into a ball by suitable reaction conditions.Concrete reaction scheme such as following reaction scheme 2 and 3, specifically each step reaction experiment and detailed conditions and product analysis result list among the embodiment respectively.
Reaction scheme 2:
In the above-mentioned reaction scheme 2, at first adopt compound 4a-4f to slough the Boc protecting group with HCl respectively and obtain midbody product carboxylic acid (5), then under the effect of reagent C DI or HATU, obtain compound 6 (IIa-IIb) by the amidation coupled reaction with compound S M-5 (SM-5a-SM-5x sees structural formula series 3 for details); Wherein, R
11, R
12, R
13Definition ditto described.
Some reagent SM-5 are selected from the listed compound (SM-5a to SM-5x) of following structural formula series 3 in the reaction scheme 2:
Structural formula series 3:
Following structural formula series 4 is passed through the respectively object lesson of synthetic key intermediate compound 6a-6af (IIa-IIb) of reaction scheme 2 for the present invention, and it is as follows that they have structural formula:
Structural formula series 4:
In following reaction scheme 3, after at first methyl compound 6 usefulness alkali (LiOH) hydrolysis being obtained product carboxylic acid (7), temperature 0-80 ℃ lower by under the effect of coupling reagent (as: EDCI or HATU) from different sulfonamide compounds SM-6 (Rd-SO
2NH
2) obtain the final novel line style compound 8 (for example compound 8a-8ba in the structural formula series 5 belongs to the Ia-Ib compound) that contains many ring functions group by amidate action.
Reaction scheme 3:
Wherein, U, Z, R
5, R
6, R
11, R
12, R
13Definition and the U in the claim 1, Z, R
5, R
6, R
11, R
12, R
13Identical, reagent SM-6 is selected from following compound (SM-6a, SM-6b or SM-6e):
Following structural formula series 5 is passed through the respectively object lesson of the novel condensed ring heterocyclic compound 8a-8ba (Ia-Ib) of synthetic various energy establishment hepatitis C viruss of reaction scheme 3 for the present invention, and it is as follows that they have structural formula:
Structural formula series 5:
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected according to catalogue.
Compound among the present invention can contain three ring functions group and one or more heterocycle asymmetric center.Therefore, these compounds can be racemization and racemic mixture, single enantiomer, tautomeric forms.The prepared compound I a-Ib of the present invention is that purity is higher than 98% chiral heterocycle compound, natural amino acid and non-natural amino acid optical purity are measured by specific rotation and chiral chromatographic column respectively in the product, the structural characterization of each final product (comprising 8a-8ba and following reference compound 6-Ref, 8-Ref etc.) respectively by LC-MS and hydrogen spectrum nucleus magnetic resonance (
1H-NMR) Analysis deterrmination.
Synthetic and the effect of classes of compounds of the present invention and intermediate is described by the following examples.
The instrument and the raw material that relate among the embodiment are described as follows:
Ir data is the Fourier Transform AVATAR that adopts company of match nimonic Lay company (Thermo Nicolet)
TM360E.S.P
TMInfrared instrument analysis obtains, with cm
-1For unit represents.
Proton nmr spectra be reinforced 400 (the Varian Mercury Plus 400) of variable mercury (400MHz) the nuclear magnetic resonance spectrometer analysis obtain.Chemical shift comes record take tetramethylsilane as interior mark, represents (CHCl take ppm as unit
3: δ=7.26ppm).The data message of record is as follows: chemical shift and splitting minute and coupling constant (s: singlet; D: doublet; T: triplet; Q: quartet; Br: broad peak; M: multiplet).
Mass-spectrometric data needs except other, all adopts the LC-MS instrument of the senior LCQ of Finnigan company (Finnigan LCQ Advantage) to analyze, and institute responds and all operates under the anhydrous and oxygen-free condition that dry argon gas is protected.Solid metal-organic compound is stored in the argon shield loft drier.
Tetrahydrofuran (THF) and ether are to obtain through distillation, add therein sodium Metal 99.5 and benzophenone during distillation.Methylene dichloride (DCM), pentane and hexane are to process with hydrolith.The special material that relates among the present invention and intermediate are provided by customized processing such as Zan Nan Science and Technology Ltd.s, and other all chemical reagent are bought from reagent suppliers such as Shanghai reagent company, A Erde Ritchie company (Aldrich), Acker sieve companies (Acros).As the required intermediate of reaction or product in the building-up process not next step etc. test, then repeatedly be blended into till the sufficient amount.The HCV proteolytic enzyme of the prepared compound of the present invention (HCV NS3-4A) suppresses the active testing experiment to be finished by relevant partner services unit of Pekinese's China Life academy of sciences.
The english abbreviation note of relevant chemical feedstocks, reagent and the solvent that relates in the present invention and the embodiment is as follows:
SM-3:N-Boc-trans-4-hydroxy-l-proline methyl esters
SM-6a:(1R, 2S)-1-amino-2-ethyl cyclopropyl methyl esters
SM-6b:(1R, 2S)-1-amino-2-vinyl cyclopropyl methyl esters
Alcalase 2.4L: subtilisin-Ka Ersi Burger (Subtilisin-Carlsberg); Hydrolysising protease
AIBN: Diisopropyl azodicarboxylate
Boc: tert-butoxycarbonyl
(Boc)
2O: tert-Butyl dicarbonate
CDI:N, N '-carbonyl dimidazoles
DBU:1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene
EDCI:N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide hydrochloride
HATU:2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester
The NBS:N-bromo-succinimide
The DMAP:4-Dimethylamino pyridine
DIEA:N, the N-diisopropylethylamine
SOCl
2: sulfur oxychloride
Pd/C: palladium charcoal
HMTA: vulkacit H
HOAc: glacial acetic acid
HBr: Hydrogen bromide
HCl: hydrochloric acid
TFA: trifluoroacetic acid
TsOH: tosic acid
NaOH: sodium hydroxide
ACN: acetonitrile
DCM: methylene dichloride
DCE: ethylene dichloride
DMF:N, dinethylformamide
DMSO: methyl-sulphoxide
Et
2O: diethyl ether
EA: ethyl acetate
PE: sherwood oil
THF: tetrahydrofuran (THF)
TBME: methyl tertiary butyl ether
Embodiment 1
Compound 4a's is synthetic
Raw material SM-3 (5.37g, 21.9mmol) and CDI (14.2g, 87.5mmol, 4eq.) are dissolved in the 100mL anhydrous methylene chloride, and room temperature reaction spends the night.The HPLC-ELSD demonstration reacts completely, and adds compound S M-1a (43.7mmol, 2eq.), and stirring at room is to reacting completely.Reaction solution is with dry sand processed after water, 1N hydrochloric acid, water, saturated sodium bicarbonate, the saturated common salt water washing successively after the methylene dichloride dilution, and column chromatographic isolation and purification obtains lightpink solid product 4a (5.2g), productive rate 71%.
After testing, product 4a
1H-NMR (CDCl
3, 500MHz): δ 6.78-6.80 (m, 1H), 6.69-6.75 (m, 1H), (6.00 s, 2H), 5.34 (m, 1H), 4.67-4.70 (d, J=13.5Hz, 2H), 4.60-4.63 (d, J=15Hz, 2H), (4.40-4.48 m, 1H), 3.66-3.78 (m, 5H), (2.48 m, 1H), 2.24-2.26 (m, 1H), (1.48 s, 4H), 1.45 (s, 5H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of 4a
+): m/z theoretical value 435.2, measured value 435.3.
Embodiment 2
Compound 4b's is synthetic
Raw material SM-3 (5.37g, 21.9mmol) and CDI (14.2g, 87.5mmol, 4eq.) are dissolved in the 100mL anhydrous methylene chloride, and room temperature reaction spends the night.The HPLC-ELSD demonstration reacts completely, and adds compound S M-1b (43.7mmol, 2eq.), and stirring at room is to reacting completely.Reaction solution is with dry sand processed after water, 1N hydrochloric acid, water, saturated sodium bicarbonate, the saturated common salt water washing successively after the methylene dichloride dilution, and column chromatographic isolation and purification obtains white solid product 4b (6.1g), productive rate 82%.
After testing, product 4b
1H-NMR (CDCl
3, 500MHz):
(6.81-6.84 m, 1H), 6.68-6.75 (m, 1H), 5.33 (m, 1H), 4.67 (s, 2H), 4.60 (s, 2H), (4.39-4.48 m, 1H), 4.30 (m, 2H), (4.28 m, 2H), 3.63-3.79 (m, 5H), (2.47-2.49 m, 1H), 2.22-2.26 (m, 1H), (1.48 s, 4H), 1.45 (s, 5H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of 4b
+): m/z theoretical value 449.2, measured value 449.3.
Embodiment 3
Compound 4c's is synthetic
Raw material SM-3 (5.37g, 21.9mmol) and CDI (14.2g, 87.5mmol, 4eq.) are dissolved in the 100mL anhydrous methylene chloride, and room temperature reaction spends the night.The HPLC-ELSD demonstration reacts completely, and adds compound S M-1c (43.7mmol, 2eq.), and stirring at room is to reacting completely.Reaction solution is with dry sand processed after water, 1N hydrochloric acid, water, saturated sodium bicarbonate, the saturated common salt water washing successively after the methylene dichloride dilution, and column chromatographic isolation and purification obtains white solid product 4c (5.6g), productive rate 76%.
Product 4c proves conclusively through mass spectroscopy, the ESI-MS (M+H of 4c
+): m/z theoretical value 463.2, measured value 463.2.
Embodiment 4
Compound 4d's is synthetic
Raw material SM-3 (5.37g, 21.9mmol) and CDI (14.2g, 87.5mmol, 4eq.) are dissolved in the 100mL anhydrous methylene chloride, and room temperature reaction spends the night.The HPLC-ELSD demonstration reacts completely, and adds compound S M-1d (43.7mmol, 2eq.), and stirring at room is to reacting completely.Reaction solution is with dry sand processed after water, 1N hydrochloric acid, water, saturated sodium bicarbonate, the saturated common salt water washing successively after the methylene dichloride dilution, and column chromatographic isolation and purification obtains white solid product 4d (5.3g), productive rate 73%.
Product 4d proves conclusively through mass spectroscopy, the ESI-MS (M+H of 4d
+): m/z theoretical value 463.2, measured value 463.2.
Embodiment 5
Compound 4e's is synthetic
Raw material SM-3 (5.37g, 21.9mmol) and CDI (14.2g, 87.5mmol, 4eq.) are dissolved in the 100mL anhydrous methylene chloride, and room temperature reaction spends the night.The HPLC-ELSD demonstration reacts completely, and adds compound S M-1e (43.7mmol, 2eq.), and stirring at room is to reacting completely.Reaction solution is with dry sand processed after water, 1N hydrochloric acid, water, saturated sodium bicarbonate, the saturated common salt water washing successively after the methylene dichloride dilution, and column chromatographic isolation and purification obtains white solid product 4e (5.7g), productive rate 75%.
After testing, product 4e
1H-NMR (CDCl
3, 500MHz): δ 6.77 (s, 1H), 6.73 (s, 1H), (5.32 m, 1H), 4.63 (s, 2H), (4.56 s, 2H), 4.37-4.48 (m, 1H), (4.26 s, 4H), 3.64-3.79 (m, 5H), (2.47 m, 1H), 2.21-2.26 (m, 1H), (1.48 s, 4H), 1.44 (s, 5H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of 4e
+): m/z theoretical value 449.2, measured value 449.3.
Embodiment 6
Compound 4f's is synthetic
Raw material SM-3 (5.37g, 21.9mmol) and CDI (14.2g, 87.5mmol, 4eq.) are dissolved in the 100mL anhydrous methylene chloride, and room temperature reaction spends the night.The HPLC-ELSD demonstration reacts completely, and adds compound S M-1f (43.7mmol, 2eq.), and stirring at room is to reacting completely.Reaction solution is with dry sand processed after water, 1N hydrochloric acid, water, saturated sodium bicarbonate, the saturated common salt water washing successively after the methylene dichloride dilution, and column chromatographic isolation and purification obtains brown solid product 4f (5.9g), productive rate 74%.
After testing, product 4f
1H-NMR (CDCl
3, 500MHz): δ 6.71 (s, 1H), 6.67 (s, 1H), (5.97 s, 2H), 5.32 (m, 1H), (4.63 s, 2H), 4.57 (s, 2H), (4.38-4.47 m, 1H), 3.64-3.76 (m, 5H), (2.47 m, 1H), 2.23-2.25 (m, 1H), (1.47 s, 4H), 1.44 (s, 5H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of 4f
+): m/z theoretical value 435.2, measured value 435.3.
Embodiment 7
Compound 6a's is synthetic
The synthetic method of preparation 6a divides following two steps to finish:
The first step: compound 5a's is synthetic
The product 4f (4.4g, 10mmol) of embodiment 6 is dissolved in HCl/Et
2Among the O (4N, 60mL), 30 ℃ react completely and obtain its hydrochloride product 5a (3.4g), productive rate 91% after sloughing protecting group Boc.
