CN1938311A

CN1938311A - Macrocyclic compounds as inhibitors of viral replication

Info

Publication number: CN1938311A
Application number: CN 200580010503
Authority: CN
Inventors: 劳伦斯·M·布拉特; 史蒂文·M·温洛斯凯; 史蒂文·W·安德鲁斯; 凯文·R·孔德罗斯基; 江郁桐; 阿普里尔·L·肯尼迪; 乔治·A·多尔蒂; 约翰·A·乔西; 彼得·J·施滕格尔; 本杰明·T·伍达德; 马钱德·R·马杜鲁
Original assignee: Intermune Inc
Current assignee: Intermune Inc
Priority date: 2004-03-30
Filing date: 2005-03-29
Publication date: 2007-03-28
Also published as: ZA200608798B; CU20090112A6; TNSN06308A1; UA91677C2

Abstract

The embodiments provide compounds of the general formulas I-XIX, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating flaviviral infection, including hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

Description

Macrocylc compound as

The crosscorrelation application case

The application's case is the 11/064th of application on February 23rd, 2005, the part of No. 445 U.S. patent application case case that continues, this is the 11/064th years old, No. 445 application cases are the cases that continue of the PCT/US04/33970 of application on October 13rd, 2004, PCT/US04/33970 advocates the right of priority of the 60/511st, No. 541 U.S. Provisional Application case of application on October 14th, 2003 according to the 119th (e) money of United States Code the 35th volume; The application's case is also advocated the 60/612nd of application on September 22nd, 2004, the 60/562nd of No. 381 U.S. Provisional Application cases, application on April 14th, 2004, the 60/558th, No. 161 U.S. Provisional Application case of No. 418 U.S. Provisional Application cases and application on March 30th, 2004; These application cases are all incorporated into herein as a reference in full.

Technical field

The present invention relates to the method that compound, its synthetic method, medical composition and treatment Flavivirus infect (infecting as hepatitis C virus (HCV)).Specifically, the method that the invention provides novel peptide analogs, contains the medical composition of these analogues and use these analogue treatment yellow fever virus to infect.

Background technology

It is the most common chronic blood-borne diseases of the U.S. that hepatitis C virus (HCV) infects.Although the newly-increased number that infects reduces, yet the burden that chronic infection brings is sizable, Center for Disease Control estimates that existing 3,900,000 (1.8%) populations of the U.S. are infected.Chronic hepatopathy is the tenth major cause that the U.S. causes grownup's death, just because of this, causes annual about 25,000 people's death, perhaps accounts for 1% of all death tolls.Studies show that 40% chronic hepatopathy is relevant with HCV, estimate has 8 every year for this reason, 000-10,000 people's death.The latter stage hepatopathy relevant with HCV is the most common indication of liver transplantation among the grownup.

Over past ten years, the antiviral therapy of chronic hepatitis C is developed rapidly, significantly improves being found in therapeutic efficiency.However, yet, 40% to 50% patient treatment failure is arranged still, that is, be nonresponder or recidivist even use the combination treatment of Pegylation IFN-α and ribavirin (ribavirin).These patients are not effectively treatment selection at present.Specifically, had during the liver biopsy late period fibrosis or the hardened patient have the great risk of development hepatopathy complication in late period and the risk of remarkable increase of development hepatocellular carcinoma; Described late period the hepatopathy complication comprise that ascites, jaundice, varix are hemorrhage, encephalopathic and PHF.

The high incidence of chronic HCV infection is for causing great public health problem for the burden future of U.S.'s chronic hepatopathy.It is early stage to show that from national healthy data with nutrient research investigation (National Health and Nutrition Examination Survey (NHANES III)) rolling up of newly-increased HCV infection ratio betides the eighties in phase late 1960s to 20th century, particularly betides among the people of age between 20 years old to 40 years old.According to estimates, suffer from the number to 2015 more than 20 years old or 20 years old that long-term HCV infects and year may increase to 1990 more than four times, that is, from 750,000 to surpassing 3,000,000.What infected ratio then will increase by 40 years old in 30 years old is faster.Because the risk of the relevant chronic hepatopathy of HCV is relevant with the infection time length, the sclerosis risk increases day by day for the people who infect to surpass 20 years, and the increase that therefore has a number that long-term HCV infects may cause in the period of nineteen sixty-five-1985 rolling up of the morbidity associated and mortality ratio of sclerosis among the infected patient.

HCV is a kind of tunicary positive chain RNA virus in the flaviviridae family.The length of nearly 9500 Nucleotide of strand HCV rna gene group, and have the open reading frame (ORF) of about 3000 the amino acid whose big polyproteins of coding.In infected cell, described polyprotein in the cracking of a plurality of sites, produces the structure and non-structure (NS) albumen of virus by cell and virus protease.Under the situation of HCV, the generation of ripe Nonstructural Protein (NS2, NS3, NS4, NS4A, NS4B, NS5A and NS5B) is reached by two kinds of virus proteases.The NS2-NS3 juncture of first kind of virus protease cracking polyprotein.Second kind of virus protease is the serine protease (being called " NS3 proteolytic enzyme " in the literary composition) that is contained in the N-terminal zone of NS3.Be all follow-up cracking incidents in the site (that is the site between the C-terminal of the C-terminal of NS3 and polyprotein) in downstream with respect to the position of NS3 in the NS3 proteolytic enzyme mediation polyprotein.NS3 proteolytic enzyme represents activity when NS3-NS4 cracking site cis, and all the other NS4A-NS4B, NS4B-NS5A and NS5A-NS5B site are showed when trans active.It is believed that NS4A albumen has multiple function, serve as the cofactor of NS3 proteolytic enzyme, and may assist the film location of NS3 and other rdrp virus component.Obviously, it is necessary to form mixture between NS3 and NS4A and be the processing events that is mediated by NS3, and improves the proteolysis efficient by all sites place that NS3 recognized.NS3 proteolytic enzyme also represents ribonucleoside triphosphote enzyme and RNA helicase activity.NS5B is the RNA RNA-dependent polysaccharase relevant with the HCV rna replicon.

Document:

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Summary of the invention

Embodiment provides the compound with formula I:

Wherein:

Q is the core ring that is selected from and the following:

Wherein, described core ring can be unsubstituted or replace through following group: H, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, C _1-6Alkyl, be substituted C _1-6Alkyl, C _1-6Alkoxyl group, be substituted C _1-6Alkoxyl group, C _{6 or 10}Aryl, pyridyl (pyridal), pyrimidyl (pyrimidal), thienyl, furyl, thiazolyl, oxazolyl, phenoxy group, sulphur phenoxy group, sulfoamido, urea, thiocarbamide, amide group, ketone group, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxy amino, alkoxyl group heterocyclic radical, alkylamino, alkyl carboxyl, carbonyl, volution cyclopropyl, volution cyclobutyl, volution cyclopentyl or volution cyclohexyl

Perhaps, Q is R ¹-R ², R wherein ¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, described group replace through maximum three following each groups separately according to circumstances: NR ⁶R ⁷, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; And R ²Be H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, these groups replace through maximum three following each groups separately according to circumstances: NR ⁶R ⁷, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl or benzyl, described phenyl or benzyl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ⁵Be H, C _1-6Alkyl, C (O) NR ⁶R ⁷, C (S) NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, S (O) ₂R ⁸Or (CO) CHR ²¹NH (CO) R ²²

R ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this group replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects;

Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁹Be C _{6 or 10}Aryl, this group replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁹For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl, NR ⁶R ⁷, NR ^1aR ^1bOr (CO) OH; Perhaps R ⁹For replacing maximum twice assorted aromatic nucleus through following group according to circumstances: halogen, cyano group, nitro, hydroxyl or C _1-6Alkoxyl group; Perhaps Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

Wherein, R ^1aAnd R ^1bBe H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, C _1-6Alkoxyl group, amide group or phenyl,

Perhaps, R ^1aAnd R ^1bBe H and C independently of one another _{6 or 10}Aryl, this aryl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group,

Perhaps, R ^1aAnd R ^1bBe H, heterocycle independently of one another, this heterocycle is 5,6 or 7 yuan of saturated or unsaturated heterocycle shape molecules, and contains one to four heteroatoms that is selected from the group that is made up of nitrogen, oxygen and sulphur,

Perhaps, NR ^1aR ^1bBe three to hexa-atomic alkyl cyclic secondary amine, it contains one to three heteroatoms of incorporating in the ring according to circumstances, and replaces one to three time through following group according to circumstances: halogen, cyano group, nitro, C _1-6Alkoxyl group, amide group or phenyl,

Perhaps, NR ^1aR ^1bFor being selected from the heteroaryl of following group:

With

Wherein, R ^1cBe H, halogen, C _1-6Alkyl, C _3-6Cycloalkyl, C _1-6Alkoxyl group, C _3-6Cycloalkyloxy, NO ₂, N (R ^1d) ₂, NH (CO) R ^1dOr NH (CO) NHR ^1d, each R wherein ^1dBe H, C independently _1-6Alkyl or C _3-6Cycloalkyl,

Perhaps R ^1cBe NH (CO) OR ^1e, R wherein ^1eBe C _1-6Alkyl or C _3-6Cycloalkyl;

P=0 or 1;

V is selected from O, S or NH;

When V was O or S, W was selected from O, NR ¹⁵Or CR ¹⁵When V was NH, W was selected from NR ¹⁵Or CR ¹⁵, R wherein ¹⁵Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl;

Dotted line is represented optional double bond;

R ²¹Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl; Perhaps R ²¹Be C _{6 or 10}Aryl, this aryl replace through maximum 3 following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ²¹Be pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group or sulphur phenoxy group; With

R ²²Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl; Its restricted condition is: described compound with formula I does not comprise formula II, III or the IV compound of hereinafter definition.

Embodiment provides the compound with formula II, III or IV:

Wherein:

A) R ¹And R ²Be H, halogen, cyano group, nitro, hydroxyl, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group, C _{6 or 10}Aryl, pyridyl, pyrimidyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group, sulphur phenoxy group, S (O) ₂NR ⁶R ⁷, NHC (O) NR ⁶R ⁷, NHC (S) NR ⁶R ⁷, C (O) NR ⁶R ⁷, NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, NHC (O) R ⁸, NHC (O) OR ⁸, SO _mR ⁸, NHS (O) ₂R ⁸, CH _nNR ⁶R ⁷, OCH _nNR ⁶R ⁷Or OCH _nR ⁹(R wherein ⁹Be imidazolyl or pyrazolyl); Described at R ¹And R ²Definition in thienyl, pyrimidyl, furyl, thiazolyl and oxazolyl replace through maximum two following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹And R ²Definition in C _{6 or 10}Aryl, pyridyl, phenoxy group and sulphur phenoxy group replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

B) m=0,1 or 2;

C) R ⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl or benzyl, described phenyl or benzyl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

D) R ⁵Be H, C _1-6Alkyl, C (O) NR ⁶R ⁷, C (S) NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, S (O) ₂R ⁸Or (CO) CHR ²¹NH (CO) R ²²

E) R ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

F) R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects;

G) Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁹Be C _{6 or 10}Aryl, this aryl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁹For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl, NR ⁶R ⁷Or (CO) OH; Perhaps R ⁹For replacing maximum twice assorted aromatic nucleus through following group according to circumstances: halogen, cyano group, nitro, hydroxyl or C _1-6Alkoxyl group; Perhaps Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

H) R ¹⁰And R ¹¹Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹⁰And R ¹¹Definition in C _{6 or 10}Aryl replaces through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹⁰And R ¹¹Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹⁰And R ¹¹Be combined into O;

I) p=0 or 1;

J) R ¹²And R ¹³Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), wherein these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ₁₄Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹²And R ¹³Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹²And R ¹³Independently of one another for according to circumstances through (CH ₂) _nOR ⁸The C that replaces _1-6Alkyl;

K) R ²⁰Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), wherein these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

l)n＝1-4；

M) V is selected from O, S or NH;

N) when V is O or S, W is selected from O, NR ¹⁵Or CR ¹⁵When V was NH, W was selected from NR ¹⁵Or CR ¹⁵, R wherein ¹⁵Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl;

O) dotted line is represented optional double bond;

P) R ²¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or phenyl; Perhaps R ²¹Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ²¹Be pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group or sulphur phenoxy group; With

Q) R ²²Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl.

Embodiment provides the compound with formula XI:

Wherein:

A) R ^1aAnd R ^1bBe H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, C _1-6Alkoxyl group, amide group or phenyl;

Perhaps R ^1aAnd R ^1bBe H and C independently of one another _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

Perhaps, R ^1aAnd R ^1bBe H or heterocycle independently of one another, this heterocycle is 5,6 or 7 yuan of saturated or unsaturated heterocycle shape molecules, and contains one to four heteroatoms that is selected from the group that is made up of nitrogen, oxygen and sulphur;

Perhaps NR ^1aR ^1bBe three to hexa-atomic alkyl cyclic secondary amine, it has one to three according to circumstances and incorporates the heteroatoms in the ring into and replace one to three time through following group according to circumstances: halogen, cyano group, nitro, C _1-6Alkoxyl group, amide group or phenyl;

Perhaps, NR ^1aR ^1bFor being selected from the heteroaryl of the group that forms by following group:

With

R wherein ^1cBe H, halogen, C _1-6Alkyl, C _3-6Cycloalkyl, C _1-6Alkoxyl group, C _3-6Cycloalkyloxy, NO ₂, N (R ^1d) ₂, NH (CO) R ^1dOr NH (CO) NHR ^1d, each R wherein ^1dBe H, C independently _1-6Alkyl or C _3-6Cycloalkyl;

B) W is O or NH;

C) V is selected from O, S or NH;

D) when V is O or S, W is selected from O, NR ¹⁵Or CR ¹⁵When V was NH, W was selected from NR ¹⁵Or CR ¹⁵, R wherein ¹⁵Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl;

E) Q is the dicyclo secondary amine with following structure:

Wherein, R ²¹And R ²²Be H, halogen, cyano group, nitro, hydroxyl, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group, C _{6 or 10}Aryl, pyridyl, pyrimidyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group, sulphur phenoxy group, S (O) ₂NR ⁶R ⁷, NHC (O) NR ⁶R ⁷, NHC (S) NR ⁶R ⁷, C (O) NR ⁶R ⁷, NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, NHC (O) R ⁸, NHC (O) OR ⁸, SO _mR ⁸(m=0,1 or 2) or NHS (O) 2R ⁸Described at R ²¹And R ²²Definition in thienyl, pyrimidyl, furyl, thiazolyl and oxazolyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ²¹And R ²²Definition in C _{6 or 10}Aryl, pyridyl, phenoxy group and sulphur phenoxy group replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R wherein ¹⁰And R ¹¹Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷Or (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), wherein these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Or R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹⁰And R ¹¹Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹⁰And R ¹¹Be combined into O; P=0 or 1 wherein;

R wherein ¹²And R ¹³Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹²And R ¹³Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected;

R wherein ²⁰Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), wherein these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

N=0-4 wherein;

R wherein ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

Perhaps R when W=NH and V=O ²Be R ^2aR ^2b, wherein

R ^2aBe C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, these groups replace through maximum three following each groups separately according to circumstances: NR ^2cR ^2d, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ^2bBe H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, these groups replace through maximum three following each groups separately according to circumstances: NR ^2cR ^2d, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

Described R ^2cAnd R ^2dBe H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ^2cAnd R ^2dForm indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

F) R ⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

G) R ⁵Be H, C _1-6Alkyl, C (O) NR ⁶R ⁷, C (S) NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸Or S (O) ₂R ⁸

H) R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C1 _-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; With

I) dotted line is represented optional double bond.

Embodiment provides the compound with formula XVIII:

Wherein:

A) R ¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, these groups replace through maximum three following each groups separately according to circumstances: NR ⁵R ⁶, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl- _C1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

B) R ²Be H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, these groups replace through maximum three following each groups separately according to circumstances: NR ⁵R ⁶, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

C) R ³Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

D) R ⁴Be C _1-6Alkyl, C (O) NR ⁵R ⁶, C (S) NR ⁵R ⁶, C (O) R ⁷, C (O) OR ⁷Or S (O) ₂R ⁷

E) R ⁵And R ⁶Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances ^1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁵And R ⁶Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

F) R ⁷Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁷Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

G) R ⁸Be C _1-3Alkyl, C _3-4Cycloalkyl or phenyl, this phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-3Alkyl or C _1-3Alkoxyl group; With

H) dotted line is represented optional double bond;

Or its pharmaceutically acceptable salt.

Embodiment provides the compound with following formula:

Wherein:

A) Z sets for NS3 proteolytic enzyme His57 imidazoles part hydrogen bond to be connected and the group that is connected with NS3 proteolytic enzyme Gly137 nitrogen-atoms hydrogen bond;

B) P ₁' for setting the group that forms with at least one NS3 proteolytic enzyme S1 ' bag (pocket) apolar interaction partly for, described part is selected from the group that is made up of Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42 and Phe43;

C) linking group formed for the atom that selects the group that free carbon, oxygen, nitrogen, hydrogen and sulphur forms by 1 to 5 of L;

D) P2 is selected from the group that is made up of following each group: the aryl that is unsubstituted, the aryl that is substituted, the heteroaryl that is unsubstituted, the heteroaryl that is substituted, the heterocyclic radical that is unsubstituted and the heterocyclic radical that is substituted; To form and at least one NS3 proteolytic enzyme S2 bag apolar interaction partly, described part is selected from the group that is made up of His57, Arg155, Val78, Asp79, Gln80 and Asp81 to P2 by the L location;

E) dotted line is represented optional double bond;

F) R ⁵Be selected from NR by H, C (O) ⁶R ⁷And C (O) OR ⁸The group that forms;

G) R ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected; With

H) R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects; Its restricted condition is that described compound does not comprise above-mentioned compound with formula II, III or IV.

Embodiment provides the compound with following formula:

Or

Wherein:

R ⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl or benzyl, described phenyl or benzyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ⁵Be C _1-6Alkyl, C (O) NR ⁶R ⁷, C (S) NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, S (O) ₂R ⁸Or (CO) CHR ²¹NH (CO) R ²²

R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects;

Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-3Alkyl, C _3-7Cycloalkyl or phenyl, this phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-3Alkyl, C _3-7Cycloalkyl or C _1-3Alkoxyl group; Perhaps Y is a carboxylic acid;

P=0 or 1;

V is selected from OH, SH or NH ₂

Dotted line is represented optional double bond;

R ²¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl; Perhaps R ²¹Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ²¹Be pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group or sulphur phenoxy group; With

R ²²Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl.

Embodiment provides the compound with following formula:

Wherein:

Q is the core ring that is selected from and the following:

Wherein, described core ring can be unsubstituted or replace through following group: H, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, C _1-6Alkyl, be substituted C _1-6Alkyl, C _1-6Alkoxyl group, be substituted C _1-6Alkoxyl group, C _{6 or 10}Aryl, pyridyl, pyrimidyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group, sulphur phenoxy group, sulfoamido, urea, thiocarbamide, amide group, ketone group, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxy amino, alkoxyl group heterocyclic radical, alkylamino, alkyl carboxyl, carbonyl, volution cyclopropyl, volution cyclobutyl, volution cyclopentyl or volution cyclohexyl

Perhaps, Q is R ¹-R ², R wherein ¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, these groups replace through maximum three following each groups separately according to circumstances: NR ⁶R ⁷, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; And R ²Be H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, these groups replace through maximum three following each groups separately according to circumstances: NR ⁶R ⁷, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C4 _-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects;

Y is COOR ⁹, R wherein ⁹Be C _1-6Alkyl; Perhaps Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-3Alkyl, C _3-7Cycloalkyl or phenyl, this phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-3Alkyl, C _3-7Cycloalkyl or C _1-3Alkoxyl group; Perhaps Y is a carboxylic acid;

P=0 or 1;

V and W are selected from O, S or NH independently of one another;

Dotted line is represented optional double bond;

Embodiment provides the medical composition that comprises preferred compound and pharmaceutically acceptable supporting agent.

Embodiment provides the method for infection with hepatitis C virus in the treatment individuality, and described method comprises to the come into operation preferred compound of significant quantity of this individuality.

Embodiment provides the method for hepatic fibrosis in the treatment individuality, and described method comprises to the come into operation preferred compound of significant quantity of this individuality.

Embodiment provides the method that strengthens the liver function in the individuality with infection with hepatitis C virus, and described method comprises to the come into operation preferred compound of significant quantity of this individuality.

The chemical formula of the expression compound described in the literary composition is also represented its pharmaceutically acceptable salt, solvate, ester and prodrug derivant.

Description of drawings

Do not have

Embodiment

Definition

As used herein, term " hepatic fibrosis (hepatic fibrosis) " is used alternatingly with " hepatic fibrosis (liver fibrosis) ", is meant the growth of scar tissue in liver, may come across in the context of chronic hepatitis infection.

Term " individuality ", " host ", " person under inspection " and " patient " are used alternatingly in the text, are meant Mammals, include, but not limited to primate, comprise the ape and the mankind.

As used herein, term " liver function " is meant the normal function of liver, include, but not limited to complex functionality, comprise, but be not limited to, (for example, albumin, thrombin, alkaline phosphatase, transaminase are (for example as serum protein, alanine aminotransferase, aspartic transaminase), 5 '-nucleosidase, gamma glutamyl transpeptidase, etc.) synthetic and bile acide synthetic of synthetic, bilirubinic synthetic, cholesterol; The hepatic metabolism function includes, but not limited to carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism and lipid metabolism; The detoxifcation of external medicine; The Hemodynamics function comprises internal organ and portal vein Hemodynamics; And similar functions.

As used herein, term " HCV NS3 proteinase inhibitor " and " NS3 proteinase inhibitor " are meant any medicament of the protease activity that suppresses HCV NS3/NS4A mixture.Unless otherwise indicated, term " NS3 inhibitor " is used alternatingly with term " HCV NS3 proteinase inhibitor " and " NS3 proteinase inhibitor ".

As used herein, term " polyol " represents to comprise at least two hydrocarbon with carbon atom bonded hydroxyl, comprises carbohydrate (reducing sugar and non-reducing sugar), glycitols and sugar-acids.Polyvalent alcohol can comprise other functional group.Examples of polyhydric alcohols comprises the glycitols such as N.F,USP MANNITOL and trehalose, and polyethers." reducing sugar " contain the reducible metal ion or can with Methionin in the protein and other amino hemiacetal group that covalent reaction takes place, and " non-reducing sugar " do not have these character of reducing sugar.The example of reducing sugar is: fructose, seminose, maltose, lactose, pectinose, wood sugar, ribose, rhamnosyl, semi-lactosi and glucose.Non-reducing sugar comprises sucrose, trehalose, sorbose, melizitose and raffinose.N.F,USP MANNITOL, Xylitol, erythritol, threitol, Sorbitol Powder and glycerine are the examples of glycitols.As for sugar-acids, comprise L Gluconate and its metal-salt.

Used term " polyethers " expression contains the hydrocarbon of at least three ehter bonds in the literary composition.Polyethers can comprise other functional group.Polyethers comprises polyoxyethylene glycol (PEG).

As used herein, term " continuing virus replys " (sustained viral response, SVR, be also referred to as " continuing to reply (sustained response) " and " continuing to reply (durable response) ") be meant with regard to serum HCV titre individual replying to HCV treatment of infection scheme.In general, " continue virus reply " be meant after stopping treatment, reach at least about one month, at least about two months, at least about three months, at least about four months, at least about five months or at least about detected among the patients serum in six months less than HCV RNA (for example, every milliliter of serum less than about 500, less than about 200 or less than about 100 genome duplications this).

As used herein " treatment failure patient " be meant the unresponsive HCV infected patient of previous HCV therapy (being called " nonresponder ") or begin previous therapy had and reply but can not keep the HCV infected patient (being called " recidivist ") that treatment is replied.Previous therapy can comprise usually with IFN-a single current system method or IFN-a combination therapy to treat, and wherein combination treatment comprises the IFN-α and such as the antiviral agent of ribavirin of coming into operation.

As used herein, term " treatment " be meant live desirable pharmacology and/or physiological effect.According to preventing disease or its symptom wholly or in part, described effect can be preventative, and/or according to cure diseases partially or completely and/or come from the detrimental action of this disease, can be curative." treatment " used herein contains any therapeutic action of disease in the Mammals (as the mankind), comprising: (a) prevention is may the susceptible disease but be not diagnosed as yet among the person under inspection of this disease this disease takes place; (b) suppress disease, that is, stop disease progression; (c) palliate a disease, that is, disease is disappeared.

Term " individuality ", " host ", " person under inspection " and " patient " are used alternatingly at this paper, are meant Mammals, include but not limited to murine, ape, the mankind, mammals farm-animals, mammals motion animal and mammals pet.

As used herein, term " the non-Buddhist nun's ketone of piperazine (pirfenidone) " is meant 5-methyl isophthalic acid-phenyl-2-(1H)-pyridone.As used herein, term " the non-Buddhist nun's keto analog of piperazine " is meant that hereinafter title is any formula I, IIA or IIB compound in the part of " the non-Buddhist nun's ketone of piperazine and its analogue ".All grammers of " the non-Buddhist nun's keto analog of concrete piperazine " and its become and claim to be meant that (but being not limited to) is meant that hereinafter title is the shown non-Buddhist nun's keto analog of any piperazine in the table 1 in the part of " the non-Buddhist nun's ketone of piperazine and its analogue ".

As used herein, term " I type Interferon Receptors agonist " is meant the part any natural generation or that non-natural takes place of human I type Interferon Receptors, and itself and described receptors bind also cause signal transduction via acceptor.I type Interferon Receptors agonist comprises Interferon, rabbit, comprise natural generation Interferon, rabbit, modified interferon, synthetic Interferon, rabbit, Peg-Intron, comprise the fusion rotein of Interferon, rabbit and heterologous protein, through shuffling Interferon, rabbit (shuffled interferon); Interferon Receptors had specific antibody; Non-chemistry of peptides agonist; And analogue.

As used herein, term " II type Interferon Receptors agonist " is meant the part any natural generation or that non-natural takes place of human II type Interferon Receptors, and itself and described receptors bind also cause signal transduction via acceptor.II type Interferon Receptors agonist comprise natural human interferoid γ, reorganization IFN-γ class, glycosylation IFN-γ class, Pegylation IFN-γ class, modified or variation IFN-γ class, IFN-γ fusion rotein, described acceptor is had specific antibody agonist, non-peptide agonists, and analogue.

As used herein, term " type iii interferon receptor stimulant " is meant human IL-28 acceptor (" IL-28R ", its aminoacid sequence is described by people such as Sheppard (vide infra)) part any natural generation or that non-natural takes place, itself and described receptors bind also cause signal transduction via acceptor.

As used herein, term " Interferon Receptors agonist " is meant any I type Interferon Receptors agonist, II type Interferon Receptors agonist or type iii interferon receptor stimulant.

Term " administration incident " is meant antiviral agent is come into operation to the patient who needs thus as used herein, and this incident comprises that one or many discharges antiviral agent from drugs distribution apparatus.Therefore, as used herein, term " administration incident " includes but not limited to, settles successive administration device (for example, pump or other controlled release injecting systems); With then settle the successive administration system after the independent subcutaneous injection.

" successive administration " as used herein (for example in the content about " material is to the successive administration of tissue ") meaning is that medicine is moved to medicine-feeding part, for example move in the tissue, making provides the material of desired amount through seclected time to tissue, and wherein patient's per minute receives the medicine of about same amount during seclected time.

As used herein, " controlled release " (for example, in the content of " controlled drug release ") meaning is with selected or controlled in addition speed, interval and/or (for example measures h substance, I type or type iii interferon receptor stimulant, as IFN-a), described speed, interval and/or amount are not influenced by environment for use substantially.Therefore " controlled release " comprises, but unnecessary being limited to, successive administration and medelling administration (patterned delivery) substantially (for example, through regularly or the intermittent type administration of the time period of not timing interval interrupt).

Comprise through predetermined amount of time (for example, being different from the time period relevant) with certain pattern (normally cardinal principle mode of rule) administration as " medelling (patterned) " used in content or " temporary transient (temporal) " with for example bullet formula injection about administration." medelling " or " temporary " administration with speed that increase progressively, that successively decrease, constant or pulsation substantially or speed range (for example comprises, the volume of pharmaceutical preparation in the amount of time per unit medicine or unit time) administration also further comprises successive or successive or administration substantially slowly.

Term " controlled doser " comprise wherein by device self control or definite medicine or device in the release (for example, arranging rate of release, time of releasing) of contained other desirable material and the device that not influenced by environment for use or discharge with reproducible speed in environment for use.

Looking like as " continuous substantially " used in the content about " cardinal principle continuous infusion " or " successive administration substantially " is to continue predetermined administration time section in the continual mode of cardinal principle to come administration, and wherein period any 8 a hour interior interim never dropped to zero by the received medication amount of patient at the fixed time.In addition, " substantially continuously " administration may comprise also that continuing predetermined administration time section with continual cardinal principle constant set rate or speed range substantially (for example, the medication amount of time per unit, or the volume of pharmaceutical preparation in the unit time) comes administration.

But as described in as " steady state substantially " meaning used in the content of the biological parameter that changes about time function being biological parameter in time process show constant value substantially, make be not more than in any 8 hour period (AUC8hr) in time course by area under curve as the value defined of the biological parameter of the function of time about more than 20% or about below 20%, preferably be not more than about more than 15% or about below 15%, more preferably no more than about more than 10% or about below 10%, the average area (AUC8hr mean value) under the curve of biological parameter in 8 hour period in the time course.AUC8hr mean value be defined as the area under curve (AUCtotal) of biological parameter in whole time course divided by time course in the merchant (q) of 8 hours numbers (total/3days) at interval, that is, q=(AUCtotal) is (total/3days).For instance, in content about drug serum concentration, when drug serum concentration area under curve (AUC8hr) in any 8 hour period in time course is not more than about more than 20% or about 20% following drug serum concentration area (AUC8hr mean value) under the averaged curve in 8 hour period in time course, promptly, with regard to the drug serum concentration in the time course, AUC8hr is not more than about more than 20% or during about 20% following AUC8hr mean value, and drug serum concentration remains on steady state substantially during time course.

As used herein, " hydrogen bond " be meant electronegative atom (as oxygen, nitrogen, sulphur or halogen) and and the hydrogen atom of another electronegative atom (as oxygen, nitrogen, sulphur or halogen) covalency keyed jointing between magnetism.Referring to, for example, people such as Stryer. ＂ Biochemistry ＂, 2002, the five editions, Freeman; Co.NY.Hydrogen bond is formed between two unshared-electrons of hydrogen atom and another atom usually.When hydrogen atom is separated by about 2.5 dusts to about 3.8 dusts with the non-covalent electronegative atom that combines, and when the angle that is formed by three atoms (being covalently bonded in electronegative atom, hydrogen and the non-covalent electronegative atom that is incorporated into hydrogen of hydrogen) is departed from about 45 degree or spent less than 45 from 180 degree, can there be hydrogen bond between hydrogen and the non-covalent electronegative atom that is incorporated into hydrogen.Hydrogen atom can be described as " hydrogen bond length " in this article with the non-covalent distance that combines between the electronegative atom, and the angle that is formed by three atoms (being covalently bonded in electronegative atom, hydrogen and the non-covalent electronegative atom that is incorporated into hydrogen of hydrogen) can be described as " hydrogen bond angle " in this article.In some cases, hydrogen bond length is short more, and the hydrogen bond of formation is strong more; Therefore in some cases, hydrogen bond length can be between about 2.7 dusts to about 3.6 dusts, or about 2.9 dusts are between about 3.4 dusts.In some cases, straight line is approached at the hydrogen bond angle more, and the hydrogen bond of formation is strong more, and therefore in some cases, 25 degree or littler more can be departed from from 180 degree in the hydrogen bond angle, or get over 10 degree or littler.

As used herein, " apolar interaction " is meant non-polar molecule or part or has low polar molecule or part is enough near the interaction of the model ylid bloom action between described part and/or is enough to get rid of interaction as the polar solvent molecule of water molecules.Referring to, for example, people such as Stryer. ＂ Biochemistry ＂, 2002, the five editions, Freeman; Co.N.Y.Distance between the atom (not comprising hydrogen atom) of apolar interaction part usually can be between about 2.9 dusts between about 6 dusts.In some cases, the distance between the apolar interaction part is less than the distance of holding a water molecules.As used herein, nonpolar part or have low polar and partly be meant to have low dipole moment (usually less than H ₂O-H key and the NH of O ₃The dipole moment of N-H key) part and/or in hydrogen bonded or electrostatic interaction common non-existent part.Example with low polar part is alkyl, thiazolinyl and the aryl moiety that is unsubstituted.

As used herein, NS3 proteolytic enzyme S1 ' bag part is meant and a residue C-terminal is positioned by the part of the interactional NS3 proteolytic enzyme of amino acid of the cracking site of the substrate polypeptide of NS3 protease cracking (for example, with peptide substrate DLEVVT-STWVLV in the interactional NS3 proteolytic enzyme of amino acid S part).Exemplary part includes, but not limited to the peptide main chain of amino acid Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42 and Phe43 or the atom of side chain, and referring to people such as Yao., Structure 1999,7, and 1353.

As used herein, NS3 proteolytic enzyme S2 bag partly is meant and two residue N-terminal is positioned by the part of the interactional NS3 proteolytic enzyme of amino acid of the cracking site of the substrate polypeptide of NS3 protease cracking (for example, with peptide substrate DLEVVT-STWVLV in the interactional NS3 proteolytic enzyme of amino acid V part).Exemplary part includes, but not limited to the peptide main chain of amino acid His57, Arg155, Val78, Asp79, Gln80 and Asp81 or the atom of side chain, and referring to people such as Yao., Structure 1999,7, and 1353.

As used herein, second section " location " first part be meant by with the dimensional orientation of the characteristic of first atom or the covalently bound second section of part decision first part.For instance, phenyl carbons can will be positioned on the locus with its bonded Sauerstoffatom, makes that the hydroxylic moiety in Sauerstoffatom and the NS3 avtive spot forms hydrogen bond.

Before further describing embodiment, should be appreciated that the present invention is not limited to described specific embodiment, certain thereby embodiment can change.Should also be clear that term used in the literary composition only is to be used to describe specific embodiment, rather than be used for restriction.

When providing the value of certain limit, should be appreciated that, except that offering some clarification in addition, any other the described or intervention value in each intervention value between the upper and lower bound of described scope (be accurate to lower limit unit 1/10th) and the described scope includes in described embodiment.These upper and lower bounds more among a small circle can be included in separately that embodiment also comprises simultaneously more among a small circle in, can get rid of the arbitrary boundary that is in the described scope.When described scope comprises one or both in the described boundary, exclude that the scope of any one is also included among the embodiment in the described boundary.

Unless otherwise indicated, all scientific and technical terminologies used herein have with the embodiment those of ordinary skill in the field the identical meanings generally understood.Though any method similar or impartial to content described herein and material also can use current description preferred method and material in the enforcement of embodiment or test.In the literary composition mentioned all open cases by reference at this with for referencial use, method and/or the material relevant that come disclosure and description to quote with these open cases.

It should be noted that as this paper and accessory claim book usedly, singulative " " comprises plural notion, unless expressly stated otherwise.Therefore, for instance, mention that " method " comprises a plurality of methods, and mention that " potion " comprises the known impartial agent of potion or multi-agent and one of ordinary skill in the art, or the like.

Open case as herein described only provides its disclosure before the application's case applying date.Should not be construed as, the present invention haves no right by previous invention and prior to this open case.What provided in addition, can be different from the reality that may need affirmation separately open day open day.

Embodiment provides the compound of formula I-XIX, and the medical composition and the preparation that comprise arbitrary compound of formula I-XIX.The compounds of this invention can be used for treating Flavivirus to be infected, and infects and other illness as HCV, as mentioned below.

Composition

Various composition embodiment are below described.For ease of discussing, these embodiment describe part A, B, C, D and E.Should be understood that and to be applicable to this part at the various terms of specific part definition, also be applicable to other place of mentioning described specific part herein.Equally, mention in should be in this part used corresponding numbering or the labeling scheme content at optional network specific digit or mark any in part and understanding, rather than in irrelevant part, understand in used possible similar or the numbering that is equal to or the labeling scheme content, except as otherwise noted.

Part A

Part A embodiment provides the compound with general formula I:

Wherein:

Q is the core ring that is selected from and the following:

With

Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁹Be C _{6 or 10}Aryl, this aryl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁹For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl, NR ⁶R ⁷, NR ^1aR ^1bOr (CO) OH; Perhaps R ⁹For replacing maximum twice assorted aromatic nucleus through following group according to circumstances: halogen, cyano group, nitro, hydroxyl or C _1-6Alkoxyl group; Perhaps Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

R wherein _1aAnd R _1bBe H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, C _1-6Alkoxyl group, amide group or phenyl;

With

P=0 or 1;

V is selected from O, S or NH;

Dotted line is represented optional double bond;

R ²¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl; Perhaps R ²¹Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ²¹Be pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group or sulphur phenoxy group; With

R ²²Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl.

In a preferred embodiment, part A embodiment provides the compound with general formula I, and wherein said core ring is

In a preferred embodiment, part A embodiment provides the compound with general formula I a:

In a preferred embodiment, part A embodiment provides the compound with general formula I b:

In a preferred embodiment, part A embodiment provides the compound with general formula I c:

In a preferred embodiment, part A embodiment provides the compound with general formula I d:

In a preferred embodiment, part A embodiment provides the compound with general formula I e:

In a preferred embodiment, part A embodiment provides the compound with general formula I f:

In a preferred embodiment, part A embodiment provides the compound with general formula I g:

In a preferred embodiment, part A embodiment provides the compound with general formula I h:

In a preferred embodiment, part A embodiment provides the compound with general formula I i:

In a preferred embodiment, part A embodiment provides the compound with general formula I j:

In a preferred embodiment, part A embodiment provides the compound with general formula I z:

In a preferred embodiment, part A embodiment provides the compound with general formula I, and wherein Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be selected from by C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl and NR ^1aR ^1bThe group that forms, wherein R ^1aAnd R ^1bBe H, C independently of one another _1-6Alkyl or C _3-7Cycloalkyl.

In a preferred embodiment, part A embodiment provides the compound with general formula I, and wherein the two keys of C13-C14 are cis.

In a preferred embodiment, part A embodiment provides the compound with general formula I, and wherein the two keys of C13-C14 are trans.

In certain embodiments, compound of Formula I does not comprise disclosed compound among the PCT/US04/33970.For instance, in certain embodiments, compound of Formula I does not comprise with the formula II among the B of lower section, III and IV compound.

Part B

Part B embodiment provides the compound with general formula I I, III and IV:

Wherein:

R ¹And R ²Be H, halogen, cyano group, nitro, hydroxyl, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group, C _{6 or 10}Aryl, pyridyl, pyrimidyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group, sulphur phenoxy group, S (O) ₂NR ⁶R ⁷, NHC (O) NR ⁶R ⁷, NHC (S) NR ⁶R ⁷, C (O) NR ⁶R ⁷, NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, NHC (O) R ⁸, NHC (O) OR ⁸, SO _mR ⁸, NHS (O) 2R ⁸, CH _nNR ⁶R ⁷, OCH _nNR ⁶R ⁷Or OCH _nR ⁹(R wherein ⁹Be imidazolyl or pyrazolyl); Described at R ¹And R ²Definition in thienyl, pyrimidyl, furyl, thiazolyl and oxazolyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹And R ²Definition in C _{6 or 10}Aryl, pyridyl, phenoxy group and sulphur phenoxy group replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

M=0,1 or 2;

R ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C ^2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-5Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁹Be C _{6 or 10}Aryl, this aryl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁹For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl, NR ⁶R ⁷Or (CO) OH; Perhaps R ⁹For replacing maximum twice assorted aromatic nucleus through following group according to circumstances: halogen, cyano group, nitro, hydroxyl or C _1-6Alkoxyl group; Perhaps Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

R ¹⁰And R ¹¹Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹⁰And R ¹¹Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹⁰And R ¹¹Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹⁰And R ¹¹Be combined into O;

P=0 or 1;

R ¹²And R ¹³Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), wherein these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹²And R ¹³Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹²And R ¹³Independently of one another for according to circumstances through (CH ₂) _nOR ⁸The C that replaces _1-6Alkyl;

R ²⁰Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), wherein these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

n＝1-4；

V is selected from O, S or NH;

Dotted line is represented optional double bond;

R ²¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or phenyl; Perhaps R ²¹Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ²¹Be pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group or sulphur phenoxy group; With

Part B embodiment provides the compound with general formula I I:

Wherein:

R ¹Be H, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ²Be H, OCH _nNR ⁶R ⁷, OCH _nR ¹⁶, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ²R in the definition ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl; Perhaps described at R ²R in the definition ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

n＝1-3；

R ⁴＝H；

R ⁵Be H, C (O) NR ⁶R ⁷Or C (O) OR ⁸, described at R ⁵R in the definition ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl;

R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects;

Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, wherein R ⁹Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, C _1-6Alkoxyl group or phenyl;

R ¹⁰, R ¹¹, R ¹²And R ¹³Be H;

P=0 or 1;

V=O; With

W is selected from O, NH or CH ₂

In a preferred embodiment, part B embodiment provides the compound with general formula I I, III and IV, and wherein p can be 0.In a preferred embodiment, part B embodiment provides the compound with general formula I I, III and IV, and wherein p can be 1.

In a preferred embodiment, part B provides the compound with general formula I I, III and IV, wherein R ¹And R ²In any one or both be H.In certain embodiments, p is 0.In other embodiments, p is 1.

In a preferred embodiment, part B embodiment provides the compound with general formula I I, III and IV, wherein R ¹And R ²All be not H.In certain embodiments, p is 0.In other embodiments, p is 1.

In a preferred embodiment, part B embodiment provides the compound with general formula I I, III and IV, wherein R ²Be OCH _nNR ⁶R ⁷Or OCH _nR ¹⁶

In a preferred embodiment, part B embodiment provides the compound with general formula I I, III and IV, wherein R ⁹Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl.

In a preferred embodiment, part B provides the compound with general formula I I, III and IV, wherein R ⁹Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

In a preferred embodiment, part B embodiment provides the compound with general formula I I, III and IV, wherein R ⁹For replacing maximum twice assorted aromatic nucleus through following group according to circumstances: halogen, cyano group, nitro, hydroxyl or C _1-6Alkoxyl group.

In a preferred embodiment, part B provides the compound with general formula I I, III and IV, wherein R ⁹For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl, NR ⁶R ⁷Or (CO) OH.

In a preferred embodiment, part B provides the compound with general formula I I, III and IV, its Chinese style (II), (III) or (IV) in dotted line represent singly-bound.

Part B embodiment provides the compound with general formula I I:

Wherein:

R ¹And R ²Be H, halogen, cyano group, nitro, hydroxyl, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group, C _{6 or 10}Aryl, pyridyl, pyrimidyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group, sulphur phenoxy group, S (O) ₂NR ⁶R ⁷, NHC (O) NR ⁶R ⁷, NHC (S) NR ⁶R ⁷, C (O) NR ⁶R ⁷, NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, NHC (O) R ⁸, NHC (O) OR ⁸, SO _mR ⁸, NHS (O) ₂R ⁸, OCH _nNR ⁶R ⁷Or OCH _nR ¹⁶(R wherein ¹⁶Be imidazolyl or pyrazolyl); Described at R ¹And R ²Definition in thienyl, pyrimidyl, furyl, thiazolyl and oxazolyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹And R ²Definition in C _{6 or 10}Aryl, pyridyl, phenoxy group and sulphur phenoxy group replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

M=0,1 or 2;

R ⁵Be H, C _1-6Alkyl, C (O) NR ⁶R ⁷, C (S) NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, S (O) ₂R ⁸Or (CO) CHR ²¹NH (CO) R ₂₂

Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁹Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁹For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl, NR ⁶R ⁷Or (CO) OH; Perhaps R ⁹For replacing maximum twice assorted aromatic nucleus through following group according to circumstances: halogen, cyano group, nitro, hydroxyl or C _1-6Alkoxyl group; Perhaps Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

R ¹⁰And R ¹¹Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ₁₄Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹⁰And R ¹¹Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹⁰And R ¹¹Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹⁰And R ¹¹Be combined into O;

P=0 or 1;

R ¹²And R ¹³Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ^{14 are}H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ₁₄Be C _{6 or 10}Aryl, this aryl replace through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹²And R ¹³Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹²And R ¹³Independently of one another for according to circumstances through (CH ₂) _nOR ⁸The C that replaces _1-6Alkyl;

R ²⁰Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), wherein these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ₁₂And R ₁₃Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

n＝0-4；

V is selected from O, S or NH;

Dotted line is represented optional double bond;

R ²¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or phenyl; Perhaps R ²¹Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C2 _-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ²¹Be pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group or sulphur phenoxy group; With

Part B embodiment provides the compound with general formula I Ia:

Wherein:

R ¹And R ²Be H, halogen, cyano group, hydroxyl, C independently of one another _1-3Alkyl or C _1-3Alkoxyl group;

R ⁵Be H, C (O) NR ⁶R ⁷, C (O) R ⁸Or C (O) OR ⁸

R ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl;

R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or 3-tetrahydrofuran base.

Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-3Alkyl, C _3-7Cycloalkyl or phenyl, this phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-3Alkyl, C _3-7Cycloalkyl or C _1-3Alkoxyl group; Perhaps Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

R ¹⁰And R ¹¹Be H or C independently of one another _1-3Alkyl, perhaps R ¹⁰And R ¹¹Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected;

W is selected from O, NH; With

Dotted line is represented optional double bond;

Part B embodiment provides the compound with general formula III a:

Wherein:

R ⁴Be H;

R ⁵Be H, C (O) NR ⁶R ⁷, C (O) R ⁸Or C (O) OR ⁸

W is selected from O, NH; With

Dotted line is represented optional double bond;

Part B embodiment provides the compound with general formula I Ib:

Wherein:

R ⁵Be H, C (O) OR ⁸Or C (O) NHR ⁸

R ⁸Be C _1-6Alkyl, C _5-6Cycloalkyl or 3-tetrahydrofuran base;

R ⁹Be C _1-3Alkyl, C _3-4Cycloalkyl or phenyl, this phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-3Alkyl or C _1-3Alkoxyl group;

W is selected from O, NH; With

Dotted line is represented optional double bond;

Part B embodiment provides the compound with general formula III b:

Wherein:

R ⁵Be H, C (O) OR ⁸Or C (O) NHR ⁸

R ⁸Be C _1-6Alkyl, C _5-6Cycloalkyl or 3-tetrahydrofuran base;

R ⁹Be C _1-3Alkyl, C _3-5Cycloalkyl or phenyl, this phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-3Alkyl or C _1-3Alkoxyl group;

R ¹⁰And R ¹¹Be H, C independently of one another _1-3Alkyl or C _4-5Cycloalkyl;

W is selected from O, NH; With

Dotted line is represented optional double bond;

Part B embodiment provides the compound with general formula I Ic:

Wherein:

R ¹And R ²Be H, chlorine, fluorine, cyano group, hydroxyl, C independently of one another _1-3Alkyl or C _1-3Alkoxyl group;

R ⁵Be H, C (O) OR ⁸Or C (O) NHR ⁸

R ⁸Be C _1-6Alkyl or C _5-6Cycloalkyl;

(e) R ¹⁰And R ¹¹Be H or C independently of one another _1-3Alkyl, perhaps R ¹⁰And R ¹¹Form cyclopropyl or cyclobutyl with the carbon that it connected; With

(f) dotted line is represented optional double bond;

Part B embodiment provides the compound with general formula III c:

Wherein:

R ⁵Be H, C (O) OR ⁸Or C (O) NHR ⁸

R ⁸Be C _1-6Alkyl or C _5-6Cycloalkyl;

R ⁹Be C _1-3Alkyl, C _3-4Cycloalkyl or phenyl, this phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-3Alkyl or C _1-3Alkoxyl group; With

Dotted line is represented optional double bond;

Part B embodiment provides the compound with general formula III d:

Wherein:

R ⁴Be H;

R ⁵Be H, C (O) NR ⁶R ⁷, C (O) R ⁸Or C (O) OR ⁸

R ²⁰Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷Or (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), wherein these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

W is selected from O or NH; With

Dotted line is represented optional double bond;

Part B embodiment provides the compound with general formula I Va:

Wherein:

R ⁴Be H;

R ⁵Be H, C (O) NR ⁶R ⁷, C (O) R ⁸Or C (O) OR ⁸

R ²⁰Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷Or (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), wherein these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

W is selected from O or NH;

Dotted line is represented optional double bond;

Wherein Z is for through condensing or additional aryl heteroaryl ring system.

Portion C

Portion C embodiment provides the compound with general formula X I:

Wherein:

R ^1aAnd R ^1bBe H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, C _1-6Alkoxyl group, amide group or phenyl;

Perhaps R ^1aAnd R ^1bBe H and C6 or 10 aryl independently of one another, this aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

With

W is O or NH;

V is selected from O, S or NH;

R ²For having the dicyclo secondary amine of following structure:

Wherein, R ²¹And R ²²Be H, halogen, cyano group, nitro, hydroxyl, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group, C _{6 or 10}Aryl, pyridyl, pyrimidyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group, sulphur phenoxy group, S (O) ₂NR ⁶R ⁷, NHC (O) NR ⁶R ⁷, NHC (S) NR ⁶R ⁷, C (O) NR ⁶R ⁷, NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, NHC (O) R ⁸, NHC (O) OR ⁸, SO _mR ⁸(m is 0,1 or 2) or NHS (O) ₂R ⁸Described at R ²¹And R ²²Definition in thienyl, pyrimidyl, furyl, thiazolyl and oxazolyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ₂₁And R ²²Definition in C _{6 or 10}Aryl, pyridyl, phenoxy group and sulphur phenoxy group replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ¹⁰And R ¹¹Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷Or (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C ^1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), these groups all according to circumstances through with

Following group replaces one to three time: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹⁰And R ¹¹Definition in C _{6 or 10}Aryl replaces through maximum three following groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹⁰And R ¹¹Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹⁰And R ¹¹Be combined into O;

P=0 or 1 wherein;

R wherein ²⁰Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷Or (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), wherein these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

N=0-4 wherein:

R wherein ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

Perhaps R when W=NH and V=O ²Be R ^2aR ^2b, wherein

R ⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ⁵Be H, C _1-6Alkyl, C (O) NR ⁶R ⁷, C (S) NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸Or S (O) ₂R ⁸

R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; With

Dotted line is represented optional double bond;

Portion C embodiment provides the compound with general formula X II:

Wherein:

Perhaps R ^1aAnd R ^1bBe H or the heteroaryl that is selected from the group that forms by following group independently of one another:

With

Perhaps NR _1aR ^1bBe three to hexa-atomic alkyl cyclic secondary amine, it has one to three according to circumstances and incorporates the heteroatoms in the ring into and replace one to three time through following group according to circumstances: halogen, cyano group, nitro, C _1-6Alkoxyl group, amide group or phenyl;

R ²¹And R ²²Be H, halogen, cyano group, hydroxyl, C independently of one another _1-3Alkyl or C _1-3Alkoxyl group;

R ⁵Be H, C (O) NR ⁶R ⁷, C (O) R ⁸Or C (O) OR ⁸

R ⁸Be C _1-6Alkyl, C ^3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or 3-tetrahydrofuran base;

R ¹⁰And R ¹¹Be H, halogen or C independently of one another _1-3Alkyl, perhaps R ¹⁰And R ¹¹Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected;

R ¹²And R ¹³Be H, halogen, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 halogen atoms according to circumstances _1-6Alkyl; With

Dotted line is represented optional double bond.