Second step: compound 6a's is synthetic
After reaction solution is concentrated product 5a (1.13g, 3mmol) is dissolved among the 20mL DMF, adds compound S M-5a (1.05eq), behind the ice-water bath cooling 15min, add DIEA (4eq) and HATU (1.1eq).Then naturally reply room temperature, stirring is spent the night.After the HPLC-ELSD demonstration reacted completely, concentrated column chromatographic isolation and purification obtained solid product 6a (1.72g), productive rate 83%.
The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 6a
+): m/z theoretical value 693.3, measured value 693.4.
Embodiment 8
Compound 6b's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6b finish, and reaction obtains product 6b through two steps, wherein adopt compound 4e to replace 4f to obtain midbody product 5b in the first step reaction; Second step reaction and the embodiment 7 identical product 6b that obtain.
The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 6b
+): m/z theoretical value 707.3, measured value 707.4.
Embodiment 9
Compound 6c's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6c finish, and reaction obtains product 6c through two steps, wherein adopt compound 4d to replace 4f to obtain midbody product 5c in the first step reaction; Second step reaction and the embodiment 7 identical product 6c that obtain.
Through mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 6c
+): m/z theoretical value 721.3, measured value 721.4.
Embodiment 10
Compound 6d's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6d finish, and reaction obtains product 6d (4.8g) through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5d that obtain; In the second step reaction, adopt compound S M-5b to replace SM-5a to obtain midbody product 6d.
Through mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 6d
+): m/z theoretical value 687.3, measured value 687.5.
Embodiment 11
Compound 6e's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6e finish, and reaction obtains product 6e through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5e that obtain; In the second step reaction, adopt compound S M-5c to replace SM-5a to obtain midbody product 6e.
Through mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 6e
+): m/z theoretical value 665.3, measured value 665.4.
Embodiment 12
Compound 6f's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6f finish, and reaction obtains product 6f through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5f that obtain; In the second step reaction, adopt compound S M-5d to replace SM-5a to obtain midbody product 6f.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6f)
+]: m/z theoretical value 777.3, measured value 777.4.
Embodiment 13
Compound 6g's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6g finish, and reaction obtains product 6g through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5g that obtain; In the second step reaction, adopt compound S M-5e to replace SM-5a to obtain midbody product 6g.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6g)
+]: m/z theoretical value 691.3, measured value 691.4.
Embodiment 14
Compound 6h's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6h finish, and reaction obtains product 6h through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5h that obtain; In the second step reaction, adopt compound S M-5f to replace SM-5a to obtain midbody product 6h.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6h)
+]: theoretical value 727.3, measured value 727.4.
Embodiment 15
Compound 6j's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6j finish, and reaction obtains product 6j through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5j that obtain; In the second step reaction, adopt compound S M-5g to replace SM-5a to obtain midbody product 6j.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6j)
+]: m/z theoretical value 777.3, measured value 777.4.
Embodiment 16
Compound 6k's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6k finish, and reaction obtains product 6k (4.8g) through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5d that obtain; In the second step reaction, adopt compound S M-5h to replace SM-5a to obtain midbody product 6k.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6k)
+]: m/z theoretical value 699.4, measured value 699.4.
Embodiment 17
Compound 6m's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6m finish, and reaction obtains product 6m through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5m that obtain; In the second step reaction, adopt compound S M-5j to replace SM-5a to obtain midbody product 6m.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6m)
+]: m/z theoretical value 659.3, measured value 659.4.
Embodiment 18
Compound 6n's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6n finish, and reaction obtains product 6n through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5n that obtain; In the second step reaction, adopt compound S M-5k to replace SM-5a to obtain midbody product 6n.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6n)
+]: m/z theoretical value 673.3, measured value 673.4.
Embodiment 19
Compound 6p's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6p finish, and reaction obtains product 6p through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5p that obtain; In the second step reaction, adopt compound S M-5m to replace SM-5a to obtain midbody product 6p.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6p)
+]: m/z theoretical value 645.3, measured value 645.4.
Embodiment 20
Compound 6q's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6q finish, and reaction obtains product 6q through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5q that obtain; In the second step reaction, adopt compound S M-5p to replace SM-5a to obtain midbody product 6q.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6q)
+]: m/z theoretical value 707.3, measured value 707.4.
Embodiment 21
Compound 6r's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6r finish, and reaction obtains product 6r through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5r that obtain; In the second step reaction, adopt compound S M-5q to replace SM-5a to obtain midbody product 6r.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6r)
+]: m/z theoretical value 809.4, measured value 809.4.
Embodiment 22
Compound 6s's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6s finish, and reaction obtains product 6s through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5s that obtain; In the second step reaction, adopt compound S M-5r to replace SM-5a to obtain midbody product 6s.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6s)
+]: m/z theoretical value 686.4, measured value 686.4.
Embodiment 23
Compound 6t's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6t finish, and reaction obtains product 6t through two steps, wherein adopt compound 4d to replace 4f to obtain midbody product 5t in the first step reaction; In the second step reaction, adopt compound S M-5b to replace SM-5a to obtain midbody product 6t.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6t)
+]: m/z theoretical value 715.4, measured value 715.4.
Embodiment 24
Compound 6u's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6u finish, and reaction obtains product 6u through two steps, wherein adopt compound 4d to replace 4f to obtain midbody product 5u in the first step reaction; In the second step reaction, adopt compound S M-5h to replace SM-5a to obtain midbody product 6u.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6u)
+]: m/z theoretical value 727.4, measured value 727.5.
Embodiment 25
Compound 6v's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6v finish, and reaction obtains product 6v through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5v that obtain; In the second step reaction, adopt compound S M-5s to replace SM-5a to obtain midbody product 6v.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6v)
+]: m/z theoretical value 548.2, measured value 548.4.
Embodiment 26
Compound 6w's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6w finish, and reaction obtains product 6w through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5w that obtain; In the second step reaction, adopt compound S M-5t to replace SM-5a to obtain midbody product 6w.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6w)
+]: m/z theoretical value 560.2, measured value 560.4.
Embodiment 27
Compound 6x's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6x finish, and reaction obtains product 6x through two steps, wherein the first step reaction and the embodiment 7 identical midbody product 5x that obtain; In the second step reaction, adopt compound S M-5v to replace SM-5a to obtain midbody product 6x.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6x)
+]: m/z theoretical value 547.3, measured value 547.4.
Embodiment 28
Compound 6y's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6y finish, and reaction obtains product 6y through two steps, wherein adopt compound 4a to replace 4f to obtain midbody product 5y in the first step reaction; Second step reaction and the embodiment 7 identical midbody product 6y that obtain.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6y)
+]: m/z theoretical value 693.3, measured value 693.4.
Embodiment 29
Compound 6z's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6z finish, and reaction obtains product 6z through two steps, wherein adopt compound 4b to replace 4f to obtain midbody product 5z in the first step reaction; At second step reaction and the embodiment 7 identical midbody product 6z that obtain.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6z)
+]: m/z theoretical value 707.3, measured value 707.4.
Embodiment 30
Compound 6aa's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6aa finish, and reaction obtains product 6aa (4.8g) through two steps, wherein adopt compound 4c to replace 4f to obtain midbody product 5aa in the first step reaction; At second step reaction and the embodiment 7 identical midbody product 6aa that obtain.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6aa)
+]: m/z theoretical value 721.3, measured value 721.4.
Embodiment 31
Compound 6ab's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6ab finish, and reaction obtains product 6ab through two steps, wherein adopt compound 4a to replace 4f to obtain midbody product 5ab in the first step reaction; In the second step reaction, adopt compound S M-5s to replace SM-5a to obtain midbody product 6ab.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6ab)
+]: m/z theoretical value 548.2, measured value 548.3.
Embodiment 32
Compound 6ac's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6ac finish, and reaction obtains product 6ac through two steps, wherein adopt compound 4a to replace 4f to obtain midbody product 5ac in the first step reaction; In the second step reaction, adopt compound S M-5t to replace SM-5a to obtain midbody product 6ac.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6ac)
+]: m/z theoretical value 560.3, measured value 560.3.
Embodiment 33
Compound 6ae's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6ae finish, and reaction obtains product 6ae through two steps, wherein adopt compound 4f to obtain midbody product 5ae in the first step reaction; In the second step reaction, adopt compound S M-5x to replace SM-5a to obtain midbody product 6ae.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6ae)
+]: m/z theoretical value 568.2, measured value 568.3.
Embodiment 34
Compound 6af's is synthetic
7 identical minutes two steps of synthetic method and embodiment of preparation compound 6af finish, and reaction obtains product 6af through two steps, wherein adopt compound 4f to obtain midbody product 5af in the first step reaction; In the second step reaction, adopt compound S M-5w to replace SM-5a to obtain midbody product 6af.
Through mass spectroscopy conclusive evidence, the ESI-MS[(M+H of product 6af)
+]: m/z theoretical value 534.2, measured value 534.3.
Embodiment 35
Compound 8a's is synthetic
The synthetic method of preparation 8a divides following two steps to finish:
The first step: compound 7a's is synthetic
The product 6a (0.35g, 0.5mmol) of above-described embodiment 7 is dissolved in the mixed solution of 10mL THF, 5mL methyl alcohol and 5mL water, adds a hydronium(ion) oxidation lithium (3eq.), stirred overnight at room temperature.After the HPLC-ELSD demonstration reacts completely, reaction solution is concentrated, add dilute hydrochloric acid (0.5M, 20mL) and ethyl acetate (30mL) washing extraction, then concentrate drying obtains solid product 7a (0.33g), productive rate＞93%.The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 7a
+): m/z theoretical value 679.3, measured value 679.4.
Second step: compound 8a's is synthetic
Above-mentioned product 7a (0.14g, 0.2mmol) and compound S M-6a (1.2eq) are dissolved among the DMF (10mL), add HATU (1.1eq) after the ice-water bath cooling, then slowly drip DIEA (5eq).Drip off reaction 2h, after the HPLC-ELSD demonstration reacts completely, add entry (15mL) and ethyl acetate (20mL) washing extraction after concentrating, then column chromatographic isolation and purification obtains shallow white foam shape solid product 8a (0.11g), productive rate 62%.
After testing, product 8a
1HNMR (CDCl
3, 500MHz): δ 9.99 (s, 1H), 9.39 (m, 1H), (8.76 m, 1H), 8.55 (m, 1H), 8.19 (d, J=9.0Hz, 1H), 7.24 (s, 1H), 6.87-6.89 (d, J=8.6Hz, 1H), 6.72 (s, 1H), 6.67 (s, 1H), 5.95-5.96 (d, J=5.1Hz, 2H), 5.40 (s, 1H), 4.64-4.70 (m, 2H), 4.53-4.59 (m, 3H), 4.44-4.49 (m, 2H), 4.18-4.20 (d, J=1.8Hz, 1H), 3.86-3.89 (m, 1H), (2.96 s, 1H), 2.88 (m, 1H), (2.04 s, 1H), 1.95 (m, 2H), (1.85 m, 1H), 1.53-1.73 (m, 9H), (1.17-1.35 m, 6H), 0.96-1.03 (m, 12H).The mass spectroscopy conclusive evidence, the ESI-MS[(M+H of compound 8a)
+]: m/z theoretical value 893.4, measured value 893.4.
Embodiment 36
Compound 8b's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8b finish, and reaction obtains product 8b through two steps, and wherein the first step is reacted and obtained midbody product 7b after embodiment 35 identical employing compound 6a are hydrolyzed; In the second step reaction, adopt compound S M-6b to replace SM-6a to obtain final product 8b.
After testing, product 8b
1HNMR (CDCl
3, 500MHz): δ 9.98 (s, 1H), 9.39 (m, 1H), (8.77 m, 1H), 8.56 (m, 1H), 8.19 (d, J=9.0Hz, 1H), 7.32 (s, 1H), 6.89 (m, 1H), 6.71 (s, 1H), 6.67 (s, 1H), (5.95-5.96 d, J=5.1Hz, 2H), 5.72-5.81 (m, 1H), (5.26-5.30 m, 1H), 5.13-5.16 (m, 1H), 5.40 (s, 1H), 4.63-4.70 (m, 2H), 4.52-4.60 (m, 3H), 4.43-4.48 (m, 2H), 4.20-4.22 (d, J=1.8Hz, 1H), 3.88-3.91 (m, 1H), (2.81-2.86 m, 1H), 2.35-2.38 (m, 1H), (2.06-2.13 m, 1H), 2.04 (s, 1H), (1.95 m, 2H), 1.87 (m, 1H), (1.61-1.73 m, 6H), 1.46-1.50 (m, 1H), (1.24-1.31 m, 4H), 0.99-1.06 (m, 12H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8b
+): m/z theoretical value 891.4, measured value 891.5.
Embodiment 37
Compound 8c's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8c finish, and reaction obtains product 8c through two steps, and wherein the first step reaction adopts compound 6b to replace obtaining midbody product 7c after the 6a hydrolysis; In the second step reaction, adopt compound S M-6b to replace SM-6a to obtain final product 8c.