Portion C embodiment provides the compound with general formula X III:

Wherein:

With

R ⁵Be H, C (O) NR ⁶R ⁷, C (O) R ⁸Or C (O) OR ⁸

R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or 3-tetrahydrofuran base; With

Dotted line is represented optional double bond.

Portion C embodiment provides the compound with general formula X IV:

Wherein:

With

R wherein ^1cBe H, halogen, C _1-6Alkyl, C _3-6Cycloalkyl, C _1-6Alkoxyl group, C _3-6Cycloalkyloxy, NO ₂, N (R ^1d) ₂, NH (CO) R ^1dOr NH (CO) NHR ^1d, each R wherein ^1dBe H, C independently ^1-6Alkyl or C ^3-6Cycloalkyl;

R ^2aFor according to circumstances through maximum three C that following each group replaces _{6 or 10}Aryl: NR ^2cR ^2d, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6

Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

Described R ^2cAnd R ^2dBe H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ^2cAnd R ^2dForm indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

Perhaps R ^2aBe unsaturated five yuan or six membered heteroaryl, perhaps this definition heteroaryl and another ring condense and form heterocycle or any other ring;

R ⁵Be H, C (O) NR ⁶R ⁷, C (O) R ⁸Or C (O) OR ⁸

Dotted line is represented optional double bond.

Portion C embodiment provides the compound with general formula X V:

Wherein:

R ⁵Be H, C (O) OR ⁸Or C (O) NHR ⁸

R ⁸Be C _1-6Alkyl, C _5-6Cycloalkyl or 3-tetrahydrofuran base;

W is selected from O or NH; With

Dotted line is represented optional double bond.

Portion C embodiment provides the compound with general formula X VI:

Wherein:

R ⁵Be H, C (O) OR ⁸Or C (O) NHR ⁸

R ⁸Be C _1-6Alkyl or C _5-6Cycloalkyl;

R ¹⁰And R ¹¹Be H or C independently of one another _1-3Alkyl, perhaps R ¹⁰And R ¹¹Form cyclopropyl or cyclobutyl with the carbon that it connected; With

Dotted line is represented optional double bond.

Portion C embodiment provides the compound with general formula X VII:

Wherein:

R ⁵Be H, C (O) OR ⁸Or C (O) NHR ⁸

R ⁸Be C _1-6Alkyl or C _5-6Cycloalkyl;

Dotted line is represented optional double bond.

Part D

Part D embodiment provides the compound with general formula X VIII:

Wherein:

R ¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, these groups replace through maximum three following each groups separately according to circumstances: NR ⁵R ⁶, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ²Be H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, these groups replace through maximum three following each groups separately according to circumstances: NR ⁵R ⁶, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ³Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ⁴Be C ^1-6Alkyl, C (O) NR ⁵R ⁶, C (S) NR ⁵R ⁶, C (O) R ⁷, C (O) OR ⁷Or S (O) ₂R ⁷

R ⁵And R ⁶Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁵And R ⁶Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

R ⁷Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁷Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ⁸Be C _1-3Alkyl, C _3-4Cycloalkyl or phenyl, this phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-3Alkyl or C _1-3Alkoxyl group; With

Dotted line is represented optional double bond.

Part E

Part E embodiment provides the compound with general formula X IX:

Wherein:

Z sets for NS3 proteolytic enzyme His57 imidazoles part hydrogen bond to be connected and the group that is connected with NS3 proteolytic enzyme Gly137 nitrogen-atoms hydrogen bond;

P ₁' for setting the group that forms with at least one NS3 proteolytic enzyme S1 ' bag (pocket) apolar interaction partly for, described part is selected from the group that is made up of Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42 and Phe43;

The linking group that L forms for the atom that selects the group that free carbon, oxygen, nitrogen, hydrogen and sulphur forms by 1 to 5;

P2 is selected from the group that is made up of following each group: the aryl that is unsubstituted, the aryl that is substituted, the heteroaryl that is unsubstituted, the heteroaryl that is substituted, the heterocyclic radical that is unsubstituted and the heterocyclic radical that is substituted; To form and at least one NS3 proteolytic enzyme S2 bag apolar interaction partly, described part is selected from the group that is made up of His57, Arg155, Val78, Asp79, Gln80 and Asp81 to P2 by the L location;

Dotted line is represented optional double bond;

R ⁵Be selected from NR by C (O) ⁶R ⁷And C (O) OR ⁸The group that forms;

R ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected; With

R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ⁴The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects;

As used herein, " hydrogen bond " be meant electronegative atom (as oxygen, nitrogen, sulphur or halogen) and and the hydrogen atom of another electronegative atom (as oxygen, nitrogen, sulphur or halogen) covalency keyed jointing between magnetism.Referring to, for example, people such as Stryer. ＂ Biochemistry ＂, 2002, the five editions, Freeman; Co.NY.Hydrogen bond is formed between two unshared-electrons of hydrogen atom and another atom usually.When hydrogen atom is separated by about 2.5 dusts to about 3.8 dusts with the non-covalent electronegative atom that combines, and when the angle that is formed by three atoms (being covalently bonded in electronegative atom, hydrogen and the non-covalent electronegative atom that is incorporated into hydrogen of hydrogen) is departed from about 45 degree or spent less than 45 from 180 degree, can there be hydrogen bond between hydrogen and the non-covalent electronegative atom that is incorporated into hydrogen.Hydrogen atom can be described as " hydrogen bond length " in this article with the non-covalent distance that combines between the electronegative atom, and the angle that is formed by three atoms (being covalently bonded in electronegative atom, hydrogen and the non-covalent electronegative atom that is incorporated into hydrogen of hydrogen) can be described as " hydrogen bond angle " in this article.In some cases, hydrogen bond length is short more, and the hydrogen bond of formation is strong more; Therefore in some cases, hydrogen bond length can between about 7 dusts to about 3.6 dusts or about 2.9 dusts between about 3.4 dusts.In some cases, straight line is approached at the hydrogen bond angle more, and the hydrogen bond of formation is strong more, and therefore in some cases, 25 degree or littler more can be departed from from 180 degree in the hydrogen bond angle, or get over 10 degree or littler.

As used herein, second section " location " first part be meant by with the dimensional orientation of the character of first atom or the covalently bound second section of part decision first part.For instance, phenyl carbons can will be positioned on the locus with its bonded Sauerstoffatom, makes that the hydroxylic moiety in Sauerstoffatom and the NS3 avtive spot forms hydrogen bond.

This paper also provides and contains the compound that is set at specific region, particular amino acid residue or the interactional part of specific atoms of NS3 proteolytic enzyme.Some compounds that this paper provided contain one or more parts that form hydrogen bond with specific region, particular amino acid residue or the specific atoms of NS3 proteolytic enzyme that are set at.Some compounds that this paper provided contain one or more parts that form non-polar action with specific region, particular amino acid residue or the specific atoms of NS3 proteolytic enzyme that are set at.For instance, the compound with general formula X IX can contain the part that peptide backbone atoms or pendant moiety one or more and the substrate binding pocket that is arranged in NS3 proteolytic enzyme form hydrogen bond.In another example, the compound with general formula X IX can contain the part that peptide main chain or side chain atom one or more and the substrate binding pocket that is arranged in NS3 proteolytic enzyme form apolar interaction.In formula XIX compound, the dotted line between carbon 13 and the carbon 14 may be singly-bound or two key.

As have that institute provides in the compound of general formula X IX, Z can be set at peptide backbone atoms or pendant moiety (including, but are not limited to NS3 proteolytic enzyme His57 imidazoles part and NS3 proteolytic enzyme Gly137 nitrogen-atoms) the formation hydrogen bond with the substrate binding pocket that is arranged in NS3 proteolytic enzyme.In some cases, Z can be set at NS3 proteolytic enzyme His57 imidazoles part and NS3 proteolytic enzyme Gly137 nitrogen-atoms and all form hydrogen bond.

P1 ' group with compound of general formula X IX can be set at and be arranged in the peptide main chain or side chain atom (including, but are not limited to form the amino-acid residue of NS3 proteolytic enzyme S1 ' bag) the formation apolar interaction of the substrate binding pocket of NS3 proteolytic enzyme.For example, P1 ' group can form apolar interaction with at least one amino acid that is selected from Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42 and Phe43.

P2 group with compound of general formula X IX can be set at and be arranged in the peptide main chain or side chain atom (including, but are not limited to form the amino-acid residue of NS3 proteolytic enzyme S2 bag) the formation apolar interaction of the substrate binding pocket of NS3 proteolytic enzyme.For example, the P2 group can form apolar interaction with at least one amino acid that is selected from His57, Arg155, Val78, Asp79, Gln80 and Asp81.The P2 group also can be set at peptide main chain or side chain atom (including, but not limited to form the amino-acid residue of NS3 proteolytic enzyme S2 bag) the formation hydrogen bond with the substrate binding pocket that is arranged in NS3 proteolytic enzyme.For example, the P2 group can form hydrogen bond with at least one amino acid that is selected from His57, Arg155, Val78, Asp79, Gln80 and Asp81.In some cases, P2 can form apolar interaction and hydrogen bond with the peptide main chain of the substrate binding pocket that is arranged in NS3 proteolytic enzyme or pendant moiety or atom (as be selected from His57, Arg155, Val78, Asp79, Gln80 and Asp81 amino acid).Described hydrogen bond and apolar interaction can betide same amino acid residue or the different aminoacids residue in the NS3 proteolytic enzyme S2 bag.In certain embodiments, the group of following each group composition of the optional freedom of P2: the aryl that is unsubstituted, the aryl that is substituted, the heteroaryl that is unsubstituted, the heteroaryl that is substituted, the heterocycle that is unsubstituted and the heterocycle that is substituted.

In certain embodiments, the position of P2 group is to be determined by linking group L.For example, P2 can locate the peptide main chain or the side chain atom (including, but are not limited to form the amino-acid residue of NS3 proteolytic enzyme S2 bag) that form with being arranged in the substrate binding pocket of NS3 proteolytic enzyme by linking group L and form apolar interaction.For example, the P2 group can be come to form apolar interaction with at least one amino acid that is selected from His57, Arg155, Val78, Asp79, Gln80 and Asp81 by the L location.In another example, P2 can be come to form hydrogen bond with the peptide main chain or the side chain atom (including, but not limited to form the amino-acid residue of NS3 proteolytic enzyme S2 bag) that are arranged in the substrate binding pocket of NS3 proteolytic enzyme by linking group L location.For example, the P2 group can be come to form hydrogen bond with at least one amino acid that is selected from His57, Arg155, Val78, Asp79, Gln80 and Asp81 by the L location.In some cases, P2 can be positioned and form apolar interaction and hydrogen bond with the peptide main chain of the substrate binding pocket that is arranged in NS3 proteolytic enzyme or side chain atom (as be selected from His57, Arg155, Val78, Asp79, Gln80 and Asp81 amino acid).Described hydrogen bond and apolar interaction can betide same amino acid residue or the different aminoacids residue in the NS3 proteolytic enzyme S2 bag.

As having that institute provides in the compound of general formula X IX, L can be the linking group that P2 is connected to the heterocycle main chain of formula XIX compound.Linking group L can contain and be fit to P2 is positioned any kind of atom and part in the NS3 protease substrate binding pocket.In one embodiment, L can contain 1 to 5 atom that selects the group of free carbon, oxygen, nitrogen, hydrogen and sulphur composition.In another embodiment, L can contain 2 to 5 atoms that select the group of free carbon, oxygen, nitrogen, hydrogen and sulphur composition.For example, L can contain formula-W-C (=V)-group, wherein V and W are selected from O, S or NH independently of one another.Concrete L group example includes, but not limited to ester, acid amides, carbamate, monothioester and thioamides.

Formula XIX compound also can contain R ⁵Group, wherein R ⁵Group can contain carboxy moiety.R ⁵The carboxy moiety example comprises: C (O) NR ⁶R ⁷And C (O) OR ⁸, R wherein ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances ^1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected; R wherein ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects.

In certain embodiments, several keys of formula XIX compound can have particular chiral.

Part E embodiment provides wherein, and the two keys of C13-C14 are the compound of cis.Part E embodiment provides wherein, and the two keys of C13-C14 are trans compound.

In a preferred embodiment, part E embodiment provides the compound with general formula X IX, and wherein L is made up of 2 to 5 atoms.

In a preferred embodiment, part E provides the compound with general formula X IX, wherein L comprise-W-C (=V)-group, wherein V and W are selected from O, S or NH independently of one another.

In a preferred embodiment, part E embodiment provides the compound with general formula X IX, and wherein L is selected from the group that is made up of ester, acid amides, carbamate, monothioester and thioamides.

In a preferred embodiment, part E embodiment provides the compound with general formula X IX, and wherein P2 is come partly to form hydrogen bonding action with at least one the NS3 proteolytic enzyme S2 bag that is selected from the group that is made up of His57, Arg155, Val78, Asp79, Gln80 and Asp81 by the L location in addition.

In a preferred embodiment, part E embodiment provides the compound with general formula X IXa:

In a preferred embodiment, part E embodiment provides the compound with general formula X IXa, and wherein L is made up of 2 to 5 atoms.

In a preferred embodiment, part E provides the compound with general formula X IXa, wherein L comprise-W-C (=V)-group, wherein V and W are selected from O, S or NH independently of one another.

In a preferred embodiment, part E embodiment provides the compound with general formula X IXa, and wherein L is selected from the group that is made up of ester, acid amides, carbamate, monothioester and thioamides.

In a preferred embodiment, part E embodiment provides the compound with general formula X IXa, and wherein P2 is come partly to form hydrogen bonding action with at least one the NS3 proteolytic enzyme S2 bag that is selected from the group that is made up of His57, Arg155, Val78, Asp79, Gln80 and Asp81 by the L location in addition.

In a preferred embodiment, part E embodiment provides the compound with general formula X IX, and wherein P2 is

In a preferred embodiment, part E embodiment provides the compound with formula XIXb:

In a preferred embodiment, part E embodiment provides the compound with general formula X IXb, and wherein L is made up of 2 to 5 atoms.

In a preferred embodiment, part E provides the compound with general formula X IXb, wherein L comprise-W-C (=V)-group, wherein V and W are selected from O, S or NH independently of one another.

In a preferred embodiment, part E embodiment provides the compound with general formula X IXb, and wherein L is selected from the group that is made up of ester, acid amides, carbamate, monothioester and thioamides.

In a preferred embodiment, part E embodiment provides the compound with general formula X IXb, and wherein P2 is come partly to form hydrogen bonding action with at least one the NS3 proteolytic enzyme S2 bag that is selected from the group that is made up of His57, Arg155, Val78, Asp79, Gln80 and Asp81 by the L location in addition.

In a preferred embodiment, part E embodiment provides the compound with general formula X IXb, and wherein the two keys of C13-C14 are cis.

In a preferred embodiment, part E embodiment provides the compound with general formula X IXb, and wherein the two keys of C13-C14 are trans.

Formula XIX compound can the general mode identical with formula I-XVII compound prepare.

In certain embodiments, general formula X IX compound does not comprise disclosed compound among the PCT/US04/33970.For instance, in certain embodiments, compound of Formula I does not comprise with the formula II among the B of top, III and IV compound.

Medical composition

Embodiment provides the composition that comprises compound with general formula I-XIX and its salt, ester or other derivative in addition, comprises medical composition.Described medical composition comprises described compound and pharmaceutically acceptable vehicle.Multiple pharmaceutically acceptable vehicle is known in affiliated field, need not to discuss in detail at this paper.There has been multiple publication that pharmaceutically acceptable vehicle has been described in detail in detail, comprised, for example, A.Gennaro (2000) ＂ Remington:TheScience and Practice of Pharmacy, ＂ the 20th edition, Lippincott, Williams ， ﹠amp; Wilkins; People such as Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C.Ansel compile, and the 7th edition, Lippincott, Williams ， ﹠amp; Wilkins; Compile the 3rd edition .Amer.Pharmaceutical Assoc with people such as Handbook of Pharmaceutical Excipients (2000) A.H.Kibbe.

The public obtains described pharmaceutically acceptable vehicle easily, as mediator, adjuvant, supporting agent or thinner.And the public also obtains pharmaceutically acceptable complementary material easily, as pH value conditioning agent and buffer reagent, tension regulator, stablizer, wetting agent, and similar substance.The example of suitable medical composition embodiment and its production method is below described in more detail.

The enzymic activity that suppresses Flavivirus

In certain embodiments, described compound suppresses the enzymic activity of Flavivirus.Whether described compound suppresses Flavivirus can be used currently known methods easily to determine.Flavivirus infects and comprises the infection that is caused by the Flavivirus that includes, but is not limited to hepatitis C virus, west Nile virus (West Nile Virus), GB virus, japanese encephalitis virus (Japanese Encephalitis), dengue virus (Dengeu virus) and yellow fever virus (Yellow Fever virus).In many examples, described compound suppresses the enzymic activity of hepatitis C virus (HCV) protease N S3.Whether described compound suppresses HCV NS3 can be used currently known methods easily to determine.Typical method comprises to be determined in the presence of described reagent, whether comprises the HCV polyprotein of NS3 recognition site or other polypeptide by the NS3 cracking.In many examples, NS3 enzymic activity when not having described compound is compared, described compound suppresses the NS3 enzymic activity at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, or more.

In many examples, described compound is with the IC less than about 50 μ m ₅₀Value suppresses the enzymic activity of HCV NS3, for example described compound with approximately less than about 40 μ M, less than about 25 μ M, less than about 10 μ M, less than about 1 μ M, less than about 100nM, less than about 80nM, less than about 60nM, less than about 50nM, less than about 25nM, less than about 10nM or less than about 1nM or littler IC ₅₀Value suppresses HCV NS3 proteolytic enzyme.

In many examples, described compound suppresses the HCV virus replication.For example, HCV virus replication when not having described compound is compared, described compound suppresses the HCV virus replication at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, or more.Whether described compound suppresses the HCV virus replication can be used the currently known methods in the affiliated field to determine, comprises in vitro virus replication analysis.

The treatment Flavivirus infects

Method and composition described in the literary composition generally is used for the treatment of Flavivirus to be infected.

Described compound whether the treatment Flavivirus is infected effectively can reduce by virus load, seroconversion (detecting less than virus in the patients serum) time decreased, to the lasting virus of treatment reply that speed increases, sickness rate in the clinical effectiveness or mortality ratio reduces or other disease is replied indicator and determined.

Generally, the significant quantity of formula I-XIX compound and one or more other antiviral agents according to circumstances is the amounts that reduce virus load effectively or realize the lasting virus of treatment is replied.

Whether described compound infects the treatment Flavivirus effectively can be by measuring virus load or determining by measuring the parameter relevant with the Flavivirus infection, described parameter includes but not limited to that hepatic fibrosis, serum transaminase are flat less to raise and the interior gangrenous inflammation activity of liver.Below discuss in detail hepatic fibrosis indicator (indicator).

Described method comprises according to circumstances in conjunction with the come into operation formula I-XIX compound of significant quantity of one or more other antiviral agents of significant quantity.In certain embodiments, the formula I-XIX compound of significant quantity and the amount of one or more other antiviral agents are according to circumstances reduced to virus titer effectively can not the survey level, for example reduce to every milliliter of serum and be about 1000 to about 5000, about 500 to about 1000 or about 100 to about 500 genome duplications this.In certain embodiments, the amount of the formula I-XIX compound of significant quantity and one or more other antiviral agents is according to circumstances reduced to virus load every milliliter of serum effectively for being less than 100 genome duplications originally.

In certain embodiments, the amount of the formula I-XIX compound of significant quantity and one or more other antiviral agents according to circumstances reduces 1.5-log, 2-log, 2.5-log, 3-log, 3.5-log, 4-log, 4.5-log or 5-log with the virus titer of individual serum effectively.

In certain embodiments, the formula I-XIX compound of significant quantity and the amount of one or more other antiviral agents according to circumstances realize continuing virus effectively and reply, for example, after stopping treatment, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months or at least about in the patients serum, do not detect in six months HCVRNA (for example, in every milliliter of serum less than about 500, less than about 400, less than about 200 or less than about 100 genome duplications this)

As indicated above, whether described compound infects effectively and can determine by measuring the parameter (as hepatic fibrosis) relevant with the Flavivirus infection the treatment Flavivirus.Hereinafter discuss the method for determining degree of hepatic fibrosis in detail.In certain embodiments, the blood serum designated object content of hepatic fibrosis indication degree of hepatic fibrosis.

As a limiting examples, use standard method of analysis to measure serum alanine aminotransferase (alanineaminotransferase, ALT) level.In general, think that the ALT level less than about 45 international unit is normal.In certain embodiments, the amount of the formula I-XIX compound of significant quantity and one or more other antiviral agents is according to circumstances reduced to every milliliter of serum less than about 45IU with the ALT level effectively.

Compare with the level of the mark of hepatic fibrosis in the untreated individuality or compare with the placebo treatment individuality, the amount of the treatment formula I-XIX compound of significant quantity and one or more other antiviral agents according to circumstances effectively with the serum level reduction of the mark of hepatic fibrosis at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or at least about 80% or more.The method of measuring blood serum designated object comprises immunological method, enzyme linked immunosorbent assay analysis method (enzyme-linked immunosorbent assay for example, ELISA), radioactive immunoassay, and similar approach is used given blood serum designated object is had specific antibody.

In many examples, the formula I-XIX compound of significant quantity and other antiviral agent are collaborative amounts.As used herein, " synergistic combination " of formula I-XIX compound and other antiviral agent or " collaborative amount " are meant both unitized doses, with can be according to (i) same dose formula I-XIX compound a therapeutic or the treatment result increment improvement predict or wish of the only additivity combination institute of preventative benefit when (ii) other antiviral agent of same dose is as monotherapy of therapeutic during as monotherapy or preventative benefit compare, described unitized dose is more effective for the therapeutic or the prophylactic treatment of HCV infection.

In certain embodiments, a selected amount of formula I-XIX compound and a selected amount of other antiviral agent are effective to disease during as combination treatment, but the former and/or the latter are invalid to disease during as monotherapy.Therefore, embodiment is contained and the following: when (1) wherein was used for disease as combination treatment, a selected amount of other antiviral agent strengthens the therapeutic benefit of a selected amount of formula I-XIX compound and wherein said a selected amount of other antiviral agent does not produce the scheme of therapeutic benefit during as monotherapy to disease; When (2) wherein being used for disease as combination treatment, a selected amount of formula I-XIX compound strengthens the therapeutic benefit of a selected amount of other antiviral agent and described a selected amount of formula I-XIX compound does not produce the scheme of therapeutic benefit when being used for disease as monotherapy; When (3) wherein being used for disease as combination treatment, a selected amount of formula I-XIX compound and a selected amount of other antiviral agent provide the therapeutic benefit and do not produce the scheme of therapeutic benefit when being used for disease as monotherapy separately.As used herein, the impartial statement of " cooperative effective quantity " of formula I-XIX compound and other antiviral agent and grammer thereof is understood to include by each any scheme that contains in above (1)-(3).

The treatment hepatites virus infections

Method and composition described in the literary composition generally is used for the treatment of HCV to be infected.

Described method whether treatment HCV is infected effectively can reduce by virus load, seroconversion (detecting less than virus in the patients serum) time decreased, to the lasting virus of treatment reply that speed increases, sickness rate in the clinical effectiveness or mortality ratio reduces or other disease is replied indicator and determined.Generally, the significant quantity of formula I-XIX compound and one or more other antiviral agents according to circumstances is the amounts that reduce virus load effectively or realize the lasting virus of treatment is replied.

Whether described method infects treatment HCV effectively can be by measuring virus load or determining by measuring the parameter relevant with the HCV infection, described parameter includes but not limited to that hepatic fibrosis, serum transaminase are flat less to raise and the interior gangrenous inflammation activity of liver.Below discuss in detail the hepatic fibrosis indicator.

Present method comprises according to circumstances in conjunction with the come into operation formula I-XIX compound of significant quantity of one or more other antiviral agents of significant quantity.In certain embodiments, the formula I-XIX compound of significant quantity and the amount of one or more other antiviral agents are according to circumstances reduced to virus titer effectively can not the survey level, for example reduce to every milliliter of serum and be about 1000 to about 5000, about 500 to about 1000 or about 100 to about 500 genome duplications this.In certain embodiments, the amount of the formula I-XIX compound of significant quantity and one or more other antiviral agents is according to circumstances reduced to virus load every milliliter of serum effectively for being less than 100 genome duplications originally.

As indicated above, whether described method infects effectively and can determine by measuring the parameter (as hepatic fibrosis) relevant with the HCV infection treatment HCV.Hereinafter discuss the method for determining degree of hepatic fibrosis in detail.In certain embodiments, the blood serum designated object content of hepatic fibrosis indication degree of hepatic fibrosis.

As a limiting examples, use standard method of analysis to measure serum alanine aminotransferase (ALT) content.In general, think that the ALT level less than about 45 standard units is normal.In certain embodiments, the amount of the formula I-XIX compound of significant quantity and one or more other antiviral agents is according to circumstances reduced to every milliliter of serum less than about 45IU with the ALT level effectively.

Compare with the level of the mark of hepatic fibrosis in the untreated individuality or compare with the placebo treatment individuality, the amount of the treatment formula I-XIX compound of significant quantity and one or more other antiviral agents according to circumstances effectively with the serum level reduction of the mark of hepatic fibrosis at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or at least about 80% or more.The method of measuring blood serum designated object comprises immunological method, and for example enzyme linked immunosorbent assay analysis method (ELISA), radioactive immunoassay, and similar approach use given blood serum designated object is had specific antibody.

The treatment fibrosis

Embodiment is provided for treating the hepatic fibrosis method of (comprise by HCV and infect cause or relative hepatic fibrosis form), generally includes the formula I-XIX compound of the therapeutic dose that comes into operation and one or more other antiviral agents according to circumstances.The formula I-XIX compound of the significant quantity of combination or one or more other antiviral agents of debond below is discussed, and dosage regimen.

Whether formula I-XIX compound and one or more other antiviral agents according to circumstances effectively can be determined by in the recognized technology of many measurement hepatic fibrosis and liver function any reducing hepatic fibrosis.It is to determine by analyzing the liver biopsy samples that hepatic fibrosis reduces.The liver biopsy is analyzed and is comprised two major portions of evaluation: gangrenous inflammation, in being assessed as tolerance seriousness and carrying out " grade (grade) " of disease activity degree; With the damage of fibrosis and substance or reconstructing blood vessel, be assessed as " stage (stage) " of reflection prolonged sickness progress.Referring to, Brunt (2000) Hepatol.31:241-246 for example; And METAVIR (1994) Hepatology 20:15-20.Analyze based on the liver biopsy, appointment is kept the score.Many stdn points-scoring systems provide the quantitative assessment of fibrosis and seriousness.These systems comprise METAVIR, Knodell, Scheuer, Ludwig and Ishak points-scoring system.

The METAVIR points-scoring system is based on the analysis of the various features of liver biopsy, comprises fibrosis (fibrosis of portal vein, leaflet central vein fibrosis and sclerosis); Downright bad (shred and leaflet necrosis, acidophilia shrink and the balloon sample becomes); Inflammation (portal vein pipeline inflammation, portal vein lymph sample aggregation and portal vein inflammation distribute); Bile duct changes; And Knodell index (keeping the score of necrosis around the portal vein, leaflet necrosis, portal vein inflammation, fibrosis and total disease activity degree).As each stage in the METAVIR system of giving a definition: keep the score: 0, represent no fibrosis; Keep the score: 1, the star of expression portal vein pipeline enlarges and does not have median septum and form; Keep the score: 2, the expansion of expression portal vein pipeline also has few median septum to form; Keep the score: 3, represent many median septums and do not have sclerosis; And keep the score: 4, the expression sclerosis.

The Knodell points-scoring system also is called hepatitis activity index (Hepatitis Activity Index), based on keeping the score sample classification of four kinds of histologic characteristicses: necrosis and/or bridging necrosis around the I. portal vein; II. sample becomes and local necrosis in the leaflet; III. portal vein inflammation; With the IV. fibrosis.In the Knodell hierarchy system, following keeping the score: keep the score: 0, represent no fibrosis; Keep the score 1, represent slight fibrosis (fibrous pylephlebectasis); Keep the score: 2, expression moderate fibrosis; Keep the score 3, represent serious fibrosis (bridging fibrosis); With keep the score 4, expression sclerosis.It is high more to keep the score, and the hepatic tissue infringement is serious more.Knodell(1981)Hepatol.1：431。

In the Scheuer points-scoring system, following keeping the score: keep the score: 0, represent no fibrosis; Keep the score 1, expression is that enlarge, fibrous portal vein pipeline; Keep the score: 2, median septum around the expression portal vein and between portal vein, but structural integrity is harmless; Keep the score: 3, the expression fibrosis, and structural distortion is arranged, but do not have obviously sclerosis; Keep the score: 4, the sclerosis that expresses possibility or determine.Scheuer(1991)J.Hepatol.13：372。

The Ishak points-scoring system is described to some extent at Ishak (1995) J.Hepatol.22:696-699.In the stage 1, the fibrous expansion in some portal vein zones is with or without staple fibre shape median septum; In the stage 2, the fibrous expansion in most of portal vein zone is with or without staple fibre shape median septum; In the stage 3, the fibrous expansion in most of portal vein zone has (P-P) bridge joint between portal vein accidentally; In the stage 4, the fibrous expansion in portal vein zone has bridge joint between tangible portal vein (P-P) and portal vein district-leaflet central area bridge joint (P-C); Stage 5, obvious bridge joint (P-P and/or P-C), accidental nodosity (cokey); Stage 6, sclerosis possible or that determine.

The benefit of anti-fibrosis therapy can also measure and evaluate by using the Child-Pugh points-scoring system, and described points-scoring system comprises based on abnormal level of serum total bilirubin is unusual, the serum albumin level is unusual, prothrombin time is unusual, existence and the existence of seriousness and encephalopathic and the polynary some number system (multicomponent point system) of seriousness of ascites.Based on the existence and the seriousness of the abnormality of these parameters, the patient can be in any in the clinical disease of three kinds of cumulative seriousness: A, B or C.

In certain embodiments, the preceding and treatment back liver biopsy method according to treatment, the formula I-XIX compound of treatment significant quantity and the amount of one or more other antiviral agents according to circumstances are effectively with the one or more units of fibrosis phasic change.In a particular embodiment, treatment significant quantity formula I-XIX compound and one or more other antiviral agents according to circumstances reduce at least one unit with hepatic fibrosis in METAVIR, Knodell, Scheuer, Ludwig or Ishak points-scoring system.

The secondary of liver function or indirect index also can be used for the therapeutic efficiency of bounds evaluation I-XIX compound.

The indication that also can be used as the effect of described methods of treatment based on the semi-automatic evaluation of morphology computer of collagen specificity dyeing and/or the painted hepatic fibrosis quantitative extent of serum hepatic fibrosis markers is measured.The secondary index of liver function includes but not limited to, serum transamination enzyme level, prothrombin time, bilirubin, platelet count, portal venous pressure, albumin level and the Child-Pugh evaluation result of keeping the score.

Compare with liver function index in the untreated individuality or compare with the placebo treatment individuality, the formula I-XIX compound of significant quantity and the amount of one or more other antiviral agents according to circumstances reduce the liver function index effectively at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or at least about 80% or more.One of ordinary skill in the art can use standard method of analysis easily to measure these liver function indexes, and the some of them analytical method is to buy from market, and is used in the clinical instrumentation routinely.

The blood serum designated object of hepatic fibrosis also can be used as the indication of the effect of described methods of treatment and measures.The blood serum designated object of hepatic fibrosis includes, but not limited to hyaluronate, N-terminal III procollagen type peptide, IV Collagen Type VI 7S territory, C-terminal I procollagen type peptide and ln (laminin).Other hepatic fibrosis biochemical marker comprises α-2-macroglobulin, haptoglobin, gamma globulin, aPoA and gamma glutamyl transpeptidase.

Compare or compare with hepatic fibrosis mark serum level in the untreated individuality with the placebo treatment individuality, the amount of the treatment formula I-XIX compound of significant quantity and one or more other antiviral agents according to circumstances effectively with the reduction of hepatic fibrosis mark serum level at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or at least about 80% or more.One of ordinary skill in the art can use standard method of analysis easily to measure these serum hepatic fibrosis markerses, and the some of them analytical method can be buied from market, and is used in the clinical instrumentation routinely.The method of measuring blood serum designated object comprises immunological method, and for example enzyme linked immunosorbent assay analysis method (ELISA), radioactive immunoassay, and similar approach use given blood serum designated object is had specific antibody.

Also can use the quantitative test of liver function deposit (functional liver reserve) to evaluate the therapeutic efficiency of Interferon Receptors agonist and the non-Buddhist nun's ketone of piperazine (or the non-Buddhist nun's keto analog of piperazine).Described test comprises: Indocyanine Green clearance rate (ICG), semi-lactosi are known ability (GEC), Aminopyrine breath test (ABT), quinizine clearance rate, single ethyl glycinamide aminoacyl xylidene(s) (MEG-X) clearance rate and caffeine clearance rate.

As used herein, " complication relevant with liver cirrhosis " is meant the sequela of losing the compensatory hepatopathy, promptly, perhaps after hepatic fibrosis and the illness that takes place as the result of hepatic fibrosis development, it includes but not limited to, ascites, varix are hemorrhage, portal hypertension, jaundice, carrying out property hepatic insufficiency, encephalopathic, hepatocellular carcinoma, the liver failure that needs liver transplantation and liver related mortality.

Compare with the untreated individuality or compare with the placebo treatment individuality, the formula I-XIX compound of treatment significant quantity and the amount of according to circumstances one or more other antiviral agents effectively will be relevant with liver cirrhosis incidence (for example, individuality will develop the possibility) reduction of illness at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or at least about 80% or more.

Whether formula I-XIX compound effectively can easily be determined by one of ordinary skill in the art reducing the illness incidence relevant with liver cirrhosis with one or more other antiviral agents according to circumstances.

Hepatic fibrosis reduces and strengthens liver function.Therefore, embodiment is provided for strengthening the method for liver function, generally includes come into operation the formula I-XIX compound of treatment significant quantity and one or more other antiviral agents according to circumstances.Liver function comprises, but be not limited to, protein synthesis, as serum protein (for example, albumin, thrombin, alkaline phosphatase, transaminase are (for example, alanine aminotransferase, aspartic transaminase), 5 '-nucleosidase, gamma glutamyl transpeptidase, etc.), the synthetic and bile acide of bilirubinic synthetic, cholesterol synthetic; The hepatic metabolism function includes, but not limited to carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism and lipid metabolism; The detoxifcation of external medicine; The Hemodynamics function comprises internal organ and portal vein Hemodynamics; And similar functions.

Whether liver function is enhanced to be used by one of ordinary skill in the art is generally acknowledged that liver function test is easy to determine.Therefore, the synthetic of liver function mark can be evaluated by marker levels in use standard immunoassay and the enzymatic analysis measurement serum, described mark for example, albumin, alkaline phosphatase, alanine aminotransferase, aspartic transaminase, bilirubin and similar substance.Internal organ circulation and portal vein Hemodynamics can use standard method to press by the portal vein wedge and/or resistance is measured.Metabolic function can be measured by ammonia level in the measurement serum.

Usually, be in normal range by the serum protein of hepatic secretion, and can be by using standard immunoassay to learn and enzymatic analysis be measured described proteic level and determine.One of ordinary skill in the art understand the normal range of these serum protein.It below is limiting examples.The normal level of alanine aminotransferase is every milliliter of about 45 IU of serum.The normal range of aspartic transaminase is that every milliliter of serum about 5 is to about 40 units.Bilirubin is to use standard method of analysis to measure.Normal bilirubin level is usually less than about 1.2mg/dL.Sero-abluminous normal level is in about 35g/L arrives about 55g/L scope.The serum albumin level is to use standard method of analysis to measure.The prolongation of prothrombin time is to use standard method of analysis to measure.Normal prothrombin time was about below 4 seconds than the contrast time.

The amount of the treatment formula I-XIX compound of significant quantity and one or more other antiviral agents according to circumstances effectively with the liver function enhancing at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or more.For instance, the amount of the treatment formula I-XIX compound of significant quantity and one or more other antiviral agents according to circumstances effectively with high-level liver function blood serum designated object reduction at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or more, perhaps liver function blood serum designated object level is reduced in the normal range.The amount of the treatment formula I-XIX compound of significant quantity and one or more other antiviral agents according to circumstances equally effectively with low-level liver function blood serum designated object raising at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or more, perhaps liver function blood serum designated object level is brought up in the normal range.

I type Interferon Receptors agonist

In any method in aforesaid method, in certain embodiments, the I type that comes into operation Interferon Receptors agonist.I type Interferon Receptors agonist comprises IFN-α, IFN-β, IFN-τ, IFN-ω; I type Interferon Receptors had specific antibody agonist; With other I type Interferon Receptors agonist, comprise non-polypeptide agonist. Alpha-interferon

Any known IFN-α can use in an embodiment.Term as used herein " alpha-interferon " is meant the related polypeptide family that suppresses virus replication and cell proliferation and regulate and control immunne response.Term " IFN-α " comprises natural generation IFN-α; Synthetic IFN-α; IFN-α (for example, Pegylation IFN-α, glycosylation IFN-α and analogue) derives; Analogue with natural generation or synthetic IFN-α; Basically any IFN-α with ntiviral characteristic is as described for natural generation IFN-α.

Suitable alpha-interferon includes, but are not limited to: natural generation IFN-α (including but not limited to natural generation IFN-α 2a, IFN-α 2b); Interferon Alfa-2b, as the Intron-A Interferon, rabbit (Schering Corporation, Kenilworth, N.J.); Interferon Alfa-2a, as the Roferon Interferon, rabbit (Hoffinann-La Roche, Nutley, N.J.); Recombinantinterferon-2c, as Berofor α-2 Interferon, rabbit (Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.); Interferon alfa-n1, be a kind of purifying adulterant of natural alpha-interferon, as Sumiferon (Sumitomo, Japan) or Wellferon interferon alfa-n1 (INS) (available from the Glaxo-Wellcome Ltd., London, GreatBritain); And Alferon N, promptly a kind of mixture of natural alpha-interferon (make by Interferon Sciences, and can trade(brand)name Alferon available from Purdue Frederick Co. (Norwalk, Conn.)).

Term " IFN-α " also comprises compound IFN-α.Compound IFN-α (claiming " CIFN ", " IFN-con " and " Interferon alfacon-1 " again) includes but not limited at United States Patent (USP) the 4th, 695, No. 623 and the 4th, 897, the aminoacid sequence of disclosed called after IFN-con1, IFN-con2 and IFN-con3 in No. 471; With the Interferon alfacon-1 that defines by the concensus sequence of determining natural generation alpha-interferon (for example, Infergen_, InterMine, Inc., Brisbane, Calif.).IFN-con1 is the Interferon alfacon-1 reagent in the Infergen_alfacon-1 product.Infergen_ Interferon alfacon-1 product is mentioned by its trade name (Infergen_) or its popular name (Interferon, rabbit alfacon-1) in the text.The dna sequence dna of coding IFN-con patent is as described above described or other standard method is synthesized.The purposes of CIFN be special be concerned about.

What be equally applicable to embodiment is the fusion polypeptide that comprises IFN-α and heterologous polypeptide.Suitable IFN-α fusion polypeptide includes but not limited to Albuferon-alpha ^TM(a kind of fusion product of people's albuminoid and IFN-α; Human GenomeSciences; Referring to, for example, people such as Osborn. (2002) J.Pharmacol.Exp.Therap.303:540-548).That be equally applicable to embodiment is the IFN-α that shuffles the gene form.Referring to, people such as Masci for example. (2003) Curr.Oncol.Rep.5:108-113.

Peg-Intron-α

Term " IFN-α " also comprise through of IFN-α deriving (for example, through chemically modified) change derivative such as some characteristics such as serum half-lifes.Therefore, term " IFN-α " comprise glycosylation IFN-α, with polyoxyethylene glycol deutero-IFN-α (" polyoxyethylene glycol China IFN-α ") and analogue.Pegylation IFN-α and its preparation method exist, and for example, United States Patent (USP) the 5th, 382 No. 657, the 5th, 981, No. 709 and the 5th, 951, is discussed in No. 974 to some extent.Pegylation IFN-α comprises the binding substances of any molecule in polyoxyethylene glycol (PEG) and the above-mentioned IFN-alpha molecule, include but not limited to, with Intederon Alpha-2a bonded PEG (Roferon, Hoffman La-Roche, Nutley, N.J.), Interferon Alpha-2b (Intron, Schering-Plough, Madison, N.J.), interferon c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany) and the Interferon alfacon-1 (Infergen_ that defines by the concensus sequence of determining natural generation alpha-interferon, InterMune, Inc., Brisbane, Calif.).

In the above-mentioned IFN-α polypeptide any can be modified by one or more polyalkylene glycol moieties, i.e. Pegylation.One or more amino acid side chains of the PEG molecule of Pegylation IFN-α polypeptide and IFN-α polypeptide connect.In certain embodiments, Pegylation IFN-α is only containing peg moiety on an amino acid.In other embodiments, Pegylation IFN-α contains peg moiety on two or more amino acid, for example, IFN-α contains the peg moiety that is connected on two, three, four, five, six, seven, eight, nine or ten the different aminoacids residues.

IFN-α can the direct and PEG coupling (that is, without linking group) via amino, sulfydryl, hydroxyl or carboxyl.

In certain embodiments, Pegylation IFN-α be the N-terminal (N-terminal) of IFN-α polypeptide locate or near Pegylation, for example one or more amino-acid residues of the peg moiety amino acid/11 that links to IFN-α polypeptide to amino acid 4 or amino acid 5 to amino acid about 10.

In other embodiments, Pegylation IFN-α is the one or more amino-acid residues place Pegylation between about 10 to about 28.

In other embodiments, Pegylation IFN-α be the C-terminal (C-terminal) of IFN-α polypeptide locate or near Pegylation, i.e. one or more amino-acid residues place between amino acid/11 56-166 or amino acid/11 50-155.

In other embodiments, Pegylation IFN-α is the one or more amino-acid residues place Pegylation between amino acid/11 00-114.

Polyoxyethylene glycol derivatization at the amino-acid residue at the receptor binding domains of IFN-alpha protein and/or active portion bit field place may disturb these zones to play a role.In certain embodiments, remain to be avoided the amino acid of Pegylation comprise amino acid 30 to amino acid 40 and amino acid/11 13 to the amino-acid residue between the amino acid/11 49.

In certain embodiments, PEG is connected to IFN-α via linking group.Described linking group is any biocompatibility linking group, wherein " biocompatibility " described compound of expression or group is nontoxic and can be in vitro or in vivo use and can not cause damage, feel sick, disease or death.PEG can via, for example, ehter bond, ester bond, mercaptan key or amido linkage are incorporated into linking group.Suitable biocompatibility linking group includes but not limited to: ester group, amide group, imide, carbamate, carboxyl, hydroxyl, carbohydrate, succinimido (comprises, for example, succinimide succinate (succinimidyl succinate, SS), succinimide propionic ester (succinimidylpropionate, SPA), succinimide butyric ester (succinimidyl butanoate, SBA), succinimide carboxyl manthanoate (succinimidyl carboxymethylate, SCM), succinimide succinic diamide (succinimidylsuccinamide, SSA) or N-hydroxy-succinamide (N-hydroxy succinimide, NHS)), the epoxide base, oxygen base carbonylic imidazole base (comprises, for example, carbonylic imidazole (carbonyldimidazole, CDI)), nitrophenyl (comprises, for example, nitrophenyl carbonate (nitrophenyl carbonate, NPC) or trichlorophenyl carbonic ether (trichlorophenyl carbonate, TPC)), tryptophane ester group (trysylate), aldehyde radical, isocyanate group, the vinyl sulfuryl, tyrosine-based, the halfcystine base, Histidine base or primary amine.

Be used for preparation through the method for succinimide propionic ester (SPA) and succinimide butyric ester (SBA) activatory PEG at United States Patent (USP) the 5th, 672, description to some extent among No. 662 people such as () Harris and the WO 97/03106.

The method that is used for PEG is connected to IFN-α polypeptide is known in affiliated field, and can use any currently known methods.Referring to, for example, people such as Park, Antimaycer Res., 1:373-376 (1981); Zaplipsky and Lee, Polyethylene Glycol Chemistry, Biotechnical and Biomedical Applications, J.M.Harris compiles, Plenum Press, NY, the 21st chapter (1992); United States Patent (USP) the 5th, 985, No. 265; United States Patent (USP) the 5th, 672, No. 662 (people such as Harris); With WO 97/03106.

Pegylation IFN-α and its preparation method exist, and for example, United States Patent (USP) the 5th, 382 No. 657, the 5th, 981, No. 709, the 5th, 985, No. 265 and the 5th, 951, is discussed in No. 974 to some extent.Pegylation IFN-α comprises the binding substances of any molecule in polyoxyethylene glycol (PEG) and the above-mentioned IFN-alpha molecule, include but not limited to, with Intederon Alpha-2a bonded PEG (Roferon, Hoffman La-Roche, Nutley, N.J.), wherein Pegylation Roferon is called Pegasys (Hoffman La-Roche); Interferon Alpha-2b (Intron, Schering-Plough, Madison, N.J.), wherein Pegylation Intron is called PEG-Intron (Schering-Plough); Interferon c (Berofor Alpha, BoehringerIngelheim, Ingelheim, Germany); With the Interferon alfacon-1 that defines by the concensus sequence of determining natural generation alpha-interferon (Infergen_, InterMune, Inc., Brisbane, Calif.), wherein Pegylation Infergen is called PEG-Infergen.

In many examples, PEG be with IFN-α polypeptide on the mono methoxy PEG molecule of primary amine group reaction.The method of reacting with mono methoxy PEG modified polypeptide via standard reductive alkylation is known in affiliated field.Referring to, people such as Chamow for example. (1994) Bioconj.Chem.5:133-140.

In a limiting examples, PEG is connected in IFN-α via the SPA linking group.The SPA ester of PEG and its preparation method be at United States Patent (USP) the 5th, 672, describes to some extent in No. 662.Provide the SPA connecting key be used for IFN-α polypeptide on the free amine bonding.

For instance, the PEG molecule is covalently bound via a connecting key, and described connecting key surface in the propionyl of peg moiety and IFN-α polypeptide exposes between the epsilon-amino of lysine residue and comprises amido linkage.Described key can, for example, form by α-methoxyl group of PEG, the condensation (mPEGspa) of ω-propionic acid Acibenzolar.

As a limiting examples; single Pegylation CIFN binding substances that is preferred for herein is to be the linear peg moiety of about 30kD via what covalent linkage was connected in the CIFN polypeptide; wherein said covalent linkage is that the surface exposes amido linkage between the epsilon-amino of lysine residue in the propionyl of peg moiety and the CIFN polypeptide, and wherein the surface exposes lysine residue and is selected from lys ³¹, lys ⁵⁰, lys ⁷¹, lys ⁸⁴, lys ¹²¹, lys ¹²², lys ¹³⁴, lys ¹³⁵Close lys ¹⁶⁵, and amido linkage is to form by the α-methoxyl group of PEG and the condensation of ω-propionic acid Acibenzolar.

Polyoxyethylene glycol

The suitable polyoxyethylene glycol that connects with IFN-α polypeptide is water soluble at room temperature, and has general formula R (O-CH ₂-CH ₂) _nO-R, wherein R is a hydrogen or as protecting groups such as alkyl or silane alcohol bases, and wherein n is a integer between 1 to 1000.When R was protecting group, it had 1 to 8 carbon usually.

In many examples, PEG has at least one hydroxyl, terminal hydroxyl for example, described hydroxyl can be modified and be resulted from the functional group of amino reaction, described amino for example is the epsilon-amino of lysine residue, the free amine group of polypeptide N-terminal, or any other amino as the amino of l-asparagine, glutamine, arginine or Histidine.

In other embodiments, PEG is by derivatize, make its can with the free carboxy reaction in the IFN-α polypeptide, described carboxyl is for example at the free carboxy at the C-terminal place of IFN-α polypeptide.Can include but not limited to the hydrazine derivative of PEG-amine and PEG (for example, PEG-NH-NH with the suitable PEG derivative of the free carboxy reaction at the C-terminal place of IFN-α ₂).

In other embodiments, PEG is made it comprise terminal thiocarboxylic acid group-COSH by derivatize, and this hydroxy-acid group optionally reacts with amino, produces amide derivatives.Because the reactivity of thioic acid sulfoacid has realized that some amino is better than other amino selectivity.For example, under suitable pH condition with the reaction of N-terminal amino in ,-SH shows enough leavings group abilities, makes epsilon-amino in the lysine residue by protonated, and keeps non-nucleophilicity.On the other hand, the reaction under suitable pH condition can make some come-at-able lysine residues optionally react.

In other embodiments, PEG is included in the reactive ester as the N-hydroxy-succinamide ester at place, PEG chain end.This PEG molecule that contains the N-hydroxy-succinamide ester (as, neutral 6.5-7.5) under specific pH condition optionally reacts with amino.For example, can under condition of neutral pH, optionally modify N-terminal amino.Yet, if reagent is reactive extremely strong, the come-at-able NH of Methionin so ₂Group also may react.

PEG can directly or via linking group and IFN-α polypeptide connect.In certain embodiments, linking group is added the polypeptide to IFN-α, form the IFN-α polypeptide that linking group is modified.Described linking group provides various functional groups, and for example sulfydryl, amino or carboxyl isoreactivity group are so that be coupled to PEG reagent the IFN-α polypeptide of modifying through linking group.

In certain embodiments, the PEG that is linked in IFN-α polypeptide is linear.In other embodiments, the PEG that is linked in IFN-α polypeptide is branched.Branch PEG derivative such as United States Patent (USP) the 5th, 643, described in No. 575, described in " star PEG derivative " and higly branched chain PEG derivative such as the Shearwater Polymers, Inc.catalog ＂ PolyethyleneGlycol Derivatives 1997-1998. ＂.Star PEG describes in affiliated field to some extent, comprises, for example, at United States Patent (USP) the 6th, 046, in No. 305.

Usually employed be molecular weight at about 2kDa to the PEG between about 100kDa, wherein term " about " is illustrated in the content of relevant PEG in the prepared product of polyoxyethylene glycol, some molecules can be than described molecular weight weight, and some may be lighter.For example, the molecular weight that is fit to the PEG that connects with IFN-α about 2kDa to about 5kDa, about 5kDa to about 10kDa, about 10kDa to about 15kDa, about 15kDa to about 20kDa, about 20kDa about 25kDa, about 25kDa about 30kDa, about 30kDa about 40kDa, about 40kDa about 50kDa, about 50kDa about 60kDa, about 60kDa about 70kDa, about 70kDa extremely about 90kDa or about 90kDa extremely in about 100kDa scope of about 80kDa, about 80kDa extremely extremely extremely extremely extremely extremely extremely.

Preparation PEG-IFN-alpha conjugates

As indicated above, with peg moiety directly or be connected to N-terminal place or near, inside or the C-terminal place or near the amino-acid residue of IFN-α polypeptide via linking group.Can in solution or in solid phase, carry out the connection effect.

The N-terminal bonding

Be used for that peg moiety is connected to the N-terminal place of IFN-α polypeptide or near the method for amino-acid residue is known in affiliated field.Referring to, for example, United States Patent (USP) the 5th, 985, No. 265.

In certain embodiments, be used for the currently known methods that selectivity obtains N-terminal chemically modified IFN-α.For instance, can use a kind of method by standard reductive alkylation reaction carrying out protein modification, described method is utilized the differential responses of the dissimilar primary amine groups (Methionin is to N-terminal) that can carry out derivatization in the specific protein.Under the appropriate reaction condition, realize that with carboxylic polymkeric substance the selective derivatization in fact of protein N end turns usefulness into.Described being reflected under certain pH value carried out, so that utilize the pK between the alpha-amino group of the epsilon-amino of lysine residue and proteinic N-terminal residue _aDifference.Turn into by this selective derivatization and to be used for controlling being connected of peg moiety and IFN-α: mainly occur in the N-terminal of IFN-α with the connection of polymkeric substance, and other remarkable modification as the amino isoreactivity group of lysine side-chain does not take place.

The C-terminal bonding

As United States Patent (USP) the 5th, 985, the N-terminal specificity coupling step described in No. 265 mainly provides single Pegylation product.Yet, can remove N-terminal sealing polypeptide with the purification step that a small amount of poly ethylene glycol product is a target to remove excess reagent.With regard to treatment, described process can cause the huge increase of production cost.For instance, the detection of the structure of the Infergen_Alfacon-1 CIFN polypeptid acid sequence through fully characterizing shows, cuts off approximately 5% at the C-terminal place, and therefore a main C-terminal sequence is only arranged.Thereby, in certain embodiments, do not use N-terminal Pegylation IFN-α, but make IFN-α polypeptide carry out the C-terminal Pegylation.

Following thus imagination is used for obtaining the effective synthesis method and the treatment approach of single Pegylation Infergen product.

Can prepare the PEG reagent that C-terminal is had selectivity and has or do not have spacer groups.For example, can use one terminal modifiedly to have the polyoxyethylene glycol of amino-functional as initial substance as the methyl ester the other end.

Can prepare or obtain water-soluble carbodiimide as condensing agent.Usually under optimal ph, containing and carrying out IFN-α (for example, Infergen_Alfacon-1 CIFN or Interferon alfacon-1) and coupling in the aqueous medium of suitable buffer system, thereby finishing amide linkage as the water-soluble carbodiimide of condensing agent.High molecular weight PEGs can be made an addition to protein with covalent manner, increase molecular weight.

Selected reagent depends on Study of optimization.A limiting examples of suitable agent is EDAC or l-ethyl-3-(3-dimethylaminopropyl) carbodiimide.EDAC water-soluble makes it possible to directly add to and need not to use in advance organic solvent dissolution in the reaction.Unnecessary reagent and crosslinking reaction by product isourea all are water miscible, can easily remove by dialysis or gel-filtration.The concentrated aqueous solutions of preparation EDAC is so that add less molar weight in reaction.The preparation stock solution also promptly uses for thirty years of age in view of the water unstable of reagent.Most of synthetic schemes in the document shows that the optimum response medium is in the pH value scope between 4.7 and 6.0.Yet condensation reaction only is that productive rate does not have heavy losses up to pH7.5 the time.Available water as solvent.Use in view of the expection of Infergen, described medium preferably is titrated to 2-(N-morpholino) the ethane sulfonic acid buffer reagent of the pH value between 4.7 and 6.0 in advance.But in view of product is with identical buffer reagent, so also can use the 0.1M phosphoric acid salt of pH7-7.5.The ratio of optimization PEG amine and IFN-alpha molecule makes C-terminal carboxyl residue be produced single polyethylene glycol derivative by the selectivity Pegylation.

Though used PEG amine mentions by title or structure that described derivative only is exemplary.Also can use other equally can with the group of the carboxyl generation condensation reaction of IFN-alpha protein, for example hydrazine derivative PEG-NH-NH ₂Except that water, reaction also can be carried out on solid phase.Polyoxyethylene glycol can be selected from the compound inventory of molecular weight between 300-40000.The selection of various polyoxyethylene glycol also will be subjected to pure derivative in vitro with intravital coupling efficiency and biological property (that is, and cycling time, antiviral activity, etc.) domination.

In addition, the suitable interval group can be added on the proteinic C-terminal.Spacer groups can have as SH, NH ₂Or the reactive group of COOH so that with the coupling of suitable PEG reagent, high molecular IFN-is provided alpha derivative.Can be preparation C-terminal Peg-Intron and composite design solid phase/liquid phase process.For instance, the C-terminal of IFN-α is to use Gly-GIy-Cys-NH ₂Spacer groups prolongs on solid phase, and then uses the activated dithio pyridyl-PEG reagent single Pegylation in solution with suitable molecular weight.Because the coupling at C-terminal place is irrelevant with the sealing at N-terminal place, so contemplated method and product are the economy of useful (1/3rd protein is unlike in the N-terminal Pegylation method and is wasted) and the therapy that helps to be used for treatment of viral infections with regard to cost.

May there be the reactive carboxyl of having more of amino-acid residue in other place of IFN-alpha molecule, reacting, and causes at single Pegylation in this site or cause poly ethylene glycolization C-terminal-COOH group except that IFN-α with PEG reagent.Envision only minimum degree of these reactions, this is because the spatial degrees of freedom of the C-terminal of IFN-alpha molecule and sterically hindered (for example in the branched chain molecule) that is applied by carbodiimide and PEG reagent place.Therefore, this is that PEG modifies Infergen and similar this type of proteinic preference pattern natural or that express in host system, and higher in vivo biological activity is raised the efficiency and kept to the sealing N-terminal that described analogous protein may have in various degree.

The another kind of method that realizes the C-terminal Pegylation is as described below.Realizing with sterically hindered reagent that the selectivity of C-terminal Pegylation, described sterically hindered reagent can be got rid of is embedded in the spiral or the reaction at the carboxyl residue place of IFN-α inside.For instance, a kind of such reagent can be the branched chain PEG of the about 40kd of molecular weight, and this reagent can followingly synthesize:

Use suitable agent, for example dicyclohexylcarbodiimide or water-soluble EDC come condensation OH ₃C-(CH ₂CH ₂O)) n-CH ₂CH ₂NH ₂And L-glutamic acid (that is HOCO-CH, ₂CH ₂CH (NH ₂)-COOH), thus branched chain PEG reagent OH is provided ₃C-(CH ₂CH ₂O) _n-CH ₂CH ₂NHCOCH (NH ₂) CH ₂OCH ₃-(CH ₂CH ₂O) _n-CH ₂CH ₂NHCOCH ₂

This reagent can excessive use with free and flexible carboxyl coupling amino and IFN-α, and form peptide bond.

Need the time, use any currently known methods never to isolate Pegylation IFN-α among the Pegylation IFN-α, described method includes but not limited to, ion exchange chromatography, size exclusion chromatography and its combination.For instance, when the PEG-IFN-alpha conjugates is single Pegylation IFN-α, at first obtain having the material (may have other poly ethylene glycol material) of single Pegylation material charge characteristic, then isolate single Pegylation material by the size exclusion chromatography with identical apparent charge by the ion exchange chromatography separated product.

Single Pegylation (30kD, linearity) IFN-α

The Pegylation IFN-α that is suitable among the embodiment comprises single Pegylation Interferon alfacon-1 (CIFN) molecule that comprises single CIFN polypeptide and single polyoxyethylene glycol (PEG) part, wherein peg moiety is linear, molecular weight is about 30kD, and directly or via one stablize covalent bonding be connected in indirectly the N-terminal residue of CIFN polypeptide or CIFN polypeptide lysine residue.In certain embodiments, single Pegylation (30kD, linearity) IFN-α is the compound IFN-α of single Pegylation (30kD, linearity).

In certain embodiments, peg moiety is connected in the epsilon-amino of the lysine residue of the alpha-amino group of N-terminal residue of CIFN polypeptide or CIFN polypeptide.In other embodiments, described bonding comprises the amido linkage between the epsilon-amino of the alpha-amino group of N-terminal residue in PEG molecule and the CIFN molecule or lysine residue.And in other embodiments, described bonding comprises the amido linkage between the epsilon-amino of the alpha-amino group of N-terminal residue in the propionyl of peg moiety and the CIFN molecule or lysine residue.In other embodiments, described amido linkage is that the condensation of the epsilon-amino of the alpha-amino group of N-terminal residue in α-methoxyl group, ω-propionic acid Acibenzolar and the CIFN polypeptide by peg moiety or lysine residue forms, and forms the hydrolysis-stable bonding thus between peg moiety and CIFN polypeptide.

In certain embodiments, peg moiety is connected in the N-terminal residue of CIFN polypeptide.In other embodiments, peg moiety is connected in the alpha-amino group of N-terminal residue in the CIFN polypeptide.In other embodiments, described bonding comprises the amido linkage between the alpha-amino group of N-terminal residue in peg moiety and the CIFN polypeptide.And in other embodiments, described bonding comprises the amido linkage between the alpha-amino group of N-terminal residue in the propionyl of peg moiety and the CIFN polypeptide.In other embodiments, described amido linkage is that the alpha-amino group condensation of N-terminal residue forms in α-methoxyl group, ω-propionic acid Acibenzolar and the CIFN polypeptide by peg moiety.

In certain embodiments, peg moiety is connected in the lysine residue of CIFN polypeptide.In other embodiments, peg moiety is connected in the epsilon-amino of lysine residue in the CIFN polypeptide.In other embodiments, described bonding comprises the amido linkage between the epsilon-amino of lysine residue in peg moiety and the CIFN polypeptide.And in other embodiments, described bonding comprises the amido linkage between the epsilon-amino of lysine residue in the propionyl of peg moiety and the CIFN polypeptide.In other embodiments, described amido linkage is that the epsilon-amino condensation of lysine residue forms in α-methoxyl group, ω-propionic acid Acibenzolar and the CIFN polypeptide by peg moiety.

In certain embodiments, peg moiety is connected in the surface exposure lysine residue of CIFN polypeptide.In other embodiments, peg moiety is connected in the epsilon-amino of exposure lysine residue in surface in the CIFN polypeptide.In other embodiments, described bonding comprises in peg moiety and the CIFN polypeptide amido linkage between the epsilon-amino that the surface exposes lysine residue.And in other embodiments, described bonding comprises the amido linkage between the epsilon-amino that surface in the propionyl of peg moiety and the CIFN polypeptide exposes lysine residue.In other embodiments, described amido linkage is that the epsilon-amino condensation that the surface exposes lysine residue in α-methoxyl group, ω-propionic acid Acibenzolar and the CIFN polypeptide by peg moiety forms.

In certain embodiments, peg moiety is connected in the lys that is selected from the CIFN polypeptide ³¹, lys ⁵⁰, lys ⁷¹, lys ⁸⁴, lys ¹²¹, lys ¹²², lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵Methionin.In other embodiments, peg moiety is connected in the lys that is selected from the CIFN polypeptide ³¹, lys ⁵⁰, lys ⁷¹, lys ⁸⁴, lys ¹²¹, lys ¹²², lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵The epsilon-amino of Methionin.In other embodiments, described bonding comprises the amido linkage between the epsilon-amino of selecting lysine residue in peg moiety and the CIFN polypeptide.And in other embodiments, described bonding comprises the amido linkage between the epsilon-amino of selected lysine residue in the propionyl of peg moiety and the CIFN polypeptide.In other embodiments, described amido linkage is that the epsilon-amino condensation of selected lysine residue in α-methoxyl group, ω-propionic acid Acibenzolar and the CIFN polypeptide by peg moiety forms.

In certain embodiments, peg moiety is connected in the lys that is selected from the CIFN polypeptide ¹²¹, lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵Methionin.In other embodiments, peg moiety is connected in the lys that is selected from the CIFN polypeptide ¹²¹, lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵The epsilon-amino of Methionin.In other embodiments, described bonding comprises the amido linkage between the epsilon-amino of selecting lysine residue in peg moiety and the CIFN polypeptide.And in other embodiments, described bonding comprises the amido linkage between the epsilon-amino of selected lysine residue in the propionyl of peg moiety and the CIFN polypeptide.In other embodiments, described amido linkage is that the epsilon-amino condensation of selected lysine residue in α-methoxyl group, ω-propionic acid Acibenzolar and the CIFN polypeptide by peg moiety forms.

Interrelate with above-mentioned single Pegylation CIFN molecule, the present invention expects the embodiment of various these quasi-molecules, and wherein the CIFN polypeptide is selected from interferon alpha-con1, interferon alpha-con2 and interferon alpha-con3, and described CIFN amino acid sequence of polypeptide is at United States Patent (USP) the 4th, open in 695, No. 623.

The colony of IFN-α

In addition, any method of described embodiment can adopt the Pegylation IFN-α composition of the colony that comprises single Pegylation IFN alpha molecule, and wherein said colony is made up of aforesaid one or more single Pegylation IFN alpha molecules.Described target composition comprises a colony of modified IFN-α polypeptide, and wherein each polypeptide has the single PEG molecule that is connected in polypeptide single amino acids residue.

In some described embodiment, described colony comprises the mixture of first kind of IFN-α polypeptide and at least one second kind of IFN-α polypeptide, described first polypeptide is connected in the PEG molecule at the first amino-acid residue place, and described at least one second polypeptide is connected in the PEG molecule at the second amino-acid residue place, wherein first and second IFN-α polypeptide is identical or different, and wherein the position of first amino-acid residue in an IFN-α amino acid sequence of polypeptide is different with the position of second amino-acid residue in the 2nd IFN-α polypeptide.As a limiting examples, one target composition comprises the colony that PEG modifies IFN-α polypeptide, and described colony is included in the IFN-α polypeptide that the N-terminal place is connected in the IFN-α polypeptide of linear PEG molecule and is connected in linear PEG molecule in the lysine residue place.

Usually, given modified IFN-α kind account for single Pegylation IFN-α peptide molecule total group about 0.5% to about 99.5%, for example, given modified IFN-α kind account for single Pegylation IFN-α peptide molecule total group about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or about 99.5%.In certain embodiments, one target composition comprises the colony of single Pegylation IFN-α polypeptide, and described colony comprises at least about 70%, at least about 80%, at least about 90%, at least about 95% or at least about the 99% IFN-α polypeptide that connects at same loci (for example at N-terminal amino acid place).

In the special embodiment that is concerned about, described composition comprises the colony of single Pegylation CIFN molecule, described colony is by one or more molecular compositions, wherein each molecule is characterised in that: single CIFN polypeptide directly or with covalent bonding is connected in the linear peg moiety of the about 30kD of individual molecule amount indirectly, and wherein said bonding is to be connected in the lysine residue of CIFN polypeptide or the N-terminal amino-acid residue of CIFN polypeptide.

The amino-acid residue that PEG connected is the N-terminal amino-acid residue in many examples.In other embodiments, the PEG molecule is to be connected in (directly or via linking group) surface to expose lysine residue.In other embodiments, peg moiety is connected in (directly or via linking group) and is selected from the lys of CIFN polypeptide ³¹, lys ⁵⁰, lys ⁷¹, lys ⁸⁴, lys ¹²¹, lys ¹²², lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵Lysine residue.In other embodiments, peg moiety is connected in (directly or via linking group) and is selected from the lys of CIFN polypeptide ¹²¹, lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵Lysine residue.

As an example, described composition comprises the colony of single Pegylation CIFN molecule, described colony is by first single Pegylation CIFN polypeptide kind quasi-molecule and second single Pegylation CIFN polypeptide kind molecular composition, first kind of quasi-molecule is characterised in that peg moiety is connected in the N-terminal amino-acid residue of a CIFN polypeptide, and second kind of quasi-molecule is characterised in that peg moiety is connected in first lysine residue of the 2nd CIFN polypeptide, and wherein first and second CIFN polypeptide is identical or different.Described composition can comprise at least one other single Pegylation CIFN polypeptide kind quasi-molecule in addition, described kind of quasi-molecule is characterised in that peg moiety is connected in the lysine residue in the CIFN polypeptide, and wherein the position of the binding site in each other single Pegylation CIFN polypeptide kind is different with the binding site position in any one other kind.In all kinds of this example, peg moiety is that molecular-weight average is the linear peg moiety of about 30kD.

About any one of above-mentioned single Pegylation CIFN molecule colony, be by first single Pegylation CIFN polypeptide kind quasi-molecule and second single Pegylation CIFN polypeptide kind molecular composition, first kind of quasi-molecule is characterised in that peg moiety is connected in the N-terminal amino-acid residue of a CIFN polypeptide, and second kind of quasi-molecule is characterised in that peg moiety is connected in the first surface exposure lysine residue of the 2nd CIFN polypeptide, and wherein first and second CIFN polypeptide is identical or different.Described composition can comprise at least one other single Pegylation CIFN polypeptide kind quasi-molecule in addition, described kind of quasi-molecule is characterised in that the surface that peg moiety is connected in the CIFN polypeptide exposes lysine residue, and wherein the position of the binding site in each other single Pegylation CIFN polypeptide kind is different with the binding site position in any one other kind.In all kinds of this example, peg moiety is that molecular-weight average is the linear peg moiety of about 30kD.

As another example, described composition comprises the colony of single Pegylation CIFN molecule, described colony is by first single Pegylation CIFN polypeptide kind quasi-molecule and second single Pegylation CIFN polypeptide kind molecular composition, first kind of quasi-molecule is characterised in that peg moiety is connected in the N-terminal amino-acid residue of a CIFN polypeptide, and second kind of quasi-molecule is characterised in that peg moiety is connected in the lys that is selected from the 2nd CIFN polypeptide ³¹, lys ⁵⁰, lys ⁷¹, lys ⁸⁴, lys ¹²¹, lys ¹²², lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵First lysine residue, wherein first and second CIFN polypeptide is identical or different.Described composition can comprise the 3rd single Pegylation CIFN polypeptide kind quasi-molecule in addition, and this kind quasi-molecule is characterised in that peg moiety is connected in the lys that is selected from the 3rd CIFN polypeptide ³¹, lys ⁵⁰, lys ⁷¹, lys ⁸⁴, lys ¹²¹, lys ¹²², lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵Second lysine residue, wherein any one in the 3rd CIFN polypeptide and the first and second CIFN polypeptide is identical or different, and wherein the position of second lysine residue in the 3rd CIFN amino acid sequence of polypeptide is different with the position of first lysine residue in the 2nd CIFN amino acid sequence of polypeptide.Described composition can comprise at least one other single Pegylation CIFN polypeptide kind quasi-molecule in addition, and described kind of quasi-molecule is characterised in that peg moiety is connected in lys ³¹, lys ⁵⁰, lys ⁷¹, lys ⁸⁴, lys ¹²¹, lys ¹²², lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵In one, wherein in each other single Pegylation CIFN polypeptide kind in the position of binding site and other kind at any one in the class position of binding site different.In all kinds of this example, peg moiety is that molecular-weight average is the linear peg moiety of about 30kD.

As another example, described composition comprises the colony of single Pegylation CIFN molecule, described colony is by first single Pegylation CIFN polypeptide kind quasi-molecule and second single Pegylation CIFN polypeptide kind molecular composition, first kind of quasi-molecule is characterised in that peg moiety is connected in the N-terminal amino-acid residue of a CIFN polypeptide, is selected from lys in the 2nd CIFN polypeptide and second kind of quasi-molecule is characterised in that peg moiety is connected in ¹²¹, lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵In any one first lysine residue, wherein first and second CIFN polypeptide is identical or different.Described composition can comprise the 3rd single Pegylation CIFN polypeptide kind quasi-molecule in addition, and this kind quasi-molecule is characterised in that peg moiety is connected in the lys that is selected from the 3rd CIFN polypeptide ¹²¹, lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵Second lysine residue, wherein any one in the 3rd CIFN polypeptide and the first and second CIFN polypeptide is identical or different, and wherein the position of second lysine residue in the 3rd CIFN amino acid sequence of polypeptide is different with the position of first lysine residue in the 2nd CIFN amino acid sequence of polypeptide.Described composition can comprise at least one other single Pegylation CIFN polypeptide kind quasi-molecule in addition, and described kind of quasi-molecule is characterised in that peg moiety is connected in lys ¹²¹, lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵In one, wherein the position of binding site is different with the position of binding site in any one other kind in each other single Pegylation CIFN polypeptide kind.In all kinds of this example, peg moiety is that molecular-weight average is the linear peg moiety of about 30kD.

As another limiting examples, described composition comprises the colony of single Pegylation CIFN molecule, described colony is by first single Pegylation CIFN polypeptide kind quasi-molecule and second single Pegylation CIFN polypeptide kind molecular composition, first kind of quasi-molecule is characterised in that peg moiety is connected in first lysine residue of a CIFN polypeptide, and second kind of quasi-molecule is characterised in that peg moiety is connected in second lysine residue of the 2nd CIFN polypeptide, wherein first and second CIFN polypeptide is identical or different, and wherein the position of first Methionin in a CIFN amino acid sequence of polypeptide is different with the position of second lysine residue in the 2nd CIFN amino acid sequence of polypeptide.Described composition can comprise at least one other single Pegylation CIFN polypeptide kind quasi-molecule in addition, described kind of quasi-molecule is characterised in that peg moiety is connected in the lysine residue in the CIFN polypeptide, and wherein the position of the binding site in each other single Pegylation CIFN polypeptide kind is different with the binding site position in any one other kind.In all kinds of this example, peg moiety is that molecular-weight average is the linear peg moiety of about 30kD.

As another limiting examples, described composition comprises the colony of single Pegylation CIFN molecule, described colony is that first kind of quasi-molecule is characterised in that peg moiety is connected in the lys that is selected from a CIFN polypeptide by first single Pegylation CIFN polypeptide kind quasi-molecule and second single Pegylation CIFN polypeptide kind molecular composition ³¹, lys ⁵⁰, lys ⁷¹, lys ⁸⁴, lys ¹²¹, lys ¹²², lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵First lysine residue, and second kind of quasi-molecule is characterised in that peg moiety is connected in the lys that is selected from the 2nd CIFN polypeptide ³¹, lys ⁵⁰, lys ⁷¹, lys ⁸⁴, lys ¹²¹, lys ¹²², lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵Second lysine residue, wherein first and second CIFN polypeptide is identical or different, and wherein the position of second lysine residue in the 2nd CIFN amino acid sequence of polypeptide is different with the position of first lysine residue in a CIFN polypeptide.Described composition can comprise at least one other single Pegylation CIFN polypeptide kind quasi-molecule in addition, and described kind of quasi-molecule is characterised in that peg moiety is connected in lys ³¹, lys ⁵⁰, lys ⁷¹, lys ⁸⁴, lys ¹²¹, lys ¹²², lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵In one, wherein the position of the binding site in each other single Pegylation CIFN polypeptide kind is different with the binding site position in any one other kind.In all kinds of this example, peg moiety is that molecular-weight average is the linear peg moiety of about 30kD.

As another limiting examples, described composition comprises the colony of single Pegylation CIFN molecule, described colony is that first kind of quasi-molecule is characterised in that peg moiety is connected in the lys that is selected from a CIFN polypeptide by first single Pegylation CIFN polypeptide kind quasi-molecule and second single Pegylation CIFN polypeptide kind molecular composition ¹²¹, lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵First lysine residue, and second kind of quasi-molecule is characterised in that peg moiety is connected in the lys that is selected from the 2nd CIFN polypeptide ¹²¹, lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵Second lysine residue, wherein first and second CIFN polypeptide is identical or different, and wherein the position of second lysine residue in the 2nd CIFN amino acid sequence of polypeptide is different with the position of first lysine residue in a CIFN polypeptide.Described composition can comprise at least one other single Pegylation CIFN polypeptide kind quasi-molecule in addition, and described kind of quasi-molecule is characterised in that peg moiety is connected in lys ¹²¹, lys ¹³⁴, lys ¹³⁵And lys ¹⁶⁵In one, wherein the position of binding site is different with the position of binding site in any one other kind in each other single Pegylation CIFN polypeptide kind.In all kinds of this example, peg moiety is that molecular-weight average is the linear peg moiety of about 30kD.

As another limiting examples, described composition comprises single Pegylation CIFN molecule colony, described colony is by first single Pegylation CIFN polypeptide kind quasi-molecule and second single Pegylation CIFN polypeptide kind molecular composition, first kind of quasi-molecule is characterised in that peg moiety is connected in the first surface exposure lysine residue of a CIFN polypeptide, and second kind of quasi-molecule is characterised in that the second surface that peg moiety is connected in the 2nd CIFN polypeptide exposes lysine residue, wherein first and second CIFN polypeptide is identical or different, and wherein the position of first surface exposure Methionin in a CIFN amino acid sequence of polypeptide is different with the position of second surface exposure Methionin in the 2nd CIFN amino acid sequence of polypeptide.Described composition can comprise at least one other single Pegylation CIFN polypeptide kind quasi-molecule in addition, described kind of quasi-molecule is characterised in that the surface that peg moiety is connected in the CIFN polypeptide exposes lysine residue, and wherein the position of binding site is different with the position of binding site in any one other kind in each other single Pegylation CIFN polypeptide kind.In all kinds of this example, peg moiety is that molecular-weight average is the linear peg moiety of about 30kD.

About any one of above-mentioned single Pegylation CIFN molecule colony, the present invention's expection wherein molecule in each such colony comprises the embodiment of the CIFN polypeptide that is selected from interferon alpha-con1, interferon alpha-con2 and interferon alpha-con3.

Some embodiment describes a kind of by making CIFN polypeptide and α-methoxyl group in addition; γ-propionyl polyoxyethylene glycol (mPEGspa) (linearity; the about 30kD of molecular weight) Fan Ying method and the product that produces; wherein reactant at first provides with about 1: 1 molar ratio to about 1: 5 CIFN: mPEGspa; and wherein reaction is to carry out under the pH value between about 7 to about 9, and then reclaims single Pegylation CIFN product of described reaction.In one embodiment, reactant at first is that the molar ratio with about 1: 3 CIFN: mPEGspa provides, and reaction is to carry out under about 8 pH value.In another embodiment, produce product by toxicologic study and the needed scale in proportion of clinical study expansion step, reactant at first is that the molar ratio with 1: 2 CIFN: mPEGspa provides and react is to carry out under about 8.0 pH value.

About the aforesaid method product, the present invention expects that CIFN reactant wherein is selected from the embodiment of interferon alpha-con1, interferon alpha-con2 and interferon alpha-con3.

IFN-β

Term interferon beta (" IFN-β ") comprises IFN-beta polypeptides natural generation, that non-natural takes place and keeps the natural generation of parent or the analogue of the natural generation of the antiviral activity of non-natural generation IFN-β or non-natural generation IFN-β.

Any of multiple interferon-all can be by the successive administration method administration of embodiment.Suitable interferon-includes but not limited to, natural generation IFN-β; IFN-β 1a, for example Avonex_ (Biogen, Inc.) and Rebif_ (Serono, SA); And IFN-β 1b (Betaseron_; Berlex); And analogue.

The IFN-beta formulations can comprise N sealing kind, N-terminal amino acid acyl group acidylate wherein, and described acyl group is formyl radical, ethanoyl, malonyl or the like for example.That be suitable for equally is compound IFN-β.

The IFN-beta polypeptides can produce by any currently known methods.Can use the dna sequence dna of standard method composite coding IFN-β.In many examples, the IFN-beta polypeptides is that the dna sequence dna of manufacturing transforms or is transfected into host bacterium (for example intestinal bacteria (E.coli)) or at eukaryotic host cell (for example, yeast; Mammalian cell is as Chinese hamster ovary celI; And analogue) expression product in.In these embodiments, IFN-β is " reorganization IFN-β ".When host cell is bacterial host cell, IFN-β is modified to comprise the N-terminal methionine(Met).

Should be appreciated that IFN-β as herein described comprises one or more modified amino-acid residues, for example glycosylation, chemically modified effect and similar effect.

IFN-τ

Term interferon-tau (" IFN-τ ") comprises IFN-τ polypeptide natural generation, that non-natural takes place and keeps the natural generation of parent or the analogue of the natural generation of the antiviral activity of non-natural generation IFN-τ or non-natural generation IFN-τ.

Suitable τ Interferon, rabbit includes but not limited to, natural generation IFN-τ, Tauferon_ (Pepgen Corp.) and analogue.

It is mentioned aminoacid sequence in any one of P15696, P56828, P56832, P56829, P56831, Q29429, Q28595, Q28594, S08072, Q08071, Q08070, Q08053, P56830, P28169, P28172 and P28171 that IFN-τ can comprise the GenBank accession number.Thereby the sequence of any known IFN-τ polypeptide can the known variety of way change in affiliated field obtain desirable sequence variation.The variation polypeptide usually substantially with literary composition in the sequence similarity that provides, promptly differ at least one amino acid, and can differ at least two but no more than about 10 amino acid.It can be to replace, insert or disappearance that sequence changes.Conserved amino acid is replaced the replacement that generally includes in the following group: (glycine, L-Ala), (Xie Ansuan, Isoleucine, leucine), (aspartic acid, L-glutamic acid), (l-asparagine, glutamine), (Serine, Threonine), (Methionin, arginine) or (phenylalanine, tyrosine).

The relevant modifications that can change or not change the one-level aminoacid sequence comprises: the chemical derivatization effect of polypeptide, as acetylize or carboxylation; The aminoacid sequence of introducing or remove glycosylation site changes; The aminoacid sequence that makes protein be easy to Pegylation changes; With similar modification.Also comprise glycosylation modified body, as by modifying the modification body that its glycosylation pattern is reached during and the processing synthetic or in other procedure of processing, as by making polypeptide be exposed to influence glycosylated enzyme, for example Mammals glycosylase or deglycosylating enzyme at polypeptide.Also comprise have the phosphorylated amino acid residue sequence of (as Tyrosine O-phosphate, phosphoserine or phosphothreonine).

IFN-τ preparation can comprise N sealing kind, N-terminal amino acid acyl group acidylate wherein, and described acyl group is formyl radical, ethanoyl, malonyl or the like for example.That be suitable for equally is compound IFN-τ.

IFN-τ polypeptide can produce by any currently known methods.Can use the dna sequence dna of standard method composite coding IFN-τ.In many examples, IFN-τ polypeptide is that the dna sequence dna of manufacturing transforms or is transfected into host bacterium (for example intestinal bacteria (E.coli)) or at eukaryotic host cell (for example, yeast; Mammalian cell is as Chinese hamster ovary celI; And analogue) expression product in.In certain embodiments, IFN-τ is " reorganization IFN-τ ".When host cell is bacterial host cell, IFN-τ is modified to comprise the N-terminal methionine(Met).

Should be appreciated that IFN-τ as herein described comprises one or more modified amino-acid residues, for example glycosylation, chemically modified effect and similar effect.

IFN-ω

Term Interferon, rabbit ω (" IFN-ω ") comprises IFN-ω polypeptide natural generation, that non-natural takes place and keeps the natural generation of parent or the analogue of the natural generation of the antiviral activity of non-natural generation IFN-ω or non-natural generation IFN-ω.

Any known omega interferon can be by the successive administration method administration among the embodiment.Suitable IFN-ω includes but not limited to, natural generation IFN-ω; Reorganization IFN-ω is as Biomed 510 (BioMedicines); And analogue.

It is aminoacid sequence mentioned among NP_002168 or the AAA70091 that IFN-ω can comprise the GenBank accession number.Thereby the sequence of any known IFN-ω polypeptide can the known variety of way change in affiliated field obtain desirable sequence variation.The variation polypeptide usually substantially with literary composition in the sequence similarity that provides, promptly differ at least one amino acid, and can differ at least two but no more than about 10 amino acid.It can be to replace, insert or disappearance that sequence changes.Conserved amino acid is replaced the replacement that generally includes in the following group: (glycine, L-Ala), (Xie Ansuan, Isoleucine, leucine), (aspartic acid, L-glutamic acid), (l-asparagine, glutamine), (Serine, Threonine), (Methionin, arginine) or (phenylalanine, tyrosine).

IFN-ω preparation can comprise N sealing kind, N-terminal amino acid acyl group acidylate wherein, and described acyl group is formyl radical, ethanoyl, malonyl or the like for example.That be suitable for equally is compound IFN-ω.

IFN-ω polypeptide can produce by any currently known methods.Can use the dna sequence dna of standard method composite coding IFN-ω.In many examples, IFN-ω polypeptide is that the dna sequence dna of manufacturing transforms or is transfected into host bacterium (for example intestinal bacteria (E.coli)) or at eukaryotic host cell (for example, yeast; Mammalian cell is as Chinese hamster ovary celI; And analogue) expression product in.In these embodiments, IFN-ω is " reorganization IFN-ω ".When host cell is bacterial host cell, IFN-ω is modified to comprise the N-terminal methionine(Met).

Should be appreciated that IFN-ω as herein described comprises one or more modified amino-acid residues, for example glycosylation, chemically modified effect and similar effect.

The type iii interferon receptor stimulant

In any method in aforesaid method, in certain embodiments the Interferon Receptors agonist be the type iii interferon acceptor agonist (as, " type iii interferon agonist ").The type iii interferon agonist comprises the IL-28b polypeptide; The IL-28a polypeptide; The IL-29 polypeptide; The type iii interferon acceptor had specific antibody; And any other type iii interferon receptor stimulant, comprise non-polypeptide agonist.

IL-28A, IL-28B and IL-29 (being commonly referred to as " type iii interferon " or " III type IFN " in the literary composition) are people such as Sheppard. describe to some extent among (2003) Nature 4:63-68.Each polypeptide is in conjunction with the assorted dimerization acceptor of being made up of IL-10 acceptor β chain and IL-28 acceptor α.People such as Sheppard (2003), the same.Under GenBank accession number NP_742150, NP_742151 and NP_742152, can find the aminoacid sequence of IL-28A, IL-28B and IL-29 respectively.

Thereby any known III type IFN amino acid sequence of polypeptide can the known variety of way change in affiliated field obtain desirable sequence variation.The variation polypeptide usually substantially with literary composition in the sequence similarity that provides, promptly differ at least one amino acid, and can differ at least two but no more than about 10 amino acid.It can be to replace, insert or disappearance that sequence changes.Can using system introducing L-Ala or the scanning of other residue suddenly change to determine key amino acid.The concrete amino acid of being concerned about is replaced and is comprised that conservative property and non-conservation change.Conserved amino acid is replaced the replacement that generally includes in the following group: (glycine, L-Ala), (Xie Ansuan, Isoleucine, leucine), (aspartic acid, L-glutamic acid), (l-asparagine, glutamine), (Serine, Threonine), (Methionin, arginine) or (phenylalanine, tyrosine).

The relevant modifications that can change or not change the one-level aminoacid sequence comprises: the chemical derivatization effect of polypeptide, as acetylize or carboxylation; The aminoacid sequence of introducing or remove glycosylation site changes; The aminoacid sequence that makes protein be easy to Pegylation changes; With similar modification.Also comprise glycosylation modified body, as by modifying the modification that its glycosylation pattern is reached during and the processing synthetic or in other procedure of processing, as by making polypeptide be exposed to influence glycosylated enzyme, for example Mammals glycosylase or deglycosylating enzyme at polypeptide.Also comprise have the phosphorylated amino acid residue sequence of (as Tyrosine O-phosphate, phosphoserine or phosphothreonine).

Embodiment comprises and uses the general chemistry technology to be modified so that improve its proteolytic degradation resistance, optimize dissolution characteristics or make it become the polypeptide of the therapeutical agent that is more suitable for.For instance, thus can with the backbone cyclized enhanced stability of peptide (referring to, people such as Friedler. (2000) J.Biol.Chem.275:23783-23789).Can use the analogue that comprises the residue except that natural generation L amino acid (as D amino acid) or non-natural generation synthesizing amino acid.The protein Pegylation can be come enhanced stability.Polypeptide and albumin are merged.

The known ordinary method in field prepared via in vitro synthesizing under polypeptide can use by recombination method, perhaps can separate from bring out the described proteic cell of type or natural generation.Specific preparation section and mode depend on factors such as convenience, economy, required purity.Need the time, can synthetic or express during different groups are introduced in the polypeptide, make it possible to be connected in other molecule or be connected in certain surface.Therefore, can use halfcystine to prepare thioether, use Histidine to connect metal ion complex, use carboxyl to form acid amides or ester, use the amino acid amides that forms, or the like.

II type Interferon Receptors agonist

II type Interferon Receptors agonist comprises any natural generation of human II type Interferon Receptors or the part that non-natural takes place, and described part is incorporated into described acceptor or transduces via described acceptor priming signal.II type Interferon Receptors agonist comprises Interferon, rabbit, and described Interferon, rabbit comprises: natural generation Interferon, rabbit, modified interferon, synthetic Interferon, rabbit, Peg-Intron, comprise the fused protein of Interferon, rabbit and heterologous protein, through shuffling Interferon, rabbit, Interferon Receptors being had specific antibody, non-chemistry of peptides agonist and analogue.

A specific examples of II type Interferon Receptors agonist is IFN-γ and its varient.Use IFN-γ polypeptide though the embodiment of the invention illustrates, should understand and in described method, can use any II type Interferon Receptors agonist.

Interferon-gamma

Can obtain the nucleotide sequence of encoding IFN-y polypeptide from public database, described database is GenBank for example, the periodical publication, etc.Though various Mammals IFN-γ polypeptide be concerned about, for the treatment human diseases for, understand end user's proteinoid usually.In Genbank accession number XI3274, V00543 and NM_000619, can find the to encode sequence of human IFN-γ.In Genbank accession number J00219, M37265 and V00536, can find corresponding genome sequence.Referring to, for example, people such as Gray. (1982) Nature 295:501 (Genbank X13274); With people such as Rinderknecht. (1984) J.B.C.259:6790.

IFN-γ 1b (Actimmune_, human interferon) has 140 amino acid whose single chain polypeptides.It is that reorganization makes and is nonglycosylated in intestinal bacteria.People such as Rinderknecht. (1984) J.Biol.Chem.259:6790-6797.As United States Patent (USP) the 6th, 497, the reorganization IFN-γ described in No. 871 also is suitable for use in herein.

The IFN-γ that preparation is used for embodiment of the invention method can be any in natural IFN-γ, reorganization IFN-γ and its derivative, as long as they have the IFN-gamma activity, especially human IFN-gamma activity.Human IFN-γ shows known many other immunoregulatory activities of antiviral and antiproliferative properties and affiliated field of expression Interferon, rabbit feature.Although IFN-γ is based on aforesaid sequence, yet proteinic generation and proteolysis processing can cause its processing varient.The crude sequence that is provided by people such as Gray (with above) is that (amino acid aa) forms by 166 amino acid.Though think that originally the reorganization IFN-γ that produces has 146 amino acid in intestinal bacteria, but find that subsequently natural human IFN-γ is in residue 23 back cracking (amino acid 20 places begin), produce 143 protein, if need have terminal methionine when perhaps in bacterium, expressing, be 144aa.During purifying, mature protein can be in addition in residue 162 backs in the C-terminal cracking (with reference to people such as Gray. sequence), cause formation to have 139 amino acid whose protein, perhaps, be 140 amino acid when for example needing have initial methionine(Met) for bacterial expression.The N-terminal methionine(Met) is that it in particular cases can not machine away escherichia coli expression by the coded artifact of mRNA translation " beginning " signal AUG.In other microflora or eukaryotic expression system, can remove methionine(Met).

For the use in described method, can use natural IFN-γ peptide, it modifies in the combination of body and varient or one or more peptides any one.The IFN-γ peptide of being concerned about comprises fragment, and complete sequence is differently blocked at C-terminal relatively.These fragments still represent the characteristic of human IFN-, as long as amino acid 24 to about 149 (from residue numberings of crude polypeptide) exist.At the aminoacid sequence that does not lose after replacing amino acid/11 55 with external sequence under the active situation.Referring to, for example, United States Patent (USP) the 5th, 690, No. 925.Natural IFN-gamma portion comprises the various molecules that extend from amino-acid residue 24-150,24-151,24-152,24-153,24-155 and 24-157.Can use in the methods of the invention in these varients any one with other under field known and have a varient of IFN-gamma activity.

Thereby the sequence of IFN-γ polypeptide can the known variety of way change in affiliated field obtain desirable sequence variation.The variation polypeptide usually substantially with literary composition in the sequence similarity that provides, promptly differ at least one amino acid, and can differ at least two but no more than about 10 amino acid.It can be to replace, insert or disappearance that sequence changes.Can using system introducing L-Ala or the scanning of other residue suddenly change to determine key amino acid.The concrete amino acid of being concerned about is replaced and is comprised that conservative property and non-conservation change.Conserved amino acid is replaced the replacement that generally includes in the following group: (glycine, L-Ala), (Xie Ansuan, Isoleucine, leucine), (aspartic acid, L-glutamic acid), (l-asparagine, glutamine), (Serine, Threonine), (Methionin, arginine) or (phenylalanine, tyrosine).

The relevant modifications that can change or not change the one-level aminoacid sequence comprises: the chemical derivatization effect of polypeptide, as acetylize or carboxylation; The aminoacid sequence of introducing or remove glycosylation site changes; The aminoacid sequence that makes protein be easy to Pegylation changes; With similar modification.An embodiment expection has the purposes of the IFN-γ varient in one or more natural generation glycosylations and/or Pegylation site, described varient provides glycosyl and/or the polyglycol derivatization polypeptide with low serum clearance rate through design, as the IFN-γ polypeptide variants described in the open case WO 01/36001 of international monopoly.Also comprise glycosylation modified body, for example by during and the processing synthetic or the modification body that modification of glycosylation patterns is reached during other procedure of processing at polypeptide, for example, polypeptide influences the enzyme of glycosylation, as Mammals glycosylase or deglycosylating enzyme by being exposed to.Also comprise have the phosphorylated amino acid residue sequence of (as Tyrosine O-phosphate, phosphoserine or phosphothreonine).

Embodiment comprises and uses the general chemistry technology to be modified so that improve its proteolytic degradation resistance, optimize dissolution characteristics or make it become the polypeptide of the therapeutical agent that is more suitable for.For instance, thus can with the backbone cyclized enhanced stability of peptide (referring to, people such as Friedler. (2000) J.Biol.Chem.275:23783-23789).Also can use the analogue that comprises the residue except that natural generation L amino acid (as D amino acid) or non-natural generation synthesizing amino acid.The protein Pegylation can be come enhanced stability.

Also can separate and purified polypeptide according to the ordinary method that is re-combined into.Can make lysate by expressive host, and use HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography or other purification technique to come the purifying lysate.For the pollutent relevant with its purifying with the product preparation, composition therefor accounts at least 20 weight percents of desired product under most of situation, more generally be at least about 75 weight percents, preferably at least about 95 weight percents, and for therapeutic purpose usually at least about 99.5 weight percents.Described percentage ratio generally is based on gross protein.

The non-Buddhist nun's ketone of piperazine and its analogue

The non-Buddhist nun's ketone of piperazine (5-methyl isophthalic acid-phenyl-2-(1H)-pyridone) and the non-Buddhist nun's keto analog of specific piperazine that openly are used for the treatment of the fibrosis illness." fibrosis illness " can have the active compound of anti-fibrosis by coming into operation and treat.

The non-Buddhist nun's ketone of piperazine

The non-Buddhist nun's keto analog of piperazine

Substituent R ₁, R ₂, X description

R ₁: carbocyclic ring (saturated or unsaturated), heterocycle (saturated or unsaturated), alkyl (saturated or unsaturated).Example comprises phenyl, phenmethyl, pyrimidyl, naphthyl, indyl, pyrryl, furyl, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl and similar group.

R ₁Can further on carbocyclic ring or heterocyclic moiety, replace through following substituting group: such as, halogen, nitro, amino, hydroxyl, alkoxyl group, carboxyl, cyano group, sulfo-, alkyl, aryl, assorted alkyl, heteroaryl and its combination, for example 4-nitrophenyl, 3-chloro-phenyl-, 2,5-dinitrophenyl, 4-p-methoxy-phenyl, 5-methyl-pyrryl, 2,5-dichloro cyclohexyl, guanidine radicals-cyclohexenyl and similar group.

R ₂: alkyl, carbocyclic ring, aryl, heterocycle.Example comprises: methyl, ethyl, propyl group, sec.-propyl, phenyl, 4-nitrophenyl, thienyl and similar group.

X: the substituting group that can be any number (1 to 3) on described carbocyclic ring or the heterocycle.Described substituting group can be identical or different.Substituting group comprises hydrogen, alkyl, assorted alkyl, aryl, heteroaryl, halogen, nitro, carboxyl, hydroxyl, cyano group, amino, sulfo-, alkylamino, halogenated aryl and similar group.

The further 1-3 through being selected from the group that forms by alkyl, aryl, nitro, alkoxyl group, hydroxyl and halogen group the substituting group replacement according to circumstances of described substituting group.Example comprises: methyl, 2,3-dimethyl, phenyl, p-methylphenyl, 4-chloro-phenyl-, 4-nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl and similar group.