After testing, product 8c
1HNMR (CDCl
3, 500MHz): δ 10.37 (s, 1H), 9.26 (s, 1H), (8.74 m, 1H), 8.57 (m, 1H), 8.34-8.36 (m, 1H), 7.31-7.32 (m, 1H), 6.76 (m, 1H), (6.79 m, 1H), 5.92 (m, 1H), 5.39 (s, 1H), 5.30-5.33 (m, 1H), 5.13-5.15 (m, 2H), (4.72-4.74 m, 1H), 4.61 (m, 2H), (4.49 m, 2H), 4.40-4.43 (m, 2H), (4.25 m, 4H), 2.87 (m, 1H), (2.47 m, 1H), 2.25 (m, 2H), (1.89 m, 4H), 1.78-1.80 (m, 4H), (1.65-1.67 m, 1H), 1.44-1.48 (m, 2H), (1.13-1.21 m, 8H), 1.02 (s, 9H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8c
+): m/z theoretical value 905.4, measured value 905.4.
Embodiment 38
Compound 8e's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8e finish, and reaction obtains product 8e through two steps, and wherein the first step reaction adopts compound 6y to replace obtaining midbody product 7e after the 6a hydrolysis; In the second step reaction, obtain final product 8e with embodiment 35 identical employing compound S M-6a.
After testing, product 8e
1HNMR (CDCl
3, 500MHz): δ 10.39 (s, 1H), 9.27 (s, 1H), 8.74 (m, 1H), 8.57 (m, 1H), 8.38 (m, 1H), 7.30-7.32 (m, 1H), 6.78 (m, 1H), 6.69-6.74 (m, 1H), 5.99 (s, 2H), 5.87-5.95 (m, 1H), 5.40 (s, 1H), 5.31-5.34 (m, 1H), 5.12-5.14 (m, 2H), 4.73-4.76 (m, 1H), 4.65-4.66 (m, 2H), 4.47-4.58 (m, 3H), 4.37-4.42 (m, 1H), 2.88 (m, 1H), 2.47 (m, 1H), 2.24 (m, 2H), 1.89 (m, 3H), 1.78-1.80 (m, 4H), 1.65-1.67 (m, 1H), 1.42-1.47 (m, 2H), 1.14-1.23 (m, 6H), 1.03 (s, 9H), 0.84-0.88 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8e
+): m/z theoretical value 891.4, measured value 891.5.
Embodiment 39
Compound 8f's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8f finish, and reaction obtains product 8f through two steps, and wherein the first step reaction adopts compound 6y to replace obtaining midbody product 7f after the 6a hydrolysis; In the second step reaction, adopt compound S M-6b to replace SM-6a to obtain final product 8f.
After testing, product 8f
1HNMR (CDCl
3, 500MHz): δ 9.97-9.99 (m, 1H), 9.40 (s, 1H), (8.76 m, 1H), 8.55 (m, 1H), (8.19 m, 1H), 7.32-7.35 (m, 1H), (7.00 m, 1H), 6.65-6.77 (m, 2H), (5.92-5.97 m, 2H), 5.41 (s, 1H), (4.47-4.76 m, 7H), 4.21-4.26 (m, 1H), (3.88-3.90 m, 1H), 2.84-2.91 (m, 1H), (2.33-2.40 m, 2H), 2.21 (m, 3H), (1.83 m, 1H), 1.55-1.65 (m, 9H), (1.12-1.42 m, 6H), 0.96-1.03 (m, 13H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8f
+): m/z theoretical value 893.4, measured value 893.5.
Embodiment 40
Compound 8g's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8g finish, and reaction obtains product 8g through two steps, and wherein the first step reaction adopts compound 6z to replace obtaining midbody product 7g after the 6a hydrolysis; In the second step reaction, adopt compound S M-6b to replace SM-6a to obtain midbody product 8g.
After testing, product 8g
1HNMR (CDCl
3, 500MHz): δ 10.38 (s, 1H), 9.27 (s, 1H), 8.74 (m, 1H), 8.57 (m, 1H), 8.34-8.36 (m, 1H), 7.30-7.32 (m, 1H), 6.82 (m, 1H), 6.64-6.71 (m, 1H), 5.90 (m, 1H), 5.39 (s, 1H), 5.30-5.32 (m, 1H), 5.13-5.15 (m, 2H), 4.73-4.75 (m, 1H), 4.64 (m, 2H), 4.46-4.52 (m, 2H), 4.37-4.39 (m, 2H), 4.27-4.29 (m, 4H), 2.88 (m, 1H), 2.46 (m, 1H), 2.23 (m, 2H), 1.87-1.90 (m, 6H), 1.78-1.80 (m, 4H), 1.65-1.67 (m, 1H), (1.43-1.49 m, 2H), 1.14-1.23 (m, 6H), 1.03 (s, 9H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8g
+): m/z theoretical value 905.4, measured value 905.4.
Embodiment 41
Compound 8h's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8h finish, and reaction obtains product 8h through two steps, and wherein the first step reaction adopts compound 6c to replace obtaining midbody product 7h after the 6a hydrolysis; In the second step reaction, obtain final product 8h with embodiment 35 identical employing compound S M-6a.
After testing, product 8h
1HNMR (CDCl
3, 500MHz): δ 9.99 (s, 1H), 9.38 (m, 1H), (8.76 m, 1H), 8.56 (m, 1H), 8.15-8.17 (m, 1H), 7.10 (s, 1H), 6.89 (s, 1H), (6.84 s, 1H), 6.73-6.75 (m, 2H), 5.40 (s, 1H), 4.62-4.72 (m, 2H), 4.52-4.60 (m, 3H), (4.41-4.46 m, 2H), 4.16-4.21 (m, 5H), (3.85-3.88 m, 1H), 2.84-2.91 (m, 1H), (2.36-2.45 m, 1H), 2.32-2.36 (m, 1H), (2.16-2.21 m, 2H), 1.87 (m, 1H), (1.72-1.75 m, 6H), 1.65-1.68 (m, 3H), (1.57-1.59 m, 2H), 1.49-1.5 (m, 2H), (1.31-1.33 m, 2H), 1.27 (m, 1H), (1.21-1.23 m, 2H), 1.08-1.09 (m, 3H), (1.01 s, 9H), 0.97-0.99 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8h
+): m/z theoretical value 921.4, measured value 921.4.
Embodiment 42
Compound 8j's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8j finish, and reaction obtains product 8j through two steps, and wherein the first step reaction adopts compound 6aa to replace obtaining midbody product 7j after the 6a hydrolysis; In the second step reaction, obtain final product 8j with embodiment 35 identical employing compound S M-6a.
After testing, product 8j
1HNMR (CDCl
3, 500MHz): δ 9.98-10.02 (m, 1H), 9.40-9.41 (m, 1H), 8.75 (m, 1H), 8.52-8.55 (m, 1H), 8.18-8.21 (m, 1H), 7.09 (s, 1H), 6.89-6.92 (m, 1H), 6.79-6.81 (d, J=8.0Hz, 1H), 6.74-6.75 (d, J=8.0Hz, 1H), 5.42 (s, 1H), 4.67-4.76 (m, 2H), 4.54-4.61 (m, 3H), (4.42-4.49 m, 2H), 4.24-4.26 (t, J=5.5Hz, 2H), 4.16-4.20 (m, 3H), 3.87-3.93 (m, 1H), (2.84-2.91 m, 1H), 2.40-2.46 (m, 1H), 2.30-2.36 (m, 1H), (2.18-2.23 m, 2H), 1.88 (m, 1H), 1.80 (m, 3H), (1.63-1.71 m, 5H), 1.57-1.61 (m, 3H), 1.36-1.41 (m, 1H), (1.30 m, 2H), 1.18-1.26 (m, 2H), 1.08-1.10 (m, 2H), (1.02-1.04 m, 2H), 0.99 (s, 9H), 0.96-0.98 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8j
+): m/z theoretical value 921.4, measured value 921.4.
Embodiment 43
Compound 8m's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8m finish, and reaction obtains product 8m through two steps, and wherein the first step reaction adopts compound 6d to replace obtaining midbody product 7m after the 6a hydrolysis; In the second step reaction, obtain final product 8m with embodiment 35 identical employing compound S M-6a.
After testing, product 8m
1HNMR (CDCl
3, 500MHz): δ 10.02 (m, 1H), 7.20 (s, 1H), 6.71 (s, 1H), 6.64 (m, 2H), 5.95-5.97 (m, 2H), 5.38 (s, 1H), 4.82-4.83 (m, 1H), 4.62-4.69 (m, 2H), 4.45-4.51 (m, 4H), 4.17-4.20 (m, 1H), 3.83-3.85 (m, 2H), 2.93 (m, 1H), 2.48 (m, 1H), 2.29 (m, 1H), 1.89 (m, 1H), 1.63-1.72 (m, 5H), 1.53-1.60 (m, 5H), 1.49 (s, 9H), 1.34-1.37 (m, 3H), 1.16-1.21 (m, 2H), 1.04-1.06 (m, 4H), 1.00 (s, 9H), 0.97-0.99 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8m
+): m/z theoretical value 887.4, measured value 887.4.
Embodiment 44
Compound 8n's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8n finish, and reaction obtains product 8n through two steps, and wherein the first step reaction adopts compound 6e to replace obtaining midbody product 7n after the 6a hydrolysis; In the second step reaction, obtain final product 8n with embodiment 35 identical employing compound S M-6a.
After testing, product 8n
1HNMR (CDCl
3, 500MHz): δ 10.10 (s, 1H), 7.39 (s, 1H), (6.94 m, 1H), 6.68 (s, 1H), (6.61 m, 1H), 5.96 (s, 2H), (5.42 s, 1H), 5.25 (br, 1H), (4.52-4.64 m, 4H), 4.42-4.49 (m, 2H), (4.17-4.19 m, 1H), 3.88-3.89 (m, 1H), (3.65 m, 1H), 2.94 (m, 1H), (2.90 s, 1H), 2.36-2.41 (m, 2H), (1.93 m, 1H), 1.73 (m, 3H), (1.58-1.64 m, 6H), 1.35 (m, 2H), (1.19-1.26 m, 5H), 1.03-1.06 (m, 3H), (1.03 s, 9H), 0.98-0.99 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8n
+): m/z theoretical value 865.3, measured value 865.4.
Embodiment 45
Compound 8p's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8p finish, and reaction obtains product 8p through two steps, and wherein the first step reaction adopts compound 6f to replace obtaining midbody product 7p after the 6a hydrolysis; In the second step reaction, obtain final product 8p with embodiment 35 identical employing compound S M-6a.
After testing, product 8p
1HNMR (CDCl
3, 500MHz): δ 10.24 (s, 1H), 8.65 (m, 1H), (8.08 m, 1H), 8.01 (m, 1H), 7.9 (m, 1H), 7.67 (m, 1H), 7.58 (m, 1H), (7.48 m, 1H), 7.40 (m, 1H), 6.68 (m, 1H), 6.62 (s, 1H), 6.44 (s, 1H), (5.86-5.91 m, 2H), 5.63 (s, 1H), 5.40 (s, 1H), 4.44-4.62 (m, 4H), 4.37-4.40 (m, 2H), (3.99-4.01 m, 1H), 3.83 (m, 1H), (3.26 m, 1H), 2.96 (m, 1H), (2.46 m, 1H), 2.35 (m, 1H), (1.86 m, 1H), 1.56-1.65 (m, 4H), (1.46-1.48 m, 4H), 1.39-1.42 (m, 4H), (1.09 m, 3H), 0.99-1.02 (m, 4H), (0.84 s, 9H), 0.72 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8p
+): m/z theoretical value 977.4, measured value 977.5.
Embodiment 46
Compound 8q's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8q finish, and reaction obtains product 8q through two steps, and wherein the first step reaction adopts compound 6g to replace obtaining midbody product 7q after the 6a hydrolysis; In the second step reaction, obtain final product 8q with embodiment 35 identical employing compound S M-6a.
After testing, the mass spectroscopy of product 8q conclusive evidence, ESI-MS (M+H
+): m/z theoretical value 891.4, measured value 891.4.
Embodiment 47
Compound 8r's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8r finish, and reaction obtains product 8r through two steps, and wherein the first step reaction adopts compound 6h to replace obtaining midbody product 7r after the 6a hydrolysis; In the second step reaction, obtain final product 8r with embodiment 35 identical employing compound S M-6a.
After testing, product 8r
1HNMR (CDCl
3, 500MHz): δ 10.51 (s, 1H), 7.65-7.67 (d, J=7.4Hz, 2H), 7.47-7.51 (m, 2H), (7.34-7.37 t, J=7.8Hz, 2H), (6.98-6.99 m, 1H), 6.54 (s, 1H), (6.30 s, 1H), 5.87 (s, 1H), (5.81 s, 2H), 5.45 (s, 1H), (4.55-4.63 m, 3H), 4.46-4.49 (m, 1H), (4.19-4.26 m, 2H), 4.05-4.07 (m, 1H), (3.85-3.87 m, 1H), 3.18 (m, 1H), (2.96 m, 1H), 2.68 (m, 1H), (2.42 m, 1H), 1.84 (m, 1H), (1.65-1.67 m, 2H), 1.51-1.55 (m, 9H), (1.25-1.37 m, 5H), 1.08-1.13 (m, 5H), (0.99 s, 9H), 0.85 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8r
+): m/z theoretical value 927.4, measured value 927.4.