Specific examples comprises compound listed in the table 1:

Table 1

?IIA	?IIB
?IIA	?IIB	The 5-methyl isophthalic acid-(2 '-pyridyl)-2-(1H) pyridine	6-methyl isophthalic acid-phenyl-3-(1H) pyridone
6-methyl isophthalic acid-phenyl-2-(1H) pyridone	5-methyl isophthalic acid-p-methylphenyl-3-(1H) pyridone	The 5-methyl isophthalic acid-(2 '-pyridyl)-2-(1H) pyridine	6-methyl isophthalic acid-phenyl-3-(1H) pyridone
6-methyl isophthalic acid-phenyl-2-(1H) pyridone	5-methyl isophthalic acid-p-methylphenyl-3-(1H) pyridone	5-methyl-3-phenyl-1-(2 '-thienyl)-2-(1H) pyridone	The 5-methyl isophthalic acid-(2 '-naphthyl)-3-(1H) pyridone
The 5-methyl isophthalic acid-(2 '-naphthyl)-2-(1H) pyridone	5-methyl isophthalic acid-phenyl-3-(1H) pyridone	5-methyl-3-phenyl-1-(2 '-thienyl)-2-(1H) pyridone
	5-methyl isophthalic acid-phenyl-3-(1H) pyridone	5-methyl isophthalic acid-p-methylphenyl-2-(1H) pyridone	The 5-methyl isophthalic acid-(5 '-quinolyl)-3-(1H) pyridone
The 5-methyl isophthalic acid-(1 '-naphthyl)-2-(1H) pyridone	5-ethyl-1-phenyl-3-(1H) pyridone	5-methyl isophthalic acid-p-methylphenyl-2-(1H) pyridone
	5-ethyl-1-phenyl-3-(1H) pyridone	5-ethyl-1-phenyl-2-(1H) pyridone	The 5-methyl isophthalic acid-(4 '-p-methoxy-phenyl)-3-(1H) pyridone
The 5-methyl isophthalic acid-(5 '-quinolyl)-2-(1H) pyridone	4-methyl isophthalic acid-phenyl-3-(1H) pyridone	5-ethyl-1-phenyl-2-(1H) pyridone
	4-methyl isophthalic acid-phenyl-3-(1H) pyridone	The 5-methyl isophthalic acid-(4 '-quinolyl)-2-(1H) pyridone	The 5-methyl isophthalic acid-(3 '-pyridyl)-3-(1H) pyridone
The 5-methyl isophthalic acid-(4 '-pyridyl)-2-(1H) pyridone	The 5-methyl isophthalic acid-(2 '-thienyl)-3-(1H) pyridone		The 5-methyl isophthalic acid-(3 '-pyridyl)-3-(1H) pyridone
The 5-methyl isophthalic acid-(4 '-pyridyl)-2-(1H) pyridone	The 5-methyl isophthalic acid-(2 '-thienyl)-3-(1H) pyridone	3-methyl isophthalic acid-phenyl-2-(1H) pyridone	The 5-methyl isophthalic acid-(2 '-pyridyl)-3-(1H) pyridone
The 5-methyl isophthalic acid-(4 '-p-methoxy-phenyl)-2-(1H) pyridone	The 5-methyl isophthalic acid-(2 '-quinolyl)-3-(1H) pyridone	3-methyl isophthalic acid-phenyl-2-(1H) pyridone	The 5-methyl isophthalic acid-(2 '-pyridyl)-3-(1H) pyridone
		1-phenyl-2-(1H) pyridone	1-phenyl-3-(1H) pyridine
1,3-phenylbenzene-2-(1H) pyridone	1-(2 '-furyl)-5-methyl-3-(1H) pyridone	1-phenyl-2-(1H) pyridone	1-phenyl-3-(1H) pyridine
1,3-phenylbenzene-2-(1H) pyridone	1-(2 '-furyl)-5-methyl-3-(1H) pyridone	1,3-phenylbenzene-5-methyl-2-(1H) pyridone	1-(4 '-chloro-phenyl-)-5-methyl-3-(1H) pyridine
The 5-methyl isophthalic acid-(3 '-trifluoromethyl)-2-(1H) pyridone		1,3-phenylbenzene-5-methyl-2-(1H) pyridone	1-(4 '-chloro-phenyl-)-5-methyl-3-(1H) pyridine
		3-ethyl-1-phenyl-2-(1H) pyridone
The 5-methyl isophthalic acid-(3 '-pyridyl)-2-(1H) pyridone		3-ethyl-1-phenyl-2-(1H) pyridone
The 5-methyl isophthalic acid-(3 '-pyridyl)-2-(1H) pyridone		5-methyl isophthalic acid-(3-nitrophenyl)-2-(1H) pyridone
3-(4 '-chloro-phenyl-)-5-methyl isophthalic acid-phenyl-2-(1H) pyridone		5-methyl isophthalic acid-(3-nitrophenyl)-2-(1H) pyridone
		The 5-methyl isophthalic acid-(2 '-thienyl)-2-(1H) pyridone
The 5-methyl isophthalic acid-(2 '-thiazolyl)-2-(1H) pyridone		The 5-methyl isophthalic acid-(2 '-thienyl)-2-(1H) pyridone
		3,6-dimethyl-1-phenyl-2-(1H) pyridone
1-(4 '-chloro-phenyl-)-5-methyl-2-(1H) pyridone		3,6-dimethyl-1-phenyl-2-(1H) pyridone
1-(4 '-chloro-phenyl-)-5-methyl-2-(1H) pyridone		1-(2 '-imidazolyl)-5-methyl-2-(1H) pyridone
1-(4 '-nitrophenyl)-2-(1H) pyridone		1-(2 '-imidazolyl)-5-methyl-2-(1H) pyridone
1-(4 '-nitrophenyl)-2-(1H) pyridone		1-(2 '-furyl)-5-methyl-2-(1H) pyridone
1-phenyl-3-(4 '-chloro-phenyl-)-2-(1H) pyridine		1-(2 '-furyl)-5-methyl-2-(1H) pyridone

United States Patent (USP) the 3rd, 974, No. 281, the 3rd, 839, No. 346, the 4th, 042, No. 699, the 4th, 052, No. 509, the 5th, 310, No. 562, the 5th, 518, No. 729, the 5th, 716, the 632 and the 6th, the method be used for synthetic non-Buddhist nun's ketone of piperazine and the non-Buddhist nun's keto analog of specific piperazine is described and with the method for its allotment in the medical composition that is applicable to embodiment of the invention method for 090, No. 822.

Extrasin alpha

Extrasin alpha (Zadaxin ^TMCan be available from CA, the SciClone Pharmaceuticals of San Mateo Inc.) is the synthesized form of thymosin, thymosin be in the circulation natural discovery and by a kind of hormone that thymus gland produced.Extrasin alpha increases T cell and NK cell activity.The ZadaxinTM that allocates for subcutaneous injection is the purifying sterile freeze-drying preparation of the chemosynthesis thymosin that is equal to human thymosin.Thymosin is to have following sequence and molecular weight is 3,108 daltonian acetylize polypeptide: Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-lle-Thr-Thr-L ys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-A sn-OH.Described freeze-dried preparation contains 1.6mg synthesizing thymosins α, 50mg N.F,USP MANNITOL and sodium phosphate buffer agent the pH value is adjusted to 6.8.

Ribavirin

Ribavirin, 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-methane amide is can be available from Calif, the ICN Pharmaceuticals of Costa Mesa, Inc. nucleoside analog, and in No. 8199 compound of the Merck index of the 11st edition, describe to some extent.Its preparation method and concocting method are described in United States Patent (USP) the 4th, 211, in No. 771.Embodiment also comprise the derivative of ribavirin purposes (referring to, for example, United States Patent (USP) the 6th, 277, No. 830).Ribavirin can be used as capsule or tablet form oral administration medicine supplying.Certainly, also expect other available ribavirin types of administration, as nose spraying, transdermal, suppository, slow release formulation, etc.Any types of administration all can work, as long as do not destroying the suitable dosage of administration under the activeconstituents.

The general dosage of ribavirin be every day about 400mg to about 1200mg, about 600mg extremely about 1000mg or about 700 to about 900mg.In certain embodiments, ribavirin runs through the whole dispensing course of treatment of NS3 inhibitor therapy.

Levovirin (levovirin)

Levovirin is the levoisomer of ribavirin, and shows the characteristic that enhancing Th1 immunne response surpasses the Th2 immunne response.Levovirin is made by ICN Pharmaceuticals.

The structure of Levovirin is as follows:

Wella rice fixed (viramidine)

Wella rice is the 3-carboxamidine derivatives of ribavirin and the prodrug that serves as ribavirin surely.Can Wella rice be converted into ribavirin surely effectively by adenosine deaminase.

The fixed structure of Wella rice is as follows:

Nucleoside analog

The nucleoside analog that is suitable for described combination treatment includes but not limited to, ribavirin, Levovirin, Wella rice is fixed, isatoribine (isatoribine), as United States Patent (USP) the 5th, 559, disclosed and United States Patent (USP) the 5th in No. 101,559, the L-ribofuranose yl nucleosides that No. 101 formula I is contained (for example, 1-β-L-ribofuranosyl uridylic, 1-β-L-ribofuranosyl-5 FU 5 fluorouracil, 1-β-L-ribofuranosyl cytosine(Cyt), 9-β-L-ribofuranosyl VITAMIN B4,9-β-L-ribofuranosyl xanthoglobulin, 9-β-L-ribofuranosyl guanine, 9-β-L-ribofuranosyl-6-Tioguanine, 2-amino-α-L-ribofuranose [1 ', 2 ': 4,5] oxazoline, O ², O ²-dehydration-1-α-L-ribofuranosyl uridylic, 1-α-L-ribofuranosyl uridylic, 1-(2; 3; 5-three-O-benzoyl-α-Fu Nan ribosyl-4-thiouracil, 1-α-L-ribofuranosyl cytosine(Cyt), 1-α-L-ribofuranosyl-4-thiouracil, 1-α-L-ribofuranosyl-5 FU 5 fluorouracil, 2-amino-beta--L-arbinofuranose base [1 '; 2 ': 4,5] oxazoline, O ², O ²-dehydration-β-L-1-, 2 '-deoxidation-β-L-uridine, 3 ', 5 '-two-O-benzoyl-2 '-deoxidation-4-sulfo--β-L-uridine, 2 '-deoxidation-β-L-cytidine(C, 2 '-deoxidation-β-L-4-thiouracil nucleosides, 2 '-deoxidation-β-L-thymidine, 2 '-deoxidation-β-L-5-fluorouracil nucleoside, 2 ', 3 '-dideoxy-β-L-uridine, 2 '-deoxidation-β-L-5-fluorouracil nucleoside and 2 '-deoxidation-β-L-inosine), as United States Patent (USP) the 6th, 423, disclosed and United States Patent (USP) the 6th in No. 695, the compound that 423, No. 695 formula I is contained, the compound that the formula I of No. the 2002/0058635th, disclosed and United States Patent (USP) is contained as No. the 2002/0058635th, United States Patent (USP), as disclosed nucleoside analog among WO 01/90121 A2 (Idenix), as the disclosed nucleoside analog of WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.), as disclosed nucleoside analog among WO 02/057287 A2 or the WO02/057425 A2 (being Merck/Isis); And analogue.

The TNF antagonist

In certain embodiments, described method comprises the NS3 inhibitor of the significant quantity that comes into operation and the tumor necrosis factor-alpha of significant quantity (TNF-α) antagonist.The TNF-alpha-2 antagonists that is suitable for this paper comprise reagent, the blocking-up that reduces the synthetic level of TNF-α or suppress TNF-α and TNF-α acceptor (TNFR) bonded reagent and blocking-up or inhibition by the reagent of TNFR Mediated Signal Transduction.Unless otherwise indicated, any " the TNF-alpha-2 antagonists " in the literary composition or " TNF antagonist " are interpreted as the TNF-alpha-2 antagonists except that non-Buddhist nun's ketone of piperazine or the non-Buddhist nun's keto analog of piperazine.

As used herein, term " TNF receptor polypeptides " and " TNFR polypeptide " are meant from the polypeptide that can derive and obtain in conjunction with the TNFR (from any kind of) of TNF.Two kinds of different cell surface TNFR:II type TNFR (or p75 TNFR or TNFRII) and I type TNFR (or p55 TNFR or TNFRI) have been described.The human p75TNFR of ripe total length is the glycoprotein of the about 75-80 kilodalton of molecular weight (kD).The human p55 TNFR of ripe total length is the glycoprotein of the about 55-60 kD of molecular weight.Exemplary TNFR polypeptide is derived from TNFR I type and/or TNFR II type and is obtained.Soluble TNF R comprises p75 TNFR polypeptide; The fusions of p75 TNFR and allos fusion partner, for example, the Fc part of immunoglobulin (Ig).

The TNFR polypeptide can be the suitable fragments of complete TNFR or TNFR.United States Patent (USP) the 5th, 605 provides the example of TNFR polypeptide, comprises the soluble TNF R polypeptide that is applicable to the embodiment of the invention for No. 690.In many examples, the TNFR polypeptide comprises the TNFR extracellular domain.In certain embodiments, the TNFR polypeptide is a kind of fusion polypeptide, and it comprises the TNFR extracellular domain of the field of invariants that is connected in immunoglobulin molecules.In other embodiments, the TNFR polypeptide is a kind of fusion polypeptide, and it comprises the p75 TNFR extracellular domain of the field of invariants that is connected in the IgG1 molecule.In certain embodiments, when the expection dispensing and the mankind, the used Ig of fusion rotein is human, and for example IgG 1.

The TNFR polypeptide of unit price and multivalence form can be used in embodiments of the present invention.The TNFR polypeptide of multivalence form has the TNF binding site more than.In certain embodiments, TNFR is TNFR divalence or the dimerization form.For instance, as United States Patent (USP) the 5th, 605, people such as No. 690 and Mohler, 1993, J.Immunol., described in the 151:1548-1561, the chimeric antibody polypeptide that utilizes the TNFR extracellular domain to replace the variable domain of any one or both in heavy chain immunoglobulin or the light chain will be provided for the TNFR polypeptide of the embodiment of the invention.In general, as so chimeric TNFR: antibody polypeptides is when being produced by cell, forms bivalent molecule by the thioether bonding between each functional domain of immunoglobulin (Ig).Chimeric TNFR like this: antibody polypeptides is called TNFR:Fc.

In one embodiment, described method comprises the soluble TNF R ENBREL_ of the significant quantity that comes into operation.The dimeric fusion protein that ENBREL_ is made up of the outer ligand binding moiety of born of the same parents of the mankind's 75 kilodaltons (p75) TNFR of the Fc part that is connected in IgG1.The Fc component of ENBREL_ contains CH2 functional domain, CH3 functional domain and hinge area, and does not contain the CH1 functional domain of IgG1.ENBREL_ results from Chinese hamster ovary, and (Chinese hamster ovary is CHO) in the mammalian cell expression system.ENBREL_ is made up of 934 amino acid, and has the apparent molecular weight of about 150 kilodaltons.People such as Smith. (1990) Science 248:1019-1023; People such as Mohler. (1993) J.Immunol.151:1548-1561; United States Patent (USP) the 5th, 395, No. 760; With United States Patent (USP) the 5th, 605, No. 690.

It is same that what be fit to just usefulness is monoclonal antibody in conjunction with TNF-α.Monoclonal antibody comprises " humanization " mouse monoclonal antibody; Chimeric antibody; Aminoacid sequence is at least about 80%, at least about 90%, at least about 95% or 100% mankind's monoclonal antibody; With similar antibody.Referring to, for example WO 90/10077, WO 90/04036 and WO 92/02190.Suitable monoclonal antibody comprises: antibody fragment, as Fv, F (ab ') 2 and Fab; Synthetic antibody; The artificial antibody; Phage displaying antibody; With similar antibody.

The example of suitable monoclonal antibody comprise Infliximab (REMICADE_, Centocor) and Adalimumab (HUMIRA ^TM, Abbott).REMICADE_ is the anti-TNF-Alpha antibodies of a kind of chimeric monoclonal, and it comprises about 25% mouse aminoacid sequence and about 75% human amino acid sequence.REMICADE_ comprises the variable region of the mouse monoclonal anti TNF-Alpha antibodies that merges with IgG 1 constant region.People such as Elliott. (1993) Arthritis Rheum.36:1681-1690; People such as Elliott. (1994) Lancet 344:1105-1110; People such as Baert. (1999) Gastroenterology 116:22-28.HUMIRA ^TMBe to use the human total length IgG1 monoclonal antibody of display technique of bacteriophage identification.Piascik(2003)J.Am.Pharm.Assoc.43：327-328。

Be included in term " TNF antagonist " scope equally and what therefore be applicable to described method is stress activated protein kinase (stress-activated protein kinase, SAPK) inhibitor.The SAPK inhibitor is known in affiliated field, includes, but are not limited to: United States Patent (USP) the 6th, 548, disclosed 2-alkyl imidazole in No. 520; United States Patent (USP) the 6th, 489, disclosed 1,4 in No. 325,5-substituted imidazole compounds class; United States Patent (USP) the 6th, 569, disclosed 1,4 in No. 871,5-substituted imidazole compounds class; Disclosed heteroaryl amino phenyl ketone compounds in No. the 2003/0073832nd, the U.S. patent application case; United States Patent (USP) the 6th, 288, disclosed Pyridinylimidazoles compounds in No. 089; With United States Patent (USP) the 6th, 432, disclosed heteroaryl amino benzophenone in 962.That is concerned about also has disclosed compound in No. the 6th, 214,854, No. the 2003/0149041st, U.S. Patent Publication case and United States Patent (USP).Stress activated protein kinase is in response to stress stimulation and the member of the mitogen activated protein kinase family that is activated.SAPK include but not limited to p38 (people such as Lee. (1994) Nature372:739) and c-jun N-terminal kinases (JNK).

The method that is used for evaluating the TNF antagonistic activity is known in affiliated field, and in this explanation for example.For example, the TNF antagonistic activity can utilize based on the competitive binding analysis of cell and evaluate.In this analyzes, will mix mutually through the TNF antagonist of radiolabeled TNF and serial dilution and express cell film cell in conjunction with TNFR.Many parts of suspension are centrifugal, separated free and bonded TNF, and measure free part and in conjunction with part in radioactivity amount.Bonded by TNF and cell in the presence of the TNF antagonist suppresses to evaluate the TNF antagonistic activity.

As another example, can resist the active ability of TNF in vitro using susceptible to analyze the TNF antagonist in as the bioassay of target cell in the cell of TNF cytotoxic activity.In this analyzes, handle the target cell of having cultivated with TNF with the TNF antagonist of different amounts, and detect cytolysis subsequently.The TNF antagonistic activity is evaluated in cytolytic minimizing by the target cell that brought out by TNF in the presence of the TNF antagonist.

The NS5B inhibitor

Some embodiment provide and comprise offer medicine described NS3 inhibitor of significant quantity and significant quantity HCV Nonstructural Protein-5 (NS5 to the HCV patient that the treatment needs are arranged; RNA RNA-dependent polysaccharase) method of inhibitor.Suitable NS5B inhibitor comprises but is not limited to: United States Patent (USP) the 6th, 479, disclosed compound in No. 508 (Boehringer-Ingelheim); On July 18th, 2002 by disclosed compound in any one of international application PCT/CA02/01127 number of Boehringer Ingelheim application, PCT/CA02/01128 number and PCT/CA02/01129 number; United States Patent (USP) the 6th, 440, disclosed compound in No. 985 (ViroPharma); Disclosed compound in WO 01/47883, for example JTK-003 (Japan Tobacco); People such as Zhong. the similar thing of dinucleotides described in (2003) Antimicrob, Agents Chemother.47:2674-2681; People such as Dhanak. (2002) J.Biol Chem.277 (41): disclosed benzothiadiazine compounds among the 38322-7; Disclosed NS5B inhibitor in WO 02/100846 A1 or WO02/100851 A2 (being Shire); Disclosed NS5B inhibitor in WO 01/85172 A1 or WO 02/098424A1 (being Glaxo SmithKline); Disclosed NS5B inhibitor in WO 00/06529 or WO 02/06246 A1 (being Merck); Disclosed NS5B inhibitor in WO 03/000254 (Japan Tobacco); At EP 1 256, disclosed NS5B inhibitor among 628 A2 (Agouron); JTK-002 (JapanTobacco); JTK-109 (Japan Tobacco); And analogue.

In many examples special what be concerned about is the NS5 inhibitor of specific NS5 inhibitor, for example, suppress NS5RNA RNA-dependent polysaccharase and other RNA RNA-dependent polysaccharase and dna dependent rna polysaccharase do not had remarkable inhibiting NS5 inhibitor.

Other antiviral agent

Other antiviral therapy agent that can combine dispensing with described NS3 inhibitor compound includes but not limited to: inosine monophosphate dehydrogenase (inosine monophosphate dehydrogenase, inhibitor IMPDH), with viral nucleotide sequence complementary ribozyme, sense-rna inhibitor and analogue.

The IMPDH inhibitor

The IMPDH inhibitor that is applicable to described combination treatment comprises but is not limited to: VX-497 ((S)-N-3-[3-(3-methoxyl group-4-oxazole-5-base-phenyl)-urea groups]-phenmethyl-carboxylamine tetrahydrofuran (THF)-3-base-ester, Vertex Pharmaceuticals, referring to, for example, people such as Markland. (2000) Antimicrob.Agents Chemother.44:859-866); Ribavirin; Levovirin (Ribapharm; Referring to, for example, Watson (2002) Curr Opin Investig Drugs3 (5): 680-3); Wella rice fixed (Ribapharm); And analogue.

Ribozyme and antisense

The ribozyme and the antisense antiviral agent that are applicable to described combination treatment include but not limited to: ISIS 14803 (ISISPharmaceuticals/Elan Corporation; Referring to, for example, Witherell (2001) Curr Opin Investig Drugs.2 (11): 1523-9); Heptazyme ^TMAnd analogue.

In certain embodiments, other antiviral agent is to offer medicine in the whole course of treatment of NS3 inhibitor compound treatment.In other embodiments, the dispensing of other antiviral agent and NS3 inhibitor compound are treated overlapping for some time, and for example, other antiviral agent treatment can begin before NS3 inhibitor compound treatment beginning and finish before the treatment of NS3 inhibitor compound finishes; Other antiviral agent treatment can begin and finish the back in the treatment of NS3 inhibitor compound and finish after NS3 inhibitor compound treatment beginning; Other antiviral agent treatment can begin after NS3 inhibitor compound treatment beginning and finish before the treatment of NS3 inhibitor compound finishes; Perhaps other antiviral agent treatment can begin and finish the back in the treatment of NS3 inhibitor compound and finish before NS3 inhibitor compound treatment beginning.

Dispensing dosage, preparation and approach

In described method, can use any convenient manner that can produce desirable therapeutic action that promoting agent (for example, formula I compound and one or more other antiviral agents according to circumstances) is offerd medicine to the host.Therefore, described reagent can be integrated with in the various preparations for treatment dispensing usefulness.More particularly, can be by with suitable, pharmaceutically acceptable supporting agent or excipient composition and the reagent in the embodiment of the invention is deployed into medical composition, and it can be deployed into the preparation of solid, semisolid, liquid or gas form, for example, tablet, capsule, pulvis, granule, paste, solution, suppository, injection, inhalation and aerosol.

Preparation

Can use and know reagent and method is allocated above-mentioned promoting agent.The preparation that can have pharmaceutically acceptable vehicle provides composition.Multiple pharmaceutically acceptable vehicle is known in affiliated field, need not to discuss in detail at this paper.There has been multiple publication that pharmaceutically acceptable vehicle has been described in detail in detail, comprised, for example, A.Gennaro (2000) ＂ Remington:The Science and Practice of Pharmacy, ＂ the 20th edition, Lippincott, Williams ， ﹠amp; Wilkins; People such as Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C.Ansel compile, and the 7th edition, Lippincott, Williams ， ﹠amp; Wilkins; Compile the 3rd edition .Amer.Pharmaceutical Assoc with people such as Handbook of Pharmaceutical Excipients (2000) A.H.Kibbe.

The public obtains described pharmaceutically acceptable vehicle easily, as mediator, adjuvant, supporting agent or thinner.And the public also obtains pharmaceutically acceptable complementary material easily, as pH value conditioning agent and buffer reagent, tension regulator, stablizer, wetting agent, and similar substance.

In certain embodiments, in aqueous buffer, allocate reagent.Suitable aqueous buffer includes but not limited to, the acetate that concentration does not wait from 5mM to 100mM, succinate, Citrate trianion and phosphate buffer.In certain embodiments, aqueous buffer comprises the reagent that isotonic solution is provided.Such reagent includes but not limited to, sodium-chlor; And carbohydrate, for example N.F,USP MANNITOL, dextrose, sucrose etc.In certain embodiments, aqueous buffer comprises nonionic surfactant in addition, as polysorbate20 or 80.Optionally, described preparation can comprise sanitas in addition.Suitable sanitas includes but not limited to, phenylcarbinol, phenol, butylene-chlorohydrin, benzalkonium chloride (benzalkonium chloride), and analogue.In many cases, preparation stores down at about 4 ℃.Also can be with the preparation freeze-drying, in the case, preparation generally includes frostproofer, as sucrose, trehalose, lactose, maltose, N.F,USP MANNITOL and analogue.Freeze-dried preparation can store the long period, or even also like this at ambient temperature.

Therefore, but the dispensing accomplished in various ways of reagent comprises oral, dispensing such as outside cheek, per rectum, enteron aisle, in intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, the tracheae.In many examples, by bullet formula injection dispensing, for example subcutaneous bullet formula injection, the injection of intramuscular bullet formula and similar injection.

The medical composition of the embodiment of the invention can be offerd medicine outward or via implanting reservoir by oral, enteron aisle.Preferred oral dispensing or injection dispensing.

The subcutaneous administration of the medical composition of the embodiment of the invention is to use standard method and device to finish, for example, and pin and syringe, subcutaneous injection port drug delivery system, etc.Referring to, for example, United States Patent (USP) the 3rd, 547, No. 119, the 4th, 755, No. 173, the 4th, 531, No. 937, the 4th, 311, No. 137 and the 6th, 017, No. 328.Subcutaneous injection port and the combination of the embodiment medical composition being offerd medicine to patient's device via this injection port are referred to herein as " subcutaneous injection port drug delivery system ".In many examples, realize subcutaneous administration via pin and syringe by the administration of bullet formula.

In pharmaceutical dosage form, described reagent can the dispensing of its pharmaceutically acceptable salt form, and perhaps they can use separately or suitably unite with other active compound pharmaceutically and be used in combination.Following method and vehicle only are exemplary and do not have any restricted.

For oral preparations, described preparation can use separately or be used in combination with appropriate addn and prepare tablet, pulvis, granule or capsule, for example, is used in combination with conventional additives (as lactose, N.F,USP MANNITOL, W-Gum or yam starch); Be used in combination with tackiness agent (with crystalline cellulose, derivatived cellulose, gum arabic, W-Gum or gelatinum); Be used in combination with disintegrating agent (as talcum or Magnesium Stearate); And need the time and thinner, buffer reagent, wetting agent, sanitas and seasonings be used in combination.

Can be by in dissolving, suspension or emulsification reagent being deployed into injection formulations at water-based or non-aqueous solvent (as the ester of vegetables oil or other similar oil, synthetic aliphatic acid glyceride, higher aliphatic acid or propylene glycol); And need the time use conventional additives, as solubilizing agent, isotonic agent, suspension agent, emulsifying agent, stablizer and sanitas.

In addition, can be by mixing reagent made suppository with various matrix (as emulsifying base or water-soluble base).Embodiment of the invention compound can utilize the dispensing of suppository per rectum.Suppository can comprise mediator, and as theobroma oil, polyoxyethylene glycol (carbowax) and polyethylene glycols, described mediator melts under body temperature and at room temperature solidifies.

The unit dosage of oral or rectal administration can be provided, and as syrup, elixir and suspension, each dose unit wherein as one, a soupspoon, tablet or suppository, contains the composition that predetermined amount comprises one or more inhibitor.Equally, be used for injecting or the unit dosage of intravenously dispensing can comprise inhibitor at the composition as the solution of aseptic aqueous solution, standard normal saline solution or another kind of pharmaceutically acceptable supporting agent.

As used herein, term " unit dosage " is meant the discrete unit of physics that is suitable as unitary dose for any animal person under inspection, constituent parts contains the embodiment compound of predetermined amount, and this predetermined amount makes to be enough to unite the desirable effect that produces with pharmaceutically acceptable thinner, supporting agent or mediator.The specification of the novel unit dosage of the embodiment of the invention depends on the pharmacodynamics relevant with each compound among used special compound and effect that will realize and the host.

Other antiviral agent

As mentioned above, in certain embodiments, described method will be implemented as the formula I-XIX compound of NS3 inhibitor and one or more other antiviral agents according to circumstances by coming into operation.

In certain embodiments, described method comprises one or more Interferon Receptors agonists that come into operation in addition.The Interferon Receptors agonist as mentioned above.

In other embodiments, described method comprises non-Buddhist nun's ketone of the piperazine that comes into operation or the non-Buddhist nun's keto analog of piperazine in addition.Non-Buddhist nun's ketone of piperazine or the non-Buddhist nun's keto analog of piperazine are as mentioned above.

Other antiviral agent that is applicable to combination treatment includes but not limited to Nucleotide and nucleoside analog.Limiting examples comprises: azidothymidine (azidothymidine, AZT) (zidovudine (zidovudine)) and its analogue and derivative; 2 ', 3 '-the dideoxy inosine (2 ', 3 '-dideoxyinosine, DDI) (didanosine (didanosine)) and its analogue and derivative; 2 ', 3 '-the dideoxy cytidine(C (2 ', 3 '-dideoxycytidine, DDC) (dideoxycytidine (dideoxycytidine)) and its analogue and derivative; 2 ', 3 '-two dehydrogenations-2 ', 3 '-the dideoxy thymidine (2 ', 3 '-didehydro-2 ', 3 '-dideoxythymidine, D4T) (stavudine (stavudine)) and its analogue and derivative; Combivir (combivir); Abacavir (abacavir); Adefovir ester (adefovirdipoxil); Cidofovir (cidofovir); Ribavirin; The ribavirin analogue; And analogue.

In certain embodiments, described method comprises the ribavirin that comes into operation in addition.Ribavirin, 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-methane amide can be available from Calif, the ICN Pharmaceuticals of Costa Mesa, Inc., and in No. 8199 compound of the Merck index of the 11st edition, describe to some extent.Its preparation method and concocting method are described in United States Patent (USP) the 4th, 211, in No. 771.Embodiment also comprise the derivative of ribavirin purposes (referring to, for example, United States Patent (USP) the 6th, 277, No. 830).Ribavirin can be used as capsule or tablet form oral administration medicine supplying, perhaps as offeing medicine with identical or different types of administration of Interferon Receptors agonist and identical or different approach.Certainly, also expect the types of administration of two kinds of medicines of other available, as nose spraying, transdermal, intravenously, suppository, slow release formulation, etc.Any types of administration all can work, as long as do not destroying the suitable dosage of administration under the activeconstituents.

The NS3 inhibitor compound of embodiment is applicable in the preparation that requires good aqueous solubility.For instance, the embodiment compound can be used for not containing glycitols and polyalcohols (for example trihydroxy-or more high-grade sugar alcohols are as glycerine, erythritol, glycerol, arabitol, Xylitol, sorbyl alcohol and N.F,USP MANNITOL) and does not contain other alcohols (for example propylene glycol and polyoxyethylene glycol (PEG)) or other is used for the preparation of the insufficient reagent of compensation water dissolubility.On the one hand, embodiment is provided at the described NS3 inhibitor compound in capsule, tablet or capsule tablet (caplet) preparation, and wherein said capsule, tablet or capsule tablet formulation provide enough bioavailabilities because of described compound good water-soluble.In certain embodiments, the solvability of described compound allows that every kg of patient body weight dispensing is equal to or greater than the dosage of 1mg medical compounds.

Methods of treatment

Monotherapy

Embodiment NS3 inhibitor compound can be used in the acute or chronic therapy of HCV disease.In many examples, the dispensing time of NS3 inhibitor compound is about 1 day to about 7 days, or about 1 thoughtful about 2 weeks, or about 2 thoughtful about 3 weeks, or about 3 thoughtful about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and can offer medicine the longer time.But dispensing every day of NS3 inhibitor compound five times, four times a day, every day three times (tid), every day twice (bid), once a day (qd), the next day once (qod), twice weekly (biw), on every Wendesdays time (tiw), weekly (qw), every other week once (qow), three times every month or every month is once.In other embodiments, the NS3 inhibitor compound is as transfusion dispensing continuously.

In many examples, the NS3 inhibitor compound of embodiment passes through oral administration medicine supplying.

About the aforesaid method of HCV disease among the treatment patient, can the about 0.01mg of every kg of patient body weight every day the dosage of about 100mg extremely, divide 1 to 5 dose every day to the offer medicine NS3 inhibitor compound of embodiment of patient.In certain embodiments, with the dosage of the about 0.5mg of every kg of patient body weight every day, divide 1 to 5 dose of NS3 inhibitor compound of offeing medicine every day to about 75mg.

The amount that can make the activeconstituents of formulation with the supporting agent combinations of substances is decided on host and the special dispensing pattern that will treat.Typical pharmaceutical preparation can contain has an appointment 5% to about 95% activeconstituents (w/w).In other embodiments, pharmaceutical preparation can contain and has an appointment 20% to about 80% activeconstituents.

It will be apparent to those skilled in the art that dosage level can be used as specific NS3 inhibitor compound, serious symptom and person under inspection to the function of the susceptibility of side effect and change.Preferred dose for given NS3 inhibitor compound can easily be determined according to the whole bag of tricks by one of ordinary skill in the art.Preferred method is a physiology usefulness of measuring given Interferon Receptors agonist.

In many examples, the come into operation NS3 inhibitor compound of multidose.For instance, the dispensing of NS3 inhibitor compound be every month once, every month twice, three times every month, every other week once (qow), (qw) once in a week, twice weekly (biw), time (tiw) on every Wendesdays, inferior on every Thursdays, inferior on every Fridays, inferior on every Saturdays, the next day once (qod), (qd) once a day, every day twice (qid) or every day three times, the time length scope be about one day to an about week, about two is thoughtful to pact, about one month to about two months, about two months to about four months, about four months to about six months, about six months to about eight months, about eight months to about 1 year, about 1 year to about 2 years, about 2 years to about 4 years or longer time.

Combination treatment with ribavirin

In certain embodiments, described method provides the combination treatment that comprises come into operation above-mentioned NS3 inhibitor compound and significant quantity ribavirin.The dispensing dosage of ribavirin can be every day about 400mg, about 800mg, about 1000mg or about 1200mg.

Embodiment provides any in the modified aforesaid method, comprises offer medicine the jointly ribavirin of treatment significant quantity to the patient, and the time length is the desirable course of treatment of NS3 inhibitor compound treatment.

Another embodiment provides any in the modified aforesaid method, comprises that the time length is the desirable course of treatment of NS3 inhibitor compound treatment by offeing medicine about 800mg jointly to about 1200mg ribavirin to the patient oral every day.

Another embodiment provides any in the modified aforesaid method, comprise by oral every day to patient's ribavirin of offeing medicine jointly: dosage is 1000mg to weight in patients every day during less than 75kg, and weight in patients dosage is 1200mg every day during more than or equal to 75kg; Wherein dosage every day of ribavirin is divided into consumption according to circumstances 2 times, and the desirable course of treatment of lasting NS3 inhibitor compound treatment.

Combination treatment with Levovirin

In certain embodiments, described method provides the combination treatment that comprises come into operation above-mentioned NS3 inhibitor compound and significant quantity Levovirin.The common dosage scope of Levovirin be every day about 30mg to about 60mg, about 60mg to about 125mg, about 125mg to about 200mg, about 200mg about 300mg, about 300mg about 400mg, about 400mg about 1200mg, about 600mg extremely about 900mg or the about 10mg of every kg body weight every day of about 1000mg, about 700mg extremely extremely extremely extremely.In certain embodiments, the oral administration medicine supplying dosage of Levovirin is every day about 400mg, about 800mg, about 1000mg or about 1200mg, and the desirable course of treatment of lasting NS3 inhibitor compound treatment.

Combination treatment with viramiditie

In certain embodiments, described method provides and comprises come into operation above-mentioned NS3 inhibitor compound and the fixed combination treatment of significant quantity Wella rice.The fixed common dosage scope of Wella rice be every day about 30mg to about 60mg, about 60mg to about 125mg, about 125mg to about 200mg, about 200mg about 300mg, about 300mg about 400mg, about 400mg about 1200mg, about 600mg extremely about 900mg or the about 10mg of every kg body weight every day of about 1000mg, about 700mg extremely extremely extremely extremely.In certain embodiments, the fixed oral administration medicine supplying dosage of Wella rice is about 800mg or about 1 every day, 600mg, and the desirable course of treatment of lasting NS3 inhibitor compound treatment.

Combination treatment with thymosin-α

In certain embodiments, described method provides the combination treatment that comprises come into operation above-mentioned NS3 inhibitor compound and significant quantity thymosin-α.Thymosin-α (Zadaxin ^TM) generally offer medicine by subcutaneous injection.The dispensing of thymosin-α can be every day three times, twice of every day, once a day, the next day once, twice weekly, on every Wendesdays time, once in a week, every other week once, every month three times, every month once, and substantially continuously or continue desirable course of treatment of NS3 inhibitor compound treatment continuously.In many examples, thymosin-α offers medicine twice weekly, continues the desirable course of treatment of NS3 inhibitor compound treatment.

The effective dosage ranges of thymosin-α is that about 0.5mg is to about 5mg, for example, about 0.5mg to about 1.0mg, about 1.0mg to about 1.5mg, about 1.5mg to about 2.0mg, about 2.0mg about 2.5mg, about 2.5mg about 3.0mg, about 3.0mg about 3.5mg, about 3.5mg about 4.0mg, about 4.0mg about 4.5mg, about 4.5mg about 5.0mg extremely extremely extremely extremely extremely extremely.In a particular embodiment, the dispensing dosage of thymosin-α comprises the amount of 1.0mg or 1.6mg.

The continuable time range of the dispensing of thymosin-α be about one day to an about week, about two thoughtful pacts, about one month to about two months, about two months to about four months, about four months to about six months, about six months to about eight months, about eight months extremely about years, about 1 year extremely about 2 years, or about 2 years to about 4 years, or the longer time.In one embodiment, the dispensing of thymosin-α continues the desirable course of treatment of NS3 inhibitor compound treatment.

Combination treatment with Interferon, rabbit

In many examples, described method provides the combination treatment that comprises come into operation above-mentioned NS3 inhibitor compound and significant quantity Interferon Receptors agonist.In certain embodiments, formula I compound and I type or type iii interferon receptor stimulant dispensing jointly in the methods of treatment of embodiment.The I type Interferon Receptors agonist that is applicable to this paper comprises any interferon-' alpha ' (IFN-α).In certain embodiments, interferon-' alpha ' is the interferon-' alpha ' of Pegylation.In other some embodiment, interferon-' alpha ' is an Interferon alfacon-1, as INFERGEN_ Interferon, rabbit alfacon-1.And in other embodiments, interferon-' alpha ' is single Pegylation (30kD, linearity) Interferon alfacon-1.

The effective dosage ranges of IFN-α be about 3 μ g to about 27 μ g, about 3MU to about 10MU, about 90 μ g about 180 μ g extremely, or about 18 μ g about 90 μ g extremely.The effective dosage ranges of the compound IFN-α of Infergen_ comprises that every dose is about 3 μ g, about 6 μ g, about 9 μ g, about 12 μ g, about 15 μ g, about 18 μ g, about 21 μ g, about 24 μ g, about 27 μ g or about 30 μ g medicines.The effective dosage ranges of IFN-α 2a and IFN-α 2b is every dose of about 3,000,000 units (MU)-10MU.The effective dose of PEGASYS_ Pegylation IFN-α 2a comprises the amount of every dose of about 90 μ g to 270 μ g or about 180 μ g medicines.The effective dose of PEG-INTRON_ Pegylation IFN-α 2b comprises the amount of every dose of about 0.5 μ g to 3.0 μ g medicine of every kg body weight.The effective dose of Pegylation Interferon alfacon-1 (PEG-CIFN) contains every dose of about 18 μ g of PEG-CIFN to about 90 μ g or about 27 μ g to about 60 μ g or the amount of the CIFN amino acid weight of about 45 μ g.The significant quantity of single Pegylation (30kD, linearity) CIFN comprise every dose of about 45 μ g to about 270 μ g or about 60 μ g to about 180 μ g or about 90 μ g to the amount of about 120 μ g medicines.The dispensing of IFN-α can be substantially continuously or continuously once a day, the next day once, once in a week, on every Wendesdays time, every other week once, every month three times, every month once.

In many examples, the dispensing time of I type or type iii interferon receptor stimulant and/or II type Interferon Receptors agonist is about 1 day to about 7 days, or about 1 thoughtful about 2 weeks, or about 2 thoughtful about 3 weeks, or about 3 thoughtful about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and can offer medicine the longer time.Dosage can comprise every day three times, twice of every day, once a day, the next day once, twice weekly, on every Wendesdays time, once in a week, every other week once, three times every month or every month dosing time.Some embodiment provide any in the aforesaid method, wherein by the administration of bullet formula once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, three times every month or every month once with the IFN-α subcutaneous administration of want dosage to the patient, perhaps by substantially continuously or successive administration every day subcutaneous administration give the patient, continue desirable treatment time.Other embodiment provides any in the aforesaid method, wherein by the administration of bullet formula once in a week, every other week once, three times every month or every month once with Pegylation IFN-α (PEG-IFN-α) subcutaneous administration of want dosage to the patient, lasting desired treatment time.

In other embodiments, NS3 inhibitor compound and II type Interferon Receptors agonist dispensing jointly in the methods of treatment of embodiment.The II type Interferon Receptors agonist that is applicable to this paper comprises any interferon-(IFN-γ).

The effective dosage ranges of IFN-γ is looked patient's size and is decided to be about 0.5 μ g/m ²To about 500 μ g/m ², common about 1.5 μ g/m ²To 200 μ g/m ²It is 10 international unit (U) that this activity is based on per 50 μ g protein.The dispensing of IFN-γ can be once a day, the next day once, Wednesday time, or substantially continuously or continuously.

In the specific embodiment of being concerned about, with about 25 μ g to about 500 μ g, about 50 μ g to about 400 μ g or about 100 μ g the unit dosage to about 300 μ g IFN-γ is offerd medicine to individuality.In the special embodiment that is concerned about, described dosage is about 200 μ gIFN-γ.In the many embodiment that are concerned about, IFN-γ 1b comes into operation.

When described dosage was every dose 200 μ gIFN-γ, the IFN-γ weight range of every body weight (the supposition weight range is that about 45kg is to about 135kg) was that the about 4.4 μ gIFN-γ of every kg body weight are to about 1.48IFN-γ.

The body surface area of person under inspection's individuality is generally at about 1.33m ²To about 2.50m ²Between.Therefore, in many examples, IFN-γ dosage is at about 150 μ g/m ²To about 20 μ g/m ²Between.For instance, IFN-γ dosage range is about 20 μ g/m ²To about 30 μ g/m ², about 30 μ g/m ²To about 40 μ g/m ², about 40 μ g/m ²To about 50 μ g/m ², about 50 μ g/m ²To about 60 μ g/m ², about 60 μ g/m ²To about 70 μ g/m ², about 70 μ g/m ²To about 80 μ g/m ², about 80 μ g/m ²To about 90 μ g/m ², about 90 μ g/m ²To about 100 μ g/m ², about 100 μ g/m ²To about 110 μ g/m ², about 110 μ g/m ²To about 120 μ g/m ², about 120 μ g/m ²To about 130 μ g/m ², about 130 μ g/m ²To about 140 μ g/m ²Or about 140 μ g/m ²To about 150 μ g/m ²In other embodiments, dosage range is at about 25 μ g/m ²To about 100 μ g/m ²Between.In other embodiments, dosage range is at about 25 μ g/m ²To about 50 μ g/m ²Between.

In certain embodiments, I type or type iii interferon receptor stimulant are then with second kind of dosage regimen dispensing with first kind of dosage regimen dispensing.First kind of dosage regimen of I type or type iii interferon receptor stimulant (being also referred to as " induction scheme (induction regimen) ") generally includes the I type or the type iii interferon receptor stimulant of dispensing higher dosage.For instance, under the situation of the compound IFN-α of Infergen_ (CIFN), first kind of dosage regimen comprises the CIFN of offer medicine about 9 μ g, about 15 μ g, about 18 μ g or about 27 μ g.First kind of dosage regimen can comprise single administration incident or two or more administration incidents at least.First kind of dosage regimen of I type or type iii interferon receptor stimulant can be once a day, the next day once, on every Wendesdays time, every other week once, every month three times, every month once substantially continuously or dispensing continuously.

First kind of dosage regimen of I type or type iii interferon receptor stimulant continues very first time section dispensing, and this time period can be at least about 4 weeks, at least about 8 weeks or at least about 12 weeks.

Second kind of dosage regimen of I type or type iii interferon receptor stimulant (being also referred to as " maintenance dose (maintenancedose) ") generally includes I type or the type iii interferon receptor stimulant of dispensing than low dosage.For instance, under the situation of CIFN, second kind of dosage regimen comprises with at least about 3 μ g, at least about 9 μ g, at least about 15 μ g or at least about the dosage of the 18 μ g CIFN that comes into operation.Second kind of dosage regimen comprises single administration incident or two or more administration incidents at least.

Second kind of dosage regimen of I type or type iii interferon receptor stimulant can be once a day, the next day once, on every Wendesdays time, every other week once, every month three times, every month once substantially continuously or dispensing continuously.

In certain embodiments, when " inducing/keep " dosage regimen of dispensing I type or type iii interferon receptor stimulant, comprise " starting (priming) " dosage of II type Interferon Receptors agonist (for example, IFN-γ).In these embodiments, beginning with before I type or the type iii interferon receptor agonist treatment, dispensing IFN-γ lasts about 1 day to about 14 days, about 2 days to about 10 days or about 3 days about 7 days time periods extremely.This time period is called " startup " phase.

In in these embodiments some, in the whole period of I type or type iii interferon receptor agonist treatment, continue II type Interferon Receptors agonist treatment.In other embodiments, before finishing, interrupt II type Interferon Receptors agonist treatment with I type or type iii interferon receptor agonist treatment.In these embodiments, the total time (comprising " startup " phase) with II type Interferon Receptors agonist treatment is about 2 days to about 30 days, about 4 days to about 25 days, about 8 days to about 20 days, about 10 days to about 18 days or about 12 days to about 16 days.And in other embodiments, in case I type or type iii interferon receptor agonist treatment begin just to interrupt II type Interferon Receptors agonist treatment.

In other embodiments, I type or type iii interferon receptor stimulant are offerd medicine with first kind of dosage regimen.For instance, under the situation of CIFN, the dosage of CIFN usually about 3 μ g to about 15 μ g or about 9 μ g to the scope of about 15 μ g in.The dosage of I type or type iii interferon receptor stimulant usually can be once a day, the next day once, on every Wendesdays time, every other week once, every month three times, every month once substantially continuously or dispensing continuously.The administration of the sustainable certain hour section of the dosage of I type or type iii interferon receptor stimulant, the described time period can be, and is for example, thoughtful at least about 48 weeks or longer at least about 24.

In certain embodiments, when first kind of dosage regimen of dispensing I type or type iii interferon receptor stimulant, comprise " startup " dosage of II type Interferon Receptors agonist (for example, IFN-γ).In these embodiments, beginning with before I type or the type iii interferon receptor agonist treatment, dispensing IFN-γ lasts about 1 day to about 14 days, about 2 days to about 10 days or about 3 days about 7 days time periods extremely.This time period is called " startup " phase.In in these embodiments some, in the whole period of I type or type iii interferon receptor agonist treatment, continue II type Interferon Receptors agonist treatment.In other embodiments, before finishing, interrupt II type Interferon Receptors agonist treatment with I type or type iii interferon receptor agonist treatment.In these embodiments, the total time (comprising " startup " phase) with II type Interferon Receptors agonist treatment is about 2 days to about 30 days, about 4 days to about 25 days, about 8 days to about 20 days, about 10 days to about 18 days or about 12 days to about 16 days.And in other embodiments, in case I type or type iii interferon receptor agonist treatment begin just to interrupt II type Interferon Receptors agonist treatment.

In a further embodiment, NS3 inhibitor compound, I type or type iii interferon receptor stimulant and II type Interferon Receptors agonist be dispensing jointly in the method for embodiment, continues desired treatment time.In certain embodiments, NS3 inhibitor compound, interferon-' alpha ' and interferon-be dispensing jointly in the method for embodiment, continues desired treatment time.

Some embodiment provide use effectively to treat the I type of the amount that HCV infects among the patient or the method for type iii interferon receptor stimulant, II type Interferon Receptors agonist and NS3 inhibitor compound.In certain embodiments, embodiment is provided at the method for using significant quantity IFN-α, IFN-γ and NS3 inhibitor compound in the treatment that patient HCV infects.Embodiment is provided at the method for using the compound IFN-α of significant quantity, IFN-γ and NS3 inhibitor compound in the treatment that patient HCV infects.

In general, be applicable to that significant quantity Interferon alfacon-1 (CIFN) in the embodiment method and IFN-γ provide by the dosage rate of 1 μ gCIFN:10 μ gIFN-γ, wherein CIFN and IFN-γ all are without Pegylation with without glycosylated kind.