Embodiment 48
Compound 8s's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8s finish, and reaction obtains product 8s through two steps, and wherein the first step reaction adopts compound 6j to replace obtaining midbody product 7s after the 6a hydrolysis; In the second step reaction, obtain final product 8s with embodiment 35 identical employing compound S M-6a.
After testing, product 8s
1HNMR (CDCl
3, 500MHz): δ 10.52 (s, 1H), 8.10 (m, 1H), (7.84-7.88 t, J=9.0Hz, 2H), 7.76-7.78 (m, 1H), (7.66-7.67 m, 1H), 7.59-7.62 (m, 1H), 7.51-7.54 (m, 1H), 6.98 (m, 1H), 6.49 (s, 1H), (6.24 s, 1H), 5.88-5.91 (m, 2H), 5.72 (s, 1H), 5.49 (s, 1H), 5.41 (s, 1H), (4.59-4.66 m, 3H), 4.49-4.51 (m, 1H), (4.19-4.24 m, 2H), 4.03-4.05 (m, 1H), (3.85-3.87 m, 1H), 3.25 (m, 1H), (2.98 m, 1H), 2.68 (m, 1H), (2.45 m, 1H), 1.87 (m, 1H), (1.64-1.66 m, 2H), 1.50-1.59 (m, 8H), (1.30-1.36 m, 4H), 0.99-1.05 (m, 5H), (0.94 s, 9H), 0.88 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8s
+): m/z theoretical value 977.4, measured value 977.4.
Embodiment 49
Compound 8t's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8t finish, and reaction obtains product 8t through two steps, and wherein the first step reaction adopts compound 6k to replace obtaining midbody product 7t after the 6a hydrolysis; In the second step reaction, obtain final product 8t with embodiment 35 identical employing compound S M-6a.
After testing, product 8t
1HNMR (CDCl
3, 500MHz): δ 10.05 (m, 1H), 7.32 (s, 1H), (6.71 m, 1H), 6.63 (m, 1H), (6.59 m, 1H), 5.96 (m, 2H), (5.39 s, 1H), 4.91 (m, 1H), (4.43-4.66 m, 7H), 4.19 (m, 1H), (3.87-3.95 m, 1H), 3.68-3.77 (m, 1H), (2.93 m, 1H), 2.49 (m, 1H), (2.33 m, 1H), 1.96 (s, 1H), (1.81 m, 1H), 1.71 (m, 3H), (1.57-1.63 m, 6H), 1.36 (m, 3H), (1.25 s, 3H), 1.15 (s, 2H), (1.11 s, 3H), 0.99-1.04 (m, 18H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8t
+): m/z theoretical value 899.4, measured value 899.4.
Embodiment 50
Compound 8v's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8v finish, and reaction obtains product 8v through two steps, and wherein the first step reaction adopts compound 6m to replace obtaining midbody product 7v after the 6a hydrolysis; In the second step reaction, obtain final product 8v with embodiment 35 identical employing compound S M-6a.
After testing, product 8v
1HNMR (CDCl
3, 500MHz): δ 10.04 (s, 1H), 7.23 (s, 1H), (6.72 s, 1H), 6.64 (m, 2H), 5.96-5.97 (m, 2H), 5.38 (s, 1H), 4.97-4.98 (m, 1H), (4.59-4.69 m, 2H), 4.47-4.52 (m, 4H), (4.18-4.20 m, 1H), 3.94 (m, 1H), (3.84 m, 1H), 2.94 (m, 1H), (2.47 m, 1H), 2.33 (m, 1H), (1.87 m, 1H), 1.66-1.69 (m, 5H), (1.56-1.58 m, 5H), 1.36 (m, 3H), (1.22-1.27 m, 3H), 1.17-1.19 (m, 2H), (1.14-1.16 m, 2H), 1.03-1.08 (m, 4H), (1.00 s, 9H), 0.97-0.98 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8v
+): m/z theoretical value 859.4, measured value 859.4.
Embodiment 51
Compound 8w's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8w finish, and reaction obtains product 8w through two steps, and wherein the first step reaction adopts compound 6n to replace obtaining midbody product 7w after the 6a hydrolysis; In the second step reaction, obtain final product 8w with embodiment 35 identical employing compound S M-6a.
After testing, product 8w
1HNMR (CDCl
3, 500MHz): δ 10.02 (m, 1H), 7.19 (s, 1H), 6.72 (s, 1H), 6.65 (m, 2H), 5.96-5.97 (m, 2H), 5.38 (s, 1H), 4.89 (m, 2H), 4.60-4.69 (m, 2H), 4.47-4.51 (m, 4H), 4.20-4.22 (m, 1H), 3.83-3.90 (m, 2H), 2.94 (m, 1H), 2.48 (m, 1H), 2.33 (m, 1H), 1.88 (m, 1H), 1.64-1.69 (m, 5H), 1.56-1.58 (m, 5H), 1.36-1.37 (m, 3H), 1.25 (s, 3H), 1.24 (s, 3H), 1.14-1.19 (m, 3H), 0.97-1.05 (m, 12H), 0.82-0.91 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8w
+): m/z theoretical value 873.4, measured value 873.5.
Embodiment 52
Compound 8x's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8x finish, and reaction obtains product 8x through two steps, and wherein the first step reaction adopts compound 6p to replace obtaining midbody product 7x after the 6a hydrolysis; In the second step reaction, obtain final product 8x with embodiment 35 identical employing compound S M-6a.
After testing, product 8x
1HNMR (CDCl
3, 500MHz): δ 10.09 (s, 1H), 7.34 (br, 1H), (6.71 s, 1H), 6.65 (m, 2H), (5.96-5.97 m, 2H), 5.38 (s, 1H), (5.05 m, 1H), 4.59-4.689 (m, 2H), (4.49-4.52 m, 4H), 4.17-4.19 (m, 1H), (3.96 m, 1H), 3.88 (m, 1H), (3.68 s, 3H), 2.92 (m, 1H), (2.43 m, 1H), 2.34 (m, 1H), (1.88 m, 1H), 1.64-1.69 (m, 5H), (1.56-1.57 m, 5H), 1.35 (m, 3H), (1.26 m, 4H), 1.17-1.20 (m, 2H), (1.01 s, 9H), 0.88-0.89 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8x
+): m/z theoretical value 845.4, measured value 845.4.
Embodiment 53
Compound 8z's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8z finish, and reaction obtains product 8z through two steps, and wherein the first step reaction adopts compound 6q to replace obtaining midbody product 7z after the 6a hydrolysis; In the second step reaction, obtain final product 8z with embodiment 35 identical employing compound S M-6a.
After testing, the mass spectroscopy of product 8z conclusive evidence, the ESI-MS (M+H of 8z
+): m/z theoretical value 907.4, measured value 907.5.
Embodiment 54
Compound 8aa's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8aa finish, and reaction obtains product 8aa through two steps, and wherein the first step reaction adopts compound 6r to replace obtaining midbody product 7aa after the 6a hydrolysis; In the second step reaction, obtain final product 8aa with embodiment 35 identical employing compound S M-6a.
After testing, product 8aa
1HNMR (CDCl
3, 500MHz): δ 10.00 (s, 1H), 7.76-7.78 (d, J=7.3Hz, 2H), 7.58-7.62 (d, J=7.4Hz, 2H), 7.38-7.42 (m, 2H), 7.30-7.34 (m, 2H), 7.03 (s, 1H), (6.69 m, 2H), 6.65 (s, 1H), (5.93-5.96 m, 2H), 5.38 (s, 1H), (5.13-5.15 m, 1H), 4.59-4.69 (m, 2H), (4.52 s, 2H), 4.39-4.48 (m, 4H), (4.17-4.20 m, 1H), 3.95 (m, 1H), (3.83-3.87 m, 1H), 2.91 (m, 1H), (2.43 m, 1H), 2.30 (m, 1H), (1.86 s, 1H), 1.68-1.73 (m, 2H), (1.61-1.64 m, 3H), 1.53-1.58 (m, 3H), (1.33-1.36 m, 2H), 1.26-1.30 (m, 2H), (1.15-1.20 m, 3H), 0.97-1.03 (m, 15H).The mass spectroscopy conclusive evidence, the ESH-MS (M+H of product 8aa
+): m/z theoretical value 1009.4, measured value 1009.6.
Embodiment 55
Compound 8ab's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8ab finish, and reaction obtains product 8ab through two steps, and wherein the first step reaction adopts compound 6s to replace obtaining midbody product 7ab after the 6a hydrolysis; In the second step reaction, adopt compound S M-6b to replace SM-6a to obtain final product 8ab.
After testing, product 8ab
1HNMR (CDCl
3, 500MHz): δ 10.49 (brs, 1H), 7.40 (brs, 1H), (6.68 s, 1H), 6.64 (m, 2H), 5.92-5.95 (m, 2H), 5.81 (brs, 1H), 5.43 (m, 1H), (5.28-5.30 m, 1H), 5.11-5.19 (m, 1H), (4.87 m, 1H), 4.55-4.64 (m, 3H), (4.25-4.51 m, 3H), 4.19 (m, 1H), (3.92-4.04 m, 2H), 2.83 (m, 1H), (2.28-2.39 m, 2H), 2.20 (m, 1H), (1.98 m, 1H), 1.67-1.81 (m, 3H), (1.41-1.62 m, 5H), 1.30 (s, 9H), (1.12-1.26 m, 3H), 1.07-1.09 (m, 3H), (1.03 s, 9H), 0.86-0.99 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8ab
+): m/z theoretical value 884.4, measured value 884.5.
Embodiment 56
Compound 8ac's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8ac finish, and reaction obtains product 8ac through two steps, and wherein the first step reaction adopts compound 6s to replace obtaining midbody product 7ac after the 6a hydrolysis; In the second step reaction, obtain final product 8ac with embodiment 35 identical employing compound S M-6a.
After testing, product 8ac
1HNMR (CDCl
3, 500MHz): δ 7.35 (brs, 1H), 6.63-6.68 (m, 2H), 5.93-5.95 (m, 2H), 5.39 (m, 1H), 4.89 (m, 1H), 4.33-4.59 (m, 6H), 4.16 (m, 1H), 3.92-4.00 (m, 2H), 2.85 (m, 1H), 2.32-2.39 (m, 3H), 1.67-1.80 (m, 5H), 1.52-1.62 (m, 5H), 1.40-1.48 (m, 3H), 1.30 (s, 9H), 1.13-1.26 (m, 4H), (1.05-1.10 m, 3H), 1.04 (s, 9H), 0.89-0.99 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8ac
+): m/z theoretical value 886.4, measured value 886.5.
Embodiment 57
Compound 8ad's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8ad finish, and reaction obtains product 8ad through two steps, and wherein the first step reaction replaces obtaining midbody product 7ad after the 6a hydrolysis with embodiment 35 identical employing compound 6t; In the second step reaction, adopt compound S M-6b to replace SM-6a to obtain final product 8ad.
After testing, product 8ad
1HNMR (CDCl
3, 500MHz): δ 10.03 (m, 1H), 7.20 (s, 1H), 6.88 (s, 1H), 6.81 (s, 1H), 6.72 (m, 1H), 5.38 (m, 1H), 4.85 (m, 1H), 4.59-4.68 (m, 2H), 4.43-4.51 (m, 4H), 4.18-4.20 (m, 5H), 3.85 (m, 2H), 2.86-2.96 (m, 2H), 2.42 (m, 1H), 2.34 (m, 1H), 2.19 (m, 2H), 1.60-1.70 (m, 5H), 1.51-1.58 (m, 5H), 1.44 (s, 9H), 1.36-1.39 (m, 3H), 1.13-1.21 (m, 2H), 1.04-1.07 (m, 4H), 1.01 (s, 9H), 0.97-0.99 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8ad
+): m/z theoretical value 915.5, measured value 915.6.
Embodiment 58
Compound 8ae's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8ae finish, and reaction obtains product 8ae through two steps, and wherein the first step reaction replaces obtaining midbody product 7ae after the 6a hydrolysis with embodiment 35 identical employing compound 6u; In the second step reaction, obtain final product 8ae with embodiment 35 identical employing compound S M-6a.
After testing, product 8ae
1HNMR (CDCl
3, 500MHz): δ 10.03 (m, 1H), 7.19 (s, 1H), 6.88 (s, 1H), 6.80 (s, 1H), 6.64 (m, 1H), 5.38 (m, 1H), 5.07 (m, 1H), 4.89 (m, 1H), 4.60-4.69 (m, 2H), 4.45-4.54 (m, 4H), 4.20 (m, 5H), 3.86 (m, 2H), 2.91-2.96 (m, 1H), 2.44-2.49 (m, 1H), 2.32-2.34 (m, 1H), 2.17-2.21 (m, 2H), 1.81-1.90 (m, 4H), 1.64-1.71 (m, 8H), 1.52-1.57 (m, 7H), 1.33-1.36 (m, 2H), 1.05-1.28 (m, 7H), 1.01 (s, 9H), 0.93-0.99 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8ae
+): m/z theoretical value 927.5, measured value 927.6.