Embodiment provides any in the modified aforesaid method, to use the compound IFN-α of INFERGEN_ and the IFN-γ of significant quantity in the treatment of infecting at patient HCV, described method comprises: by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, three times every month or every month once or every day substantially continuously or continuously to the offer medicine INFERGEN_ of doses of patient, it comprises every dose of INFERGEN_ is the medication amount of about 1 μ g to about 30 μ g; And by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, three times every month or every month once or every day substantially continuously or continuously to the offer medicine IFN-γ of doses of patient, it comprises every dose of IFN-γ is the medication amount of about 10 μ g to about 300 μ g; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the compound IFN-α of INFERGEN_ and the IFN-γ of significant quantity, described method comprises: by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, three times every month or every month once or every day substantially continuously or continuously to the offer medicine INFERGEN_ of doses of patient, it comprises every dose of INFERGEN_ is that about 1 μ g is to about 9 μ g medication amount; And by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, three times every month or every month once or every day substantially continuously or continuously to the offer medicine IFN-γ of doses of patient, it comprises every dose of IFN-γ is that about 10 μ g are to about 100 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the compound IFN-α of INFERGEN_ and the IFN-γ of significant quantity, described method comprises: by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, three times every month or every month once or every day substantially continuously or continuously to the offer medicine INFERGEN_ of doses of patient, it comprises every dose of INFERGEN_ is about 1 μ g medication amount; And by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, three times every month or every month once or every day substantially continuously or continuously to the offer medicine IFN-γ of doses of patient, it comprises every dose of IFN-γ is that about 10 μ g are to about 50 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the compound IFN-α of INFERGEN_ and the IFN-γ of significant quantity, described method comprises: by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, three times every month or every month once or every day substantially continuously or continuously to the offer medicine INFERGEN_ of doses of patient, it comprises every dose of INFERGEN_ is about 9 μ g medication amount; And by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, three times every month or every month once or every day substantially continuously or continuously to the offer medicine IFN-γ of doses of patient, it comprises every dose of IFN-γ is that about 90 μ g are to about 100 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the compound IFN-α of INFERGEN_ and the IFN-γ of significant quantity, described method comprises: by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, three times every month or every month once or every day substantially continuously or continuously to the offer medicine INFERGEN_ of doses of patient, it comprises every dose of INFERGEN_ is about 30 μ g medication amount; And by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, three times every month or every month once or every day substantially continuously or continuously to the offer medicine IFN-γ of doses of patient, it comprises every dose of IFN-γ is that about 200 μ g are to about 300 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the compound IFN-α of Pegylation and the IFN-γ of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, once to the offer medicine compound IFN-α of Pegylation (PEG-CIFN) of doses of patient, it comprises every dose of PEG-CIFN is the amounts of about 4 μ g to the CIFN amino acid weight of about 60 μ g for three times every month or every month; And by subcutaneous once a day, the next day once, on every Wendesdays time, twice or the continuously or continuous IFN-γ of the certain total weekly dose of gradation dispensing weekly substantially weekly, this total dose contains weekly about 30 μ g to about 1000 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the compound IFN-α of Pegylation and the IFN-γ of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, once to the offer medicine compound IFN-α of Pegylation (PEG-CIFN) of doses of patient, it comprises every dose of PEG-CIFN is the amounts of about 18 μ g to the CIFN amino acid weight of about 24 μ g for three times every month or every month; And by subcutaneous once a day, the next day once, on every Wendesdays time, twice or the continuously or continuous IFN-γ of the certain total weekly dose of gradation dispensing weekly substantially weekly, this total dose contains weekly about 100 μ g to about 300 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

In general, be applicable to that significant quantity IFN-α 2a in the embodiment method or 2b or 2c and IFN-γ provide by the dosage rate of the IFN-α 2a of 100 ten thousand units (MU) or 2b or 2c:30 μ gIFN-γ, wherein IFN-α 2a or 2b or 2c and IFN-γ all are without Pegylation with without glycosylated kind.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use IFN-α 2a or 2b or the 2c and the IFN-γ of significant quantity, described method comprises: by subcutaneous once a day, the next day twice or every day be substantially continuously or continuously to patient offer medicine IFN-α 2a or the 2b or the 2c of doses once, on every Wendesdays time, weekly, it comprises every dose of IFN-α 2a or 2b or 2c and is about 1MU medication amount of about 20MU extremely; And by subcutaneous once a day, the next day once, on every Wendesdays time, the IFN-γ of twice or the doses of offeing medicine continuously or continuously substantially every day weekly, it contains every dose of IFN-γ is that about 30 μ g are to about 600 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use IFN-α 2a or 2b or the 2c and the IFN-γ of significant quantity, described method comprises: by subcutaneous once a day, the next day once, on every Wendesdays time, twice or every day, continuously or continuously to patient offer medicine IFN-α 2a or the 2b or the 2c of doses, it comprised every dose of IFN-α 2a or 2b or the 2c medication amount for about 3MU substantially weekly; And by subcutaneous once a day, the next day once, on every Wendesdays time, the IFN-γ of twice or the doses of offeing medicine continuously or continuously substantially every day weekly, it contains every dose of IFN-γ is about 100 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use IFN-α 2a or 2b or the 2c and the IFN-γ of significant quantity, described method comprises: by subcutaneous once a day, the next day once, on every Wendesdays time, twice or every day, continuously or continuously to patient offer medicine IFN-α 2a or the 2b or the 2c of doses, it comprised every dose of IFN-α 2a or 2b or the 2c medication amount for about 10MU substantially weekly; And by subcutaneous once a day, the next day once, on every Wendesdays time, the IFN-γ of twice or the doses of offeing medicine continuously or continuously substantially every day weekly, it contains every dose of IFN-γ is about 300 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the PEGASYS_ Pegylation IFN-α 2a and the IFN-γ of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, once to the offer medicine PEGASYS_ of doses of patient, it comprises every dose of PEGASYS_ is the medication amount of about 90 μ g to about 360 μ g for three times every month or every month; And by subcutaneous once a day, the next day once, on every Wendesdays time, twice or the continuously or continuous IFN-γ of the certain total weekly dose of gradation dispensing weekly substantially weekly, this total dose contains weekly about 30 μ g to about 1,000 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the PEGASYS_ Pegylation IFN-α 2a and the IFN-γ of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, three times every month or every month is once to the offer medicine PEGASYS_ of doses of patient, the medication amount that it comprises every dose of PEGASYS_ is about 180 μ g; And by subcutaneous once a day, the next day once, on every Wendesdays time, twice or the continuously or continuous IFN-γ of the certain total weekly dose of gradation dispensing weekly substantially weekly, this total dose contains weekly about 100 μ g to about 300 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the PEG-INTRON_ Pegylation compound IFN-α 2b and the IFN-γ of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, once to the offer medicine PEG-INTRON_ of doses of patient, it comprises every dose of every kg body weight of PEG-INTRON_ is the medication amount of about 0.75 μ g to about 3.0 μ g for three times every month or every month; And by subcutaneous once a day, the next day once, on every Wendesdays time, twice or the continuously or continuous IFN-γ of the certain total weekly dose of gradation dispensing weekly substantially weekly, this total dose contains weekly about 30 μ g to about 1000 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the PEG-INTRON_ Pegylation IFN-α 2b and the IFN-γ of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, once to the offer medicine PEG-INTRON_ of doses of patient, it comprises every dose of every kg body weight of PEG-INTRON_ is the medication amount of about 1.5 μ g for three times every month or every month; And by subcutaneous once a day, the next day once, on every Wendesdays time, twice or the continuously or continuous IFN-γ of the certain total weekly dose of gradation dispensing weekly substantially weekly, this total dose contains weekly about 100 μ g to about 300 μ g medication amount; Described dispensing continues NS3 inhibitor compound treatment time.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; By scheme once a day subcutaneous or time come into operation on every Wendesdays compound IFN-α of 9 μ gINFERGEN_ and the oral ribavirin that comes into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With the scheme by the once a day subcutaneous or inferior on every Wendesdays compound IFN-α of 9 μ g INFERGEN_ that comes into operation, subcutaneous inferior on every Wendesdays come into operation human IFN-γ 1b of 50 μ gActimmune_ and the oral ribavirin that comes into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With the scheme by the once a day subcutaneous or inferior on every Wendesdays compound IFN-α of 9 μ g INFERGEN_ that comes into operation, subcutaneous inferior on every Wendesdays come into operation human IFN-γ 1b of 100 μ g Actimmune_ and the oral ribavirin that comes into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by scheme once a day subcutaneous or time come into operation on every Wendesdays compound IFN-α of 9 μ g INFERGEN_ and the subcutaneous human IFN-γ of the 50 μ g Actimmune_ 1b that time comes into operation on every Wendesdays, wherein the therapy time length was 48 weeks.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by scheme once a day subcutaneous or time come into operation on every Wendesdays compound IFN-α of 9 μ g INFERGEN_ and the subcutaneous human IFN-γ of the 100 μ g Actimmune_ 1b that time comes into operation on every Wendesdays, wherein the therapy time length was 48 weeks.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With the scheme by the once a day subcutaneous or inferior on every Wendesdays compound IFN-α of 9 μ g INFERGEN_ that comes into operation, subcutaneous inferior on every Wendesdays come into operation human IFN-γ 1b of 25 μ g Actimmune_ and the oral ribavirin that comes into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With the scheme by the once a day subcutaneous or inferior on every Wendesdays compound IFN-α of 9 μ g INFERGEN_ that comes into operation, subcutaneous inferior on every Wendesdays come into operation human IFN-γ 1b of 200 μ g Actimmune_ and the oral ribavirin that comes into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by scheme once a day subcutaneous or time come into operation on every Wendesdays compound IFN-α of 9 μ g INFERGEN_ and the subcutaneous human IFN-γ of the 25 μ g Actimmune_ 1b that time comes into operation on every Wendesdays, wherein the therapy time length was 48 weeks.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by scheme once a day subcutaneous or time come into operation on every Wendesdays compound IFN-α of 9 μ g INFERGEN_ and the subcutaneous human IFN-γ of the 200 μ g Actimmune_ 1b that time comes into operation on every Wendesdays, wherein the therapy time length was 48 weeks.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; By the scheme of subcutaneous per ten days once or once in a week come into operation single compound IFN-α of Pegylation (30kD, linearity) of 100 μ g and the oral ribavirins that come into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; By the subcutaneous per ten days single Pegylation (30kD of the 100 μ g that once or once in a week come into operation, linear) compound IFN-α, by the scheme of subcutaneous time come into operation on every Wendesdays human IFN-γ 1b of 50 μ g Actimmune_ and the oral ribavirin that comes into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by the single Pegylation (30kD of the 100 μ g that once or once in a week came into operation in subcutaneous per ten days, linear) compound IFN-α, by the scheme of subcutaneous time come into operation on every Wendesdays human IFN-γ 1b of 100 μ g Actimmune_ and the oral ribavirin that comes into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by single compound IFN-α of Pegylation (30kD, linearity) of the 100 μ g that once or once in a week came into operation in subcutaneous per ten days and the scheme by the subcutaneous human IFN-γ of the 50 μ g Actimmune_ 1b that time comes into operation on every Wendesdays, wherein the therapy time length was 48 weeks.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by single compound IFN-α of Pegylation (30kD, linearity) of the 100 μ g that once or once in a week came into operation in subcutaneous per ten days and the scheme by the subcutaneous human IFN-γ of the 100 μ g Actimmune_ 1b that time comes into operation on every Wendesdays, wherein the therapy time length was 48 weeks.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With the scheme by subcutaneous per ten days once or once in a week come into operation single compound IFN-α of Pegylation (30kD, linearity) of 150 μ g and the oral ribavirins that come into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by the single Pegylation (30kD of the 150 μ g that once or once in a week came into operation in subcutaneous per ten days, linear) compound IFN-α, by the scheme of subcutaneous time come into operation on every Wendesdays human IFN-γ 1b of 50 μ g Actimmune_ and the oral ribavirin that comes into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by the single Pegylation (30kD of the 150 μ g that once or once in a week came into operation in subcutaneous per ten days, linear) compound IFN-α, by the scheme of subcutaneous time come into operation on every Wendesdays human IFN-γ 1b of 100 μ g Actimmune_ and the oral ribavirin that comes into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by single compound IFN-α of Pegylation (30kD, linearity) of the 150 μ g that once or once in a week came into operation in subcutaneous per ten days and the scheme by the subcutaneous human IFN-γ of the 50 μ g Actimmune_ 1b that time comes into operation on every Wendesdays, wherein the therapy time length was 48 weeks.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by single compound IFN-α of Pegylation (30kD, linearity) of the 150 μ g that once or once in a week came into operation in subcutaneous per ten days and the scheme by the subcutaneous human IFN-γ of the 100 μ g Actimmune_ 1b that time comes into operation on every Wendesdays, wherein the therapy time length was 48 weeks.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With the scheme by subcutaneous per ten days once or once in a week come into operation single compound IFN-α of Pegylation (30kD, linearity) of 200 μ g and the oral ribavirins that come into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by the single Pegylation (30kD of the 200 μ g that once or once in a week came into operation in subcutaneous per ten days, linear) compound IFN-α, by the scheme of subcutaneous time come into operation on every Wendesdays human IFN-γ 1b of 50 μ g Actimmune_ and the oral ribavirin that comes into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by the single Pegylation (30kD of the 200 μ g that once or once in a week came into operation in subcutaneous per ten days, linear) compound IFN-α, by the scheme of subcutaneous time come into operation on every Wendesdays human IFN-γ 1b of 100 μ g Actimmune_ and the oral ribavirin that comes into operation once a day, wherein the therapy time length was 48 weeks.In this embodiment, the dosage of ribavirin is 1000mg to body weight less than the individuality of 75kg, and is 1200mg to the individuality that body weight is equal to or greater than 75kg.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by single compound IFN-α of Pegylation (30kD, linearity) of the 200 μ g that once or once in a week came into operation in subcutaneous per ten days and the scheme by the subcutaneous human IFN-γ of the 50 μ g Actimmune_ 1b that time comes into operation on every Wendesdays, wherein the therapy time length was 48 weeks.

Embodiment provides any in the modified aforesaid method, to comprise to having the come into operation NS3 inhibitor of significant quantity of individuality that HCV infects; With by single compound IFN-α of Pegylation (30kD, linearity) of the 200 μ g that once or once in a week came into operation in subcutaneous per ten days and the scheme by the subcutaneous human IFN-γ of the 100 μ g Actimmune_ 1b that time comes into operation on every Wendesdays, wherein the therapy time length was 48 weeks.

Comprise dispensing INS3 inhibitor, I type Interferon Receptors agonist (as, IFN-α) and II type Interferon Receptors agonist (as, the dispensing of any the increased significant quantity TNF-alpha-2 antagonists in aforesaid method IFN-γ) (as, the TNF-alpha-2 antagonists except that non-Buddhist nun's ketone of piperazine or the non-Buddhist nun's keto analog of piperazine).Be applicable to that the illustrative of described combination treatment, non-limiting TNF-alpha-2 antagonists comprise ENBREL_, REMICADE_ and HUMIRA ^TM

Embodiment is provided in the treatment that patient HCV infects and uses significant quantity ENBREL_, significant quantity IFN-α, the method of significant quantity IFN-γ and significant quantity NS3 inhibitor, described method comprises by once a day subcutaneous, the next day once, inferior on every Wendesdays, twice weekly, once in a week, every other week once, three times every month, every month once or every other month once or every day substantially continuously or continuously to the patient doses ENBREL_ that comes into operation, it comprises every dose of about 0.1 μ g to about 23mg, about 0.1 μ g is to about 1 μ g, about 1 μ g is to about 10 μ g, about 10 μ g are to about 100 μ g, about 100 μ g are to about 1mg, about 1mg is to about 5mg, about 5mg is to about 10mg, about 10mg is to about 15mg, the ENBREL_ of about 15mg to about 20mg or about 20mg to about 23mg, this offers medicine lasting desired treatment time.

Embodiment is provided in the treatment that patient HCV infects and uses significant quantity REMICADE_, significant quantity IFN-α, there is or do not have significant quantity IFN-γ, and the method for significant quantity NS3 inhibitor, described method comprises that intravenously once a day, the next day once, inferior on every Wendesdays, twice weekly, once in a week, every other week once, three times every month, every month once or every other month once or every day substantially continuously or continuously to the patient doses REMICADE_ that comes into operation, it comprises every dose of about 0.1mg/kg of REMICADE_ to about 4.5mg/kg, about 0.1mg/kg is to about 0.5mg/kg, about 0.5mg/kg is to about 1.0mg/kg, about 1.0mg/kg is to about 1.5mg/kg, about 1.5mg/kg is to about 2.0mg/kg, about 2.0mg/kg is to about 2.5mg/kg, about 2.5mg/kg is to about 3.0mg/kg, about 3.0mg/kg is to about 3.5mg/kg, the amount of about 3.5mg/kg to about 4.0mg/kg or about 4.0mg/kg to about 4.5mg/kg, this offers medicine lasting desired treatment time.

Embodiment is provided in the treatment that patient HCV infects and uses significant quantity HUMIRA ^TM, significant quantity IFN-α, significant quantity IFN-γ and significant quantity NS3 inhibitor method, described method comprise by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, every month three times, every month once or every other month once or every day substantially continuously or continuously to the patient doses HUMIRA that comes into operation ^TM, it comprises every dose of HUMIRA ^TMAbout 0.1 μ g to about 35mg, about 0.1 μ g to about 1 μ g, about 1 μ g to about 10 μ g, about 10 μ g to about 100 μ g, about 100 μ g to about 1mg, about 1mg to about 5mg, about 5mg to about 10mg, about 10mg about 15mg, about 15mg about 20mg, about 20mg amount, about 25mg about 30mg or the about 30mg amount of about 35mg extremely extremely of about 25mg extremely extremely extremely, this offers medicine lasting desired treatment time.

Combination treatment with the non-Buddhist nun's ketone of piperazine

In many examples, described method provides the combination treatment that comprises come into operation above-mentioned NS3 inhibitor compound and non-Buddhist nun's ketone of significant quantity piperazine or the non-Buddhist nun's keto analog of piperazine.In certain embodiments, NS3 inhibitor compound, one or more Interferon Receptors agonists and the non-Buddhist nun's ketone of piperazine or the non-Buddhist nun's keto analog of piperazine dispensing jointly in the methods of treatment of embodiment.In certain embodiments, the common dispensing of NS3 inhibitor compound, I type Interferon Receptors agonist and the non-Buddhist nun's ketone of piperazine (or the non-Buddhist nun's keto analog of piperazine).In other embodiments, the common dispensing of NS3 inhibitor compound, I type Interferon Receptors agonist, II type Interferon Receptors agonist and the non-Buddhist nun's ketone of piperazine (or the non-Buddhist nun's keto analog of piperazine).The I type Interferon Receptors agonist that is applicable to this paper comprises any IFN-α, as interferon-' alpha ' 2a, interferon-' alpha ' 2b, Interferon, rabbit alfacon-1; And Pegylation IFN-α, as Peg-Intron-α 2a, Peg-Intron-α 2b; With the Pegylation Interferon alfacon-1, as single Pegylation (30kD, linearity) Interferon alfacon-1.The II type Interferon Receptors agonist that is applicable to this paper comprises any interferon-(IFN-γ).

The dispensing of non-Buddhist nun's ketone of piperazine or the non-Buddhist nun's keto analog of piperazine can be every month once, every month twice, three times every month, once in a week, twice weekly, inferior on every Wendesdays, inferior on every Thursdays, inferior on every Fridays, inferior on every Saturdays, be divided into once a day to 5 times once a day or with per daily dose, dispensing last the time period be about one day to an about week, around the about two thoughtful pacts, about one month to about two months, about two months to about four months, about four months to about six months, about six months to about eight months, about eight months to about 1 year, about 1 year to about 2 years or about 2 years to about 4 years, or the longer time.

Non-Buddhist nun's ketone of the piperazine of significant quantity or the non-Buddhist nun's keto analog of specific piperazine comprise based on body weight at the dosage of about 5mg/kg every day between about 125mg/kg, or for every day about 400mg to about 3600mg or about 800mg to about 2400mg or about 1000mg about 1800mg or about 1200mg fixed dosage of about 1600mg extremely extremely, every day, branch was once offerd medicine to five consumptions.Be applicable to other dosage of treatment non-Buddhist nun's ketone of piperazine of fibrotic disease and the non-Buddhist nun's keto analog of specific piperazine and preparation at United States Patent (USP) the 5th, 310, No. 562, the 5th, 518, No. 729, the 5th, 716, No. 632 and the 6th, 090, description to some extent in No. 822.

Embodiment provides any in the modified aforesaid method, comprises offer medicine the jointly non-Buddhist nun's ketone of piperazine or the non-Buddhist nun's keto analog of piperazine of treatment significant quantity to the patient, and the time length is the desirable course of treatment of NS3 inhibitor compound treatment.

Combination treatment with the TNF-alpha-2 antagonists

In many examples, described method is provided at the combination treatment that the combination treatment that is used for the HCV treatment of infection comprises above-mentioned NS3 inhibitor compound of the significant quantity that comes into operation and significant quantity TNF-alpha-2 antagonists.

The effective dosage ranges of TNF-alpha-2 antagonists is every dose 0.1 μ g to 40mg, for example, every dose of about 0.1 μ g is to about 0.5 μ g, about 0.5 μ g is to about 1.0 μ g, about 1.0 μ g are to about 5.0 μ g, about 5.0 μ g are to about 10 μ g, about 10 μ g are to about 20 μ g, about 20 μ g are to about 30 μ g, about 30 μ g are to about 40 μ g, about 40 μ g are to about 50 μ g, about 50 μ g are to about 60 μ g, about 60 μ g are to about 70 μ g, about 70 μ g are to about 80 μ g, about 80 μ g are to about 100 μ g, about 100 μ g are to about 150 μ g, about 150 μ g are to about 200 μ g, about 200 μ g are to about 250 μ g, about 250 μ g are to about 300 μ g, about 300 μ g are to about 400 μ g, about 400 μ g are to about 500 μ g, about 500 μ g are to about 600 μ g, about 600 μ g are to about 700 μ g, about 700 μ g are to about 800 μ g, about 800 μ g are to about 900 μ g, about 900 μ g are to about 1000 ì g, about 1mg is to about 10mg, about 10mg is to about 15mg, about 15mg is to about 20mg, about 20mg is to about 25mg, about 25mg is to about 30mg, about 30mg is to about 35mg or about 35mg about 40mg extremely.

In certain embodiments, the effective dose of TNF-alpha-2 antagonists is expressed as the mg/kg body weight.In these embodiments, the effective dose of TNF-alpha-2 antagonists is that about 0.1mg/kg body weight is to about 10mg/kg body weight, for example, about 0.1mg/kg body weight to about 0.5mg/kg body weight, about 0.5mg/kg body weight to about 1.0mg/kg body weight, about 1.0mg/kg body weight about 2.5mg/kg body weight, about 2.5mg/kg body weight about 5.0mg/kg body weight, about 5.0mg/kg body weight about 7.5mg/kg body weight or about 7.5mg/kg body weight about 10mg/kg body weight extremely extremely extremely extremely.

In many examples, the dispensing time of TNF-alpha-2 antagonists is about 1 day to about 7 days, or about 1 thoughtful about 2 weeks, or about 2 thoughtful about 3 weeks, or about 3 thoughtful about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and can offer medicine the longer time.The dispensing of TNF-alpha-2 antagonists can be every day three times, twice of every day, once a day, the next day once, twice weekly, on every Wendesdays time, once in a week, every other week once, every month three times, every month once, substantially continuously or continuously.

In many examples, the TNF-alpha-2 antagonists of dispensing multidose.For instance, the dispensing of TNF-alpha-2 antagonists be every month once, every month twice, three times every month, every other week once (qow), (qw) once in a week, twice weekly (biw), time (tiw) on every Wendesdays, inferior on every Thursdays, inferior on every Fridays, inferior on every Saturdays, the next day once (qod), (qd) once a day, every day twice (bid) or every day three times, substantially continuously or continuously, the time length scope be about one day to an about week, about two is thoughtful to pact, about one month to about two months, about two months to about four months, about four months to about six months, about six months to about eight months, about eight months to about 1 year, about 1 year to about 2 years, about 2 years to about 4 years or longer time.

TNF-alpha-2 antagonists and NS3 inhibitor are offerd medicine in independent preparation usually.TNF-alpha-2 antagonists and NS3 inhibitor can be substantially continuously or continuously dispensing in succession in about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 8 hours, about 16 hours, about 24 hours, about 36 hours, about 72 hours, about 4 days, about 7 days or about 2 weeks.

An embodiment is provided at the method for using significant quantity TNF-alpha-2 antagonists and significant quantity NS3 inhibitor in the patient HCV treatment of infection, described method comprise by subcutaneous once a day, the next day once, on every Wendesdays time or weekly twice or every day substantially continuously or continuously to the come into operation TNF-alpha-2 antagonists of doses of patient, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg, and the institute that this dispensing continues the treatment of NS3 inhibitor compound wants the time.

Embodiment is provided at the method for using significant quantity ENBREL_ and significant quantity NS3 inhibitor in the treatment that patient HCV infects, described method comprises by once a day subcutaneous, the next day once, inferior on every Wendesdays, twice weekly, once in a week, every other week once, three times every month, every month once or every other month once or every day substantially continuously or continuously to the patient doses ENBREL_ that comes into operation, it comprises every dose of about 0.1 μ g to about 23mg, about 0.1 μ g is to about 1 μ g, about 1 μ g is to about 10 μ g, about 10 μ g are to about 100 μ g, about 100 μ g are to about 1mg, about 1mg is to about 5mg, about 5mg is to about 10mg, about 10mg is to about 15mg, the ENBREL_ of about 15mg to about 20mg or about 20mg to about 23mg, this lasting NS3 inhibitor compound of offeing medicine is treated the desired time.

Embodiment is provided at the method for using significant quantity REMICADE_ and significant quantity NS3 inhibitor in the treatment that patient HCV infects, described method comprises that intravenously once a day, the next day once, inferior on every Wendesdays, twice weekly, once in a week, every other week once, three times every month, every month once or every other month once or every day substantially continuously or continuously to the patient doses REMICADE_ that comes into operation, it comprises every dose of about 0.1mg/kg of REMICADE_ to about 4.5mg/kg, about 0.1mg/kg is to about 0.5mg/kg, about 0.5mg/kg is to about 1.0mg/kg, about 1.0mg/kg is to about 1.5mg/kg, about 1.5mg/kg is to about 2.0mg/kg, about 2.0mg/kg is to about 2.5mg/kg, about 2.5mg/kg is to about 3.0mg/kg, about 3.0mg/kg is to about 3.5mg/kg, the amount of about 3.5mg/kg to about 4.0mg/kg or about 4.0mg/kg to about 4.5mg/kg, this lasting NS3 inhibitor compound of offeing medicine is treated the desired time.

Embodiment is provided in the treatment that patient HCV infects and uses significant quantity HUMIRA ^TMWith the method for significant quantity NS3 inhibitor, described method comprise by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, every month three times, every month once or every other month once or every day substantially continuously or continuously to the patient doses HUMIRA that comes into operation ^TM, it comprises every dose of HUMIRA ^TMAbout 0.1 μ g to about 35mg, about 0.1 μ g to about 1 μ g, about 1 μ g to about 10 μ g, about 10 μ g to about 100 μ g, about 100 μ g to about 1mg, about 1mg to about 5mg, about 5mg to about 10mg, about 10mg about 15mg, about 15mg about 20mg, about 20mg amount, about 25mg about 30mg or the about 30mg amount of about 35mg extremely extremely of about 25mg extremely extremely extremely, this lasting NS3 inhibitor compound of offeing medicine is treated the desired time.

Combination treatment with thymosin-α

In many examples, described method is provided at the combination treatment that the combination treatment that is used for the HCV treatment of infection comprises the above-mentioned NS3 inhibitor compound of the significant quantity that comes into operation and significant quantity thymosin-α.

Embodiment is provided in the treatment that patient HCV infects and uses significant quantity ZADAXIN ^TMThe method of thymosin-α and significant quantity NS3 inhibitor, described method comprise by subcutaneous weekly twice to the patient doses ZADAXIN that comes into operation ^TM, it contains the amount of every dose of about 1.0mg to about 1.6mg, and this dispensing continues the NS3 inhibitor compound and treats the desired time.

Combination treatment with TNF-alpha-2 antagonists and Interferon, rabbit

Some embodiment provide the method for the HCV infection for the treatment of in the individuality with HCV infection, and described method comprises NS3 inhibitor and the TNF-alpha-2 antagonists of significant quantity and one or more Interferon, rabbit of significant quantity of the significant quantity of offeing medicine.

Embodiment provides any in the modified aforesaid method, in patient HCV treatment of infection, to use significant quantity IFN-γ and significant quantity TNF-alpha-2 antagonists, described method comprise by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, every month three times, every month once or every day substantially continuously or continuously to the patient doses IFN-γ that comes into operation, it contains the medication amount of every dose of about 10 μ g of IFN-γ to about 300 μ g; And by subcutaneous once a day, the next day twice or the doses TNF-alpha-2 antagonists that comes into operation continuously or continuously substantially every day once, on every Wendesdays time or weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Embodiment provides any in the modified aforesaid method, in patient HCV treatment of infection, to use significant quantity IFN-γ and significant quantity TNF-alpha-2 antagonists, described method comprise by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, every month three times, every month once or every day substantially continuously or continuously to the patient doses IFN-γ that comes into operation, it contains the medication amount of every dose of about 10 μ g of IFN-γ to about 100 μ g; And by subcutaneous once a day, the next day twice or the doses TNF-alpha-2 antagonists that comes into operation continuously or continuously substantially every day once, on every Wendesdays time or weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Another embodiment provides any in the modified aforesaid method, in patient HCV treatment of infection, to use significant quantity IFN-γ and significant quantity TNF-alpha-2 antagonists, described method comprise by subcutaneous once a day, the next day once, on every Wendesdays time, weekly twice or every day substantially continuously or continuously with fractionated dose weekly to patient certain total weekly dose IFN-γ that comes into operation, it contains the medication amount of 30 μ g to about 1,000 μ g of having an appointment; And by subcutaneous once a day, the next day twice or the doses TNF-alpha-2 antagonists that comes into operation continuously or continuously substantially every day once, on every Wendesdays time or weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use significant quantity IFN-γ and significant quantity TNF-alpha-2 antagonists, described method comprise by subcutaneous once a day, the next day once, on every Wendesdays time, weekly twice or every day substantially continuously or continuously with fractionated dose weekly to patient certain total weekly dose IFN-γ that comes into operation, it contains the medication amount of 100 μ g to about 300 μ g of having an appointment; And by subcutaneous once a day, the next day twice or the doses TNF-alpha-2 antagonists that comes into operation continuously or continuously substantially every day once, on every Wendesdays time or weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Embodiment provides any in the modified aforesaid method, in patient HCV treatment of infection, to use compound IFN-α of significant quantity INFERGEN_ and TNF-alpha-2 antagonists, described method comprise by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, every month three times, every month once or every day substantially continuously or continuously to the patient doses INFERGEN_ that comes into operation, it contains the medication amount of every dose of about 1 μ g of INFERGEN_ to about 30 μ g; And by subcutaneous once a day, the next day twice or the doses TNF-alpha-2 antagonists that comes into operation continuously or continuously substantially every day once, on every Wendesdays time or weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Embodiment provides any in the modified aforesaid method, in patient HCV treatment of infection, to use compound IFN-α of significant quantity INFERGEN_ and TNF-alpha-2 antagonists, described method comprise by subcutaneous once a day, the next day once, on every Wendesdays time, twice weekly, once in a week, every other week once, every month three times, every month once or every day substantially continuously or continuously to the patient doses INFERGEN_ that comes into operation, it contains the medication amount of every dose of about 1 μ g of INFERGEN_ to about 9 μ g; And by subcutaneous once a day, the next day twice or the doses TNF-alpha-2 antagonists that comes into operation continuously or continuously substantially every day once, on every Wendesdays time or weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the compound IFN-α of Pegylation and the significant quantity TNF-alpha-2 antagonists of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, once to the offer medicine compound IFN-α of Pegylation (PEG-CIFN) of doses of patient, it comprises the amount of every dose of about 4 μ g of PEG-CIFN to the CIFN amino acid weight of about 60 μ g for three times every month or every month; And by subcutaneous once a day, the next day once, on every Wendesdays time, the TNF-alpha-2 antagonists of twice or the doses that comes into operation continuously or continuously substantially weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the compound IFN-α of Pegylation and the significant quantity TNF-alpha-2 antagonists of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, once to the offer medicine compound IFN-α of Pegylation (PEG-CIFN) of doses of patient, it comprises the amount of every dose of about 18 μ g of PEG-CIFN to the CIFN amino acid weight of about 24 μ g for three times every month or every month; And by subcutaneous once a day, the next day once, on every Wendesdays time, the TNF-alpha-2 antagonists of twice or the doses that comes into operation continuously or continuously substantially weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the IFN-α 2a of significant quantity or the TNF-alpha-2 antagonists of 2b or 2c and significant quantity, described method comprises: by subcutaneous once a day, the next day twice or every day be substantially continuously or continuously to patient offer medicine IFN-α 2a or the 2b or the 2c of doses once, on every Wendesdays time, weekly, it comprises every dose of IFN-α 2a or 2b or 2c and is about 1MU medication amount of about 20MU extremely; And by subcutaneous once a day, the next day once, on every Wendesdays time, the TNF-alpha-2 antagonists of twice or the doses of offeing medicine continuously or continuously substantially every day weekly, it contains every dose of TNF-alpha-2 antagonists is the amount of about 0.1 μ g to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the IFN-α 2a of significant quantity or the TNF-alpha-2 antagonists of 2b or 2c and significant quantity, described method comprises: by subcutaneous once a day, the next day once, on every Wendesdays time, twice or every day, continuously or continuously to patient offer medicine IFN-α 2a or the 2b or the 2c of doses, it comprised every dose of IFN-α 2a or 2b or the 2c medication amount for about 3MU substantially weekly; And by subcutaneous once a day, the next day once, on every Wendesdays time, the TNF-alpha-2 antagonists of twice or the doses of offeing medicine continuously or continuously substantially every day weekly, it contains every dose of TNF-alpha-2 antagonists is the amount of about 0.1 μ g to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the IFN-α 2a of significant quantity or the TNF-alpha-2 antagonists of 2b or 2c and significant quantity, described method comprises: by subcutaneous once a day, the next day once, on every Wendesdays time, twice or every day, continuously or continuously to patient offer medicine IFN-α 2a or the 2b or the 2c of doses, it comprised every dose of IFN-α 2a or 2b or the 2c medication amount for about 10MU substantially weekly; And by subcutaneous once a day, the next day once, on every Wendesdays time, the TNF-alpha-2 antagonists of twice or the doses of offeing medicine continuously or continuously substantially every day weekly, it contains every dose of TNF-alpha-2 antagonists is the amount of about 0.1 μ g to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the PEGASYS_ Pegylation IFN-α 2a and the significant quantity TNF-alpha-2 antagonists of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, once to the offer medicine PEGASYS_ of doses of patient, it comprises the medication amount of every dose of about 90 μ g of PEGASYS_ to about 360 μ g for three times every month or every month; And by subcutaneous once a day, the next day once, on every Wendesdays time, the TNF-alpha-2 antagonists of twice or the doses that comes into operation continuously or continuously substantially weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the PEGASYS_ Pegylation IFN-α 2a and the significant quantity TNF-alpha-2 antagonists of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, once to the offer medicine PEGASYS_ of doses of patient, it comprises the medication amount of every dose of about 180 μ g of PEGASYS_ for three times every month or every month; And by subcutaneous once a day, the next day once, on every Wendesdays time, the TNF-alpha-2 antagonists of twice or the doses that comes into operation continuously or continuously substantially weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the PEG-INTRON_ Pegylation IFN-α 2b and the significant quantity TNF-alpha-2 antagonists of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, once to the offer medicine PEG-INTRON_ of doses of patient, it comprises the medication amount of every dose of about 0.75 μ g of PEG-INTRON_ to about 3.0 μ g for three times every month or every month; And by subcutaneous once a day, the next day once, on every Wendesdays time, the TNF-alpha-2 antagonists of twice or the doses that comes into operation continuously or continuously substantially weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Another embodiment provides any in the modified aforesaid method, in the treatment of patient's virus infection, to use the PEG-INTRON_ Pegylation IFN-α 2b and the significant quantity TNF-alpha-2 antagonists of significant quantity, described method comprises: by subcutaneous once in a week, every other week once, once to the offer medicine PEG-INTRON_ of doses of patient, it comprises the medication amount of every dose of about 1.5 μ g of the every kg body weight of PEG-INTRON_ for three times every month or every month; And by subcutaneous once a day, the next day once, on every Wendesdays time, the TNF-alpha-2 antagonists of twice or the doses that comes into operation continuously or continuously substantially weekly, it contains the amount of every dose of about 0.1 μ g of TNF-alpha-2 antagonists to about 40mg; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

Combination treatment with other antiviral agent

For combination treatment, be attractive medicine equally as other reagent of HCV NS3 helicase inhibitor, and expection is used in the combination treatment as herein described.Complementary and suppress ribose enzyme that viral core protein expresses with the HCV protein sequence (as Heptazyme ^TM) and the phosphorothioate oligonucleotide class also be suitable for use in the combination treatment as herein described.

In certain embodiments, other antiviral agent was offerd medicine in the whole course of treatment of the NS3 of embodiment inhibitor compound treatment, and described treatment time section beginning and finish to take place simultaneously.In other embodiments, the dispensing of other antiviral agent and NS3 inhibitor compound are treated overlapping for some time, and for example, other antiviral agent treatment can begin before NS3 inhibitor compound treatment beginning and finish before the treatment of NS3 inhibitor compound finishes; Other antiviral agent treatment can begin and finish the back in the treatment of NS3 inhibitor compound and finish after NS3 inhibitor compound treatment beginning; Other antiviral agent treatment can begin after NS3 inhibitor compound treatment beginning and finish before the treatment of NS3 inhibitor compound finishes; Perhaps other antiviral agent treatment can begin and finish the back in the treatment of NS3 inhibitor compound and finish before NS3 inhibitor compound treatment beginning.

The NS3 inhibitor compound can be offerd medicine with one or more other antiviral agents and (that is, offerd medicine simultaneously in the preparation separately; Dispensing simultaneously in same preparation; In independent preparation and about 48 hours, about 36 hours, about 24 hours, about 16 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes or about 15 minutes or dispensing in less than 15 minutes).

As limiting examples, but with IFN-α scheme any correct in the aforesaid method of characteristics, with single Pegylation (30kD, linearity) scheme of compound IFN-α replaces described IFN-α scheme, comprise once or single Pegylation (30kD of the doses that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 100 μ g, and this dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α scheme any correct in the aforesaid method of characteristics, with single Pegylation (30kD, linearity) scheme of compound IFN-α replaces described IFN-α scheme, comprise once or single Pegylation (30kD of the doses that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 150 μ g, and this dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α scheme any correct in the aforesaid method of characteristics, with single Pegylation (30kD, linearity) scheme of compound IFN-α replaces described IFN-α scheme, comprise once or single Pegylation (30kD of the doses that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 200 μ g, and this dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α scheme any correct in the aforesaid method of characteristics, scheme with INFERGEN_ Interferon, rabbit alfacon-1 replaces described IFN-α scheme, comprise by INFERGEN_ Interferon, rabbit the alfacon-1 once a day subcutaneous or doses that time comes into operation on every Wendesdays, it contains the medication amount of every dose 9 μ g, and this dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α scheme any correct in the aforesaid method of characteristics, scheme with INFERGEN_ Interferon, rabbit alfacon-1 replaces described IFN-α scheme, comprise by INFERGEN_ Interferon, rabbit the alfacon-1 once a day subcutaneous or doses that time comes into operation on every Wendesdays, it contains the medication amount of every dose 15 μ g, and this dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-γ scheme any correct in the aforesaid method of characteristics, scheme with following IFN-γ replaces described IFN-γ scheme, comprise by the subcutaneous IFN-γ of the inferior doses that comes into operation on every Wendesdays, it contains the medication amount of every dose 25 μ g, and this dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-γ scheme any correct in the aforesaid method of characteristics, scheme with following IFN-γ replaces described IFN-γ scheme, comprise by the subcutaneous IFN-γ of the inferior doses that comes into operation on every Wendesdays, it contains the medication amount of every dose 50 μ g, and this dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-γ scheme any correct in the aforesaid method of characteristics, scheme with following IFN-γ replaces described IFN-γ scheme, comprise by the subcutaneous IFN-γ of the inferior doses that comes into operation on every Wendesdays, it contains the medication amount of every dose 100 μ g, and this dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) once or single Pegylation (30kD of the doses that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 100 μ g; (b) by the subcutaneous IFN-γ of the inferior doses that comes into operation on every Wendesdays, it contains the medication amount of every dose 50 μ g; This dispensing continues the NS3 inhibitor compound and treats the desired time.As limiting examples, but with TNF antagonist scheme any correct in the aforesaid method of characteristics, replace described TNF antagonist scheme with following TNF antagonist scheme, comprising comes into operation is selected from the doses TNF antagonist of the group that is made up of and the following: (a) etanercept (etanercept) by subcutaneous twice every dose of 25 mg medication amount weekly, (b) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks every dose of every kg body weight 3mg medication amount once the sharp former times monoclonal antibody (infliximab) of English, or (c) by the subcutaneous adalimumab (adalimumab) of every dose of 40mg medication amount biweekly once in a week or whenever; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 100 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 150 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 150 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 200 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 200 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 25 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 25 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 25 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 25 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α and IFN-γ assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and IFN-γ assembled scheme with following IFN-α and IFN-γ assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; Described dispensing continues the used time of NS3 inhibitor compound treatment.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 100 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 100 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 150 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 150 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 200 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 200 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount the sharp former times monoclonal antibody (infliximab) of English, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 25 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount the sharp former times monoclonal antibody (infliximab) of English, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 25 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 9 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 25 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 25 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α, IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α, IFN-γ and TNF antagonist assembled scheme with following IFN-α, IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation once a day, it contains the medication amount of every dose 15 μ g; (b) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; (c) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and TNF antagonist assembled scheme with following IFN-α and TNF antagonist assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 100 μ g; (b) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and TNF antagonist assembled scheme with following IFN-α and TNF antagonist assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 150 μ g; (b) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but with IFN-α and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and TNF antagonist assembled scheme with following IFN-α and TNF antagonist assembled scheme, comprise: (a) once or the doses list Pegylation (30kD that once came into operation in per ten by subcutaneous weekly, per eight days, linear) compound IFN-α, it contains the medication amount of every dose 200 μ g; (b) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount the sharp former times monoclonal antibody (infliximab) of English, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As a limiting examples, but with IFN-α and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and TNF antagonist assembled scheme with following IFN-α and TNF antagonist assembled scheme, comprise: (a) by the once a day subcutaneous or inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 9 μ g; (b) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As a limiting examples, but with IFN-α and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-α and TNF antagonist assembled scheme with following IFN-α and TNF antagonist assembled scheme, comprise: (a) by the once a day subcutaneous or inferior on every Wendesdays doses INFERGEN_ Interferon, rabbit alfacon-1 that comes into operation, it contains the medication amount of every dose 15 μ g; (b) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As a limiting examples, but with IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-γ and TNF antagonist assembled scheme with following IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 25 μ g; (b) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As a limiting examples, but with IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-γ and TNF antagonist assembled scheme with following IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 50 μ g; (b) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As a limiting examples, but with IFN-γ and TNF antagonist assembled scheme any correct in the aforesaid method of characteristics, replace described IFN-γ and TNF antagonist assembled scheme with following IFN-γ and TNF antagonist assembled scheme, comprise: (a) by the subcutaneous inferior on every Wendesdays doses IFN-γ that comes into operation, it contains the medication amount of every dose 100 μ g; (b) the doses TNF antagonist that comes into operation and be selected from the group that forms by and the following: (i) by the subcutaneous etanercept of twice 25mg amount weekly, (ii) by the 0th week of intravenously, the 2nd week and the 6th week and later on per 8 weeks once every kg body weight 3mg medication amount English monoclonal antibody of sharp former times, or the (iii) adalimumab by subcutaneous weekly or every amount of 40mg biweekly; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, comprise single Pegylation (30kD, linear) but any correct in the aforesaid method of the scheme of compound IFN-α, scheme with the polyoxyethylene glycol Intederon Alpha-2a replaces described single Pegylation (30kD, linearity) scheme of compound IFN-α, comprise that it contains the medication amount of every dose 180 μ g by the subcutaneous doses polyoxyethylene glycol Intederon Alpha-2a that comes into operation once in a week, described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, comprise single Pegylation (30kD, linear) but any correct in the aforesaid method of the scheme of compound IFN-α, scheme with the polyoxyethylene glycol Interferon Alpha-2b replaces described single Pegylation (30kD, linearity) scheme of compound IFN-α, comprise by the once in a week subcutaneous or doses polyoxyethylene glycol Interferon Alpha-2b that comes into operation for twice weekly, it contains the medication amount of every dose of every kg body weight 1.0 μ g to 1.5 μ g, and described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but any correct in the aforesaid method, to comprise that every day is oral and every day is at twice or the come into operation ribavirin of doses of more times consumption according to circumstances, it contains the medication amount of 400mg, 800mg, 1000mg or 1200mg, and described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but any correct in the aforesaid method, to comprise the doses ribavirin that comes into operation, it contains (i) to the patient every day oral 1000mg medication amount of body weight less than 75kg, or (ii) for body weight more than or equal to for the patient of 75kg every day oral 1200mg medication amount; Described dispensing continues the NS3 inhibitor compound and treats the desired time.

As limiting examples, but any correct in the aforesaid method, to replace described NS3 inhibitor scheme with following NS3 inhibitor scheme, comprise that every day is oral and at twice or the come into operation drug dose of every kg body weight 0.01mg to 0.1mg of more times consumption described dispensing continued the NS3 inhibitor compound and treated the desired time every day according to circumstances.

As limiting examples, but any correct in the aforesaid method, to replace described NS3 inhibitor scheme with following NS3 inhibitor scheme, comprise that every day is oral and at twice or the come into operation drug dose of every kg body weight 0.1mg to 1mg of more times consumption described dispensing continued the NS3 inhibitor compound and treated the desired time every day according to circumstances.

As limiting examples, but any correct in the aforesaid method, to replace described NS3 inhibitor scheme with following NS3 inhibitor scheme, comprise that every day is oral and at twice or the come into operation drug dose of every kg body weight 1mg to 10mg of more times consumption described dispensing continued the NS3 inhibitor compound and treated the desired time every day according to circumstances.

As limiting examples, but any correct in the aforesaid method, to replace described NS3 inhibitor scheme with following NS3 inhibitor scheme, comprise that every day is oral and at twice or the come into operation drug dose of every kg body weight 10mg to 100mg of more times consumption described dispensing continued the NS3 inhibitor compound and treated the desired time every day according to circumstances.

As limiting examples, but with NS5B inhibitor scheme any correct in the aforesaid method of characteristics, to replace described NS5B inhibitor scheme with following NS5B inhibitor scheme, comprise that every day is oral and at twice or the come into operation drug dose of every kg body weight 0.01mg to 0.1mg of more times consumption described dispensing continued the NS3 inhibitor compound and treated the desired time every day according to circumstances.

As limiting examples, but with NS5B inhibitor scheme any correct in the aforesaid method of characteristics, to replace described NS5B inhibitor scheme with following NS5B inhibitor scheme, comprise that every day is oral and at twice or the come into operation drug dose of every kg body weight 0.1mg to 1mg of more times consumption described dispensing continued the NS3 inhibitor compound and treated the desired time every day according to circumstances.

As limiting examples, but with NS5B inhibitor scheme any correct in the aforesaid method of characteristics, to replace described NS5B inhibitor scheme with following NS5B inhibitor scheme, comprise that every day is oral and at twice or the come into operation drug dose of every kg body weight 1mg to 10mg of more times consumption described dispensing continued the NS3 inhibitor compound and treated the desired time every day according to circumstances.

As limiting examples, but with NS5B inhibitor scheme any correct in the aforesaid method of characteristics, to replace described NS5B inhibitor scheme with following NS5B inhibitor scheme, comprise that every day is oral and at twice or the come into operation drug dose of every kg body weight 10mg to 100mg of more times consumption described dispensing continued the NS3 inhibitor compound and treated the desired time every day according to circumstances.

Patient's identification

In certain embodiments, the concrete scheme that is used for the treatment of HCV patient's pharmacotherapy is that some disease parameters that shows according to the patient is selected, and these parameters infect genotype, patient's hepatitis history and/or patient's hepatic fibrosis stage such as the initial virus load of patient, patient HCV.

Therefore, some embodiment are provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is used for treatment treatment failure patient, continues for 48 weeks.

Other embodiment is provided for any in the aforesaid method of HCV, and wherein said method correct is used for treating the no response patient, and wherein the patient accepted for 48 courses of treatment in week.

Other embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is used for treatment recurrence patient, and wherein the patient accepted for 48 courses of treatment in week.

Other embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is used for treating HCV infection genotype 1 and (the na that receives treatment first

Ve) patient, wherein the patient accepted for 48 courses of treatment in week.

Other embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is used for treating HCV infection genotype 4 and the patient that receives treatment first, and wherein the patient accepted for 48 courses of treatment in week.

Other embodiment is provided for treating any in the aforesaid method that HCV infects, wherein said method correct is used for treating HCV infection genotype 1 and the patient that receives treatment first, wherein the patient has high virus load (HVL), and wherein " HVL " is meant in every milliliter of serum greater than 2 * 10 ⁶Individual HCV genome duplication HCV virus load originally, wherein the patient accepted for 48 courses of treatment in week.

Embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) keeps the score 3 or 4 measured as Knodell, identification has the patient of late period or serious stage hepatic fibrosis; With then (2) to the come into operation pharmacotherapy of described method of patient, continued for about 24 thoughtful about 60 weeks, or about 30 thoughtful about 1 year, or about 36 thoughtful about 50 weeks, or about 40 thoughtful about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about time period in 60 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) keeps the score 3 or 4 measured as Knodell, identification has the patient of late period or serious stage hepatic fibrosis; With then (2) to the come into operation pharmacotherapy of described method of patient, continued for about 40 thoughtful about 50 weeks, or the time period in about 48 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification have that HCV genotype 1 infects and every milliliter of patients serum greater than the patient of the initial virus load of 200 ten thousand viral genome copys; With then (2) to the come into operation pharmacotherapy of described method of patient, continued for about 24 thoughtful about 60 weeks, or about 30 thoughtful about 1 year, or about 36 thoughtful about 50 weeks, or about 40 thoughtful about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about time period in 60 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification have that HCV genotype 1 infects and every milliliter of patients serum greater than the patient of the initial virus load of 200 ten thousand viral genome copys; With then (2) to the come into operation pharmacotherapy of described method of patient, continued for about 40 thoughtful about 50 weeks, or the time period in about 48 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification have that HCV genotype 1 infects and every milliliter of patients serum greater than the initial virus load of 200 ten thousand viral genome copys and as the keep the score patient of 0,1 or 2 measured nothings or commitment hepatic fibrosis of Knodell; With then (2) to the come into operation pharmacotherapy of described method of patient, continued for about 24 thoughtful about 60 weeks, or about 30 thoughtful about 1 year, or about 36 thoughtful about 50 weeks, or about 40 thoughtful about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or the time period in few entirely about 60 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification have that HCV genotype 1 infects and every milliliter of patients serum greater than the initial virus load of 200 ten thousand viral genome copys and as the keep the score patient of 0,1 or 2 measured nothings or commitment hepatic fibrosis of Knodell; With then (2) to the come into operation pharmacotherapy of described method of patient, continued for about 40 thoughtful about 50 weeks, or the time period in about 48 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification has that HCV genotype 1 infects and every milliliter of patients serum is less than or equal to the patient of the initial virus load of 200 ten thousand viral genome copys; With then (2) to the come into operation pharmacotherapy of described method of patient, continued for about 20 thoughtful about 50 weeks, or about 24 thoughtful about 48 weeks, or about 30 thoughtful about 40 weeks, or reach about 20 weeks, or reach about 24 weeks, or reach about 30 weeks, or reach about 36 weeks, or reach the time period in about 48 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification has that HCV genotype 1 infects and every milliliter of patients serum is less than or equal to the patient of the initial virus load of 200 ten thousand viral genome copys; With then (2) to the come into operation pharmacotherapy of described method of patient, continue the time period in about 20 thoughtful about 24 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification has that HCV genotype 1 infects and every milliliter of patients serum is less than or equal to the patient of the initial virus load of 200 ten thousand viral genome copys; With then (2) to the come into operation pharmacotherapy of described method of patient, continue the time period in about 24 thoughtful about 48 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification has HCV genotype 2 or 3 patients that infect; With then (2) to the come into operation pharmacotherapy of described method of patient, continued for about 24 thoughtful about 60 weeks, or about 30 thoughtful about 1 year, or about 36 thoughtful about 50 weeks, or about 40 thoughtful about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about time period in 60 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification has HCV genotype 2 or 3 patients that infect; With then (2) to the come into operation pharmacotherapy of described method of patient, continued for about 20 thoughtful about 50 weeks, or about 24 thoughtful about 48 weeks, or about 30 thoughtful about 40 weeks, or reach about 20 weeks, or reach about 24 weeks, or reach about 30 weeks, or reach about 36 weeks, or reach the time period in about 48 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification has HCV genotype 2 or 3 patients that infect; With then (2) to the come into operation pharmacotherapy of described method of patient, continue the time period in about 20 thoughtful about 24 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification has HCV genotype 2 or 3 patients that infect; With then (2) to the come into operation pharmacotherapy of described method of patient, continue time period at least about 24 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification has HCV genotype 1 or 4 patients that infect; With then (2) to the come into operation pharmacotherapy of described method of patient, continued for about 24 thoughtful about 60 weeks, or about 30 thoughtful about 1 year, or about 36 thoughtful about 50 weeks, or about 40 thoughtful about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about time period in 60 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification has and is characterized as the patient that the HCV of any one infects in HCV genotype 5,6,7,8 and 9; With then (2) to the come into operation pharmacotherapy of described method of patient, continue the time period in about 20 thoughtful about 50 weeks.