Embodiment 59
Compound 8af's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8af finish, and reaction obtains product 8af through two steps, and wherein the first step reaction adopts compound 6v to replace obtaining midbody product 7af after the 6a hydrolysis; In the second step reaction, adopt compound S M-6b to replace SM-6a to obtain final product 8af.
After testing, product 8af
1HNMR (CDCl
3, 500MHz): δ 10.03 (s, 1H), 7.20 (s, 1H), (6.70 s, 1H), 6.58 (s, 1H), 5.97 (s, 2H), 5.74 (m, 1H), 5.40 (br, 1H), (5.21-5.28 m, 2H), 5.14-5.16 (m, 1H), 4.66 (m, 2H), 4.44-4.55 (m, 3H), 4.21-4.23 (m, 2H), (3.87 m, 1H), 2.89 (m, 1H), (2.37 m, 2H), 2.08 (m, 1H), (1.94 m, 1H), 1.78 (m, 1H), (1.40-1.48 m, 2H), 1.34 (s, 9H), (1.07 m, 2H), 1.02 (s, 9H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8af
+): m/z theoretical value 746.3, measured value 746.4.
Embodiment 60
Compound 8ag's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8ag finish, and reaction obtains product 8ag through two steps, and wherein the first step reaction adopts compound 6v to replace obtaining midbody product 7ag after the 6a hydrolysis; In the second step reaction, obtain midbody product 8ag with embodiment 35 identical employing compound S M-6a.
Through mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8ag
+): m/z theoretical value 748.3, measured value 748.4.
Embodiment 61
Compound 8ah's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8ah finish, and reaction obtains product 8ah through two steps, and wherein the first step reaction adopts compound 6ab to replace obtaining midbody product 7ah after the 6a hydrolysis; In the second step reaction, adopt compound S M-6b to replace SM-6a to obtain final product 8ah.
After testing, product 8ah
1HNMR (CDCl
3, 500MHz): δ 10.02 (s, 1H), 7.16-7.18 (m, 1H), (6.76 m, 1H), 6.62-6.72 (m, 1H), 5.98 (s, 1H), 5.97 (m, 1H), 5.76 (m, 1H), (5.41 s, 1H), 5.29 (m, 1H), (5.21 m, 1H), 5.14-5.16 (m, 1H), (4.66-4.69 m, 2H), 4.53-4.58 (m, 2H), (4.46 m, 1H), 4.20-4.25 (m, 2H), (3.85 m, 1H), 2.92 (m, 1H), (2.37-2.43 m, 2H), 2.08 (m, 1H), (1.96 m, 1H), 1.71 (m, 1H), (1.44-1.48 m, 2H), 1.30-1.33 (m, 9H), (1.04-1.05 m, 2H), 1.02 (s, 9H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8ah
+): m/z theoretical value 746.3, measured value 746.4.
Embodiment 62
Compound 8ak's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8ak finish, and reaction obtains product 8ak through two steps, and wherein the first step reaction adopts compound 6w to replace obtaining midbody product 7ak after the 6a hydrolysis; In the second step reaction, adopt compound S M-6b to replace SM-6a to obtain final product 8ak.
After testing, product 8ak
1HNMR (CDCl
3, 500MHz): δ 10.01 (s, 1H), 7.21 (s, 1H), 6.71 (s, 1H), 6.68 (s, 1H), 5.96 (m, 2H), 5.76 (m, 1H), 5.40 (s, 1H), 5.26-5.30 (m, 2H), 5.15-5.17 (m, 1H), 4.73 (br, 1H), 4.60-4.69 (m, 2H), 4.47-4.52 (m, 2H), 4.23 (m, 2H), 3.83 (m, 1H), 2.93 (m, 1H), 2.42 (m, 1H), 2.36 (m, 1H), 2.09 (m, 1H), 1.98 (m, 1H), 1.63-1.68 (m, 7H), 1.44-1.47 (m, 4H), 1.36 (m, 3H), 1.02 (s, 9H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8ak
+): m/z theoretical value 758.3, measured value 758.4.
Embodiment 63
Compound 8an's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8an finish, and reaction obtains product 8an through two steps, and wherein the first step reaction adopts compound 6ac to replace obtaining midbody product 7an after the 6a hydrolysis; In the second step reaction, adopt compound S M-6b to replace SM-6a to obtain final product 8an.
After testing, product 8an
1HNMR (CDCl
3, 500MHz): δ 9.98 (s, 1H), 7.25 (s, 1H), 6.77 (m, 1H), 6.62-6.75 (m, 1H), 5.95 (m, 2H), 5.75 (m, 1H), 5.40 (s, 1H), 5.25-5.32 (m, 2H), 5.14-5.16 (m, 1H), 4.65-4.75 (m, 3H), 4.47-4.62 (m, 3H), 4.22-4.27 (m, 2H), 3.85 (m, 1H), 2.90 (m, 1H), 2.42 (m, 1H), 2.37 (m, 1H), 2.08 (m, 1H), 1.96 (m, 1H), 1.73 (m, 1H), 1.54-1.62 (m, 6H), 1.44 (m, 3H), 1.34 (m, 2H), 1.01-1.05 (m, 11H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8an
+): m/z theoretical value 758.3, measured value 758.4.
Embodiment 64
Compound 8ar's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8ar finish, and reaction obtains product 8ar through two steps, and wherein the first step reaction adopts compound 6x to replace obtaining midbody product 7ar after the 6a hydrolysis; In the second step reaction, adopt compound S M-6b to replace SM-6a to obtain final product 8ar.
After testing, product 8ar
1HNMR (CDCl
3, 500MHz): δ 10.18 (s, 1H), 7.11 (brs, 1H), (6.71 s, 1H), 6.60 (s, 1H), (5.97 s, 2H), 5.80-5.88 (m, 1H), (5.25-5.27 d, J=9.5Hz, 1H), 5.14-5.16 (d, J=10.5Hz, 1H), 4.57-4.67 (m, 3H), (4.45-4.50 m, 1H), 4.36-4.37 (m, 2H), (4.25-4.29 m, 1H), 3.89 (m, 1H), (2.92 m, 1H), 2.34-2.41 (m, 2H), (2.08-2.13 m, 1H), 1.96-1.98 (m, 1H), (1.51-1.54 m, 1H), 1.30-1.39 (m, 3H), (1.26 s, 9H), 1.14-1.23 (m, 2H), (1.05 m, 1H), 1.02 (s, 9H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8ar
+): m/z theoretical value 745.3, measured value 745.5.
Embodiment 65
Compound 8as's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8as finish, and reaction obtains product 8as through two steps, and wherein the first step reaction adopts compound 6x to replace obtaining midbody product 7as after the 6a hydrolysis; In the second step reaction, obtain final product 8as with embodiment 35 identical employing compound S M-6a.
After testing, the mass spectroscopy of product 8as conclusive evidence, the ESI-MS (M+H of 8as
+): m/z theoretical value 747.3, measured value 747.4.
Embodiment 66
Compound 8at's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8at finish, and reaction obtains product 8at through two steps, and wherein the first step is reacted and obtained midbody product 7at after embodiment 35 identical employing compound 6a are hydrolyzed; In the second step reaction, adopt compound S M-6c to replace SM-6a to obtain final product 8at.
After testing, product 8at
1HNMR (CDCl
3, 500MHz): δ 9.40 (s, 1H), 8.77 (s, 1H), 8.55 (s, 1H), 8.16-8.17 (m, 1H), 7.32-7.33 (m, 1H), 7.04 (m, 1H), 6.72 (s, 1H), (6.68 s, 1H), 5.94-5.95 (m, 2H), 5.36 (m, 1H), (4.77-4.80 m, 1H), 4.69-4.72 (m, 1H), 4.59-4.64 (m, 2H), (4.51-4.53 m, 2H), 4.44-4.47 (m, 2H), 4.18-4.20 (m, 1H), (3.80-3.83 m, 1H), 2.78 (m, 1H), 2.64 (m, 1H), (2.26 m, 1H), 1.88-1.92 (m, 1H), 1.77-1.79 (m, 1H), (1.66-1.69 m, 3H), 1.59-1.61 (m, 4H), 1.38-1.42 (m, 2H), (1.10-1.19 m, 3H), 1.00-1.07 (m, 3H), 0.97-0.99 (m, 9H), (0.89-0.93 m, 3H), 0.85-0.86 (m, 2H), 0.61 (m, 2H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8at
+): m/z theoretical value 845.4, measured value 845.4.
Embodiment 67
Compound 8au's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8au finish, and reaction obtains product 8au through two steps, and wherein the first step reaction adopts compound 6b to replace obtaining midbody product 7au after the 6a hydrolysis; In the second step reaction, adopt compound S M-6c to replace SM-6a to obtain final product 8au.
After testing, product 8au
1HNMR (CDCl
3, 500MHz): δ 9.39 (m, 1H), 8.77 (m, 1H), (8.57 m, 1H), 8.33 (m, 1H), (7.75 m, 1H), 6.76 (s, 2H), (6.69 s, 1H), 6.62 (m, 1H), (6.06 br, 1H), 5.70 (br, 1H), (4.86 m, 1H), 4.54-4.66 (m, 3H), (4.44-4.51 m, 2H), 4.25-4.41 (m, 1H), (4.25 m, 4H), 4.09 (m, 1H), (2.82 m, 1H), 2.58 (m, 1H), (2.22 m, 1H), 1.97 (m, 2H), (2.19 m, 2H), 1.78 (m, 4H), (1.68 m, 2H), 1.25-1.29 (m, 6H), (1.05-1.16 m, 4H), 1.05 (s, 9H), (0.84-0.85 m, 2H), 0.76-0.79 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8au
+): m/z theoretical value 859.4, measured value 859.5.
Embodiment 68
Compound 8av's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8av finish, and reaction obtains product 8av through two steps, and wherein the first step reaction adopts compound 6y to replace obtaining midbody product 7av after the 6a hydrolysis; In the second step reaction, adopt compound S M-6c to replace SM-6a to obtain final product 8av.
After testing, product 8av
1HNMR (CDCl
3, 500MHz): δ 9.28 (s, 1H), 8.75 (s, 1H), 8.56 (m, 2H), 7.72 (m, 1H), 6.76-6.78 (m, 1H), 6.65-6.67 (m, 1H), 6.68 (s, 1H), 5.99 (m, 2H), 5.32 (s, 1H), 4.86 (m, 1H), 4.44-4.67 (m, 6H), 4.09 (m, 2H), 2.82 (m, 1H), 2.61 (m, 1H), 2.24 (m, 1H), 2.03 (m, 2H), 1.84-1.87 (m, 2H), 1.65-1.78 (m, 5H), 1.21-1.34 (m, 5H), 1.09-1.25 (m, 4H), 1.05-1.09 (m, 9H), 0.84-0.85 (m, 2H), 0.76 (m, 4H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8av
+): m/z theoretical value 845.4, measured value 845.4.
Embodiment 69
Compound 8aw's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8aw finish, and reaction obtains product 8aw through two steps, and wherein the first step reaction adopts compound 6z to replace obtaining midbody product 7aw after the 6a hydrolysis; In the second step reaction, adopt compound S M-6c to replace SM-6a to obtain final product 8aw.
After testing, product 8aw
1HNMR (CDCl
3, 500MHz): δ 9.28 (m, 1H), 8.76 (m, 1H), (8.56 m, 2H), 7.77 (m, 1H), 6.80 (m, 1H), 6.76 (m, 1H), 6.65 (m, 1H), (6.60 br, 1H), 4.47-4.69 (m, 6H), (4.26 m, 4H), 4.09 (m, 1H), (2.83 m, 1H), 2.59 (m, 1H), (2.22 m, 1H), 1.85-1.87 (m, 2H), (1.62-1.72 m, 8H), 1.26 (m, 6H), (1.05-1.19 m, 4H), 1.01-1.05 (m, 9H), (0.85-0.86 m, 2H), 0.76-0.79 (m, 3H).The mass spectroscopy conclusive evidence, the ESI-MS (M+H of product 8aw
+): m/z theoretical value 859.4, measured value 859.5.
Embodiment 70
Compound 8ax's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8ax finish, and reaction obtains product 8ax through two steps, and wherein the first step reaction adopts compound 6v to replace obtaining midbody product 7ax after the 6a hydrolysis; In the second step reaction, obtain final product 8ax with embodiment 35 identical employing compound S M-6d.
After testing, the mass spectroscopy of product 8ax conclusive evidence, the ESI-MS (M+H of 8ax
+): m/z theoretical value 750.3, measured value 750.4.