Another embodiment is provided for treating any in the aforesaid method that HCV infects, and wherein said method correct is may further comprise the steps: (1) identification has and is characterized as the patient that the HCV of any one infects in HCV genotype 5,6,7,8 and 9; With then (2) to the come into operation pharmacotherapy of described method of patient, continue at least about 24 weeks and be time period in about 48 weeks.

The person under inspection who is fit to treatment

Any of above-mentioned treatment plan can come into operation to providing the individuality that HCV infects after diagnosing.The individual recognition of having infectd HCV is to contain in the blood to contain whose anti-HCV antibody in HCV RNA and/or the serum.In the above-mentioned treatment plan any can come into operation to the individuality of previous HCV treatment of infection failure (" treatment failure patient " comprises nonresponder and recidivist).

Special care is that clinical diagnosis is an individuality of infecing HCV in many examples.The individual recognition of having infectd HCV is to contain in the blood to contain whose anti-HCV antibody in HCV RNA and/or the serum.Described individuality comprises whose anti-HCV ELISA positive individuals and has positive recombinant immune ink dot analyzes (recombinant immunoblot assay, individuality RIBA).Described individuality also can but must not have high Serum ALT levels.

Clinical diagnosis is to have individuality that HCV infects to comprise that the individuality of receiving treatment first (for example, previous individuality of not treating at HCV was not particularly before accepted based on IFN-α and/or based on the individuality of the therapy of ribavirin) and the individuality (" treatment is failed " patient) of previous HCV treatment failure.Treatment failure patient comprises: the nonresponder (promptly, the individuality that the HCV titre is not treated significantly or sufficiently reduced because of previous HCV, for example, previous IFN monotherapy, previous IFN-α and ribavirin combination treatment, or previous Pegylation IFN-α and ribavirin combination treatment); And the recidivist (promptly, before accepted the individuality of HCV treatment, for example, before accepted the individuality of IFN-α monotherapy, IFN-α and ribavirin combination treatment or Pegylation IFN-α and ribavirin combination treatment, these individual HCV have reduced but have increased again subsequently).

In the special embodiment that is concerned about, individuality has every milliliter of serum at least about 10 ⁵, at least about 5 * 10 ⁵Or at least about 10 ⁶Or at least about 2 * 10 ⁶Individual HCV genome duplication HCV titre originally.Described patient can infect any HCV genotype (genotype 1, comprise 1a and 1b, 2,3,4,6 etc., and hypotype (for example, 2a, 2b, 3a etc.)), particularly be difficult to the therapeutic gene type, as HCV genotype 1 and special HCV hypotype and quasispecies (quasispecies).

Same be concerned about because of chronic HCV infection show serious fibrosis or premature cure (losing compensatory, Child ' s-Pugh A level or even lower level) although and before used based on the therapy of IFN-α carry out antiviral therapy but still have a viremia or be impatient at based on the therapy of IFN-α or described therapy had incompatible HCV positive individuals (as mentioned above).In the special embodiment that is concerned about, the HCV positive individuals that has stage 3 or 4 hepatic fibrosis according to the METAVIR points-scoring system is fit to use the method for the embodiment of the invention to be treated.In other embodiments, the individuality that is fit to described embodiment method treatment is the mistake compensatory hardened patient with the clinical symptom of showing, and comprises the patient with utmost point end-age cirrhosis, comprises the patient that liver transplantation is carried out in preparation.And in other embodiments, be fit to comprise having the Fibrotic patient of slight extent with the individuality of described embodiment method treatment, comprise that having early stage Fibrotic patient (is the stage 1 and 2 in METAVIR, Ludwig and the Scheuer points-scoring system; Or it in the Ishak points-scoring system stage 1,2 or 3).

The preparation of part A viral inhibitors

Compound of Formula I can be synthesized at the described same general mode of general formula I I-XIX compound with following.Various particular compound synthetic of general formula I hereinafter described in the example.It will be understood by one of ordinary skill in the art that the variation on the order, and should further recognize the variation of the described hereinafter method that is used for preparation I compound on can suitably used appropriate reaction condition that shown or known similar reaction in addition.

The product that reacts described in the literary composition is by separating as usual manners such as extraction, distillation, chromatographys.

The salt of said structure formula compound prepares by suitable alkali or acid and the normal formula I compound of stoichiometric calculation are reacted.

The preparation of part B viral inhibitors

Identical among the employed term in this part and the implication of structure title and the part B above.Mentioning at optional network specific digit or mark any in this part should be in this part or above understand in used corresponding numbering or the labeling scheme content in the part B, rather than in this paper other local used possible similar or the numbering that is equal to or labeling scheme content, understand, except as otherwise noted.

Formula II-X compound can synthesize according to method hereinafter described.

Methodology

The preparation of compound

Use two kinds of method preparation formula II-X compounds.In two kinds of methods, prepare intermediate 1 and 4 according to disclosed program among the international application case PCT/CA00/00353 (No. 00/59929, open case WO).Also buy intermediate 4 from RSP Ammo Acids.

Example 1-1: by method A synthetic compound #101 (compd A R00220042):

Compound #101 (compd A R00220042)

Method A:

Synthesizing of step 1:2S-(1-ethoxy carbonyl-2-vinyl-cyclopropyl carbamyl)-4R-hydroxyl-tetramethyleneimine-1-carboxylic acid tert-butyl ester (3)

To ethyl-(1R is housed, 2S)/(1S, 2R)-1-amino-2-vinyl cyclopropyl carboxylic acid esters (1,1.0g, 5.2mmol), trans-N-(tert-butoxycarbonyl)-4-hydroxyl-L-proline(Pro) (2,1.3g, 1.1 equivalents) and HATU (2.7g, 1.1 add 30mL DMF in flask equivalent), make solution.Solution is cooled to 0 ℃ in ice-water bath, then follows and stir DMF (15ml) solution that slowly adds DIEA (4.4ml, 4 equivalents).Making reaction be warmed up to room temperature and stir spends the night.

Behind the 16h, react completely by the HPLC monitoring.With EtOAc (100mL) dilution, water (3 * 40mL), saturated sodium bicarbonate (NaHCO ₃(2 * 40mL) washings are then through Na for (2 * 40mL)) and salt solution ₂SO ₄Dry and concentrated, obtain dark coppery oil.With crude product purifying (eluent: acetone/hexane 3: 7), obtain being the pure products 3 (770mg, 32%) of brown spumescence powder on silica gel.

Step 2:3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 1-tert-butoxycarbonyl-5-(1R-ethoxy carbonyl-2S-vinyl-cyclopropyl carbamyl)-tetramethyleneimine-3R-base ester (5) and 3, the synthesizing of 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 1-tert-butoxycarbonyl-5-(1S-ethoxy carbonyl-2R-vinyl-cyclopropyl carbamyl)-tetramethyleneimine-3R-base ester (6)

(300mg 0.81mmol) is dissolved among the DCM (8mL), follows disposable interpolation CDI (163mg, 1.2 equivalents) with dipeptides 3.To react at room temperature to stir and spend the night.Behind the 15h, (DCM/MeOH9: 1) monitoring reacts completely by TLC.With 1,2,3,4-tetrahydroisoquinoline (0.32mL, 3 equivalents) adds in the reaction, and at room temperature stirring reaction spends the night by part.

Behind the 22h, the TLC demonstration reacts completely.To react dilution, with 1N aqueous hydrochloric acid (15mL), salt solution (15mL) washing, dry (Na with DCM (15mL) ₂SO ₄), and concentrate.With crude product purifying (eluent: DCM/Et on silica gel ₂O/ acetone 30: 10: 1).Top spot isolate (5) is white foam sprills (169mg, 40%), and bottom spot (6) is white solid (156mg, 38%).MS?m/e?550(M ⁺+Na)。

Step 3:3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 1-(2S-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-enoyl-)-5-(1R-ethoxy carbonyl-2S-vinyl-cyclopropyl carbamyl)-tetramethyleneimine-3R-base ester (7) synthetic

With the top isomer (118mg, 0.22mmol) be dissolved in 4N HCl (dioxan, 8mL) in, and keep 90min, to remove the BOC protecting group in room temperature.Then it is concentrated, in acetonitrile, handle, and concentrate twice once more.In this light brown resistates, add 4 (66.8mg, 1.1 equivalents) and HATU (93.5mg, 1.1 equivalents), then under nitrogen, add the DMF of 2mL.To be reflected at and cool off 15min on the ice-water bath, and follow stirring in reaction, dropwise to add the 0.5mLDMF solution of DIEA (0.13mL, 4 equivalents) afterwards.Remove ice bath and make it slowly be warming up to room temperature, and will react to stir and spend the night.

Behind the 24h, reaction is transformed into Vandyke brown.Its sample TLC demonstration reacts completely.To react with EtOAc (30mL) dilution and water (3 * 15mL), saturated sodium bicarbonate (2 * 15mL), salt solution (15mL) washing, dry (Na ₂SO ₄) and concentrate, obtain being 7 (156mg) of orange oily resistates.This product is directly used in next step without being further purified.MS?m/e?703(M ⁺+Na)。

Step 4:(1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid, ethyl ester (8) synthetic

(135mg 0.2mmol) is dissolved among the 20 mL DriSolve DCE, obtains solution, then under nitrogen and at room temperature add NolanShi catalyzer (5mg, 0.3 equivalent) with crude product 7.

The solution becomes purple.Reaction is placed in the pre-heated oil bath (50 ℃) and stirs and spend the night.

Behind the 10h, reaction is transformed into Vandyke brown.TLC (DCM/EtOAc 1: 1) shows that cleaning is converted into R _fBe worth lower a little new spot.Crude product concentrated and on silica gel purifying (eluent: the DCM/EtOAc gradient was by 5: 1 to 2: 1), obtain being the product 8 (75mg, 58%) of brown spumescence powder.MS?m/e?653.1(M ⁺+1)。

Step 5:(1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compound #101) synthetic

(60mg 0.092mmol) is dissolved in 0.9mL (THF/MeOH/H with macrocyclic ester 8 ₂O 2: 1: 1) in the mixed solvent, then adds LiOH-H ₂O (23mg, 6 equivalents).Mixture at room temperature stirred spend the night.Behind the 18h, TLC (DCM/MeOH 9: 1) shows to have low R _fThe clean new spot of value.Reaction is concentrated to almost dry, and between 1N aqueous hydrochloric acid (15mL) and DCM (20mL), divides molten.(2 * 10mL) extract water layer with DCM.Merge organic layer, through Na ₂SO ₄Drying also concentrates, and obtains being the compound #101 (50mg, 87%) of light brown spumescence powder.

¹H?NMR(CD ₃OD，400?MHz)δ1.20-1.67(m，21H)，1.70-1.83(m，1H)，1.88-2.10(m，1H)，2.12-2.58(m，4H)，2.82(m，2H)，3.60-3.80(m，2H)，3.86(m，1H)，4.20(m，1H)，4.35(m，1H)，4.54(s，7H)，4.58(m，3H)，5.29-5.41(m，2H)，5.57(m，1H)，7.0-7.24(m，4H)。MS?m/e625.1(M ⁺+1)。

Example 1-1a:

Similarly, according to the program described in the example 1-1, in step 3,, prepare (1S with 6 compounds 5 that replace, 4S, 6R, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00220122).MS?m/e?625.1(M ⁺+1)。

Example 1-2: by method B synthetic compound #101 (compd A R00220042):

Method B:

Prepare compound #101 equally according to above program.Similar described in the synthetic and international application case PCT/CA00/00353 of the big ring intermediate 10 described in the literary composition (No. 00/59929, open case WO).

Behind the 16h, react completely by the HPLC monitoring.With EtOAc (100mL) dilution, water (3 * 40mL), saturated sodium bicarbonate (2 * 40mL) and salt solution (2 * 40mL) washings are followed through Na ₂SO ₄Dry and concentrated, obtain dark coppery oil.With crude product purifying (eluent: acetone/hexane 3: 7), obtain being the pure products 3 (770mg, 32%) of brown spumescence powder on silica gel.

Step 2:1R-{[1-(2S-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-enoyl-)-4R-hydroxyl-tetramethyleneimine-2S-carbonyl]-amino }-2S-vinyl-cyclopropane carboxylic acid acetoacetic ester (9) synthetic

(2.85g 7.7mmol) is dissolved among the 10mL4N HCl (dioxan), and keeps 90min in room temperature, to remove the Boc protecting group with compound 3.Then it is concentrated, in acetonitrile, handle, and concentrate twice once more.In this light brown resistates, add 4 (2.2g, 8.1mmol) and HATU (3.2g 8.5mmol), then adds the DMF of 80mL under nitrogen.To be reflected at and cool off 15min on the ice-water bath, and follow stirring in reaction, dropwise to add DIEA (5.4mL, 5mLDMF solution 30.9mmol) afterwards.Remove ice bath and make it slowly be warming up to room temperature, and will react to stir and spend the night.

Behind the 18h, the TLC demonstration reacts completely.To react with EtOAc (300mL) dilution and water (3 * 150mL), saturated sodium bicarbonate (2 * 150mL), salt solution (150mL) washing, dry (Na ₂SO ₄) and remove and desolvate.On the Biotage40M by flash chromatography on silica gel method purifying (eluent=3% is to 5% MeOH in DCM) crude product, obtain being brown spumescence solid 9 (3.5g, 87%).

Step 3:(1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-hydroxyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid, ethyl ester (10) synthetic

(2.6g 5.0mmol) is dissolved among the 500mL DriSolve DCE that is in the 1L round-bottomed flask, obtains solution with compound 9.Outgased 1 hour by blasting nitrogen.Then under nitrogen, at room temperature add HoveydaShi catalyzer (0.25 equivalent).Reaction is placed in the pre-heated oil bath (50 ℃) and stirs and spend the night.Behind the 16h, reaction is transformed into Vandyke brown.TLC (DCM/EtOAc 1: 1) demonstration cleaning is converted into has a little low R _fThe new spot of value.To react concentrate and on silica gel purifying (Biotage 40M, eluent=DCM/EtOAc gradient was by 1: 1 to 1: 2), obtain being the product 10 (0.64g, 52%) of brown spumescence powder. ¹H?NMR(CDCl ₃，400MHz)δ1.21(t，J＝7.0Hz，3H)，1.43(s，9H)，1.20-1.50(m，6H)，1.53-1.68(m，2H)，1.83-1.96(m，2H)，1.98-2.28(m，4H)，2.60(m，1H)，3.13(brs，1H)，3.68(m，1H)，3.94(m，1H)，4.01-4.19(m，2H)，4.48(m，1H)，4.56(brs，1H)，4.79(m，1H)，5.26(t，J＝9.4Hz，1H)，5.36(d，J＝7.8Hz，1H)，5.53(m，1H)，7.19(brs，1H)。MS?m/e?494.0(M ⁺+1)。

Step 4:(1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid, ethyl ester (11) synthetic

To encircle greatly intermediate 10 (110mg 0.22mmol) is dissolved among the DCM (2.2mL), follow disposable interpolation CDI (45mg, 0.27mmol).To react at room temperature to stir and spend the night.Behind the 15h, (DCM/MeOH9: 1) monitoring reacts completely by TLC.Dropwise with 1,2,3, (0.14mL 1.1mmol) adds in the reaction 4-tetrahydroisoquinoline, and at room temperature stirring reaction spends the night.Behind the 22h, the TLC demonstration reacts completely.To react dilution with DCM (6mL), with the 1N aqueous hydrochloric acid (2 * 2mL), saturated sodium bicarbonate (2mL), salt solution (2mL) washing, dry (Na ₂SO ₄), and concentrate.With crude product purifying (Biotage 40S, eluent: 2% to 4% MeOH in DCM), obtain being 11 (131mg, 90%) of light yellow spumescence powder on silica gel.

Step 5: with same way as described in the step 5 of example 1-1 with compound 11 hydrolysis, obtain compound #101.

Also according to aforesaid method B, replace 1,2,3 with various other secondary amine, the 4-tetrahydroisoquinoline prepares following compound.Major part can be buied from commercial source in these amine, or therefore known documentation compound also can use the program of stating to be prepared (1.Stokker, G E.Tetrahedron Lett.1996,37 (31), 5453-5456 herein; 2.Chan, N W.Bioorganic ﹠amp; Medicinal Chemistry 2000,8,2085-2094; 3.Vecchietti, V.et al, J.Med.Chem.1991,34,2624-2633.).For can not be directly according to the amine raw material of document program preparation or the specified raw material that just before we fully understand, does not have reported in literature to cross as yet, their synthetic meeting provides in each example.

Example 1-3:

According to method B, just in step 4, use 6,7-dimethoxy-1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(6,7-dimethoxy-3,4-dihydro-1 H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00226824).MS?m/e?585.2(M ⁺+1-100)。

Example 1-4:

Compd A R00226825

According to method B, and in step 4, use 2,3,4,9-tetrahydrochysene-1H-b-carboline, synthesize (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-2,15-dioxo-18-(1,3,4,9-tetrahydrochysene-b-carboline-2-carbonyl oxygen base)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00226825).MS?m/e?564.2(M ⁺+1-100)。

Example 1-5:

According to method B, and in step 4, use 2,3-dihydro-1H-isoindole, synthesize (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00291871). ¹H?NMR(CDCl ₃，500MHz)δ1.21-1.44(m，8H)，1.32(s，9H)，1.54-1.62(m，2H)，1.78-1.88(m，2H)，2.04-2.13(m，1H)，2.16-2.23(m，1H)，2.24-2.36(m，2H)，2.66-2.74(m，1H)，3.87-3.90(m，1H)，4.15(d，J＝11.0Hz，1H)，4.37-4.43(m，1H)，4.61-4.77(m，5H)，5.18(t，J＝10.3Hz，1H)，5.24-5.31(m，1H)，5.40-5.45(m，1H)，5.58-5.66(m，1H)，7.11-7.30(m，4H)。MS?m/e?611.0(M ⁺+1)。

Example 1-6:

According to method B, and in step 4, use 2,3-dihydro-1H-indoles, synthesize (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(2,3-dihydro-indoles-1-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00291875).MS?m/e?610.9(M ⁺+1)。

Example 1-7:

According to method B, and in step 4, use the 8-Trifluoromethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00294382).MS?m/e693.0(M ⁺)。

Example 1-8:

According to method B, and in step 4, use the 6-Trifluoromethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-2,15-dioxo-18-(6-trifluoromethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00294383). ¹H?NMR(500MHz，CDCl ₃)：δ7.46-7.38(m，2H)，7.26-7.18(m，1H)，6.98(s，1H)，5.62(q，1H)，5.42(s，1H)，5.21-5.15(m，2H)，4.78-4.60(m，3H)，4.40(s，1H)，4.16-4.00(m，1H)，3.92-3.81(m，1H)，3.80-3.60(m，2H)，3.00-2.85(m，2H)，2.72-2.64(br?s，1H)，2.40-1.18(m，20H)。MS：m/e693.0(M ⁺)。

Example 1-9:

According to method B, and in step 4, use 5-methyl fluoride-1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(5-fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00294384). ¹H?NMR(500MHz，CDCl ₃)：δ7.19-7.11(m，1H)，7.05(m，1H)，6.91(t，2H)，5.62(q，1H)，5.40(s，1H)，5.24(d，1H)，5.20(t，1H)，4.78(s，1H)，4.64-4.56(m，2H)，4.42(s，1H)，4.12-4.02(m，1H)，3.92-3.81(m，1H)，3.78-3.61(m，2H)，2.84-2.80(m，2H)，2.74-2.64(m，1H)，2.36-2.18(m，2H)，1.91-1.81(m，2H)，1.64-1.54(m，2H)，1.48-1.10(m，15H)。MS：m/e?643.0(M ⁺)。

Example 1-10:

According to method B, and in step 4, use 5-amino-1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-and 18-(5-amino-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-14-tert-butoxycarbonyl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00301745).MS：m/e?640.1(M ⁺)。

Example 1-11:

According to method B, and in step 4, use 7-amino-1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-and 18-(7-amino-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-14-tert-butoxycarbonyl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00301749).MS：m/e?640.1(M ⁺)，641.1(M ⁺+1)。

Example 1-12:

According to method B, and in step 4, use phenyl-(4,5,6,7-tetrahydrochysene-thiazole is [5,4-c] pyridine-2-yl also)-amine, come synthetic (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-2,15-dioxo-18-(2-phenyl amino-6,7-dihydro-4H-thiazole also [5,4-c] pyridine-5-carbonyl oxygen base)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304000).MS?m/e?721.2(M-1)。

Example 1-13:

According to method B, and in step 4, use 7-chloro-1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(7-chloro-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304062).MS?m/e?659.0(M ⁺)，661.0(M ⁺+2)。

Example 1-14:

According to method B, and in step 4, use 6-fluoro-1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(6-fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304063).MS?m/e?643.0(M ⁺)，644.0(M ⁺+1)。

Example 1-15:

According to method B, and in step 4, use 4,4-spiral shell-cyclobutyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(4,4-spiral shell-cyclobutyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304065). ¹H NMR (400MHz, d ₆-acetone) δ 7.99 (d, 1H), 7.57-7.66 (m, 1H); 7.27 (t, 1H), 7.09-7.22 (m, 2H), 5.99 (bs, 1H), 5.56 (dd, 1H), 5.42 (bs, 1H), 5.19-5.30 (m, 1H), 4.52-4.70 (m, 1H), 4.27-4.42 (m, 1H), 4.17-4.27 (m, 1H), 3.91 (dd, 1H), 3.63-3.82 (m, 2H), 2.22-2.51 (m, 6H), 1.93-2.20 (m, 3H), 1.79-1.91 (m, 1H), and 1.52-1.66 (m, 1H), 1.16-1.50 (m, 19H).MS?m/z?665.1(M ⁺+1)。

Example 1-15a:

4,4-spiral shell-cyclobutyl-1,2,3, the preparation of 4-tetrahydrochysene-isoquinoline 99.9

A: at room temperature, (2.00g 12.7mmol) dropwise adds LiAlH (19.1ml, 1.0M solution 19.1mmol) in the solution in 100ml THF to 1-phenyl-1-cyclopropyl nitrile.To react and at room temperature stir 15 hours, use 10ml H at 0 ℃ afterwards ₂O follows the slow quenching of 10ml 10N NaOH, and stirring at room 1.5 hours.Solution is filtered, and remove THF by rotary evaporation.Extract aqueous mixture with EtOAc, and use H ₂O and salt water washing organic extract are through Na ₂SO ₄Drying, and concentrate and to obtain 0.70g (34%) clarified oil, this product just is used for next step without being further purified.

B: under 0 ℃ to C-(1-phenyl-cyclobutyl)-methylamine (0.70g, 4.34mmol) and TEA (0.67ml 4.78mmol) dropwise adds methyl-chloroformate in the solution in 40ml THF.At room temperature stirring reaction is 15 hours.Add water and EtOAc next day, separate organic layer and use 1N HCl and salt water washing, through Na ₂SO ₄Drying concentrates and obtains oil, just is directly used in next step without being further purified.

C: with (1-phenyl-cyclobutylmethyl)-Urethylane (0.95g, 4.34mmol) and the mixture of PPA (20ml) add in the sand bath that is heated to 150 ℃ in advance.After 30 minutes, will react cool to room temperature (r.t.).After the cooling, dropwise add water, and with twice of DCM extraction solution.With salt water washing organic extract, through Na ₂SO ₄Dry and concentrated, obtain clarified oil, just be directly used in next step without being further purified.

D: under 0 ℃, to 3, (0.406g 2.17mmol) dropwise adds LiAlH (3.26ml, 1.0M solution 3.26mmol) to 4-dihydro-2H-isoquinoline 99.9-1-ketone in the solution in 20ml THF.Make reaction be warming up to room temperature, and stirred 15 hours, use 5ml H at 0 ℃ afterwards ₂O follows the slow quenching of 5ml 1.0N NaOH, and at room temperature stirs 1.5 hours.Solution is filtered, and remove THF by rotary evaporation.Extract aqueous mixture with EtOAc, and use H ₂O and salt water washing organic extract are through Na ₂SO ₄Drying, and concentrate and to obtain 0.21g (56%) clarified oil, this product just is used for next step without being further purified.

Example 1-16:

According to method B, and in step 4, use 4,4-dimethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(4,4-dimethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304066). ¹H NMR (400MHz, d ₆-acetone) δ 7.98 (d, 1H), 7.39 (bs, 1H), 7.09-7.24 (m, 3H), 5.99 (bs, 1H), 5.57 (dd, 1H), 5.37-5.46 (bs, 1H), 5.24 (dd, 1H), 4.55-4.69 (m, 1H), 4.26-4.36 (m, 1H), 4.16-4.26 (m, 1H), 3.90 (dd, 1H), 3.40-3.49 (m, 1H), and 2.28-2.50 (m, 4H), 1.98-2.09 (2H), 1.79-1.92 (m, 1H), and 1.52-1.65 (m, 3H), 1.16-1.51 (m, 22H).MS?m/z?653.0(M ⁺+1)。

Example 1-16a:

According to steps A among the example 1-15a to the experimental procedure of D preparation 4,4-dimethyl-1,2,3, the 4-tetrahydroisoquinoline, with 2-methyl-2-phenyl-propionitrile (according to Caron, S.; Vazquez, E.; Wojcik, J.M.J.Am.Chem.Soc.2000,122,712-713 preparation) be converted into title compound.

Example 1-17:

According to method B, and in step 4, use the 4-methyl isophthalic acid, 2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(4-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304067). ¹H NMR (400MHz, d ₆-acetone) δ 7.93-8.03 (m, 1H), 7.04-7.28 (m, 4H), 6.02 (bs, 1H), 5.56 (dd, 1H), 5.40 (m, 1H), 5.23 (dd, 1H), 4.66-4.85 (m, 1H), 4.54-4.64 (m, 1H), 4.34-4.54 (m, 1H), 4.17-4.34 (m, 1H), 3.91 (dd, 1H), 3.57-3.78 (m, 1H), 3.42-3.57 (m, 1H), 2.26-2.52 (m, 4H), 1.96-2.09 (m, 2.0), (1.77-1.92 m, 1.0), 1.50-1.64 (m, 3.0), 1.13-1.50 (m, 17h).MS?m/z?639.0(M ⁺+1)。

Example 1-17a:

According to Grunewald, G.L.; Sall, D.J.; Monn, J.A.J.Med.Chem.1988,31,433-444 prepares the 4-methyl isophthalic acid from 2-phenyl-propyl group amine, and 2,3, the 4-tetrahydroisoquinoline.

Example 1-18:

According to method B, and in step 4, use the tertiary butyl-(4,5,6,7-tetrahydrochysene-thiazole is [5,4-c] pyridine-2-yl also)-amine, come synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(2-tertiary butyl amino-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-carbonyl oxygen base also)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304103).MS?m/e?731.2(M ⁺+1)。

Example 1-19:

According to method B, and in step 4, use 4,5,6,7-tetrahydrochysene-thiazole is [5,4-c] pyridine-2-base amine also, come synthetic (1S, 4R, 6S, 14S, 18R)-18-(2-amino-6,7-dihydro-4H-thiazole is [5,4-c] pyridine-5-carbonyl oxygen base also)-14-tert-butoxycarbonyl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304154).MS?m/e?675.1(M ⁺+1)。

Example 1-20:

According to method B, and in step 4, use 2-methyl-4,5,6,7-tetrahydrochysene-thiazole is [5,4-c] pyridine also, come synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(2-methyl-6,7-dihydro-4H-thiazole be [5,4-c] pyridine-5-carbonyl oxygen base also)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304158).MS?m/e?546.2(M ⁺+1-100)。

Example 1-21:

According to method B, and in step 4, use 5,6,7,8-tetrahydrochysene-pyrido [4,3-d] pyrimidine, come synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304183).MS?m/e625.2(M-1)。

Example 1-22:

Compd A R00312023

According to method B, just before ensuing coupling step, further use H from the closed loop metathesis reaction product 10 of step 3 ₂/ Rh-Al ₂O ₃Reduce (WO 0059929, the 76-77 page or leaf), synthesize (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] nonadecane-4-carboxylic acid (compd A R00312023).MS?m/e?625.3(M-1)。

Example 1-23:

According to method B, and in step 4, use 1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-base amine comes synthetic (1S, 4R, 6S, 14S, 18R)-18-(6-amino-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-14-tert-butoxycarbonyl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 4,6] 19-7-alkene-4-carboxylic acid (compd A R00314578).MS (POS ESI) m/z540.2[parent, (M ⁺+ 1)-100 (Boc group)].

Example 1-24:

According to method B, and in step 4, use N-(4,5; 6,7-tetrahydrochysene-thiazole is [5,4-c] pyridine-2-yl also)-ethanamide; come synthetic (1S, 4R, 6S; 14S; 18R)-18-(2-acetylamino-6,7-dihydro-4H-thiazole be [5,4-c] pyridine-5-carbonyl oxygen base also)-14-tert-butoxycarbonyl amino-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00314685).MS?m/e?589.2(M ⁺+1-100)。

Example 1-25:

According to method B, and in step 4, use dimethyl-(1,2,3,4-tetrahydrochysene-isoquinoline 99.9-5-yl)-and amine (example 1-25a), come synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(5-dimethylamino-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00315997).MS?m/e?668.0(M ⁺)。

Example 1-25a

The synthetic of dimethyl-(1,2,3,4-tetrahydrochysene-isoquinoline 99.9-5-yl)-amine described in following flow process:

To the amino tetrahydroisoquinoline of 5-(3.68g, 24.8mmol) 1, add in the solution in the 4-dioxan (100mL) 3 N NaOH (8.27mL, 24.8mmol).After being cooled to 0 ℃, dropwise be added on 1, (Boc) in the 4-dioxan (10mL) ₂(5.42g 24.8mmol), and at room temperature stirs and spends the night O.Reaction mixture is toppled in the entry, and with EtOAc extracts (2 *).With the organic layer after saturated sodium bicarbonate aqueous solution, water and the salt water washing merging, then dry and concentrated.By silica gel column chromatography purifying resistates, obtain 5.44g (88%) the solid Boc protection product that is white in color.

Under 0 ℃, (0.2g 0.81mmol) adds NaH in the solution in THF (5mL) to the product from above-mentioned preposition step.After 15 minutes, add CH ₃I also continues at room temperature to stir to spend the night.After finishing, with frozen water quenching reaction mixture, with EtOAc (25mL) extraction, dry (Na ₂SO ₄) and concentrate.Under 0 ℃, utilize 60%TFA-DCM (2mL) to remove the Boc group, obtain 110mg (77.5%) and be light green solid end product.MS：177.1(MH ⁺)。

Example 1-26:

According to method B, and use 5-chloro-2 in step 4,3-dihydro-1H-isoindole comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(5-chloro-1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00315998). ¹H?NMR(400MHz，CDCl ₃)：δ7.24-7.02(m，3H)，6.82(s，1H)，5.68-5.51(m，1H)，5.36(s，1H)，5.11-4.96(m，2H)，4.67-4.44(m，5H)，4.29-4.20(m，1H)，4.20-4.11(m，1H)，3.82-3.74(m，1H)，2.69-2.55(m，1H)，2.31-2.15(m，1H)，2.14-2.06(m，1H)，2.03(s，1H)，2.01-1.86(m，1H)，1.86-1.24(m，11H)，1.22(s，9H)。MS：m/e?644.9(M ⁺)，646.9(M ⁺+2)。

Example 1-27:

According to method B, and in step 4, use 5,6-two chloro-2,3-dihydro-1H-isoindole comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(5,6-two chloro-1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00315999). ¹H?NMR(400MHz，CDCl ₃)：δ7.29(s，1H)，7.02(s，1H)，7.06(s，1H)，5.57-5.50(m，1H)，5.33(s，1H)，5.23-5.09(m，2H)，4.73-4.65(m，1H)，4.64-4.48(m，1H)4.33-4.29-4.11(m，1H)，3.82-3.74(m，1H)，2.69-2.55(m，1H)，2.73-2.61(m，1H)，2.29-2.08(m，3H)，2.01(s，1H)，1.83-1.65(m，1H)，1.63-1.46(m，11H)，1.40-1.12(s，9H)。MS：m/e?678.9(M ⁺)，681(M ⁺+2)。

Example 1-28:

According to method B, and in step 4, use the 4R-methyl isophthalic acid, 2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(4R-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4.6] 19-7-alkene-4-carboxylic acid (compd A R00320122). ¹H?NMR(400MHz，CD ₃OD)δ7.02-7.24(m，3H)，5.59(dd，1H)，5.30-5.44(m，2H)，4.66-4.81(m，1H)，4.14-4.64(m，3H)，3.83-3.92(m，1H)，3.58-3.81(m，1H)，3.44-3.56(m，1H)，2.86-3.86(m，1H)，2.23-2.58(m，4H)，1.87-2.13(m，2H)，1.70-1.87(m，1H)，1.50-1.70(m，3H)，1.07-1.51(m，19H)，0.80-0.96(m，2H)。MS?m/z?639.0(M ⁺+1)。

Example 1-29:

According to method B, and in step 4, use the 4S-methyl isophthalic acid, 2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(4S-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320123). ¹H?NMR(400MHz，CD ₃OD)δ7.01-7.23(m，3H)，5.58(dd，1H)，5.32-5.45(m，2H)，4.66-4.82(m，1H)，4.12-4.64(m，3H)，3.86-3.94(m，1H)，3.52-3.74(m，1H)，3.43-3.56(m，1H)，2.88-3.85(m，1H)，2.24-2.60(m，4H)，1.87-2.15(m，2H)，1.71-1.87(m，1H)，1.52-1.70(m，3H)，1.07-1.52(m，19H)，0.80-0.96(m，2H)。MS?m/z?639.0(M ⁺+1)。

Example 1-30:

According to method B, and in step 4, use 4-(2-methoxyl group-phenyl)-piperidines, come synthetic (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-[4-(2-methoxyl group-phenyl)-piperidines-1-carbonyl oxygen base]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320576).MS?m/e?583.3(M ⁺+1-100)。

Example 1-31:

According to method B, and in step 4, use 6-methoxyl group-2,3,4,9-tetrahydrochysene-1H-b-carboline comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(6-methoxyl group-1,3,4,9-tetrahydrochysene-b-carboline-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320577).MS?m/e?594.2(M ⁺+1-100)。

Example 1-32:

According to method B, and in step 4, use 1-piperidines-1-ylmethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-2,15-dioxo-18-(1-piperidines-1-ylmethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00301383). ¹HNMR(500MHz，CD ₃OD)δ7.33-7.24(m，4H)，7.20(br?s，1H)，6.61(br?s，1H)，5.75-5.52(m，2H)，5.50-5.33(m，2H)，4.63-4.43(m，2H)，4.42-4.07(m，4H)，3.96(br?s，1H)，3.67-3.11(m，5H)，3.06-2.88(m，2H)，2.86-2.74(m，2H)，2.56-2.35(m，3H)，2.23(q，1H)，2.04-1.90(m，2H)，1.89-1.52(m，10H)，1.51-1.32(m，12H)；MS(POS?APCI)m/z?722.3(M ⁺+1)。

Example 1-33:

According to the program described in the example 1-2, and in step 4, use 6-methoxyl group-1-methoxymethyl-1,2,3,4-tetrahydrochysene-chlorination isoquinoline 99.9 replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(6-methoxyl group-1-methoxymethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00333842).MS(APCI-)：m/z?697.2(M-1)。

Example 1-34:

According to the program described in the example 1-2, and in step 4, use 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydrochysene-chlorination isoquinoline 99.9 replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(5-fluoro-1-methoxymethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00365349).MS(APCI-)：m/z?685.3(M-1)。

Example 1-35:

According to the program described in the example 1-2, and in step 4, use dimethyl-(1,2,3,4-tetrahydrochysene-isoquinolyl-1 methyl)-amine (synthetic) replacement 1,2 according to example 1-35a, 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(1-dimethylaminomethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00333224).MS(APCI+)：m/z582.3(MH ⁺-Boc)。

Example 1-35a:

By the similar fashion as shown in example 3-76a, just in step 1, use phenylethylamine replacement 2-(3-methoxyl group-phenyl)-ethamine and in the first part of step 3, use dimethylamine to replace sodium methylate as nucleophilic reagent, come synthesization of dimethyl-(1,2,3,4-tetrahydrochysene-isoquinolyl-1 methyl)-amine.This crude product is directly used in ensuing coupling step without being further purified.

Example 1-36:

Compd A R00333225

According to the program described in the example 1-2, and in step 4, use 1-morpholine-4-ylmethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9 (synthetic according to example 1-36a) replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(1-morpholine-4-ylmethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00333225).MS(APCI-)：m/z722.3(M-1)。

Example 1-36a:

By the similar fashion shown in example 3-76a, just in step 1, use phenylethylamine replacement 2-(3-methoxyl group-phenyl)-ethamine and in the first part of step 3, use morpholino to replace sodium methylate, synthesize 1-morpholine-4-ylmethyl-1,2 as nucleophilic reagent, 3,4-tetrahydrochysene-isoquinoline 99.9.This crude product is directly used in ensuing coupling step without being further purified.

Example 1-37:

According to the program described in the example 1-2, and in step 4, use 6-methoxyl group-1-piperidines-1-ylmethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9 (synthetic according to example 1-37a) replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(6-methoxyl group-1-piperidines-1-ylmethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00333248).

MS(APCI-)：m/z?750.4(M-1)。

Example 1-37a

By the similar fashion shown in example 3-76a, just in the first part of step 3, use piperidines to replace sodium methylate as nucleophilic reagent, synthesize 6-methoxyl group-1-piperidines-1-ylmethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9.This crude product is directly used in ensuing coupling step without being further purified.

Example 1-38:

According to the program described in the example 1-2, and in step 4, use 6-methoxyl group-1-morpholine-4-ylmethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9 (synthetic according to example 1-38a) replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(6-methoxyl group-1-morpholine-4-ylmethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00333276).MS(APCI-)：m/z?750.3(M-1)。

Example 1-38a

By the similar fashion shown in example 3-76a, just in the first part of step 3, use morpholino to replace sodium methylate as nucleophilic reagent, synthesize 6-methoxyl group-1-morpholine-4-ylmethyl-1,2,3,4-tetrahydrochysene-isoquinoline 99.9.This crude product is directly used in ensuing coupling step without being further purified.

Example 1-39:

According to the program described in the example 1-2, and in step 4, use (6-methoxyl group-1,2,3,4-tetrahydrochysene-isoquinolyl-1 methyl)-dimethyl-amine (synthetic) replacement 1,2 according to example 1-39a, 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(1-dimethylaminomethyl-6-methoxyl group-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00333277).MS(APCI+)：m/z?712.3(MH ⁺)。

Example 1-39a:

By the similar fashion shown in example 3-76a, just in the first part of step 3, use dimethylamine to replace sodium methylate as nucleophilic reagent, synthesize 6-methoxyl group-1,2,3,4-tetrahydrochysene-isoquinolyl-1 methyl)-dimethyl-amine.This crude product is directly used in ensuing coupling step without being further purified.

Example 1-40:

Compd A R00365369

According to the program described in the example 1-2, and use 4-fluoro-2 in step 4,3-dihydro-1H-isoindole (synthetic according to example 3-55a) replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-(4-fluoro-1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00365369). ¹H?NMR(500MHz，DMSO)δ12.21(br?s，1H)，8.66(br?s，1H)，7.35(q，1H)，7.19(d，1H)，7.11(q，2H)，7.03(br?s，1H)，5.51(q，1H)，5.33-5.21(m，2H)，4.66(s，4H)，4.22(q，1H)，4.24(t，1H)，3.99-3.89(m，1H)，3.73-3.64(m，1H)，2.65-2.55(m，1H)，2.28-2.08(m，3H)，1.77-1.61(m，2H)，1.54-1.42(m，1H)，1.42-1.03(m，16H)；MS(APCI-)：m/z?627.3(M-1)。

Example 1-41:

Compd A R00371946

According to the program described in the example 1-2, and in step 4, use 5-(2-morpholine-4-base-oxyethyl group)-2, and 3-dihydro-1H-isoindole (according to J.Med.Chem.2002, the 45th volume, the 26th phase, 5771, preparation method D; And the preparation of the step described in Bioorg.Med.Chem.Lett.11 (2001) 685-688.Protect the amine raw material for N-Boc: ¹H NMR (500MHz, CDCl ₃) δ 7.13 (dd, 1H), 6.85-6.74 (m, 2H), 4.61 (t, 4H), 4.10 (t, 2H), 3.73 (t, 4H) 2.81 (t, 2H), 2:61-2.54 (m, 4H), 1.51 (s, 9H); MS (APCI+): m/z 349.1 (M+1)) replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-[5-(2-morpholine-4-base-oxyethyl group)-1,3-dihydro-isoindole-2-carbonyl oxygen base]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00371946).MS(APCI+)：m/z?640.3[(M+1)-Boc]。

Example 1-42:

Compd A R00371947

According to the program described in the example 1-2, (according to J.Med.Chem.2002, the 45th rolls up, the 26th phase, 5771, preparation method D and use [2-(2,3-dihydro-1H-isoindole-5-base oxygen base)-ethyl]-dimethyl-amine in step 4; And the preparation of the step described in Bioorg.Med.Chem.Lett.11 (2001) 685-688.Protect the amine raw material for N-Boc: ¹H NMR (500MHz, CDCl ₃) δ 7.14 (dd, 1H), 6.88-6.76 (m, 2H), 4.61 (t, 4H), 4.04 (t, 2H), 2.72 (t, 2H), 2.34 (s, 6H), 1.50 (s, 9H); MS (APCI+): m/z 307.1 (M+1)) replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-[5-(2-dimethylamino-oxyethyl group)-1,3-dihydro-isoindole-2-carbonyl oxygen base]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00371947).MS(APCI+)：m/z?698.2(M+1)。

Example 1-43:

Compd A R00371948

According to the program described in the example 1-2, (according to J.Med.Chem.2002, the 45th rolls up, the 26th phase, 5771, preparation method D and use [2-(2,3-dihydro-1H-isoindole-5-base oxygen base)-ethyl]-sec.-propyl-amine in step 4; And the preparation of the step described in Bioorg.Med.Chem.Lett.11 (2001) 685-688.Protect the amine raw material for N-Boc: ¹H NMR (500MHz, CDCl ₃) δ 7.13 (dd, 1H), 6.86-6.75 (m, 2H), 4.62 (t, 4H), 4.06 (t, 2H), 2.99 (t, 2H), 2.88 (septet, 1H), 1.62 (br s, 1H), 1.51 (s, 9H), 1.10 (d, 6H); MS (APCI+): m/z 321.2 (M+1)) replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-[5-(2-sec.-propyl amino-oxyethyl group)-1,3-dihydro-isoindole-2-carbonyl oxygen base]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00371948).MS(APCI-)：m/z?710.3(M-1)。

Preparation with compound of universal architecture III

Prepare compound according to the generalized flowsheet shown in above with universal architecture II.At first remove the Boc blocking group of the compound with structure I a, then the amino on the nucleophillic attack electrophilic reagent forms carbamate, acid amides or urea.

Example 2-1:

Compd A R00247310

Step 1:(1S, 4R, 6S, 14S, 18R)-and 14-amino-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] preparation of 19-7-alkene-4-carboxylic acid, ethyl ester

N-Boc is protected initial substance, and (102mg 0.16mmol) is dissolved among the 6mL 4N HCl (dioxan), and at room temperature keeps 90 minutes.HPLC demonstration Boc blocking group is removed fully.Then reaction mixture is concentrated, in acetonitrile, handle, and concentrate twice once more.The light brown spumescence powder of gained is used for next step.

Step 2:(1S, 4R, 6S, 14S, 18R)-and 14-cyclopentyloxy carbonylamino-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] preparation of 19-7-alkene-4-carboxylic acid, ethyl ester

(42mg 0.48mmol) dropwise adds carbonyl chloride (0.42mL, 1.9M, toluene solution 0.80mmol) in the solution in THF (16mL) to cyclopentanol.Stirred the mixture under the room temperature 2 hours, and formed chloroformate cyclopentyl ester reagent.Reaction is concentrated into the volume of half approximately.Then be diluted to original volume, and be concentrated into half volume once more, so that remove excess phosgene fully with DCM.Further use THF (16mL) to dilute this chloroformate cyclopentyl ester solution, be cooled to 0 ℃, and in the solid residue (0.16mmol) that more than 0 ℃ it is added to from step 1.Then in reaction mixture, add TEA (0.11mL, 0.81mmol), and 0 ℃ of following stirring reaction 2 hours.React completely by the HPLC monitoring.It is concentrated, handle in EtOAc (15mL), then water, saturated sodium bicarbonate, water and salt solution (each 10mL) washing is through Na ₂SO ₄Drying, and concentrate.On Biotage 40S by the rough yellow dense oily resistates of purified by flash chromatography (eluent=hexane/EtOAc1: 1), the product of (65.2mg, 63%) of the crisp spumescence powder that obtains being white in color.MS(MH ⁺665.2)。

Step 3:(1S, 4R, 6S, 14S, 18R)-and 14-cyclopentyloxy carbonylamino-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] preparation of 19-7-alkene-4-carboxylic acid (compd A R00247310)

According to the same hydrolysis program in the step 5 of example 1-1.

According to the following compound of the preparation of the same program among the previous examples 2-1, wherein other electrophilic reagent of the illustrated usefulness of step 4 as method B among the example 1-2 replaces chloroformate cyclopentyl ester, and/or replaces the P2-tetrahydroisoquinoline with other amine raw material equally.

Example 2-2:

Compd A R00294376

According to program described in the example 2-1, and in step 2, use methyl-chloroformate, come synthetic (1S, 4R, 6S, 14S, 18R)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-and 14-methoxycarbonyl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00294376).