Embodiment 71
Compound 8ay's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8ay finish, and reaction obtains product 8ay through two steps, and wherein the first step reaction adopts compound 6ae to replace obtaining midbody product 7ay after the 6a hydrolysis; In the second step reaction, obtain final product 8ay with embodiment 35 identical employing compound S M-6a.
After testing, the mass spectroscopy of product 8ay conclusive evidence, the ESI-MS (M+H of 8ay
+): m/z theoretical value 768.3, measured value 768.4.
Embodiment 72
Compound 8az's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8az finish, and reaction obtains product 8az through two steps, and wherein the first step reaction adopts compound 6v to replace obtaining midbody product 7az after the 6a hydrolysis; In the second step reaction, obtain final product 8az with embodiment 35 identical employing compound S M-6e.
After testing, the mass spectroscopy of product 8az conclusive evidence, the ESI-MS (M+H of 8az
+): m/z theoretical value 784.3, measured value 784.4.
Embodiment 73
Compound 8ba's is synthetic
35 identical minutes two steps of synthetic method and embodiment of preparation compound 8ba finish, and reaction obtains product 8ba through two steps, and wherein the first step reaction adopts compound 6af to replace obtaining midbody product 7ba after the 6a hydrolysis; In the second step reaction, obtain final product 8ba with embodiment 35 identical employing compound S M-6d.
After testing, the mass spectroscopy of product 8ba conclusive evidence, the ESI-MS (M+H of 8ba
+): m/z theoretical value 734.3, measured value 734.4.
Effect embodiment
Because HCV self-replicating level in external common liver cell is extremely low, and but its unique infection animal is chimpanzee, therefore the clinical front drug efficacy study of anti hepatitis C virus drug does not have suitable animal test model at present, someone studies human liver tissue with Infection in Vitro HCV and is implanted into immunodeficient mouse and is based upon the body mouse model, but raise this mouse and have technical difficulty, model is unstable, and lack normal immune response, too large with the pathogenic process difference of hepatitis C, therefore be not used to estimate the animal model of the third liver drug efficacy study.Do not have before 1999 effectively to breed the cell culture system that copies HCV, can't understand fully mechanism of causing a disease and the viral life cycle of HCV, so that the progress of antiviral is slow.Investigators have carried out a large amount of trials, until just overcame difficulties breakthrough progress in 1999, set up an effective cell culture model-replicon (replicon) system, the basis of this system is the subgenomic HCV RNA that uses genetically engineered to make up, can self-replicating in the Bel7402 Huh-7 of transfection cell.
Adopt above-mentioned effective cell culture model-replicon (replicon) system that has accepted in the industry, carried out isolated experiment, according to experimental result medicine is estimated, wherein the main isolated experiment result data of hepatitis C virus target spot HCV NS3/4A serpin is comprised:
1) compound is to the restraining effect (IC of HCV NS3/4A serine protease
50);
2) compound is to the restraining effect (EC of hepatitis C virus replicon (Replicon)
50); So far external clinical before and clinical test results studies show that, the interior activity test result of such isolated test result and dependent body has consistence.
The prepared compound of the present invention can suppress active testing experiment rough determination outward by following clinical precursor and screen it to the curative effect of infection with hepatitis C virus, is then further confirmed by clinical trial.Additive method also is apparent for the personnel of tool general technology in this area.
The compounds of this invention or its stereoisomers, compounds tautomeric, esterification or amidated prodrug or its pharmacy acceptable salt and composition thereof, through measuring, all infection with hepatitis C virus there is preferably curative effect, has the effect of obvious inhibition hepatitis C virus.And 8a-8ba and reference compound 6-Ref, 8-Ref etc. are through the inhibition active testing of HCV proteolytic enzyme (HCV NS3-4A), and test result finds that novel line style polypeptide compound 8a-8ba and reference compound 6-Ref, the 8-Ref etc. that contain three ring functions group that contain cyclopropyl-sulfonylamide base and isopropyl sulfoamido have the good hepatitis C virus inhibition of effect.The test result of concrete each compound 8a-8ba and the inhibition NS3/4A hepatitis C virus cytotoxic activities such as reference compound 6-Ref, 8-Ref is listed in the table below 1; Wherein, field of activity (IC
50) being denoted as " A " at 〉=200nM, field of activity is denoted as " B " at 20-200nM, and field of activity 0.1-20nM is denoted as " C ".
Table 1: novel large ring-type polynuclear compound suppresses the active testing result of hepatitis C virus
| Numbering | Compound | Suppress active (IC 50) |
| 1 | 8a | C |
| 2 | 8b | C |
| 3 | 8c | C |
| 4 | 8e | C |
| 5 | 8f | C |
| 6 | 8g | C |
| 7 | 8h | C |
| 8 | 8j | C |
| 9 | 8m | C |
| 10 | 8n | C |
| 11 | 8p | C |
| 12 | 8r | C |
| 13 | 8s | C |
| 14 | 8t | C |
| 15 | 8v | C |
| 16 | 8w | C |
| 17 | 8x | C |
| 18 | 8z | C |
| 19 | 8aa | C |
| 20 | 8ab | C |
| 21 | 8ac | C |
| 22 | 8ad | B |
| 23 | 8ae | B |
| 24 | 8af | C |
| 25 | 8ag | C |
| 26 | 8ah | C |
| 27 | 8ak | C |
| 28 | 8an | C |
| 29 | 8ar | C |
| 30 | 8as | C |
| 31 | 8at | A |
| 32 | 8au | A |
| 33 | 8av | B |
| 34 | 8aw | A |
| 35 | 8ax | C |
| 36 | 8ay | B |
| 37 | 8az | C |
| 38 | 8ba | C |
| 39 | 6-Ref | A |
| 40 | 8-Ref | C |
Above-mentioned table 1 result shows, all kinds of novel condensed ring heterocyclic compound 8a-8ba of the present invention is active fine to the hepatitis C virus inhibition, present activity novel hepatitis C virus inhibitors preferably in this field, therefore the present invention designs the value that synthetic novel large ring-type polynuclear compound Ia-Ib has further drug test and applies.
HCV proteolytic enzyme (HCV NS3-4A) suppresses active (IC
50) testing method:
The inhibition activity of HCV proteolytic enzyme (HCV NS3-4A) is to measure by an inner quench fluorescence system.EDANS and DABCYL group are connected to the opposite end of a peptide.When protein cleavage, DABCYL is carried out measurement to EDANS quenching of fluorescence.That is adopt HCV NS3-4A proteinase inhibitor high flux screening model, and be subjected to reagent to establish respectively 5 concentration dilution degree, establish simultaneously positive control and negative control.In the reaction system of optimizing, at ex=355, under the em=520 condition, measure fluorescent value with the Polarstar fluorescence detector.Calculate the inhibiting rate of each concentration, with the half-inhibition concentration (IC of Reed-Muench method calculation sample to proteolytic enzyme
50).
Material: HCV proteolytic enzyme: HCV NS3-4A, voluntarily preparation ,-70 ℃ of preservations.HCV protease substrate (FRET-S): Ac-Asp-Glu-Asp (EDANS)-Glu-Glu-Abu-ψ-[COO]-Ala-Ser-Lys-(DABCYL)-NH
2Available from U.S. AnaSpec company, be made into 100 μ M with DMSO ,-20 ℃ keep in Dark Place after the packing.Reaction buffer: 30mM NaCl, 5mM CaCl
2, 10mM DTT, 50mM Tris (pH7.8).Instrument: the Polarstar fluorescence detector is German BMG company product.
Preparation and operation: after being made into 10mg/mL with DMSO first, with damping fluid be diluted to 10000,2000,400,80, the tested concentration of 16ng/mL, add 20 μ L/ holes, the total reaction system is 200 μ L, makes that final concentration is 200,40,8,1.6ng, 0.32ng/mL.In 96 hole fluorescence enzyme reaction plates, add respectively damping fluid 140 μ L, liquid 20 μ L, HCV proteolytic enzyme 20 μ L, begin reaction at 37 ℃ after adding at last final concentration and be the FRET-S substrate 20 μ L of 0.25 μ M, and establish proteolytic enzyme and substrate reactions control wells and separately substrate and proteolytic enzyme control wells, fluorescence detector is measured fluorescent signal (ex=355, em=520).The fluorescent value of each sample well and enzyme contrast fluorescent value relatively calculate the inhibiting rate of each concentration sample, adopt Reed-Muench method calculation sample to the half-inhibition concentration (IC of HCV proteolytic enzyme
50).
Hepatitis C virus replicon (Replicon) antiviral activity (EC of system
50) testing method:
Two reporter gene Replicon system with new structure finishes, and the virus replication level detects by reporter gene renilla luciferase (Renilla luciferase) and realizes in the cells infected.Rna replicon level and the viral protein expression level of the expression level of reporter gene and HCV are good linear relationship.The concentration gradient of 82 times of dilutions, 3 multiple holes, 1 to 2 kind of positive drug contrast is established in 3 repetitions.The EC of final computerized compound
50
The toxicity of compound shaker test
In order to test the toxicity of active higher compound in some novel condensed ring heterocyclic compounds (8a-8ba and reference compound 6-Ref, 8-Ref), the present invention adopts the 18-22g healthy mice, all adopt single dose 10000mg/kg, gavage administration 1 time, the toxic reaction that the observation experiment animal produces in continuous 7 days is assessed tested material to the toxicity size of body, carry out acute toxicity (Acute Toxocity Study, MTD) investigate, the result shows the very little (LD of overall toxicity of this compounds
50＞10000), survival rate is 80%-100% after most mouse administrations, wherein has 1/3rd to suppress the active better (IC of hepatitis C virus
50The novel condensed ring heterocyclic compound of:＜20nM) respectively behind mouse gavaging dosage 10000mg/kg survival rate be 100%.For this reason, the compounds of this invention not only has preferably curative effect to infection with hepatitis C virus through measuring, has the effect of obvious inhibition hepatitis C virus, and the overall toxicity of the higher new compound of 1/3rd activity is arranged, and very low (the mouse survival rate is 100%, LD
50＞15,000), generally regard as nontoxic.
Claims (18)
1. one kind suc as formula the fused ring heterocycle compounds shown in Ia or the Ib, or its stereoisomers, compounds tautomeric, pharmacy acceptable salt or their mixture;
Wherein,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
Ra is hydrogen, C
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl amino sulfonyl, C
2-C
20Heterocyclic amino group alkylsulfonyl or C
6-C
20The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
1-C
20Alkoxyl group, C
1-C
20Alkylthio, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkylamino, C
2-C
20Heterocyclic amino group, C
6-C
20Arylamino, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl-carbonylamino, C
1-C
20Alkylsulfonamido, C
2-C
20Heterocyclic sulfonamide base, C
6-C
20Aryl-sulfonyl amino or C
1-C
20The alkyl sulfonyl amino amido;
During r=0, E does not exist, D and E
1Directly connect;
U be carbonyl ,-SO-,-SO
2-,-P (O) (ORd)-or-B (ORe)-; Wherein, Rd and Re are hydrogen, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
2-C
20Heterocyclic radical, C
6-C
20Aryl, C
3-C
20Heterocyclic aryl;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen or CH;
Z is hydrogen, hydroxyl, amino, C
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
1-C
20Alkoxyl group, C
3-C
20Cycloalkyloxy, C
1-C
20Alkylamino, C
3-C
20Cycloalkyl amino, C
2-C
20Heterocyclic amino group, C
1-C
20Alkoxyl group-carbonyl, C
3-C
20Cycloalkyloxy-carbonyl, C
1-C
20Alkylamino-carbonyl, C
3-C
20Cycloalkyl amino-carbonyl, C
2-C
20Heterocyclic amino group-carbonyl, C
6-C
20Aryl, C
6-C
20Virtue is amino, C
3-C
20The heterocycle virtue is amino, C
1-C
20Alkylsulfonamido, C
3-C
20Naphthene sulfamide amido, C
6-C
20Aryl-sulfonyl amino, C
1-C
20Alkoxyl group sulfoamido, C
3-C
20Cycloalkyloxy sulfoamido, C
6-C
20Aryloxy sulfoamido, C
1-C
20Alkylamino sulfoamido, C
3-C
20Naphthene amino sulfoamido, C
6-C
20Virtue aminosulfonyl amido, urea groups, C
1-C
20Alkyl-urea groups or C
1-C
20Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
1-C
20Alkoxyl group, C
1-C
20Alkylamino, C
2-C
20Heterocyclic amino group, C
6-C
20Aryl, C
6-C
20Arylamino, C
1-C
20Alkylsulfonamido, C
2-C
20Heterocyclic sulfonamide base, C
6-C
20Aryl-sulfonyl amino or C
1-C
20The alkyl sulfonyl amino amido;
R
5And R
6Be hydrogen, halogen, hydroxyl, itrile group, nitro, amino, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
1-C
20Alkoxyl group, C
1-C
20Alkylamino, C
2-C
20Heterocyclic amino group, C
6-C
20Aryl, C
6-C
20Arylamino, C
1-C
20Alkoxyl group-carbonylamino, C
1-C
20Alkyl-amino carbonyl amino, C
1-C
20Alkylsulfonamido, C
2-C
20Heterocyclic sulfonamide base, C
6-C
20Aryl-sulfonyl amino or C
1-C
20The alkyl sulfonyl amino amido; Wherein, R
5With R
6Between can be interconnected to ring texture;
R
7, R
8And R
9Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
20Alkyl, C
1-C
20Alkoxyl group, C
1-C
20Alkylthio, C
1-C
20Alkoxyl group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl-carbonylamino, C
2-C
20Heterocyclyloxy base-carbonyl, C
6-C
20Aryl, C
6-C
20Aryloxy, C
6-C
20Aryloxy-carbonyl or C
2-C
20Heterocyclic radical;
R
11, R
12And R
13Be hydrogen, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl amino sulfonyl, C
2-C
20Heterocyclic amino group alkylsulfonyl or C
6-C
20The virtue amino-sulfonyl.