Example 2-3:

Compd A R00304074

According to program described in example 1-2 and the 2-1, and use 5-fluoro-1,2 in the step 4 in example 1-2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-cyclopentyloxy carbonylamino-18-(5-fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304074).MS?m/e?583.2(M ⁺+1)。

Example 2-4:

Compd A R00304075

According to program described in example 1-2 and the 2-1, and use the 8-Trifluoromethyl-1 in the step 4 in example 1-2,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-cyclopentyloxy carbonylamino-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304075).MS?m/e?705.1(M ⁺+1)。

Example 2-5:

Compd A R00304076

According to program described in example 1-2 and the 2-1, and use 2 in the step 4 in example 1-2,3-dihydro-1H-isoindole comes synthetic (1S, 4R, 6S, 14S, 18R)-14-cyclopentyloxy carbonylamino-18-(1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304076).MS?m/e?623.2(M ⁺+1)。

Example 2-6:

Compd A R00304125

According to program described in the example 2-1, and in step 2, use the 2-fluoroethanol to replace cyclopentanol to form chloro-formic ester reagent, come synthetic (1S, 4R, 6S, 14S, 18R)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-and 14-(2-fluoro-ethoxy carbonyl amino)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304125).MS?m/e?615.1(M ⁺+1)。

Example 2-7:

Compd A R00304126

According to program described in the example 2-1, and in step 2, use tetrahydrofuran (THF)-3S-alcohol to replace cyclopentanol to form chloro-formic ester reagent, come synthetic (1S, 4R, 6S, 14S, 18R)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-14-(tetrahydrofuran (THF)-3S-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304126).MS?m/e?639.2(M ⁺+1)。

Example 2-8:

Compd A R00304127

According to program described in the example 2-1, and in step 2, use tetrahydrofuran (THF)-3R-alcohol to replace cyclopentanol to form chloro-formic ester reagent, come synthetic (1S, 4R, 6S, 14S, 18R)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-14-(tetrahydrofuran (THF)-3R-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304127).MS?m/e?639.2(M ⁺+1)。

Example 2-9:

Compd A R00320002

According to program described in the example 2-1, and in step 2, use tetrahydropyrans-4-alcohol to replace cyclopentanol to form chloro-formic ester reagent, come synthetic (1S, 4R, 6S, 14S, 18R)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-14-(tetrahydropyran-4-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320002).MS?m/e?653.2(M ⁺+1)。

Example 2-10:

Compd A R00320074

According to program described in example 1-2 and the 2-1, and in the step 4 of example 1-2, use 2,3-dihydro-1H-isoindole and use tetrahydrofuran (THF)-3R-alcohol to replace cyclopentanol to form chloro-formic ester reagent in the step 2 of example 2-1 comes synthetic (1S, 4R, 6S, 14S, 18R)-18-(1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-14-(tetrahydrofuran (THF)-3R-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320074).MS?m/e?625.2(M ⁺+1)。

Example 2-11:

Compd A R00320075

According to program described in example 1-2 and the 2-1, and in the step 4 of example 1-2, use 2,3-dihydro-1H-isoindole and use tetrahydrofuran (THF)-3S-alcohol to replace cyclopentanol to form chloro-formic ester reagent in the step 2 of example 2-1 comes synthetic (1S, 4R, 6S, 14S, 18R)-18-(1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-14-(tetrahydrofuran (THF)-3S-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene 4-carboxylic acid (compd A R00320075).MS?m/e?625.2(M ⁺+1)。

Example 2-12:

Compd A R00320076

According to program described in example 1-2 and the 2-1, and in the step 4 of example 1-2, use 2,3-dihydro-1H-isoindole and use the 2-fluoroethanol to replace cyclopentanol to form chloro-formic ester reagent in the step 2 of example 2-1 comes synthetic (1S, 4R, 6S, 14S, 18R)-18-(1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-14-(tetrahydrofuran (THF)-3S-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320076).MS?m/e601.1(M ⁺+1)。

Example 2-13:

Compd A R00320077

According to program described in example 1-2 and the 2-1, and in the step 4 of example 1-2, use 2,3-dihydro-1H-isoindole and use tetrahydropyrans-4-alcohol to replace cyclopentanol to form chloro-formic ester reagent in the step 2 of example 2-1 comes synthetic (1S, 4R, 6S, 14S, 18R)-18-(1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-14-(tetrahydropyran-4-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320077).MS?m/e601.1(M ⁺+1)。

Example 2-14:

Compd A R00320445

According to program described in example 1-2 and the 2-1, and in the step 4 of example 1-2, use 5,6-two chloro-2,3-dihydro-1H-isoindole and in the step 2 of example 2-1, use tetrahydrofuran (THF)-3R-alcohol to replace cyclopentanol to form chloro-formic ester reagent, come synthetic (1S, 4R, 6S, 14S, 18R)-18-(5,6-two chloro-1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-14-(tetrahydrofuran (THF)-3R-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320445).MS：m/e?693.0(M ⁺)，695.1(M ⁺+2)。

Example 2-15:

Compd A R00320448

According to program described in example 1-2 and the 2-1, and in the step 4 of example 1-2, use 5-two chloro-2,3-dihydro-1H-isoindole and use tetrahydrofuran (THF)-3R-alcohol to replace cyclopentanol to form chloro-formic ester reagent in the step 2 of example 2-1 comes synthetic (1S, 4R, 6S, 14S, 18R)-18-(5-chloro-1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-14-(tetrahydrofuran (THF)-3R-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320448). ¹H?NMR(500MHz，CD ₃OD)：δ7.38(s，1H)，7.32-7.28(m，2H)，7.22(d，1H)，7.10(br?s，1H)，5.56-5.50(q，1H)，5.42-5.38(t，1H)，5.35(br?s，1H)，4.80-4.48(m，6H)，4.44(m，1H)，4.16(d，1H)，3.84(dd，1H)，3.78-3.69(m，1H)，3.68-3.60(m，1H)，3.50(t，1H)，2.55-2.36(m，3H)，2.21-2.12(m，1H)，1.98-1.85(m，1H)，1.72-1.62(m，2H)，1.61-1.51(m，2H)，1.50-1.20(m，9H)。MS：m/e?659.1(M ⁺)，661.1(M ⁺+2)。

Example 2-16:

AR00248689

(1S, 4R, 6S, 14S, 18R)-and 14-(pentamethylene carbonyl-amino)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R248689) synthetic

At first the cyclopentyl carboxylic acid is carried in (available from Argonaut Technologies) on the PS-TFP resin, forms active ester.Will resin (0.03mmol) active ester on at first expands in the 0.5mL chloroform for 26mg, 1.16mmol/g, then add the MP-carbonate resin (available from Argonaut Technologies, 300mg, 2.5mmol/g, 0.75mmol).Then in this resin compound, add described macrocyclic material (15mg, 0.5M chloroformic solution 0.02mmol), and at room temperature oscillatory reaction is spent the night.After 16 hours, react completely by the HPLC monitoring.Then, obtain clean N-acylate with its filtration and concentrated.With its hydrolysis, the solid that obtains being white in color is wanted product A R248689 (12.5mg, 88%) according to the same hydrolysis program in the step 5 of example 1-1.MS(APCI+)：m/z?621.3(MH ⁺)。

Example 2-17:

Compd A R00248687

According to the same program described in the example 2-16; and at first tertiary butyl carboxylic acid is carried on the PS-TFP resin; come synthetic (1S, 4R, 6S; 14S; 18R)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-14-(2,2-dimethyl-propionyl amino)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00248687).MS(APCI+)：m/z?609.3(MH ⁺)。

Example 2-18:

Compd A R00248688

According to the same program described in the example 2-16, and at first the sec.-propyl carboxylic acid is carried on the PS-TFP resin, comes synthetic (1S, 4R; 6S, 14S, 18R)-18-(3; 4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-and 14-isobutyryl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00248688).MS(APCI+)：m/z?595.3(MH ⁺)。

Example 2-19:

Compd A R298989

(1S, 4R, 6S, 14S, 18R)-and 14-(2-tert-butoxycarbonyl amino-3-methyl-butyryl radicals amino)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R298989) synthetic

With 14-amino-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid, ethyl ester (120mg, 217 μ mol) and N-α-t-Boc-L-Xie Ansuan N-hydroxyl succinic diamide ester (96mg, 300 μ mol) stirred 14 hours in the 1.1mL methylene dichloride together.Remove under the vacuum and desolvate, and add water and each 1mL of ethyl acetate.Separating obtained phase, water layer 500uL ethyl acetate washed twice.Organic phase after the merging is through MgSO ₄Drying, and under vacuum, remove and desolvate, the solid that obtains being white in color is wanted compound (132mg, 81%).MS?m/z?752.2(MH ⁺)。

Example 2-20:

Compd A R00301338

According to the same program described in the example 2-19; only be to use 3-methyl-2-[(pyrazine-2-carbonyl)-amino]-butyric acid 2; 5-dioxo-tetramethyleneimine-1-base ester replaces N-α-t-Boc-L-Xie Ansuan N-hydroxyl succinic diamide ester, comes synthetic (1S, 4R; 6S; 14S, 18R)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-14-{3-methyl-2-[(pyrazine-2-carbonyl)-amino]-butyryl radicals amino)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00301338).MS?m/e?730.3(M ⁺+1)。

Example 2-21:

Compd A R00304072

According to the same program described in the example 2-19; only be to use 2-[(6-dimethylamino-pyridine-3-carbonyl)-amino]-3-methyl-butyric acid 2; 5-dioxo-tetramethyleneimine-1-base ester replaces N-α-t-Boc-L-Xie Ansuan N-hydroxyl succinic diamide ester; come synthetic (1S; 4R; 6S; 14S; 18R)-18-(3; 4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-14-{2-[(6-dimethylamino-pyridine-3-carbonyl)-amino]-3-methyl-butyryl radicals amino }-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304072). ¹H?NMR(CD ₃OD，500MHz)：δ8.69(s，1H)，8.46(s，1H)，8.37-8.39(m，1H)，8.14-8.21(m，2H)，7.07-7.18(m，5H)，5.63(q，1H)，5.36-5.42(m，2H)，4.49-4.56(m，3H)，4.42-4.45(m，1H)，4.31-4.32(m，1H)，3.92-3.95(m，1H)，3.65-3.72(m，2H)；2.85-2.91{m，2H}，2.33-2.55(m，4H)，1.93-2.03(m，3H)，1.61-1.68(m，3H)，1.27-1.52(m，12H)，0.86-0.96(m，8H)。MS?m/e?770.4(M-1)。

Example 2-22:

Compd A R00304073

According to the same program described in the example 2-19; only be to use 3-methyl-2-[(pyridine-3-carbonyl)-amino]-butyric acid 2; 5-dioxo-tetramethyleneimine-1-base ester replaces N-α-t-Boc-L-Xie Ansuan N-hydroxyl succinic diamide ester, comes synthetic (1S, 4R; 6S; 14S, 18R)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-14-{3-methyl-3-[(pyridine-3-carbonyl)-amino]-butyryl radicals amino }-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304073).MS?m/e?729.2(M ⁺+1)。

Example 2-23:

Compd A R00298990

According to the same program of the step 1 of example 2-1, and preparation (1S, 4R, 6S, 14S, 18R)-and 14-(2-amino-3-methyl-butyryl radicals amino)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compound 298990).MS?m/e?624.2(M ⁺+1)。

Example 2-24:

Compd A R00294378

(1S, 4R, 6S, 14S, 18R)-and 14-(3-cyclopentyl-urea groups)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R294378) synthetic

With 14-amino-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid, ethyl ester hydrochloride (49mg, 74 μ mol), diisopropylethylamine (29mg, 222 μ mol) and cyclic isocyanate pentyl ester (25mg, 222 μ mol) handle in the 375uL methylene dichloride, and stirred 1 hour down at 19 ℃.Directly reaction is loaded on the quick tubing string of C18, and with the water/acetonitrile that contains 0.1%TFA (10% to 100%) wash-out, the solid title product that obtains being white in color (42mg, 77%).MS?m/z?732.2(MH ⁺)。

Example 2-25:

Compd A R00294377

According to the program described in example 1-2 and the 2-24, just in example 2-24 program, use tert-butyl isocyanate to replace the cyclic isocyanate pentyl ester, come synthetic (1S, 4R, 6S, 14S, 18R)-14-(the 3-tertiary butyl-urea groups)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00294377).MS?m/e?624.1(M ⁺+1)。

Example 2-26:

Compd A R00304077

According to the program described in example 1-2 and the 2-24, just in the step 4 of example 1-2, use 5-fluoro-1,2,3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-(3-cyclopentyl-urea groups)-18-(5-fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304077).MS?m/e?654.2(M ⁺+1)。

Example 2-27:

Compd A R00304078

According to program described in example 1-2 and the 2-24, just use the 8-Trifluoromethyl-1,2 in the step 4 in example 1-2,3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-(3-cyclopentyl-urea groups)-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304078).MS?m/e?704.1(M ⁺+1)。

Example 2-28:

Compd A R00304079

According to program described in example 1-2 and the 2-24, just use 2 in the step 4 in example 1-2,3-dihydro-1H-isoindole replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9, come synthetic (1S, 4R, 6S, 14S, 18R)-14-(3-cyclopentyl-urea groups)-18-(1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304079).MS?m/e?622.2(M ⁺+1)。

Example 2-29:

Compd A R00320078

According to program described in example 1-2 and the 2-24, just use 2 in the step 4 in example 1-2,3-dihydro-1H-isoindole replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9 and use tert-butyl isocyanate replacement cyclic isocyanate pentyl ester in example 2-24 program, come synthetic (1S, 4R, 6S, 14S, 18R)-14-(the 3-tertiary butyl-urea groups)-18-(1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320078).MS?m/e?610.1(M ⁺+1)。

Example 2-30:

Compd A R00320221

According to the program described in example 1-2 and the 2-24, just in example 2-24 program, use 3-isocyano-tetrahydrofuran (THF) to replace the cyclic isocyanate pentyl ester, come synthetic (1S, 4R, 6S, 14S, 18R)-18-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-14-[3-(tetrahydrofuran (THF)-3-yl)-urea groups]-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320221).MS?m/e?638.2(M ⁺+1)。

Example 2-31:

Compd A R00320449

According to program described in example 1-2 and the 2-24, just use 5-chloro-2 in the step 4 in example 1-2,3-dihydro-1H-isoindole replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9 and use tert-butyl isocyanate replacement cyclic isocyanate pentyl ester in example 2-24 program, come synthetic (1S, 4R, 6S, 14S, 18R)-14-(the 3-tertiary butyl-urea groups)-18-(5-chloro-1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320449). ¹H?NMR(500MHz，CD ₃OD)：δ7.34(s，1H)，7.28-7.25(m，2H)，7.24(s，1H)，7.20(s，1H)，5.51(m，2H)，5.40(s，1H)，4.73-4.60(m，3H)，4.53(t，1H)，4.38(d，1H)，4.28(d，1H)，3.98(dd，1H)，2.43(m，2H)，2.38-2.30(m，1H)，2.12-2.00(m，2H)，1.81-1.70(m，1H)，1.64-1.56(m，3H)，1.48-1.20(m，8H)，1.18(s，9H)。MS：m/e?644.0(M ⁺)，645.9(M ⁺+2)。

Example 2-32:

Compd A R00320450

According to program described in example 1-2 and the 2-24, just use 5,6-two chloro-2 in the step 4 in example 1-2,3-dihydro-1H-isoindole replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9 and use tert-butyl isocyanate to replace the cyclic isocyanate pentyl ester in example 2-24 program comes synthetic (1S, 4R, 6S, 14S, 18R)-14-(the 3-tertiary butyl-urea groups)-18-(5,6-two chloro-1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00320450). ¹H?NMR(500MHz，CD ₃OD)：δ7.50(s，1H)，7.38(s，1H)，5.56(q，1H)，5.42-5.38(m，2H)，4.72-4.61(m，4H)，4.55(t，1H)，4.34(dd，1H)，4.28(d，1H)，3.92(dd，1H)，2.45-2.32(m，2H)，2.32-2.18(m，1H)，2.08-2.00(m，1H)，1.75-1.68(m，1H)，1.63-1.54(m，3H)，1.50-1.22(m，8H)，1.18(s，9H)。MS：m/e?678.0(M ⁺)，680.0(M ⁺+2)。

Example 2-33:

Compd A R00365381

According to the program described in example 1-2 and the 2-1, just in the step 4 of example 1-2, use 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydrochysene-chlorination isoquinoline 99.9 replaces 1,2,3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R, 6S, 14S, 18R)-14-cyclopentyloxy carbonylamino-18-(5-fluoro-1-methoxymethyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00365381).MS(APCI-)：m/z?697.4(M-1)。

Preparation with compound of universal architecture IV

The compound (people such as 1.Khan, the Bioorg.﹠amp that have universal architecture IV according to flow preparation shown in above; Med.Chem.Lett., 1997,7 (23), 3017-3022; 2. international application case PCT/US02/39926, WO 03/053349).

Example 3-1:

Compd A R00261408

(1S, 4R, 6S, 14S, 18R)-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (AR00261408) synthetic

With big naphthenic acid compound #101 (7mg 0.011mmol) is dissolved among the 0.1mL DMF, then add CDI (1.8mg, 0.011mmol).Heated mixt is 1 hour in 40 ℃ of oil baths.Then in reaction, add the cyclopropyl sulphonamide (2.0mg, 0.017mmol), add subsequently DBU (1.7mg, 0.011mmol).Spend the night at 40 ℃ of following stirring reactions 4.Behind the 14h, the LCMS demonstration reacts completely.To react cool to room temperature, between 2mL EA and 2mL 5%HCL (aqueous solution), divide molten.Organic layer water, sodium bicarbonate washing (each 2mL), then dry (Na ₂SO ₄).Crude product is passed through (eluent=DCM: MeOH 20: 1) fast on Biotage 12M, obtain AR00261408 (4.2 mg, 52%). ¹H?NMR(CDCl ₃，500MHz)：δ0.80-2.10(m，25H)，2.20-2.27(m，1H)，2.37-2.59(m，3H)，2.84(m，1H)，3.60-3.70(m，1H)，3.82-3.90(m，1H)，4.20-4.30(m，2H)，4.45-4.70(m，5H)，4.95-5.05(m，2H)，5.74(m，1H)，6.74(m，1H)，7.0-7.23(m，4H).MS?m/e728.0(M ⁺+H)。

Example 3-2:

Compd A R00261407

According to the described program of example 3-1; just in the coupling step, use the sec.-propyl sulphonamide to replace the cyclopropyl sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-2,15-dioxo-4-(propane-2-sulfonyl amino carbonyl)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00261407).MS?m/e?728.4(M-1)。

Example 3-3:

Compd A R00254906

According to the described program of example 3-1; just in the coupling step, use sulfonyloxy methyl amine to replace the cyclopropyl sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-methane sulfonyl aminocarboxyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00254906). ¹H?NMR(CDCl ₃，500MHz)：δ1.20-1.52(m，16H)，1.54-1.98(m，5H)，2.20-2.30(m，1H)，2.38-2.46(m，1H)，2.47-2.59(m，3H)，2.84(m，1H)，3.18(s，3H)，3.56-3.70(m，1H)，3.82-3.90(m，1H)，4.22-4.33(m，2H)，4.47-4.69(m，4H)，4.90-5.10(m，2H)，5.47(brs，1H)，5.74(m，1H)，6.74(m，1H)，7.03-7.23(m，4H)。MS m/e 701.9 (M ⁺), 602.2 (parent, MH ⁺-Boc group).

Example 3-4:

Compd A R00261409

According to the described program of example 3-1; just in the coupling step, use the normal-butyl sulphonamide to replace the cyclopropyl sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-(butane-1-sulfonyl amino carbonyl)-14-tert-butoxycarbonyl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00261409). ¹H?NMR(CDCl ₃，500MHz)：δ0.80-1.03(m，7H)，1.20-2.10(m，22H)，2.20-2.60(m，4H)，2.84(m，1H)，3.20(m，1H)，3.44(m，1H)，3.65(m，1H)，3.80-3.95(m，1H)，4.20-4.34(m，2H)，4.50-4.65(m，4H)，4.95-5.05(m，1H)，5.30-5.39(m，1H)，5.44-5.49(m，1H)，5.74(m，1H)，6.74(m，1H)，7.0-7.23(m，4H)。MS?m/e?743.3(M ⁺，APCI-)。

Example 3-5:

Compd A R00282131

According to the program described in example 2-1 and the 3-1, come synthetic (1S, 4R; 6S, 14S, 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-cyclopentyloxy carbonylamino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00282131).MS?m/e?738.4(M-1)。

Example 3-6:

Compd A R00294381

According to the program described in example 1-5 and the 3-1, synthesize (1S, 4R, 6S, 14S, 18R)-3,4-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00294381). ¹H?NMR(CDCl ₃，500MHz)：δ0.89-2.08(m，25H)，2.21-2.28(m，1H)，2.41-2.49(m，1H)，2.51-2.61(m，2H)，2.91(m，1H)，3.83(m，1H)，4.21(m，1H)，4.40(d，/＝11.7Hz，1H)，4.53-4.80(m，5H)，4.95-5.04(m，2H)，5.47(brs，1H)，5.72(m，1H)，6.77(m，1H)，7.16(m，1H)，7.23-7.31(m，3H)。MS?m/e?712.3(APCI-，M-H)。

Example 3-7:

Compd A R00298996

According to example 1-2 and the described program of 3-1, just in the step 4 of example 1-2, use 5-fluoro-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-5-fluoro-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00298996). ¹H?NMR(400MHz，CDCl ₃)：δ10.05(s，1H)，8.12(s，1H)，7.04(s，1H)，6.84-6.73(m，2H)，6.70(s，1H)，5.65(q，1H)，5.40(s，1H)，4.59(m，2H)，4.54-4.40(m，2H)，3.82-3.74(m，1H)，3.72-3.51(m，2H)，2.92-2.68(m，3H)，2.55-2.30(m，3H)，2.21-2.15(m，1H)，2.00-1.60(m，3H)，1.40-0.75(m，18H)。MS：m/e?746.0(M ⁺)。

Example 3-8:

Compd A R00298997

According to example 1-2 and the described program of 3-1, just in the step 4 of example 1-2, use 8-Trifluoromethyl-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-8-trifluoromethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00298997). ¹H?NMR(500MHz，CD3OD)：δ7.55(dd，1H)，7.42(dd，1H)，7.35(t，1H)，5.71-5.61(m，1H)，5.40(m，1H)，4.60(s，1H)，4.52(m，1H)，4.42(m，1H)，4.15(m，1H)，3.91(m，1H)，3.78-3.62(m，2H)，3.00-2.82(m，3H)，2.58-2.52(m，3H)，2.51-2.32(m，2H)，1.86-1.56(m，3H)，1.41(m，2H)，1.32-1.21(m，5H)，1.04-0.98(m，14H)。MS：m/e?795.9(M ⁺)。

Example 3-9:

Compd A R00301746

According to example 1-2 and the described program of 3-1, just in the step 4 of example 1-2, use 7-chloro-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-7-chloro-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00301746). ¹H?NMR(400MHz，CDCl ₃)：δ10.10(s，1H)，7.08(d，1H)，7.02-6.96(m，2H)，6.60(d，1H)，5.64(q，1H)，5.40(s，1H)，4.92-4.41(m，2H)，4.55-4.40(m，3H)，4.28-4.12(m，2H)，3.82-3.75(m，1H)，3.65-3.46(m，3H)，2.88-2.80(m，1H)，2.78-2.56(m，2H)，2.52-2.42(m，1H)，2.38-2.30(m，1H)，2.21-2.12(q，1H)，1.82-1.74(m，2H)，1.45-1.12(m，16H)，1.10-0.98(m，2H)，0.90-0.75(m，2H)。MS?m/e761.9(M ⁺)。

Example 3-10:

Compd A R00301747

According to example 1-2 and the described program of 3-1, just in the step 4 of example 1-2, use 6-Trifluoromethyl-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-6-trifluoromethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00301747). ¹H?NMR(500MHz，CD3OD)：δ7.44(m ₅?2H)，7.38-7.30(m，1H)，7.28-7.24(m，1H)，5.65(q，1H)，5.40(m，1H)，5.08(m，1H)，4.56(br?s，2H)，4.60-4.50(m，1H)，4.48(m，1H)，4.15(d，1H)，3.88(d，1H)，3.75-3.67(m，2H)，2.93-2.82(m，3H)，2.66-2.54(m，1H)，2.52-2.44(m，1H)，2.42-2.40(m，2H)，1.91-1.76(m，2H)，1.74-1.70(dd，1H)，1.64-1.58(m，1H)，1.54-1.36(m，4H)，1.34-1.25(m，12H)，1.50-1.20(m，2H)，1.00-0.70(m，1H)，0.52-0.34(m，1H)。MS：m/e?795.9(M ⁺)。

Example 3-11:

Compd A R00301751

According to example 1-2 and the described program of 3-1, just in the step 4 of example 1-2, use 6-fluoro-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-6-fluoro-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00301751). ¹H?NMR(500MHz，CD ₃OD)：δ7.21-7.02(m，1H)，6.92(m，2H)，6.92(m，2H)，5.68(q，1H)，5.40(m，1H)，5.08(t，1H)，4.58(m，2H)，4.45(m，1H)，4.12(d，1H)，3.88(d，1H)，3.78-3.60(m，3H)，2.86-2.72(m，3H)，2.71-2.61(m，1H)，2.52-2.42(m，1H)，2.41-2.34(m，1H)，1.88-1.76(m，2H)，1.74-1.70(m，1H)，1.64-1.58(m，1H)，1.56-1.38(m，2H)，1.37-1.24(m，14H)，1.13-1.04(m，2H)，1.02-0.89(m，1H)，0.88-0.82(m，1H)。MS：m/e?746.0(M ⁺)。MS?m/e?757.2(M ⁺+1)。

Example 3-12:

Compd A R00304080

According to the program described in example 1-2,2-24 and the 3-1, just in the step 4 of example 1-2, use 5-fluoro-1,2; 3,4 ,-tetrahydrochysene-isoquinoline 99.9 replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9 replaces; come synthetic (1S, 4R, 6S; 14S, 18R)-5-fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-(3-cyclopentyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00304080).

Example 3-13:

Compd A R00304081

According to the program described in example 1-2,2-24 and the 3-1, just in the step 4 of example 1-2, use 8-Trifluoromethyl-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-8-trifluoromethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-(3-cyclopentyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00304081).MS?m/e807.2(M ⁺+1)。

Example 3-14:

Compd A R00304082

According to the program described in example 1-2,2-24 and the 3-1, just in the step 4 of example 1-2, use 2,3-dihydro-1H-isoindole replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-(3-cyclopentyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00304082).MS?m/e?725.2(M ⁺+1)。

Example 3-15:

Compd A R00304161

According to the program described in example 1-2,2-1 and the 3-1; just in the step 2 of example 2-1, use the 2-fluoroethanol to replace cyclopentanol to form chloro-formic ester reagent; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-14-(2-fluoro-ethoxy carbonyl amino)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00304161).MS?m/e?718.1(M ⁺+1)。

Example 3-16:

Compd A R00304162

According to the program described in example 1-2,2-1 and the 3-1; just in the step-2 of example 2-1, use tetrahydrofuran (THF)-3S-alcohol to replace cyclopentanol to form chloro-formic ester reagent; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-14-(tetrahydrofuran (THF)-3-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00304162).MS?m/e?742.1(M ⁺+1)。

Example 3-17:

Compd A R00304163

According to the program described in example 1-2,2-1 and the 3-1; just in the step-2 of example 2-1, use tetrahydrofuran (THF)-3R-alcohol to replace cyclopentanol to form chloro-formic ester reagent; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-14-(tetrahydrofuran (THF)-3R-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00304163). ¹H NMR (d ⁶-benzene, 500MHz): δ 10.53 (s, 1H), 6.78-6.96 (m, 4H), and 5.83-5.90 (m, 1H), 5.66 (q, 1H), and 5.18-5.21 (m, 1H), 5.13 (brs, 1H), 5.04 (brs, 1H), 4.41-4.87 (m, 3H), and 3.85-4.05 (m, 4H), 3.67-3.74 (m, 1H), and 3.46-3.53 (m, 3H), 3.23-3.34 (m, 1H), and 2.80-2.85 (m, 1H), 2.34-2.59 (m, 4H), and 1.84-1.99 (m, 4H), 0.98-1.60 (m, 14H), 0.42-0.47 (m, 1H), and 0.27-0.32 (m, 1H).MSm/e?741.2(M-1)。

Example 3-18:

Compd A R00311814

According to the program described in example 1-2 and the 3-1, just in the step 4 of example 1-2, use phenyl-(4,5; 6,7-tetrahydrochysene-thiazole is [5,4-c] pyridine-2-yl also)-amine replacement 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S, 4R, 6S; 14S, 18R)-2-phenyl amino-6,7-dihydro-4H-thiazole also [5; 4-c] pyridine-5-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00311814).MS?m/e?826.2(M ⁺+1)。

Example 3-19:

Compd A R00311815

According to the program described in example 1-2 and the 3-1, just in the step 4 of example 1-2, use 1-piperidines-1-ylmethyl-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-1-piperidines-1-ylmethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00311815). ¹HNMR(500MHz，CD ₃OD)δ8.94(d，1H)，7.59(s，1H)，7.31-7.23(m，3H)，7.22-7.15(m，2H)，5.74-5.64(m，2H)，5.47(br?s，1H)，5.06(t，1H)，4.54(dt，1H)，4.40-4.17(m，4H)，4.11-4.04(m，1H)，3.96-3.88(m，1H)，3.75-3.40(m，5H)，3.14-2.32(m，7H)，2.05(dd，1H)，1.99-1.68(m，5H)，1.65-0.95(m，24H)；MS(POS?ESI)m/z?825.4(M ⁺)。

Example 3-20:

Compd A R00312024

According to the program described in example 1-2 and the 3-1, just in the step 4 of example 1-2, use 4,4-spiral shell-cyclobutyl-1; 2,3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S, 4R, 6S; 14S, 18R)-4,4-spiral shell-cyclobutyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00312024). ¹H?NMR(400MHz，CD ₃OD)δ7.54-7.60(m，1H)，7.26(dd，1H)，6.97-7.21(m，1H)，5.66(dd，1H)，5.37-5.48(m，1H)，5.11(dd，1H)，4.58(s，2H)，4.39(t，3H)，4.11-4.26(m，1H)，3.77-3.96(m，1H)，3.87(t，3H)，3.60-3.70(m，1H)，2.83-2.93(m，1H)，2.23-2.68(m，6H)，1.70-2.23(m，7H)，1.18-1.69(m，18H)，0.81-1.12(m，3H)。MS?m/e?767.9(M ⁺+1)。

Example 3-21:

Compd A R00312025

According to the program described in example 1-2 and the 3-1, just in the step 4 of example 1-2, use 4,4-dimethyl-1; 2,3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S, 4R, 6S; 14S, 18R)-4,4-dimethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00312025). ¹H?NMR(400MHz，CD ₃OD)δ7.31-7.40(m，1H)，6.97-7.23(m，3H)，5.67(dd，1H)，5.34-5.49(m，1H)，5.09(dd，1H)，4.64(s，1H)，4.50-4.61(m，1H)，4.33-4.44(m，3H)，4.11-4.24(m，1.0)，3.82-3.95(m，3H)，3.36-3.55(m，2H)，2.84-2.94(m，1H)，2.25-2.69(m，4H)，1.68-2.24(m，4H)，1.15-1.68(m，23H)，0.81-1.15(m，3H)。MS?m/z?756.0(M ⁺+1)。

Example 3-22:

Compd A R00312026

According to the program described in example 1-2 and the 3-1, just in the step 4 of example 1-2, use 4-methyl isophthalic acid, 2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-4-methyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00312026). ¹H?NMR(400MHz，CD ₃OD)δ7.76(s，1H)，6.98-7.24(m，3H)，5.67(dd，1H)，5.2-5.51(m，1H)，5.04-5.15(dd，1H)，4.28-4.63(m，5H)，4.10-4.24(m，1H)，3.81-3.96(m，3H)，3.37-3.78(m，2H)，2.83-3.06(m，2H)，2.54-2.71(m，1H)，2.25-2.54(m，3H)，1.69-1.94(m，3H)，1.16-1.69(m，20H)，0.81-1.15(3H)。MS?m/z?742.0(M ⁺+1)。

Example 3-23:

Compd A R00314635

According to the program described in example 1-2,2-1 and the 3-1; just in the step 4 of example 1-2, use 4; 4-spiral shell-cyclobutyl-1; 2,3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1; 2; 3,4-tetrahydrochysene-isoquinoline 99.9 and use tetrahydrofuran (THF)-3R-alcohol to replace cyclopentanol to form chloro-formic ester reagent in the step 2 of example 2-1 comes synthetic (1S; 4R; 6S, 14S, 18R)-4; 4-spiral shell-cyclobutyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-14-(tetrahydrofuran (THF)-3-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00314635). ¹HNMR(500MHz，CD ₂Cl ₂)δ10.24-10.29(s，1H)，7.49-7.55(m，1H)，7.24(dd，1H)，7.14(dd，1H)，7.04(dd，1H)，6.81(d?1H)，5.71(dd，1H)，4.95(dd，1H)，4.90(bs，1H)，4.48-4.59(m，3H)，4.17-4.30(m，2H)，3.51-3.74(m，3H)，3.51-3.72(6H)，2.80-2.86(m，1H)，2.36-2.54(m，3H)，2.10-2.33(m，4H)，1.80-2.10(m，6H)，1.24-1.80(m，7H)，0.65-1.24(m，10H)。MS?m/z741.2(M ⁺+1)。

Example 3-24:

Compd A R00314654

According to the program described in example 1-2,2-1 and the 3-1; just in the step 4 of example 1-2, use 4; 4-dimethyl-1; 2,3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1; 2; 3,4-tetrahydrochysene-isoquinoline 99.9 and use tetrahydrofuran (THF)-3S-alcohol to replace cyclopentanol to form chloro-formic ester reagent in the step 2 of example 2-1 comes synthetic (1S; 4R; 6S, 14S, 18R)-4; 4-dimethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-14-(tetrahydrofuran (THF)-3S-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00314654). ¹H?NMR(500MHz，CD ₂Cl ₂)δ8.51-8.64(bs，1H)，7.26-7.36(m，1H)，7.09-7.19(m，2H)，6.98-7.08(m，1H)，5.70(dd，1H)，4.95(dd，1H)，4.83(d，1H)，4.44-4.72(m，3H)，4.17-4.30(m，2H)，3.25-3.91(m，9H)，2.80-2.86(m，1H)，2.35-2.55(m，4H)，2.13-2.34(m，4H)，1.91-2.07(m，2H)，1.80-1.90(m，2H)，1.66-1.80(m，2H)，1.51-1.63(m，2H)，1.30-1.51(m，2H)，0.96-1.15(m，3H)，0.65-0.95(m，9H)。MS?m/z?770.1(M ⁺+1)。

Example 3-25:

Compd A R00314656

According to the program described in example 1-2,2-24 and the 3-1, just in the step 4 of example 1-2, use 4-methyl isophthalic acid, 2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 and use tert-butyl isocyanate to replace the cyclic isocyanate pentyl ester in example 2-24 comes synthetic (1S; 4R, 6S, 14S; 18R)-4-methyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-(the 3-tertiary butyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00314656). ¹H?NMR(500MHz，CD ₂Cl ₂)δ7.60-7.72(m，1H)，7.06-7.48(m，4H)，5.73(dd，1H)，5.39-5.48(m?1H)，5.18-5.27(bs?1H)，4.98(dd，1H)，4.79-4.90(bs，1H)，4.30-4.72(m，4H)，3.40-3.77(m，5H)，2.97(d，1H)，2.83-2.90(m，1H)，2.37-2.58(m，3H)，2.17-2.30(dt，1H)，2.22-2.35(dt，1H)，1.97-2.07(m，1H)，1.82-1.95(m，2H)，1.68-1.79(m，1H)，1.55-1.66(m，2H)，1.05-1.55(m，15H)，0.83-0.98(m，3H)。MS?m/z741.2(M ⁺+1)。

Example 3-26:

Compd A R00314719

According to the program described in example 1-22 and the 3-1, come synthetic (1S, 4R; 6S, 14S, 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] nonadecane-18-base ester (compd A R00314719).MS?m/e?630.2(M ⁺+1-100)。

Example 3-27:

Compd A R00320001

According to the program described in example 1-2,2-24 and the 3-1; just in example 2-24, use tert-butyl isocyanate to replace the cyclic isocyanate pentyl ester; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-(the 3-tertiary butyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320001).MS?m/e?725.7(M-1)。

Example 3-28:

Compd A R00320073

According to the program described in example 1-2,2-1 and the 3-1, just in the step 4 of example 1-2, use 2,3-dihydro-1H-isoindole replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9 and in the step 2 of example 2-1, use the 2-fluoroethanol to replace cyclopentanol to form chloro-formic ester reagent; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-14-(2-fluoro-ethoxy carbonyl amino)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320073).MS?m/e?704.0(M ⁺+1)。

Example 3-29:

Compd A R00320079

According to the program described in example 1-2,2-1 and the 3-1; just in the step 4 of example 1-2, use 2; 3-dihydro-1H-isoindole replaces 1; 2; 3; 4-tetrahydrochysene-isoquinoline 99.9 and in the step 2 of example 2-1, use tetrahydrofuran (THF)-3R-alcohol to replace cyclopentanol to form chloro-formic ester reagent; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-14-(tetrahydrofuran (THF)-3-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6]-nine-7-alkene-18-base ester (compd A R00320079).MS?m/e?728.1(M ⁺+1)。

Example 3-30:

Compd A R00320080

According to the program described in example 1-2,2-1 and the 3-1; just in the step 4 of example 1-2, use 2; 3-dihydro-1H-isoindole replaces 1; 2; 3; 4-tetrahydrochysene-isoquinoline 99.9 and in the step 2 of example 2-1, use tetrahydrofuran (THF)-3S-alcohol to replace cyclopentanol to form chloro-formic ester reagent; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-14-(tetrahydrofuran (THF)-3S-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320080).MS?m/e?728.1(M ⁺+1)。

Example 3-31:

Compd A R00320081

According to the program described in example 1-2,2-1 and the 3-1; just in the step 4 of example 1-2, use 2; 3-dihydro-1H-isoindole replaces 1; 2; 3; 4-tetrahydrochysene-isoquinoline 99.9 and in the step 2 of example 2-1, use tetrahydropyrans-4-alcohol to replace cyclopentanol to form chloro-formic ester reagent; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-14-(tetrahydropyran-4-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320081).MS?m/e?742.1(M ⁺+1)。

Example 3-32:

Compd A R00320082

According to the program described in example 1-2,2-1 and the 3-1; just in the step 2 of example 2-1, use tetrahydropyrans-4-alcohol to replace cyclopentanol to form chloro-formic ester reagent; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-14-(tetrahydropyran-4-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320082).MS?m/e?756.1(M ⁺+1)。

Example 3-33:

Compd A R00320119

According to the program described in example 1-2 and the 3-1, just in the step 4 of example 1-2, use 5-chloro-2,3-dihydro-1H-isoindole replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S; 4R, 6S, 14S; 18R)-5-chloro-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320119). ¹H?NMR(500MHz，CD ₃OD)：δ7.36(s，1H)，7.30(s，1H)，7.28(s，1H)，7.22(s，1H)，7.12-7.20(m，1H)，6.64(br?s，1H)，5.72-5.64(m，1H)，5.41(s，1H)，5.14-5.04(m，1H)，4.80-4.62(m，2H)，4.61-4.56(t，1H)，4.54-4.48(m，1H)，4.10(d，1H)，3.85(d，1H)，2.90(m，1H)，2.65(br?s，1H)，2.54-2.48(m，1H)，2.46-2.32(m，2H)，1.91-1.72(m，2H)，1.64-1.56(m，2H)，1.56-1.21(m，8H)，1.18(s，9H)，1.12-1.05(m，1H)1.00(m，1H)，0.94-0.82(m，2H)。MS?m/e?747.9(M ⁺)。

Example 3-34:

Compd A R00320120

According to example 1-2 and the described program of 3-1, just in the step 4 of example 1-2, use dimethyl-(1,2; 3,4-tetrahydrochysene-isoquinoline 99.9-5-yl)-amine (example 1-25a) replacement 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-5-dimethylamino-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320120). ¹H?NMR(400MHz，CDCl ₃)：δ10.08(s，1H)，7.13-7.05(m，1H)，6.88-6.81(d，1H)，6.77(d，1H)，6.68(d，1H)，6.61-6.53(s，1H)，5.71-5.60(q，1H)，5.40(s，1H)，5.00-4.88(m，2H)，4.55-4.38(m，3H)，4.24-4.16(m，2H)，3.88-3.77(d，1H)，3.64-3.41(m，3H)，2.91-2.69(m，3H)，2.61(s，6H)，2.53-2.41(m，2H)，2.40-2.39(m，1H)，2.22-2.11(m，1H)，1.89-1.72(m，1H)，1.61-1.22(m，10H)，1.18(s，9H)，1.09-0.97(m，2H)，0.91-0.76(m，2H)。MS：771.1(M ⁺)，772.1(M ⁺+1)，773.1(M ⁺+2)。

Example 3-35:

Compd A R00320121

According to example 1-2 and the described program of 3-1, just in the step 4 of example 1-2, use 5,6-two chloro-2; 3-dihydro-1H-isoindole replaces 1,2,3; 4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R; 6S, 14S, 18R)-5; 6-two chloro-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320121). ¹H?NMR(500MHz，CD ₃OD)：δ7.52(s，1H)，7.38(s，1H)，6.61(br?s，1H)，5.72-5.65(q，1H)，5.40(s，1H)，5.08(t，1H)，4.78-4.62(m，3H)，4.63-4.57(t，1H)，4.50(d，1H)，4.20(d，1H)，3.65(d，1H)，2.90(m，1H)，2.55(m，1H)，2.52-2.45(m，1H)，2.46-2.31(m，2H)，1.91-1.75(m，3H)，1.67-1.60(m，1H)，1.58-1.25(m，8H)，1.18(s，9H)，1.12-1.05(m，2H)，1.04-0.81(m，2H)。MS：m/e?781.9(M ⁺)。

Example 3-36:

Compd A R00320220

According to the program described in example 1-2,2-24 and the 3-1, just in the step 4 of example 1-2, use 2,3-dihydro-1H-isoindole replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9 and use tert-butyl isocyanate replacement cyclic isocyanate pentyl ester in example 2-24; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-(the 3-tertiary butyl-urea groups-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320220).MS?m/e?713.1(M ⁺+1)。

Example 3-37:

Compd A R00320222

According to the program described in example 1-2,2-24 and the 3-1; just in example 2-24, use 3-isocyano-tetrahydrofuran (THF) to replace the cyclic isocyanate pentyl ester; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-14-[3-(tetrahydrofuran (THF)-3-yl)-urea groups]-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320222).MS?m/e?740.8(M ⁺+1)。

Example 3-38:

Compd A R00320403

According to the program described in example 1-2,2-24 and the 3-1, come synthetic (1S, 4R; 6S, 14S, 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-(3-cyclopentyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320403).MS?m/e?739.2(M ⁺+1)。

Example 3-39:

Compd A R00320446

According to the program described in example 1-2,2-24 and the 3-1, just in the step 4 of example 1-2, use 5-chloro-2,3-dihydro-1H-isoindole replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9 and use tert-butyl isocyanate replacement cyclic isocyanate pentyl ester in example 2-24; come synthetic (1S; 4R, 6S, 14S;-5R)-5-chloro-1; 3-dihydro-isoindole-2-carboxylic acid 14-(the 3-tertiary butyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320446). ¹H?NMR(500MHz，CD ₃OD)：δ7.35(s，1H)，7.28(s，1H)，7.26(s，1H)，7.02(s，1H)，7.18(s，1H)，5.65-5.72(q，1H)，5.45(s，1H)，5.06(t，1H)，4.74-4.60(m，4H)，4.56(t，1H)，4.46(m，1H)，4.22(d，1H)，3.87-3.91(dd，1H)，2.86-2.94(m，1H)，2.65-2.54(m，1H)，2.52-2.45(m，1H)，2.42-2.34(m，2H)，1.92-1.83(m，1H)，1.78-1.70(m，2H)，1.62-1.56(m，1H)，1.54-3.92(m，4H)，1.39-1.23(m，7H)，1.12(s，9H)，1.02-0.98(m，1H)，0.94-0.86(m，1H)。MS：m/e?747.1(M ⁺)，749.1(M ⁺+2)。

Example 3-40:

Compd A R00320447

According to the program described in example 1-2,2-24 and the 3-1, just in the step 4 of example 1-2, use 5,6-two chloro-2; 3-dihydro-1H-isoindole replaces 1,2,3; 4-tetrahydrochysene-isoquinoline 99.9 and use tert-butyl isocyanate to replace the cyclic isocyanate pentyl ester in example 2-24 comes synthetic (1S, 4R; 6S, 14S, 18R)-5; 6-two chloro-1; 3-dihydro-isoindole-2-carboxylic acid 14-(the 3-tertiary butyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320447).MS：m/e?781.1(M ⁺)。783.1(M ⁺+2)。

Example 3-41:

Compd A R00320506

According to the program described in example 1-2,2-1 and the 3-1, just in the step 4 of example 1-2, use 1-piperidines-1-ylmethyl-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-1-piperidines-1-ylmethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-cyclopentyloxy carbonylamino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320506).MS(POS?ESI)m/z?837.4(M ⁺)。

Example 3-42:

Compd A R00320547

According to the program described in example 1-2 and the 3-1; just in the coupling step of example 3-1, use benzsulfamide to replace the cyclopropyl sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-benzenesulfonyl aminocarboxyl-14-tert-butoxycarbonyl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320547).MS?m/e?762.3(M-1)。

Example 3-43:

Compd A R00320548

According to the program described in example 1-2 and the 3-1; just in the coupling step of example 3-1, use 4-methoxyl group-benzsulfamide to replace the cyclopropyl sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-methoxyl group-benzenesulfonyl aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320548).MS?m/e?792.3(M-1)。

Example 3-44:

Compd A R00320549

According to the program described in example 1-2 and the 3-1; just in the coupling step of example 3-1, use 4-methyl-benzsulfamide to replace the cyclopropyl sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-2,15-dioxo-4-(toluene-4-sulfonyl amino carbonyl)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320549).MS?m/e?776.3(M ⁺+1)。

Example 3-45:

Compd A R00320556

According to the program described in example 1-2,2-1 and the 3-1, just in the step 4 of example 1-2, use 1-piperidines-1R-ylmethyl-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-1-piperidines-1R-ylmethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-cyclopentyloxy carbonylamino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320556). ¹H?NMR(500MHz，CD ₃OD)δ8.99(br?s，1H)，7.34-7.13(m，6H)，5.75-5.65(m，2H)，5.44(br?s，1H)，5.06(t，1H)，4.60(t，1H)，4.51(d，1H)，4.44-4.16(m，2H)，4.12-3.97(m，2H)，3.86(d，1H)，3.75-3.38(m，2H)，3.07(t，2H)，2.96-2.86(m，1H)，2.78(d，1H)，2.66(brs，1H)，2.56-2.26(m，3H)，2.06(d，1H)，1.99-1.66(m，10H)，1.65-1.21(m，18H)，1.15-0.95(m，3H)；MS(POS?ESI)m/z?837.4(M ⁺)。

Example 3-46:

Compd A R00320557

According to the program described in example 1-2,2-1 and the 3-1, just in the step 4 of example 1-2, use 1-piperidines-1s-ylmethyl-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 replaces 1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-1-piperidines-1S-ylmethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-cyclopentyloxy carbonylamino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0. ^4,6] 19-7-alkene-18-base ester (compd A R00320557). ¹H?NMR(500MHz，CD ₃OD)δ7.32-7.14(m，6H)，6.87(br?s，1H)，5.72-5.60(m，2H)，5.47-5.39(m，1H)，5.11(br?s，1H)，4.58(t，1H)4.53-3.86(m，8H)，3.67-3.40(m，2H)，3.08-2.85(m，1H)，2.78(d，1H)，2.65-2.24(m，4H)，2.10-1.22(m，27H)，1.19(dt，1H)，1.10-1.02(m，2H)，1.01-0.93(m，1H)，0.89(q，1H)；MS(POS?ESI)m/z837.4(M ⁺)。

Example 3-47:

Compd A R00320574

According to the program described in example 1-2,2-24 and the 3-1, just in the step 4 of example 1-2, use 5-chloro-2,3-dihydro-1H-isoindole replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S; 4R, 6S, 14S; 18R)-5-chloro-1; 3-dihydro-isoindole-2-carboxylic acid 14-(3-cyclopentyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320574).MS：m/e?759.1(M ⁺)，761.1(M ⁺+2)。

Example 3-48:

Compd A R00320575

According to the program described in example 1-2,2-24 and the 3-1, just in the step 4 of example 1-2, use 5,6-two chloro-2; 3-dihydro-1H-isoindole replaces 1,2,3; 4-tetrahydrochysene-isoquinoline 99.9 comes synthetic (1S, 4R; 6S, 14S, 18R)-5; 6-two chloro-1; 3-dihydro-isoindole-2-carboxylic acid 14-(3-cyclopentyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320575).MS：m/e?793.1(M ⁺)。

Example 3-49:

Compd A R00320578

According to the program described in example 1-2,2-1 and the 3-1, just in the step 2 of example 2-1, use 2,2; 2-three fluoro-ethanol replace cyclopentanol to form chloro-formic ester reagent, come synthetic (1S, 4R; 6S; 14S, 18R)-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-14-(2; 2,2-three fluoro-ethoxy carbonyl amino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320578).MS?m/e?754.0(M ⁺+1)。

Example 3-50:

Compd A R00320579

According to the program described in example 1-2,2-1 and the 3-1; just use 2 in the step 2 of example 2-1,2-two fluoro-ethanol replace cyclopentanol to form chloro-formic ester reagent, come synthetic (1S; 4R; 6S, 14S, 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-14-(2; 2-two fluoro-ethoxy carbonyl amino)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320579).MS?m/e?736.0(M ⁺+1)。

Example 3-51:

Compd A R00320580

According to the program described in example 1-2,2-1 and the 3-1; just in the step 2 of example 2-1, use 1; 3-two fluoro-propan-2-ols replace cyclopentanol to form chloro-formic ester reagent, come synthetic (1S, 4R; 6S; 14S, 18R)-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-14-(2-fluoro-1-methyl fluoride-ethoxy carbonyl amino)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320580).MS?m/e?750.1(M ⁺+1)。

Example 3-52:

Compd A R00320581

According to the program described in example 1-2,2-1 and the 3-1, just in the step 2 of example 2-1, use 1,1; 1-three fluoro-propan-2-ols replace cyclopentanol to form chloro-formic ester reagent, come synthetic (1S, 4R; 6S; 14S, 18R)-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-14-(2; 2,2-three fluoro-1-methyl-ethoxy carbonyl amino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320581).MS?m/e768.1(M ⁺+1)。

Example 3-53:

Compd A R00320582

According to the program described in example 1-2,2-1 and the 3-1, just in the step 2 of example 2-1, use 1,1; 1-three fluoro-2-methyl-propan-2-ol replaces cyclopentanol to form chloro-formic ester reagent, comes synthetic (1S, 4R; 6S, 14S, 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-14-(2,2,2-three fluoro-1; 1-dimethyl-ethoxy carbonyl amino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00320582).MS?m/e?782.1(M ⁺+1)。

Example 3-54:

Compd A R00324375

According to the program described in example 1-22,2-1 and the 3-1, come synthetic (1S, 4R; 6S, 14S, 18R)-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-cyclopentyloxy carbonylamino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] nonadecane-18-base ester (compd A R00324375).MS?m/e?740.5(M ⁺+1)。

Example 3-55:

Compd A R00334191

According to the program described in example 1-2 and the 3-1, just in the step 4 of example 1-2, use 4-fluoro-2,3-dihydro-1H-isoindole replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S; 4R, 6S, 14S; 18R)-4-fluoro-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334191). ¹H NMR (500MHz, d ₆-acetone) δ 10.70 (br s, 1H), 8.34 (d, 1H), 7.39-7.33 (m, 1H), 7.20 (d, 1H), 7.10-7.02 (m, 2H), 6.13 (d, 1H), 5.70 (q, 1H), 5.44 (br s, 1H), 4.99 (t, 1H), 4.78-4.59 (m, 5H), 4.18-4.08 (m, 1H), 3.88-3.81 (m, 1H), 2.86-2.78 (m, 3H), 2.71-2.60 (m, 1H), 2.52-2.35 (m, 3H), 1.92-1.81 (m, 2H), 1.75 (t, 1H), 1.61-1.14 (m, 17H), and 1.04-0.95 (m, 2H);-APCI MS m/z730.4 (M-1).

Example 3-55a:

Utilize following two steps to prepare 4-fluoro-2 used among the example 3-55,3-dihydro-1H-isoindole:

Step 1:

When initial substance be in methane amide 0.5M solution and during at 125 ℃ of following visual gauge mould different heating 1h to 5h, obtain optimum.When temperature was higher than 60 ℃, initial substance was just solvable in methane amide.React completely in case monitor, just stop heating, and add the water of three times of reaction volumes by LC/MS (apcineg).Then, make reaction temperature to room temperature and stirring, up to forming light-yellow precipitate.Filter out yellow solid product, and wash with water, follow dried overnight, productive rate is between 70%-77%.

Step 2:

Use and add funnel, in the initial substance in round-bottomed flask, dropwise add 4 normal 1M BH ₃-THF forms golden yellow solution, and color becomes coppery after heating and stirring.Then under refluxing, heat described reaction 18 hours.