2. fused ring heterocycle compounds as claimed in claim 1, or its stereoisomers, compounds tautomeric, pharmacy acceptable salt or their mixture is characterized in that: in formula Ia or Ib,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
Be singly-bound or two key;
Ra is hydrogen, C
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl amino sulfonyl, C
2-C
15Heterocyclic amino group alkylsulfonyl, C
6-C
15The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
1-C
15Alkoxyl group, C
1-C
15Alkylthio, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkylamino, C
2-C
15Heterocyclic amino group, C
6-C
15Arylamino, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl-carbonylamino, C
1-C
15Alkylsulfonamido, C
2-C
15Heterocyclic sulfonamide base, C
6-C
15Aryl-sulfonyl amino or C
1-C
15The aminosulfonyl amido;
During r=0, E does not exist, D and E
1Directly connect;
U be carbonyl ,-SO-,-SO
2-,-P (O) (ORd)-or-B (ORe)-; Wherein, Rd and Re are hydrogen (H), C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
2-C
15Heterocyclic radical, C
6-C
15Aryl, C
3-C
15Heterocyclic aryl;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen or CH;
Z is hydrogen, hydroxyl, amino, C
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
3-C
15Cycloalkyloxy, C
1-C
15Alkylamino, C
3-C
15Cycloalkyl amino, C
2-C
15Heterocyclic amino group, C
1-C
15Alkoxyl group-carbonyl, C
3-C
15Cycloalkyloxy-carbonyl, C
1-C
15Alkylamino-carbonyl, C
3-C
15Cycloalkyl amino-carbonyl, C
2-C
15Heterocyclic amino group-carbonyl, C
6-C
15Aryl, C
6-C
15Virtue is amino, C
3-C
15The heterocycle virtue is amino, C
1-C
15Alkylsulfonamido, C
3-C
15Naphthene sulfamide amido, C
6-C
15Aryl-sulfonyl amino, C
1-C
15Alkoxyl group sulfoamido, C
3-C
15Cycloalkyloxy sulfoamido, C
6-C
15Aryloxy sulfoamido, C
1-C
15Alkylamino sulfoamido, C
3-C
15Naphthene amino sulfoamido, C
6-C
15Virtue aminosulfonyl amido, urea groups, C
1-C
15Alkyl-urea groups or C
1-C
15Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylamino, C
2-C
15Heterocyclic amino group, C
6-C
15Aryl, C
6-C
15Arylamino, C
1-C
15Alkylsulfonamido, C
2-C
15Heterocyclic sulfonamide base, C
6-C
15Aryl-sulfonyl amino or C
1-C
15Alkyl-aminosulfonyl amido;
R
5And R
6Be hydrogen, halogen, hydroxyl, itrile group, nitro, amino, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylamino, C
2-C
15Heterocyclic amino group, C
6-C
1Aryl, C
6-C
15Arylamino, C
1-C
15Alkoxyl group-carbonylamino, C
1-C
15Alkyl-amino carbonyl amino, C
1-C
15Alkylsulfonamido, C
2-C
15Heterocyclic sulfonamide base, C
6-C
15Aryl-sulfonyl amino or C
1-C
15The alkyl sulfonyl amino amido; Wherein, R
5With R
6Between can be interconnected to ring texture;
R
7, R
8And R
9Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
15Alkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylthio, C
1-C
15Alkoxyl group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl-carbonylamino, C
2-C
15Heterocyclyloxy base-carbonyl, C
6-C
15Aryl, C
6-C
15Aryloxy, C
6-C
15Aryloxy-carbonyl or C
2-C
15Heterocyclic radical;
R
11, R
12And R
13Be hydrogen, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl-amino-sulfonyl, C
2-C
15Heterocyclic amino group alkylsulfonyl or C
6-C
15The virtue amino-sulfonyl.
3. fused ring heterocycle compounds as claimed in claim 2, or its stereoisomers, compounds tautomeric, pharmacy acceptable salt or their mixture is characterized in that: in formula Ia or Ib,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
During for singly-bound, D, E, E
1With G be independently of one another oxygen, sulphur ,-NRa-,-CRbRc-; R
10Be hydrogen, halogen, oxygen, hydroxyl, itrile group, trifluoromethyl, C
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group-carbonyl, C
1-C
8Alkylamino-carbonyl, C
1-C
8Alkyl-carbonylamino, C
6-C
12Aryl, C
6-C
12Aryloxy, C
6-C
12Aryloxy-carbonyl or C
2-C
8Heterocyclic radical;
Ra is hydrogen, C
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
6-C
12Aryl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl amino sulfonyl, C
2-C
8Heterocyclic amino group alkylsulfonyl or C
6-C
12The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently of one another
1-C
8Alkyl, C
2-C
8Cycloalkyl, C
6-C
12Aryl, C
1-C
8Alkoxyl group, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkylamino, C
2-C
8Heterocyclic amino group, C
6-C
12Arylamino, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl-carbonylamino, C
1-C
8Alkylsulfonamido, C
2-C
8Heterocyclic sulfonamide base, C
6-C
12Aryl-sulfonyl amino or C
1-C
8The aminosulfonyl amido;
During r=0, E does not exist, D and E
1Directly connect;
U be carbonyl ,-SO-,-SO
2-,-P (O) (ORd)-or-B (ORe)-; Wherein, Rd and Re are hydrogen, C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
2-C
8Heterocyclic radical, C
6-C
12Aryl, C
3-C
12Heterocyclic aryl;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen or CH;
Z is hydrogen, hydroxyl, amino, C
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
3-C
8Cycloalkyloxy, C
1-C
8Alkylamino, C
3-C
8Cycloalkyl amino, C
2-C
8Heterocyclic amino group, C
1-C
8Alkoxyl group-carbonyl, C
3-C
8Cycloalkyloxy-carbonyl, C
1-C
8Alkylamino-carbonyl, C
3-C
8Cycloalkyl amino-carbonyl, C
2-C
8Heterocyclic amino group-carbonyl, C
6-C
12Aryl, C
6-C
12Virtue is amino, C
3-C
12The heterocycle virtue is amino, C
1-C
8Alkylsulfonamido, C
3-C
8Naphthene sulfamide amido, C
6-C
12Aryl-sulfonyl amino, C
1-C
8Alkoxyl group sulfoamido, C
3-C
8Cycloalkyloxy sulfoamido, C
6-C
12Aryloxy sulfoamido, C
1-C
8Alkylamino sulfoamido, C
3-C
8Naphthene amino sulfoamido, C
6-C
12Virtue aminosulfonyl amido, urea groups, C
1-C
8Alkyl-urea groups or C
1-C
8Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylamino, C
2-C
8Heterocyclic amino group, C
6-C
12Aryl, C
6-C
12Arylamino, C
1-C
8Alkylsulfonamido, C
2-C
8Heterocyclic sulfonamide base, C
6-C
12Aryl-sulfonyl amino or C
1-C
8The alkyl sulfonyl amino amido;
R
5And R
6Be hydrogen, halogen, hydroxyl, itrile group, nitro, amino, C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylamino, C
2-C
8Heterocyclic amino group, C
6-C
12Aryl, C
6-C
12Arylamino, C
1-C
8Alkoxycarbonyl amino, C
1-C
8Alkyl-amino carbonyl amino, C
1-C
8Alkylsulfonamido, C
2-C
8Heterocyclic sulfonamide base, C
6-C
12Aryl-sulfonyl amino or C
1-C
8The alkyl sulfonyl amino amido; Wherein, R
5With R
6Between can be interconnected to ring texture;
R
7, R
8And R
9Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
8Alkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl-carbonylamino, C
2-C
8Heterocyclyloxy base-carbonyl, C
6-C
12Aryl, C
6-C
12Aryloxy, C
6-C
12Aryloxy-carbonyl or C
2-C
8Heterocyclic radical;
R
11, R
12And R
13Be hydrogen, C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
6-C
12Aryl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl amino sulfonyl, C
2-C
8Heterocyclic amino group alkylsulfonyl or C
6-C
12The virtue amino-sulfonyl.
4. fused ring heterocycle compounds as claimed in claim 3, or its stereoisomers, compounds tautomeric, pharmacy acceptable salt or their mixture is characterized in that: among formula Ia or the Ib,
N=1; P=1; Q=1; R=0,1 or 2;
During r=0, E does not exist, D and E
1Directly connect;
U is carbonyl;
V is carbonyl;
W is oxygen;
X is oxygen;
Y is nitrogen or CH;
Z is hydroxyl, C
1-C
6Alkoxyl group, C
3-C
6Cycloalkyl amino-carbonyl, C
1-C
6Alkylsulfonamido, C
3-C
6Naphthene sulfamide amido or C
6-C
10Aryl-sulfonyl amino;
R
1, R
2, R
3And R
4Be hydrogen independently of one another;
R
5And R
6Be hydrogen, C independently of one another
1-C
6Alkyl, C
3-C
6Cycloalkyl or R
5With R
6Between be interconnected to C
1-C
6Alkyl replaces or unsubstituted C
3-C
6Cycloalkyl;
R
7, R
8And R
9Be hydrogen independently;
R
11Be C
1-C
6Alkyl, C
1-C
6Cycloalkyl or C
6-C
12Aryl;
R
12Be hydrogen;
R
13Be C
1-C
8Alkyl, C
1-C
8Alkoxyl group or C
2-C
8Heterocyclic aryl, the heteroatoms in the described heterocyclic aryl are N, and number of heteroatoms is 1～2.
5. fused ring heterocycle compounds as claimed in claim 4, or its stereoisomers, compounds tautomeric, pharmacy acceptable salt or their mixture is characterized in that: described Ia is following arbitrary compound:
Described compounds ib is following arbitrary compound:
。
6. a fused ring heterocycle compounds IIa or IIb;
In formula IIa or IIb,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
During for two key, D, E, E
1With G be independently of one another nitrogen or-CRb-; R
10Be oxygen or sulphur;
Ra is hydrogen, C
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl amino sulfonyl, C
2-C
20Heterocyclic amino group alkylsulfonyl or C
6-C
20The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
1-C
20Alkoxyl group, C
1-C
20Alkylthio, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkylamino, C
2-C
20Heterocyclic amino group, C
6-C
20Arylamino, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl-carbonylamino, C
1-C
20Alkylsulfonamido, C
2-C
20Heterocyclic sulfonamide base, C
6-C
20Aryl-sulfonyl amino or C
1-C
20The alkyl sulfonyl amino amido;
During r=0, E does not exist, D and E
1Directly connect;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen or CH;
Z
1Be hydrogen, hydroxyl, amino, C
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
1-C
20Alkoxyl group, C
3-C
20Cycloalkyloxy, C
1-C
20Alkylamino, C
3-C
20Cycloalkyl amino, C
2-C
20Heterocyclic amino group, C
6-C
20Aryl, C
6-C
20Virtue is amino, C
3-C
20The heterocycle virtue is amino, C
1-C
20Alkylsulfonamido, C
3-C
20Naphthene sulfamide amido, C
6-C
20Aryl-sulfonyl amino, C
1-C
20Alkoxyl group sulfoamido, C
3-C
20Cycloalkyloxy sulfoamido, C
6-C
20Aryloxy sulfoamido, C
1-C
20Alkylamino sulfoamido, C
3-C
20Naphthene amino sulfoamido, C
6-C
20Virtue aminosulfonyl amido, urea groups, C
1-C
20Alkyl-urea groups or C
1-C
20Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
1-C
20Alkoxyl group, C
1-C
20Alkylamino, C
2-C
20Heterocyclic amino group, C
6-C
20Aryl, C
6-C
20Arylamino, C
1-C
20Alkylsulfonamido, C
2-C
20Heterocyclic sulfonamide base, C
6-C
20Aryl-sulfonyl amino or C
1-C
20The alkyl sulfonyl amino amido;
R
7, R
8And R
9Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
20Alkyl, C
1-C
20Alkoxyl group, C
1-C
20Alkylthio, C
1-C
20Alkoxyl group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl-carbonylamino, C
2-C
20Heterocyclyloxy base-carbonyl, C
6-C
20Aryl, C
6-C
20Aryloxy or C
6-C
20Aryloxy-carbonyl or C
2-C
20Heterocyclic radical;
R
11, R
12And R
13Be C independently of one another
1-C
20Alkyl, C
3-C
20Cycloalkyl, C
6-C
20Aryl, C
2-C
20Heterocyclic aryl, C
1-C
20Alkoxyl group-carbonyl, C
6-C
20Aryloxy-carbonyl, C
2-C
20Heterocyclic oxy group-carbonyl, C
1-C
20Alkyl-aminocarboxyl, C
1-C
20Alkyl amino sulfonyl, C
2-C
20Heterocyclic amino group alkylsulfonyl or C
6-C
20The virtue amino-sulfonyl.
7. fused ring heterocycle compounds as claimed in claim 6 is characterized in that: in formula IIa or IIb,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
During for singly-bound, D, E, E
1With G be independently of one another oxygen, sulphur ,-NRa-,-CRbRc-; R
10Be hydrogen, halogen, oxygen, hydroxyl, itrile group, trifluoromethyl, C
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylthio, C
1-C
15Alkoxyl group-carbonyl, C
1-C
15Alkylamino-carbonyl, C
1-C
15Alkyl-carbonylamino, C
6-C
15Aryl, C
6-C
15Aryloxy, C
6-C
15Aryloxycarbonyl or C
2-C
15Heterocyclic radical;
Ra is hydrogen, C
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl amino sulfonyl, C
2-C
15Heterocyclic amino group alkylsulfonyl or C
6-C
15The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
1-C
15Alkoxyl group, C
1-C
15Alkylthio, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkyl-amino, C
2-C
15Heterocyclic amino group, C
6-C
15Arylamino, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl-carbonylamino, C
1-C
15Alkylsulfonamido, C
2-C
15Heterocyclic sulfonamide base, C
6-C
15Aryl-sulfonyl amino or C
1-C
15The alkyl sulfonyl amino amido;
During r=0, E does not exist, D and E
1Directly connect;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen or CH;
Z
1Be hydrogen, hydroxyl, amino, C
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
3-C
15Cycloalkyloxy, C
1-C
15Alkylamino, C
3-C
15Cycloalkyl amino, C
2-C
15Heterocyclic amino group, C
6-C
15Aryl, C
6-C
15Virtue is amino, C
3-C
15The heterocycle virtue is amino, C
1-C
15Alkylsulfonamido, C
3-C
15Naphthene sulfamide amido, C
6-C
15Aryl-sulfonyl amino, C
1-C
15Alkoxyl group sulfoamido, C
3-C
15Cycloalkyloxy sulfoamido, C
6-C
15Aryloxy sulfoamido, C
1-C
15Alkylamino sulfoamido, C
3-C
15Naphthene amino sulfoamido, C
6-C
15Virtue aminosulfonyl amido, urea groups, C
1-C
15Alkyl-urea groups or C
1-C
15Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylamino, C
2-C
15Heterocyclic amino group, C
6-C
15Aryl, C
6-C
15Arylamino, C
1-C
15Alkylsulfonamido, C
2-C
15Heterocyclic sulfonamide base, C
6-C
15Aryl-sulfonyl amino or C
1-C
15Alkyl-aminosulfonyl amido;
R
7, R
8And R
9Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
15Alkyl, C
1-C
15Alkoxyl group, C
1-C
15Alkylthio, C
1-C
15Alkoxyl group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl-carbonylamino, C
2-C
15Heterocyclyloxy base-carbonyl, C
6-C
15Aryl, C
6-C
15Aryloxy, C
6-C
15Aryloxy-carbonyl or C
2-C
15Heterocyclic radical;
R
11, R
12And R
13Be hydrogen, C independently of one another
1-C
15Alkyl, C
3-C
15Cycloalkyl, C
6-C
15Aryl, C
2-C
15Heterocyclic aryl, C
1-C
15Alkoxyl group-carbonyl, C
6-C
15Aryloxy-carbonyl, C
2-C
15Heterocyclic oxy group-carbonyl, C
1-C
15Alkyl-aminocarboxyl, C
1-C
15Alkyl amino sulfonyl, C
2-C
15Heterocyclic amino group alkylsulfonyl or C
6-C
15The virtue amino-sulfonyl.
8. fused ring heterocycle compounds as claimed in claim 7 is characterized in that: in formula IIa or IIb,
N=0,1 or 2; P=0,1 or 2; Q=0,1 or 2; R=0,1,2 or 3;
Ra is hydrogen, C
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
6-C
12Aryl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl-amino-sulfonyl, C
2-C
8Heterocyclic amino group alkylsulfonyl or C
6-C
12The virtue amino-sulfonyl;
Rb and Rc are hydrogen, halogen, itrile group, nitro, C independently of one another
1-C
8Alkyl, C
2-C
8Cycloalkyl, C
6-C
12Aryl, C
1-C
8Alkoxyl group, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkylamino, C
2-C
8Heterocyclic amino group, C
6-C
12Arylamino, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl-carbonylamino, C
1-C
8Alkylsulfonamido, C
2-C
8Heterocyclic sulfonamide base, C
6-C
12Aryl-sulfonyl amino or C
1-C
8The alkyl sulfonyl amino amido;
During r=0, E does not exist, D and E
1Directly connect;
V be carbonyl or-SO
2-;
W is oxygen or sulphur;
X be oxygen, sulphur, nitrogen or-NRa-; Wherein, the definition of Ra and above-mentioned D, E, E
1Identical with the Ra among the G;
Y is nitrogen or CH;
Z
1Be hydrogen, hydroxyl, amino, C
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
3-C
8Cycloalkyloxy, C
1-C
8Alkylamino, C
3-C
8Cycloalkyl amino, C
2-C
8Heterocyclic amino group, C
6-C
12Aryl, C
6-C
12Virtue is amino, C
3-C
12The heterocycle virtue is amino, C
1-C
8Alkylsulfonamido, C
3-C
8Naphthene sulfamide amido, C
6-C
12Aryl-sulfonyl amino, C
1-C
8Alkoxyl group sulfoamido, C
3-C
8Cycloalkyloxy sulfoamido, C
6-C
12Aryloxy sulfoamido, C
1-C
8Alkylamino sulfoamido, C
3-C
8Naphthene amino sulfoamido, C
6-C
12Virtue aminosulfonyl amido, urea groups, C
1-C
8Alkyl-urea groups or C
1-C
8Alkyl-thioureido;
R
1, R
2, R
3And R
4Be hydrogen, halogen, hydroxyl, itrile group, nitro, C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylamino, C
2-C
8Heterocyclic amino group, C
6-C
12Aryl, C
6-C
12Arylamino, C
1-C
8Alkylsulfonamido, C
2-C
8Heterocyclic sulfonamide base, C
6-C
12Aryl-sulfonyl amino or C
1-C
8The alkyl sulfonyl amino amido;
R
7, R
8And R
9Be hydrogen, halogen, itrile group, nitro, fluoroform alkyl, C independently of one another
1-C
8Alkyl, C
1-C
8Alkoxyl group, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl-carbonylamino, C
2-C
8Heterocyclyloxy base-carbonyl, C
6-C
12Aryl, C
6-C
12Aryloxy, C
6-C
12Aryloxy-carbonyl or C
2-C
8Heterocyclic radical;
R
11, R
12And R
13Be hydrogen, C independently of one another
1-C
8Alkyl, C
3-C
8Cycloalkyl, C
6-C
12Aryl, C
2-C
12Heterocyclic aryl, C
1-C
8Alkoxyl group-carbonyl, C
6-C
12Aryloxy-carbonyl, C
2-C
8Heterocyclic oxy group-carbonyl, C
1-C
8Alkyl-aminocarboxyl, C
1-C
8Alkyl amino sulfonyl, C
2-C
8Heterocyclic amino group alkylsulfonyl or C
6-C
12The virtue amino-sulfonyl.
9. fused ring heterocycle compounds as claimed in claim 8 is characterized in that: among formula IIa or the IIb,
N=1; P=1; Q=1; R=0,1 or 2;
During r=0, E does not exist, D and E
1Directly link;
V is carbonyl;
W is oxygen;
X is oxygen;
Y is nitrogen or CH;
Z
1Be hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylsulfonamido, C
3-C
6Naphthene sulfamide amido or C
6-C
10Aryl-sulfonyl amino;
R
1, R
2, R
3And R
4Be hydrogen independently of one another;
R
7, R
8And R
9Be hydrogen independently;
R
11Be C
1-C
6Alkyl, C
1-C
6Cycloalkyl or C
6-C
12Aryl;
R
12Be hydrogen;
R
13Be C
1-C
8Alkyl, C
1-C
8Alkoxyl group or C
2-C
8Heterocyclic aryl, in the described heterocyclic aryl, heteroatoms is N, number of heteroatoms is 1～2.
10. fused ring heterocycle compounds as claimed in claim 9, it is characterized in that: described compound I Ia is following arbitrary compound:
Described compound I Ib is following arbitrary compound:
11. such as each described compound I a of claim 1～5 or Ib, its stereoisomers, compounds tautomeric, pharmacy acceptable salt or its mixture for the preparation of the application in the medicine that suppresses hepatitis C virus.
12. pharmaceutical composition, it is characterized in that: it comprises each described formula Ia of one or more claims 1～5 or Ib compound or its stereoisomers, compounds tautomeric or its pharmacy acceptable salt, and pharmaceutically acceptable vehicle.
13. a pharmaceutical composition is characterized in that: it comprises that one or more are such as each described formula Ia of claim 1～5 or Ib compound or its stereoisomers, compounds tautomeric or its pharmacy acceptable salt; And following in listed one or more: (1) immunomodulator; (2) hcv protease inhibitors, (3) hepatitis C virus AG14361, (4) do not belong to (2)-nucleosides and the nucleoside derivates of (3), (5) hepatitis B virus (HBV) inhibitor, (6) human immune deficiency virus (HIV) inhibitor, (7) cancer drug, (8) anti-inflammatory drug, or (9) do not belong to other compounds of above-mentioned (1)-(8).
14. pharmaceutical composition as claimed in claim 13 is characterized in that: described immunomodulator is Interferon, rabbit or interferon derivative.
15. pharmaceutical composition as claimed in claim 14 is characterized in that: described Interferon, rabbit is the polyoxyethylene glycol Interferon, rabbit.
16. pharmaceutical composition as claimed in claim 13 is characterized in that: described hiv inhibitor is the ritonavir medicine.
17. pharmaceutical composition as claimed in claim 13 is characterized in that: described hepatitis B virus inhibitor is lamivudine, Telbivudine, adefovir ester, emtricitabine, Entecavir, tenofovir disoproxil or L-FMAU.
18. the application in the medicine of preparation inhibition hepatitis C virus such as claim 12 or 13 described pharmaceutical compositions.
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| CN103396344B (en) * | 2013-08-08 | 2014-10-29 | 苏州永健生物医药有限公司 | One-pot synthetic method for N-t-butyl-aminocarbonyl-3-methyl-L-valine |
| CN104447952A (en) * | 2014-12-11 | 2015-03-25 | 上海唐润医药科技有限公司 | Hepatitis C virus protease inhibitor and synthesis method thereof |
| WO2017222914A1 (en) | 2016-06-21 | 2017-12-28 | Inception 4, Inc. | Carbocyclic prolinamide derivatives |
| EP4257191A3 (en) | 2016-06-21 | 2023-11-22 | Orion Ophthalmology LLC | Heterocyclic prolinamide derivatives |
| CN113960201B (en) * | 2021-10-22 | 2023-08-11 | 山东鲁抗医药股份有限公司 | Method for detecting 4-dimethylaminopyridine in entecavir |
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|---|---|---|---|---|
| CN1238780A (en) * | 1996-10-18 | 1999-12-15 | 沃泰克斯药物股份有限公司 | Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease |
| CN1315965A (en) * | 1998-08-10 | 2001-10-03 | 贝林格尔·英格海姆加拿大有限公司 | Hepatitis C inhibitor peptides |
| CN1323316A (en) * | 1998-08-10 | 2001-11-21 | 贝林格尔·英格海姆加拿大有限公司 | Hepatitis C inhibitor tri-peptides |
| CN1984922A (en) * | 2004-05-20 | 2007-06-20 | 先灵公司 | Substituted prolines as inhibitors of hepatitis c virus NS3 serine protease |
| CN101506223A (en) * | 2006-07-13 | 2009-08-12 | 艾其林医药公司 | 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1238780A (en) * | 1996-10-18 | 1999-12-15 | 沃泰克斯药物股份有限公司 | Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease |
| CN1315965A (en) * | 1998-08-10 | 2001-10-03 | 贝林格尔·英格海姆加拿大有限公司 | Hepatitis C inhibitor peptides |
| CN1323316A (en) * | 1998-08-10 | 2001-11-21 | 贝林格尔·英格海姆加拿大有限公司 | Hepatitis C inhibitor tri-peptides |
| CN1984922A (en) * | 2004-05-20 | 2007-06-20 | 先灵公司 | Substituted prolines as inhibitors of hepatitis c virus NS3 serine protease |
| CN101506223A (en) * | 2006-07-13 | 2009-08-12 | 艾其林医药公司 | 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication |
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