To react cool to room temperature (rt) afterwards and then in ice bath, be cooled to 0 ℃.Dropwise add 4 equivalent MeOH, and remove ice bath, the reaction of quenching can be warm to room temperature thus.Reaction color deepens in this warm process.Then, at room temperature dropwise add 6N HCl, show that up to the pH test paper reaction is acid, and will react backflow (63 ℃) 1 hour.Then make reaction be cooled to room temperature.At this moment, concentration response is used Et ₂O (2 *) and DCM (2 *) washing.Then water layer pH value is adjusted to 11 with the NaOH spherolite.Add more water, and with extracted with diethyl ether water layer (4 *).Extract after the merging is through Na ₂SO ₄Drying, and concentrate and to obtain the shallow brown oil product, this product directly uses.The quality experimental value always is higher than theoretical value a little, but is to use crude material like this to obtain productive rate greater than 80% in next step.

Example 3-56:

Compd A R00333833

According to example 1-2 and 3-1, just in similar example 1-2 step, in step 4, use 2,3-dihydro-1H-isoindole and before coupling step subsequently, further use H from the closed loop metathesis product 10 of the step 3 of example 1-2 ₂/ Ph-Al ₂O ₃Reduction (according to document program (WO 0059929, the 76-77 page or leaf)) comes synthetic (1S, 4R; 6S, 14S, 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] nonadecane-18-base ester (compd A R00333833). ¹H?NMR(400MHz，CD ₃SOCD ₃)δ11.11(s，1H)，8.89(s，1H)，7.16-7.29(m，4H)，6.95(d，1H)，5.25(bs，1H)，4.50-4.60(bs，4H)，4.40(dd，1H)，4.23(d，1H)，3.93(m，1H)，3.68(d，1H)，2.92(m，1H)，2.32(dd，1H)，2.11(m.1H)，1.40-1.68(m，2H)，0.92-1.40(m，19H)。MS?m/e?717.0(M ⁺+1)。

Example 3-57:

Compd A R00334286

According to the program shown in the following flow process, synthetic (1S, 4R, 6S, 14S, 18R)-and 5-amino-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334286).

Step 1. (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-2,15-dioxo-18-tri isopropyl silane oxygen base-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid, ethyl ester synthetic.(compound 10 of example 1-2,5.0g 10.1mmol) add imidazoles (827mg, 1.2 equivalents) and TIPSCl (2.15g, 1.1 equivalents) in the solution in DriSolve DCM (30ml) to the big ring intermediate of free hydroxyl group.Reaction mixture was at room temperature stirred 18 hours.TLC (5%MeOH-DCM) shows that a large amount of SM still remain.In this reaction mixture, add more imidazoles (410mg), TIPSCl (1g) and DMAP (121mg).After stirring was spent the night, the reaction mixture demonstration left a small amount of SM.Water (2 * 25ml) washing reaction mixtures.DCM (25ml) back scrubbing (backwash) of water layer after the merging.Organic layer after dry the merging, and concentrate, light yellow oil obtained.This thick material just is used for next step without being further purified.

Step 2. (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-2,15-dioxo-18-tri isopropyl silane oxygen base-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid synthetic.At first will be dissolved in the mixture of THF (20ml) and MeOH (20ml) from the ester SM of step 1.Then in this mixture, be added on the LiOH-H in the water (10ml) ₂(2.1g 50mmol) also at room temperature stirred 12 hours O.The LCMS demonstration reacts completely.Concentrated reaction mixture is to almost dry.Then solid residue is dissolved in the 50mL water, uses 2N HCl acidifying, and (2 * 50ml) extract with EtOAc.Organic layer after the merging is through anhydrous sodium sulfate drying, and concentrates.This thick material just is used for next step without being further purified.

Step 3:(1S, 4R, 6S, 14S, 18R)-(4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-18-tri isopropyl silane oxygen base-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-14-yl)-t-butyl carbamate synthetic

At first will be dissolved in 25mL DriSolve 1, in the 2-ethylene dichloride from the sour SM of above step 2.(2.2g 13.8mmol), and stirs described reaction 3 hours to disposable interpolation CDI in this solution under 50 ℃.Then in reaction, add the cyclopropyl sulphonamide (3.3g, 27.5mmol), then add DBU (4.2g, 27.5mmol), and 50 ℃ of following stirring reactions 4 hours.The LCMS demonstration reacts completely.For handling, (2 * 50mL) washing reaction mixtures, dry organic layer (anhydrous sodium sulphate) also concentrates water.This thick material just is used for next step without being further purified.

Step 4:(1S, 4R, 6S, 14S, 18R)-(4-cyclopropane sulfonyl amino carbonyl-18-hydroxyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-14-yl)-t-butyl carbamate synthetic.At first will be dissolved in from the crude product of above step 3 among the THF (40mL).Then adding TBAF (3.6g, 13.7mmol, 1.5 equivalents) in this solution also at room temperature stirred 2 hours.The TLC demonstration reacts completely.Then reaction mixture is concentrated into drying, is dissolved among the EtOAc once more and washes with water.Dry organic layer (anhydrous sodium sulphate) also concentrates.For carrying out purifying, crude product is dissolved among the DCM (50mL) also with 3N NaOH solution washing.With among the 2N HCl and water layer, and with DCM (2 * 25mL) extractions.Organic layer (sodium sulfate) after dry merging the and the concentrated pure white solid (2.4g, 46%) that obtains.MS?m/z(APCI+)469.1(MH ⁺-Boc)。

Step 5. (1S, 4R, 6S, 14S, 18R)-and 5-amino-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334286) synthetic.In DCE solution, add CDI (7mg, 1.3 equivalents), and at room temperature stir described reaction and spend the night from the product (19mg, 33 μ mol) of above step 4.The LCMS demonstration reacts completely.Then add 2,3-dihydro-1H-isoindole-5-base amine (18mg, 4 equivalents).After following 4 hours of the room temperature, the LCMS demonstration reacts completely.Directly reaction mixture is loaded on the silica gel and with methyl alcohol/DCM wash-out of 1% to 5%.Isolate the solid pure products that is white in color.MS?m/z(APCI+)：629.2(MH ⁺-Boc)。

Example 3-58:

Compd A R00334385

By the similar fashion described in example 3-57; and with 2,2 in 3-dihydro-1H-isoindole-4-base amine step of replacing 5,3-dihydro-1H-isoindole-5-base amine; come synthetic (1S; 4R, 6S, 14S; 18R)-4-amino-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334385).Equally, on the reversed-phase column chromatography instrument, carry out end product purifying (eluent=in water 5% to 100% acetonitrile), obtain being cream-coloured spumescence solid end product.MSm/z(APCI-)：728.2(M ⁺)。

Example 3-59:

Compd A R00340479

According to the program described in the example 3-6; only be to use the trifluoromethane sulphonamide to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-2,15-dioxo-4-trifluoromethane sulfonyl group aminocarboxyl-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00340479). ¹H NMR (400MHz, d ⁶-acetone): δ 7.98 (br s, 1H), 7.23-7.35 (m, 4H), 6.13 (br d, 1H), 5.70 (q, 1H), 5.44 (br s 1H), 4.98-5.02 (m, 1H), 4.61-4.72 (m, 5H), 4.49 (d, 1H), 4.16-4.18 (m, 1H), and 3.87-3.90 (m, 1H), 2.57-2.59 (m, 2H), 2.38-2.51 (m, 2H), 1.82-1.92 (m, 2H), 1.72-1.79 (m, 2H), 1.21-1.59 (m, 8H), 1.21 (s, 9H).MS?m/z(APCI-)：741.1(M ⁺)。MS?m/z(APCI-)：741.1(M ⁺)。

Example 3-60:

Compd A R00365387

According to the program described in the example 3-6; only be to use 4-sulfamyl-phenylformic acid to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-carboxyl-benzenesulfonyl aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00365387).MS?m/z(APCI-)：792.3(M-1)。

Example 3-61:

Compd A R00365388

According to the program described in the example 3-6; only be to use 4-chloro-3-sulfamyl-phenylformic acid to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(5-carboxyl-2-chloro-benzenesulfonyl aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00365388).MS?m/z(APCI-)：826.2(M-2)。

Example 3-62:

Compd A R00365425

According to the program described in the example 3-6; only be to use 2-methoxyl group-5-sulfamyl-phenylformic acid to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(3-carboxyl-4-methoxyl group-benzenesulfonyl aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00365425).MS?m/z(APCI-)：822.3(M-1)。

Example 3-63:

Compd A R00365426

According to the program described in the example 3-6; only be to use 2-chloro-4-fluoro-5-sulfamyl-phenylformic acid to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(5-carboxyl-4-chloro-2-fluoro-benzenesulfonyl aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00365426).MS?m/z(APCI-)：844.2(M-2)。

Example 3-64:

Compd A R00365572

According to the program described in the example 3-6; only be to use 4-dimethylamino-benzsulfamide to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-dimethylamino-benzenesulfonyl aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00365572).MS?m/z(APCI-)：791.3(M-1)。

Example 3-65:

Compd A R00333801

According to the program described in the example 3-6; only be to use propane-2-sulfonic acid amides to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-2,15-dioxo-4-(propane-2-sulfonyl amino carbonyl)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00333801).MS?m/z(APCI-)：714.4(M-1)。

Example 3-66:

Compd A R00333802

According to the program described in the example 3-6; only be to use benzsulfamide to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 4-benzenesulfonyl aminocarboxyl-14-tert-butoxycarbonyl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00333802).MS?m/z(APCI-)：748.3(M-1)。

Example 3-67:

Compd A R00333803

According to the program described in the example 3-6; only be to use amsacrine to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-methane sulfonyl aminocarboxyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00333803).MS?m/z(APCI-)：686.4(M-1)。

Example 3-68:

Compd A R00334188

According to the program described in the example 3-6; only be to use 5-chloro-thiophene-2-sulfonic acid amides to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(5-chloro-thiophene-2-sulfonyl amino carbonyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334188).MS?m/z(APCI-)：788.3(M-2)。

Example 3-69:

Compd A R00334247

According to the program described in the example 3-6, only be to use N-(5-sulfamyl-[1,3; 4] thiadiazoles-2-yl)-and ethanamide replacement cyclopropane sulphonamide, come synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 4-(5-acetylamino-[1; 3; 4] thiadiazoles-2-sulfonyl amino carbonyl)-and 14-tert-butoxycarbonyl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334247). ¹H NMR (400MHz, d ⁶-acetone): δ 7.24-7.31 (m, 4H), 5.96 (br d, 1H), 5.42 (br s 1H), 5.28 (m, 1H), 5.15 (m, 1H), 4.68 (m, 6H), 4.49 (m, 1H), 4.14 (m, 2H), 2.60 (m, 1H), 2.25-2.36 (m, 5H), 1.70-2.19 (m, 8H), 1.19-1.48 (m, 4H), 1.30 (s, 9H).MS?m/z(APCI-)：813.3(M-1)。

Example 3-70:

Compd A R00334248

According to the program described in the example 3-6; only be to use 4-cyano group-benzsulfamide to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-cyano group-benzenesulfonyl aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334248). ¹H NMR (400MHz, d ⁶-acetone): δ 11.32 (brs, 1H), 8.36 (br s, 1H), 8.04-8.15 (m, 4H), 7.22-7.35 (m, 4H), 6.12 (br d, 1H), 5.47 (br s 1H), 5.28 (q, 1H), 4.60-4.72 (m, 5H), 4.48-4.54 (m, 2H), and 4.14-4.17 (m, 1H), 3.86-3.90 (m, 1H), 2.37-2.52 (m, 4H), 1.72-1.85 (m, 2H), 1.59-1.62 (m, 1H), 1.20-1.55 (m, 8H), 1.20 (s, 9H).MS?m/z(APCI-)：773.3(M-1)。

Example 3-71:

Compd A R00334249

According to the program described in the example 3-6; only be to use 4-nitro-benzsulfamide to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-nitro-benzenesulfonyl aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334249). ¹H NMR (400MHz, d ⁶-acetone): δ 11.39 (br s, 1H), 8.46 (d, 2H), 8.35 (br s, 1H), 8.23 (d, 2H), 7.23-7.36 (m, 4H), 6.11 (br d, 1H), (5.47 br s 1H), 5.23 (q, 1H), 4.59-4.72 (m, 5H), 4.49-4.54 (m, 2H), 4.15 (m, 1H), 3.86-3.90 (m, 4H), 2.40-2.53 (m, 4H), 1.72-1.85 (m, 2H), 1.59-1.62 (m, 1H), 1.20-1.56 (m, 8H), 1.20 (s, 9H).MS?m/z(APCI-)：793.3(M-1)。

Example 3-72:

Compd A R00334250

According to the program described in the example 3-6; only be to use 4-chloro-benzsulfamide to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-chloro-benzenesulfonyl aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334250). ¹H NMR (400MHz, d ⁶-acetone): δ 11.16 (br s, 1H), 8.34 (d, 2H), 7.96 (d, 2H), 7.65 (d, 2H), 7.22-7.36 (m, 4H), 6.13 (br d, 1H), (5.46 br s 1H), 5.27 (q, 1H), 4.59-4.71 (m, 5H), 4.48-4.54 (m, 2H), 4.14 (m, 1H), 3.87-3.89 (m, 1H), 232-2.52 (m, 4H), 1.72-1.85 (m, 2H), 1.59-1.61 (m, 1H), 1.20-1.53 (m, 8H), 1.20 (s, 9H).MS?m/z(APCI-)：782.3(M-2)。

Example 3-73:

Compd A R00334341

According to the program described in the example 3-6; only be to use 4-methoxyl group-benzsulfamide to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-methoxyl group-benzenesulfonyl aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334341). ¹H NMR (400MHz, d ⁶-acetone): δ 8.26 (br s, 1H), 7.84 (d, 2H), 7.19-7.32 (m, 4H), 7.05 (d, 2H), 6.08 (br d, 1H), 5.43 (br s 1H), 5.25 (q, 1H), 4.55-4.67 (m, 5H), 4.48 (q, 2H), 4.10-4.14 (m, 1H), 3.87 (s, 3H), 3.82-3.87 (m, 1H), 2.29-2.47 (m, 4H), and 1.74-1.84 (m, 2H), 1.51-1.55 (m, 1H), 1.37-1.47 (m, 4H), 1.20-1.32 (m, 5H), 1.17 (s, 9H).MS?m/z(APCI-)：779.1(M-1)。

Example 3-74:

Compd A R00364266

According to the program described in the example 3-6; only be to use 1-methyl-5-sulfamyl-1H-pyrroles-2-carboxylic acid to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(5-carboxyl-1-methyl isophthalic acid H-pyrroles-2-sulfonyl amino carbonyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00364266). ¹H NMR (400MHz, d ⁶-acetone): δ 10.84 (br s, 1H), 8.27 (br s, 1H), 7.59 (d, 1H), 7.24-7.35 (m, 4H), 7.18 (d, 1H), 6.10 (br d, 1H), 5.50 (br, 1H), 5.46 (m 1H), 5.36 (q, 1H), 4.59-4.71 (m, 6H), 4.48 (d, 1H), 4.13-4.17 (m, 1H), 4.00 (s, 3H), 3.85-3.89 (m, 1H), 2.35-2.59 (m, 4H), 1.71-1.90 (m, 2H), 1.62-1.65 (m, 1H), 1.20-1.51 (m, 8H), 1.20 (s, 9H).MS?m/z(APCI-)：795.4(M-1)。

Example 3-75:

Compd A R00365427

According to the program described in the example 3-6; only be to use thiophene-2-sulfonic acid amides to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-2,15-dioxo-4-(thiophene-2-sulfonyl amino carbonyl)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00365427).MS?m/z(APCI-)：754.4(M-1)。

Example 3-76:

According to the program described in the example 3-6, only be to use 6-methoxyl group-1-methoxymethyl-1,2; 3,4-tetrahydrochysene-isoquinoline 99.9 (about synthesizing please referring to example 3-76a) replaces 2,3-dihydro-1H-isoindole; come synthetic (1S; 4R, 6S, 14S; 18R)-6-methoxyl group-1-methoxymethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334339).MS?m/z(APCI-)：800.5(M-1)。

Example 3-76a:

6-methoxyl group-1-methoxymethyl-1,2,3 is described, 4-tetrahydrochysene-chlorination isoquinoline 99.9 synthetic in following flow process:

Step 1:2-chloro-N-[2-(3-methoxyl group-phenyl)-ethyl]-ethanamide synthetic.With amine, 2-(3-methoxyl group-phenyl)-ethamine is processed into the 0.6M solution in DCM, then adds TEA (2 equivalent).Then mixture is cooled off in IPA/ the dry ice bath.When temperature of reaction reaches-60 ℃, dropwise add the solution (2.6M) of chloroacetyl chloride in DCM, so that temperature is remained on below-60 ℃.After interpolation is finished, stir described reaction 1 hour down at-60 ℃.Then make reaction temperature to-20 ℃,, remove some TEA hydrochlorides through the GF filter paper filtering.Then make the filtrate temperature to room temperature, and transfer in the separating funnel, with 1N HCl (2 *) and salt water washing.Organic layer is through MgSO ₄Drying, and concentrate, the intense violet color solid obtained.This crude product is directly used in next step without being further purified.

Step 2:1-chloromethyl-6-methoxyl group-3,4-dihydro-chlorination isoquinoline 99.9 synthetic.With two equivalent P ₂O ₅(12.9g) in dimethylbenzene (180mL), seethe with excitement, become the solution of 0.25M.At first also will in dimethylbenzene (45mL), seethe with excitement, make the solution of 0.5M, then it dropwise is added into described P via adding funnel from the crude product of above step 1 ₂O ₅In the solution.Stir the mixture and heating 1 hour under refluxing.Then make reaction be cooled to room temperature, and decant fall dimethylbenzene at this moment.Then flask is placed in the ice bath, and stirs when adding ice, water, EtOAc and last 4MNaOH careful, up to the pH value greater than 12.Keep temperature of reaction less than 25 ℃, until pH=12.Then with EtOAc (3 *) extractive reaction mixture.Organic extract after the merging is through dried over mgso, and concentrates, and obtains dark solution.It is cooled off in ice bath, add the cold Et of 400mL simultaneously ₂O also then adds the cold HCl/Et of 100mL ₂O.Form precipitation, and filter out, use Et ₂The O washing.Immediately solid is placed in the high vacuum 2 hours, obtains being coloured spumescence solid target product.This crude product is directly used in next step without being further purified.

Step 3:6-methoxyl group-1-methoxymethyl-1,2,3,4-tetrahydrochysene-chlorination isoquinoline 99.9 synthetic.Under 0 ℃ with the disposable TEA (5 equivalent) and Nal (0.1 equivalent) that adds in MeOH from the crude product of above step 2 in.Then, add 2.2 equivalent NaOMe, all qualitative response becomes muddy.Then 0 ℃ of following stirring reaction 1 hour.LC/MS shows the free fully alkalization of imines.

Then in ice bath, reaction is cooled to 0 ℃ once more, and add NaBH carefully ₄(1.5 equivalent).And then make reaction temperature, and stirred 2 hours to room temperature.When reacting completely, it is concentrated, handle with 1N NaOH, and extract with EtOAc by the LC/MS monitoring.Use MgSO ₄Organic layer after dry the merging also concentrates.The gained resistates is handled in MeOH, and in ice bath, cooled off.In wherein blasting HCl gas 10 minutes.Concentrated reaction mixture also is dissolved among the MeOH once more.After concentrating once more reaction is placed in the high vacuum and spends the night.Then grind thick material, after the high vacuum placement is spent the night, obtain being brown spumescence solid product with EtOAc (3 *).This crude product is directly used in next step without being further purified.MS?m/z(POSESI)：208.1(MH ⁺)。

Example 3-77:

Compd A R00365193

According to the program described in the example 3-76, only be to use 5-fluoro-1-methoxymethyl-1,2; 3,4-tetrahydrochysene-chlorination isoquinoline 99.9 (about synthesizing please referring to example 3-77a) replaces 6-methoxyl group-1-methoxymethyl-1,2; 3,4-tetrahydrochysene-chlorination isoquinoline 99.9 comes synthetic (1S; 4R, 6S, 14S; 18R)-5-fluoro-1-methoxymethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00365193). ¹H?NMR(500MHz，CD ₃OD)δ8.99-8.91(m，1H)，7.23-7.15(m，1H)，7.13-6.99(m，2H)，6.99-6.90(m，1H)，5.68(q，1H)，5.41(br?s，1H)，5.35-5.21(m，1H)，5.06(t，1H)，4.60-4.31(m，3H)，4.30-4.05(m，3H)，3.96-3.81(m，1H)，3.80-3.56(m，3H)，3.35(d，3H)，2.98-2.30(m，9H)，1.91-1.68(m，4H)，1.64-0.95(m，16H)；MS(APCI-)m/z?788.3(M-1)。

Example 3-77a:

As the similar fashion described in the 3-76a, just in step 1, use 2-(2-fluoro-phenyl)-ethamine to replace 2-(3-methoxyl group-phenyl)-ethamine, synthesize 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydrochysene-chlorination isoquinoline 99.9.

Example 3-78:

Compd A R00365438

According to the program described in the example 3-55; only be to use 4-sulfamyl-phenylformic acid to replace the cyclopropane sulphonamide; come synthetic (1S; 4R, 6S, 14S; 18R)-4-fluoro-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-carboxyl-benzenesulfonyl aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00365438). ¹H-NMR(500MHz，CD ₃OD)δ8.92(d，1H)，8.25-8.19(m，1H)，8.15(d，2H)，8.04(d，2H)，7.36-7.27(m，1H)，7.14(d，1H)，7.05-6.95(m，2H)，5.42(br?s，1H)，5.26(q，1H)，4.82-4.50(m，8H)，4.10-4.00(m，1H)，3.85(d，1H)，3.75-3.69(m，1H)，2.60-2.39(m，4H)，2.26(p，2H)，1.89-1.84(m，1H)，1.81-1.05(m，15H)；MS(APCI-)：m/z810.2(M-1)。

Example 3-79:

Compd A R00340303

(1S, 4R, 6S, 14S, 18R)-and 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino }-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00340303) synthetic.

Initial substance (AR00334191, example 3-55,10mg, 13.7 μ mol) is dissolved among the 50%TFA (DCM) of 1mL and at room temperature stirred 1 hour.Then concentrated reaction mixture is handled in acetonitrile to dry, and concentrates once more.Repeat above process again, so that remove any unnecessary TFA.Then the gained solid residue is dissolved among the DCE (137 μ L), in ice bath, is cooled to 0 ℃, then add described amino acid, cyclohexyl-[(pyrazine-2-carbonyl)-amino]-acetate (1.05 equivalent), HATU (10mg) and DIEA (4).Making mixture slowly be warmed up to room temperature and stir spends the night.For handling, directly reaction mixture is loaded on and also uses reversed-phase column chromatography method purifying on the C-18 post, the solid target compound obtains being white in color.MS(APCI-)：m/z?876.1(M-1)。

Example 3-80:

Compd A R00340122

According to the program described in the example 3-79; only be to use acetylamino-cyclohexyl-acetate to replace cyclohexyl-[(pyrazine-2-carbonyl)-amino]-acetate; come synthetic (1S; 4R, 6S, 14S; 18R)-4-fluoro-1; 3-dihydro-isoindole-2-carboxylic acid 14-(2-acetylamino-2-cyclohexyl-acetylamino)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00340122).MS(APCI-)：m/z?811.3(M-1)。

Example 3-81:

Compd A R00340156

(1S, 4R, 6S, 14S, 18R)-and 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-14-[2-(4-methoxyl group-phenyl)-acetylamino]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00340156) synthetic.

Initial substance (AR00334191, example 3-55,10mg, 13.7 μ mol) is dissolved among the 50%TFA (DCM) of 1mL and at room temperature stirred 1 hour.Then concentrated reaction mixture is handled in acetonitrile to dry, and concentrates once more.Repeat above process again, so that remove any unnecessary TFA.Then the gained solid residue is dissolved among the DCE (137 μ L) again, add chloride of acid afterwards, (4-methoxyl group-phenyl)-Acetyl Chloride 98Min. (2), and DIEA (4).Mixture at room temperature stirred spend the night.After finishing, will react and directly be loaded on the C-18 post, and with reversed-phase column chromatography method purifying.Further with compound purifying (eluent=contain the 40%EtOAc/ hexane of 1% formic acid) on the normal phase silica gel chromatography instrument, the solid target compound obtains being white in color. ¹H?NMR(500MHz，CD ₃OD)δ7.33(p，1H)，7.15(d，1H)，7.05-6.92(m，3H)，6.65(dd，2H)，5.68(q，1H)，5.40(br?s，1H)，5.09(t，1H)，4.78-4.46(m，7H)，4.43-4.24(m，2H)，3.89-3.80(m，1H)，3.68(d，3H)，3.21(d，1H)，2.69-2.57(m，1H)，2.52-2.30(m，5H)，2.06-0.80(m，15H)；MS(APCI-)：m/z?778.3(M-1)。

Example 3-82:

Compd A R00340178

According to the program described in the example 3-81; only be to use (3-methoxyl group-phenyl)-Acetyl Chloride 98Min. to replace (4-methoxyl group-phenyl)-Acetyl Chloride 98Min.; come synthetic (1S; 4R, 6S, 14S; 18R)-4-fluoro-1; 3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-14-[2-(3-methoxyl group-phenyl)-acetylamino]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00340178). ¹H?NMR(500MHz，CD ₃OD)δ7.32(p，1H)，7.14(d，1H)，7.05-6.92(m，3H)，6.76-6.58(m，2H)，5.68(q，1H)，5.41(br?s，1H)，5.09(t，1H)，4.76-4.46(m，7H)，4.43-4.26(m，2H)，3.91-3.82(m，1H)，3.69(d，3H)，2.94-2.85(m，1H)，2.70-2.57(m，1H)，2.52-2.30(m，5H)，2.06-0.80(m，15H)；MS(APCI-)m/z778.3(M-1)。

Example 3-83:

Compd A R00340188

According to the program described in the example 3-81; only be to use phenyl-Acetyl Chloride 98Min. to replace (4-methoxyl group-phenyl)-Acetyl Chloride 98Min.; come synthetic (1S; 4R, 6S, 14S; 18R)-4-fluoro-1; 3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-14-phenyl acetyl amino-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00340188).MS(APCI-)m/z?748.4(M-1)。

Example 3-84:

Compd A R00334314

Program according to described in the example 3-6 only is to use 5-methoxyl group-2, and 3-dihydro-1H-isoindole is (by at JOC; the 53rd volume, the 22nd phase, 1988; similar fashion preparation described in the 5381-5383 page or leaf) replace 2,3-dihydro-1H-isoindole comes synthetic (1S; 4R, 6S, 14S; 18R)-5-methoxyl group-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334314).MS?m/z(APCI-)：742.3(M-1)。

Example 3-85:

Compd A R00334399

Program according to described in the example 3-6 only is to use 4,7-two fluoro-2; 3-dihydro-1H-isoindole (by at JOC, the 53rd volume, the 22nd phase; similar fashion preparation described in 1988, the 5381-5383 pages or leaves) replaces 2,3-dihydro-1H-isoindole; come synthetic (1S, 4R, 6S; 14S, 18R)-4,7-two fluoro-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334399). ¹H?NMR(500MHz，CD ₃OD)δ8.97(s，1H)，6.99-6.85(m，2H)，5.69(q，1H)，5.42(br?s，1H)，5.07(t，1H)，4.83-4.57(m，6H)，4.51(d，1H)，4.13-4.02(m，1H)，3.85(t，1H)，2.94-2.86(m，1H)，2.73-2.59(m，1H)，2.55-2.28(m，4H)，1.89-1.70(m，3H)，1.65-1.22(m，10H)，1.18-0.96(m，10H)；MS?m/z(APCI-)：746.1(M-1)。

Example 3-86

Compd A R00338066

According to the program described in the example 3-36; only be to use 4-fluoro-2,3-dihydro-1H-isoindole replaces 2,3-dihydro-1H-isoindole; come synthetic (1S; 4R, 6S, 14S; 18R)-4-fluoro-1; 3-dihydro-isoindole-2-carboxylic acid 14-(the 3-tertiary butyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00338066). ¹H?NMR(500MHz，CD ₃OD)δ7.38-7.28(m，1H)，7.13(d，1H)，7.01(p，1H)，5.69(q，1H)，5.45(br?s，1H)，5.07(t，1H)，4.83-4.66(m，4H)，4.59(q，1H)，4.49(d，1H)，4.37-4.17(m，2H)，3.94-3.84(m，1H)，3.72(t，1H)，2.95-2.87(m，1H)，2.68-2.29(m，5H)，2.09-1.22(m，11H)，1.12-0.95(m，12H)；MS(APCI-)：m/z?729.3(M-1)。

Example 3-87:

Compd A R00338070

According to the program described in the example 3-81; only be to use 3,3-dimethyl-butyryl chloride replaces (4-methoxyl group-phenyl)-Acetyl Chloride 98Min., comes synthetic (1S; 4R; 6S, 14S, 18R)-4-fluoro-1; 3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-14-(3; 3-dimethyl-butyryl radicals amino)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00338070).MS(APCI-)?m/z?728.3(M-1)。

Example 3-88:

Compd A R00338071

Program according to described in the example 3-81 only is to use 4,4; 4-three fluoro-butyryl chlorides replace (4-methoxyl group-phenyl)-Acetyl Chloride 98Min., come synthetic (1S, 4R; 6S; 14S, 18R)-4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-14-(4; 4,4-three fluoro-butyryl radicals amino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00338071).MS(APCI-)?m/z?754.3(M-1)。

Example 3-89:

Compd A R00341649

Program according to described in the example 3-6 only is to use (2,3-dihydro-1H-isoindole-5-yl)-sec.-propyl-amine (by as Org.Letters; 2003, the 5 volumes, the 6th phase; similar fashion preparation described in the 793-796) replace 2,3-dihydro-1H-isoindole comes synthetic (1S; 4R, 6S, 14S; 18R)-5-sec.-propyl amino-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00341649). ¹H?NMR(500MHz，CD ₃OD)δ8.94(br?d，1H)，7.52(s，1H)，7.48(d，1H)，7.41-7.32(m，2H)，7.23-7.24(m，2H)，5.69(q，1H)，5.41(br?s，1H)，5.07(t，1H)，4.82-4.66(m，3H)，(t，1H)，4.52(t，1H)，4.08(d，1H)，3.85(d，1H)，3.80-3.68(m，1H)，2.94-2.87(m，1H)，2.71-2.59(m，1H)，2.55-2.45(m，1H)，2.45-2.30(m，3H)，1.88-1.69(m，3H)，1.61(t，1H)，1.58-0.94(m，25H)；MS(APCI-)：m/z?770.1(M-1)。

Example 3-90:

Compd A R00364936

Program according to described in the example 3-6 only is to use 2, and 3-dihydro-1H-isoindole-5-alcohol is (by as JOC; the 53rd volume, the 22nd phase, 1988; similar fashion preparation described in the 5381-5383 page or leaf) replace 2,3-dihydro-1H-isoindole comes synthetic (1S; 4R, 6S, 14S; 18R)-5-hydroxyl-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00364936).MS?m/z(APCI-)：728.2(M-1)。

Example 3-91:

Compd A R00365083

According to the program described in the example 3-57, just in step 5, use 2,3-dihydro-1H-isoindole-5-carboxylate methyl ester (preparing shown in example 3-91a) replaces 2; 3-dihydro-1H-isoindole-5-base amine; come synthetic (1S, 4R, 6S; 14S; 18R)-1,3-dihydro-isoindole-2,5-dicarboxylic acid 2-(14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-yl) ester 5-methyl ester (compd A R00365083).MS?m/z(APCI+)：672.2(MH ⁺-Boc)。

Example 3-91a

According to following flow process Synthetic 2,3-dihydro-1H-isoindole-5-carboxylate methyl ester

Under 80 ℃, stir down 5-bromo-1 at CO (air bag), 3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (200mg, 0.67mmol), Pd (OAc) ₂(30mg, 0.2 equivalent), DPPP (55mg, 0.2 equivalent), TEA (0.93mL, 10 equivalents) and MeOH: DMSO (1: 1, mixture 4mL) 16 hours.LC-MS and TLC (20%EtOAc-hexane) demonstration reacts completely.Concentrated reaction mixture is removed MeOH, and with EtOAc (10mL) dilution, washes (2 * 25mL) with water.With organic layer drying (Na ₂SO ₄), concentrate, and by silica gel chromatography purifying (eluent=20%EtOAc-hexane), obtain pure 1,3-dihydro-isoindole-2,5-dicarboxylic acid 2-tert-butyl ester 5-methyl esters (150mg, 81%).MS(APCI+)：m/z?178.1(MH ⁺-Boc)。

By under 0 ℃-room temperature, handling the protecting group of removing in the above product in 1 hour with 50%TFA-DCM.Concentrated reaction mixture is dissolved among the DCM once more, and neutralizes with saturated sodium bicarbonate solution to dry.Separate organic layer, drying also concentrates, and obtains being the target compound of free alkali form, and this compound just is directly used in ensuing coupling step without being further purified.

Example 3-92:

Compd A R00333831

Program according to described in the example 3-5 only is to use 2, and 3-dihydro-1H-isoindole replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid 14-cyclopentyloxy carbonylamino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00333831). ¹H?NMR(400MHz，CD3OD)：δ7.36-7.22(m，3H)，7.21-7.16(m，1H)，5.74-5.60(m，1H)，5.40(s，1H)，5.20-5.03(m，1H)，4.80-4.54(m，6H)，4.38-4.28(m，1H)，4.18(m，1H)，3.90-3.80(m，1H)，2.96-2.85(m，1H)，2.70-2.31(m，4H)，1.92-0.98(m，24H)。MS?m/z(APCI-)：724.4(M-1)。

Example 3-93:

Compd A R00340494

According to the program described in the example 3-6, only be to use 5-morpholine-4-base-2,3-dihydro-1H-isoindole is (by as J.Org.Chem.2000; 65, the similar fashion preparation described in the 1144-1157) replace 2,3-dihydro-1H-isoindole; come synthetic (1S; 4R, 6S, 14S; 18R)-5-morpholine-4-base-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00340494). ¹H?NMR(400MHz，DMSO-d ⁶)：δ7.80-7.22(m，1H)，7.22-7.15(m，1H)，7.00-6.81(m，2H)，5.45-(m，1H)，5.26(m，1H)4.62-4.50(m，4H)，4.42(m，1H)，4.28-4.10(m，2H)，3.98(m，1H)，3.76(m，4H)，3.12(m，4H)，2.71-2.60(m，1H)，2.40-1.45(m，3H)，1.40-1.21(m，10H)，0.98-0.61(m，4H)。MS?m/z(APCI+)：699.2(MH ⁺-Boc)。

Example 3-94:

Compd A R00365082

Program according to described in the example 3-6 only is to use 2, and 3-dihydro-1H-isoindole-5-nitrile is (by as J.Org.Chem.1998; 63, the similar fashion preparation described in the 8224-8228) replace 2,3-dihydro-1H-isoindole; come synthetic (1S; 4R, 6S, 14S; 18R)-5-cyano group-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00365082).MS?m/z(APCI+)：639.1(MH ⁺-Boc)。

Example 3-95:

Compd A R00365252

According to the described program of following flow process, synthetic (1S, 4R; 6S, 14S, 18R)-5-ethyl carbamyl-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00365252):

With compd A R00365083 (70mg, 91 μ mol) (its synthetic in presents, describe to some extent previously) be dissolved in THF: MeOH (2: 1,3mL) in the mixture, then add 1mL LiOH-H ₂The aqueous solution of O.At room temperature stirring reaction is 1 hour.LC-MS indicates complete hydrolysis, and the continuation reaction is 30 minutes again, afterwards it is concentrated, and neutralizes with 0.1N HCl, and extracts with the EtOAc of 5mL.With organic layer drying (Na ₂SO ₄), concentrate and with silica gel chromatography purifying (5%-7%MeOH-DCM), the solid hydrolysate obtains being white in color.MS(APCI+)：m/z?658.1(MH ⁺-Boc)。

At first will be dissolved in the dry DMF (2mL), then add ethamine (3 equivalent), HOAT (3 equivalent) and HATU (3 equivalent), dropwise add DIEA (6 equivalent) at last from the product (23mg, 30 μ mol) of above step.Reaction mixture at room temperature stirred spend the night.The LC-MS demonstration reacts completely.Reaction mixture is diluted with EtOAc (5mL) and water (2 * 10mL) washings.With the organic layer drying, concentrate, and by preparation type TLC purifying crude product.MS(APCI+)：685.2(MH ⁺-Boc)。

Example 3-96:

Compd A R00334218

Program according to described in the example 3-5 only is to use 5-chloro-2, and 3-dihydro-1H-isoindole replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S; 4R, 6S, 14S; 18R)-5-chloro-1; 3-dihydro-isoindole-2-carboxylic acid 14-cyclopentyloxy carbonylamino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334218). ¹H?NMR(400MHz，CD ₃CN)δ7.55(bs，1H)，7.19-7.33(m，3H)，5.63-5.73(m，2H)，5.27-5.34(m，1H)，4.98(t，1H)，4.52-4.72(m，5H)，4.48(t，1H)，4.34-4.44(m，1H)，4.06-4.15(m，1H)，2.77-2.90(m，2H)，2.54(bs，1H)，2.24-2.44(m，3H)，1.64-1.75(m，2H)，1.13-1.57(m，18H)，0.91-1.09(m，4H)。MS?m/z?759.9(M+1)。

Example 3-97:

Compd A R00334220

Program according to described in the example 3-16 only is to use 5-chloro-2, and 3-dihydro-1H-isoindole replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S; 4R, 6S, 14S; 18R)-5-chloro-1; 3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-14-(tetrahydrofuran (THF)-3-base oxygen base carbonylamino)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334220). ¹H?NMR(400MHz，CD ₃CN)δ7.57(bs，1H)，7.20-7.34(m，3H)，5.87-5.93(m，1H)，5.65(q，1H)，5.31(bs，1H)，5.23-5.29(m，1H)，4.98(t，1H)，4.44-4.71(m，5H)，4.29-4.39(m，1H)，4.07-4.18(m，1H)，3.70-3.87(m，4H)，3.61-3.70(m，1H)，3.44-3.55(m，2H)，3.30-3.42(m，1H)，2.76-2.89(m，2H)，2.54(bs，1H)，2.36-2.46(m，1H)，2.24-2.36(m，2H)，1.69-1.76(m，1H)，1.59-1.69(m，1H)，1.13-1.56(m，8H)，0.90-1.10(m，4H)。MS?m/z?762.0(M+1)。

Example 3-98:

Compd A R00334222

According to the program described in the example 3-28; only be to use 5-chloro-2,3-dihydro-1H-isoindole replaces 2,3-dihydro-1H-isoindole; come synthetic (1S; 4R, 6S, 14S; 18R)-5-chloro-1; 3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-14-(2-fluoro-ethoxy carbonyl amino)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334222). ¹H?NMR(400MHz，CD ₃CN)δ7.53(bs，1H)，7.20-7.33(m，3H)，5.93(d，1H)，5.67(q，1H)，5.32(bs，1H)，4.93-5.05(m，1H)，4.52-4.72(m，5H)，4.47(t，1H)，4.39(t，1H)，4.25-4.36(m，2H)，4.12-4.25(m，2H)，3.65-3.96(m，2H)，2.76-2.89(m，2H)，2.54(bs，1H)，2.22-2.44(m，3H)，1.67-1.76(m，1H)，1.13-1.60(m，10H)，0.91-1.13(m，4H)。MS?m/z?737.9(M+1)。

Example 3-99:

Compd A R00334225

Program according to described in the example 3-81 only is to use 3, and 3-dimethyl-butyryl chloride replaces (4-methoxyl group-phenyl)-Acetyl Chloride 98Min. and uses 5-chloro-2; 3-dihydro-1H-isoindole replaces 4-fluoro-2, and 3-dihydro-1H-isoindole comes synthetic (1S; 4R; 6S, 14S, 18R)-5-chloro-1; 3-dihydro-isoindole-2-carboxylic acid 4-cyclopropane sulfonyl amino carbonyl-14-(3; 3-dimethyl-butyryl radicals amino)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334225). ¹H?NMR(400MHz，CD ₃CN)δ7.60(bs，1H)，7.15-7.33(m，3H)，6.54-6.65(m，1H)，5.63-5.73(m，1H)，5.33(bs，1H)，4.93-5.02(m，1H)，4.53-4.65(m，3H)，4.39-4.48(m，2H)，4.28-4.38(m，1H)，3.74-3.83(m，2H)，2.77-2.89(m，1H)，2.54(bs，1H)，2.23-2.44(m，3H)，1.68-1.91(m，4H)，1.12-1.54(m，11H)，0.91-1.11(m，4H)，0.76-0.90(m，9H)。MSm/z?746.2(M+1)。

Example 3-100:

Compd A R00334226

According to the program described in the example 3-81; only be to use cyclopentyl-Acetyl Chloride 98Min. to replace (4-methoxyl group-phenyl)-Acetyl Chloride 98Min. and use 5-chloro-2,3-dihydro-1H-isoindole replaces 4-fluoro-2,3-dihydro-1H-isoindole; come synthetic (1S; 4R, 6S, 14S; 18R)-5-chloro-1; 3-dihydro-isoindole-2-carboxylic acid 14-(2-cyclopentyl-acetylamino)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00334226). ¹HNMR(400MHz，CDCl ₃)δ10.85(bs，1H)，6.95-7.30(m，3H)，5.87-6.02(m，1H)，5.63-5.79(m，1H)，5.43-5.52(m，1H)，4.93-5.08(m，1H)，4.52-4.85(m，5H)，4.31-4.52(m，1H)，3.79-3.95(m，1H)，3.60-3.75(m，2H)，3.14(q，1H)，2.90(bs，1H)，2.37-2.63(m，3H)，2.14-2.29(m，1H)，1.73-2.12(m，6H)，1.16-1.74(m，13H)，0.96-1.16(m，4H)，0.68-0.96(m，9H)。MS?m/z?758.2(M+1)。

Example 3-101:

Compd A R00340173

According to the program described in the example 3-6; only be to use 5-chloro-thiophene-2-sulfonic acid amides to replace cyclopropane sulphonamide and use 5-chloro-2,3-dihydro-1H-isoindole replaces 2,3-dihydro-1H-isoindole; come synthetic (1S; 4R, 6S, 14S; 18R)-5-chloro-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(5-chloro-thiophene-2-sulfonyl amino carbonyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00340173). ¹H?NMR(400MHz，CD ₃CN)δ8.07(d，1H)，7.50(d，1H)，7.16-7.32(m，3H)，6.98(d，1H)，5.86(bs，1H)，5.27-5.39(m，2H)，4.81-4.92(m，1H)，4.58-4.64(m，2H)，4.51-4.58(m，2H)，4.44(t，1H)，4.33(d，1H)，4.10-4.20(m，1H)，3.73-3.81(m，1H)，2.47(bs，1H)，2.16-2.41(m，3H)，1.63-1.77(m，2H)，1.47-1.57(m，2H)，1.07-1.47(m，17H)。MS?m/z?724.1(M+1-Boc)。

Example 3-102:

Compd A R00340526

According to the program described in the example 3-6; only be to use 5-bromo-2,3-dihydro-1H-isoindole replaces 2,3-dihydro-1H-isoindole; come synthetic (1S; 4R, 6S, 14S; 18R)-5-bromo-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00340526). ¹H?NMR(400MHz，CDCl ₃)δ10.31(bs，1H)，7.36-7.44(m，1H)，6.99-7.32(m，3H)，5.70(q，1H)，5.42-5.49(m，1H)，5.06-5.13(m，1H)，4.99(t，1H)，4.52-4.78(m，5H)，4.32-4.44(m，1H)，4.16-4.27(m，1H)，3.78-3.89(m，1H)，3.33-3.42(m，1H)，2.85-2.94(m，1H)，2.40-2.64(m，3H)，2.20-2.32(m，1H)，1.68-1.97(m，4H)，1.17-1.67(m，16H)，1.01-1.17(m，3H)，0.80-0.98(m，2H)。MS?m/z?694.0(M+1-Boc)。

Example 3-103:

Compd A R00333462

Step according to described in the example 3-1 only is to use the 4R-methyl isophthalic acid, 2; 3,4-tetrahydrochysene-isoquinoline 99.9 (the similar program preparation according among the example 1-17a only is to use the enantiomer-pure initial substance to replace the racemize initial substance) replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S, 4R, 6S; 14S, 18R)-4R-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00333462).MS?m/z?642.2(M+1-Boc)。

Example 3-104:

Compd A R00333463

Step according to described in the example 3-1 only is to use the 4S-methyl isophthalic acid, 2; 3,4-tetrahydrochysene-isoquinoline 99.9 (the similar program preparation according among the example 1-17a only is to use the enantiomer-pure initial substance to replace the racemize initial substance) replaces 1; 2,3,4-tetrahydrochysene-isoquinoline 99.9; come synthetic (1S, 4R, 6S; 14S, 18R)-4S-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00333463).MS?m/z?642.2(M+1-Boc)。

Example 3-105:

Compd A R00345032

According to the program described in the example 3-6; only be to use morpholine-4-carboxylic acid 2-(2; 3-dihydro-1H-isoindole-5-base oxygen base)-ethyl ester is (according to J.Med.Chem.2002; the 45th volume; the 26th phase; program preparation described in method D in 5771 and Bioorg.Med.Chem.Lett.11 (2001) 685-688) replaces 2; 3-dihydro-1H-isoindole comes synthetic (1S, 4R; 6S; 14S, 18R)-5-[2-(morpholine-4-ketonic oxygen base)-oxyethyl group]-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00345032).MS(APCI-)：m/z?885.4(M-1)。

Example 3-106:

Compd A R00345075

According to the program described in the example 3-6; only be to use 5-(3-morpholine-4-base-propoxy-)-2; 3-dihydro-1H-isoindole is (according to J.Med.Chem.2002; the 45th volume; the 26th phase; program preparation described in method D in 5771 and Bioorg.Med.Chem.Lett.11 (2001) 685-688) replaces 2; 3-dihydro-1H-isoindole comes synthetic (1S, 4R; 6S; 14S, 18R)-5-(3-morpholine-4-base-propoxy-)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00345075).MS(APCI-)：m/z?855.6(M-1)。

Example 3-107:

Compd A R00345090

According to the program described in the example 3-6; only be to use 5-(2-morpholine-4-base-oxyethyl group)-2; 3-dihydro-1H-isoindole is (according to J.Med.Chem.2002; the 45th volume; the 26th phase; program preparation described in method D in 5771 and Bioorg.Med.Chem.Lett.11 (2001) 685-688) replaces 2; 3-dihydro-1H-isoindole comes synthetic (1S, 4R; 6S; 14S, 18R)-5-(2-morpholine-4-base-oxyethyl group)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00345090).MS(APCI-)：m/z?841.5(M-1)。

Example 3-108:

Compd A R00345094

According to the program described in the example 3-6; only be to use that [2-(2; 3-dihydro-1H-isoindole-5-base oxygen base)-ethyl]-sec.-propyl-amine is (according to J.Med.Chem.2002; the 45th volume; the 26th phase; program preparation described in method D in 5771 and Bioorg.Med.Chem.Lett.11 (2001) 685-688) replaces 2; 3-dihydro-1H-isoindole comes synthetic (1S, 4R; 6S; 14S, 18R)-5-(2-sec.-propyl amino-oxyethyl group)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00345094).MS(APCI-)：m/z?813.5(M-1)。

Example 3-109:

Compd A R00345095

According to the program described in the example 3-6; only be to use that [2-(2; 3-dihydro-1H-isoindole-5-base oxygen base)-ethyl]-dimethyl-amine is (according to J.Med.Chem.2002; the 45th volume; the 26th phase; program preparation described in method D in 5771 and Bioorg.Med.Chem.Lett.11 (2001) 685-688) replaces 2; 3-dihydro-1H-isoindole comes synthetic (1S, 4R; 6S; 14S, 18R)-5-(2-dimethylamino-oxyethyl group)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00345095).MS(APCI-)：m/z?799.5(M-1)。

Example 3-110:

Compd A R00345096

According to the program described in the example 3-6; only be to use 5-(2-imidazoles-1-base-oxyethyl group)-2; 3-dihydro-1H-isoindole is (according to J.Med.Chem.2002; the 45th volume; the 26th phase; program preparation described in method D in 5771 and Bioorg.Med.Chem.Lett.11 (2001) 685-688) replaces 2; 3-dihydro-1H-isoindole comes synthetic (1S, 4R; 6S; 14S, 18R)-5-(2-imidazoles-1-base-oxyethyl group)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00345096).MS(APCI-)：m/z?822.5(M-1)。

Example 3-111:

Compd A R00364924

According to the program described in the example 3-6; only be to use 5-(2-pyrazol-1-yl-oxyethyl group)-2; 3-dihydro-1H-isoindole is (according to J.Med.Chem.2002; the 45th volume; the 26th phase; program preparation described in method D in 5771 and Bioorg.Med.Chem.Lett.11 (2001) 685-688) replaces 2; 3-dihydro-1H-isoindole comes synthetic (1S, 4R; 6S; 14S, 18R)-5-(2-pyrazol-1-yl-oxyethyl group)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00364924).MS(APCI-)：m/z?742.1[(M-100)+18]。

Example 3-112:

Compd A R00340495

By the similar fashion described in the example 3-57; and with 5-(4-methyl-piperazine-1-yl)-2; 3-dihydro-1H-isoindole (passes through J.Org.Chem.2000; 65; similar fashion preparation among the 1144-1157) replaces 2 in the step 5; 3-dihydro-1H-isoindole-5-base amine; come synthetic (1S; 4R, 6S, 14S; 18R)-5-(4-methyl-piperazine-1-yl)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00340495). ¹H?NMR(400MHz，DMSO-d ⁶)：δ7.72-7.40(m，1H)，7.22-7.05(m，1H)，6.95-6.70(m，2H)，5.55-5.45(m，1H)，5.35-5.22(m，2H)，4.62-4.50(m，4H)，4.40(m，1H)，4.30-4.08(m，2H)，4.0-3.89(m，1H)，3.10(m，3H)，2.65(m，1H)，2.42(m，3H)，2.33-2.20(m，6H)，1.85-1.50(m，5H)，1.42-1.0(m，14H)，0.82-0.55(m，4H)。MS(APCI+)：712.3(MH ⁺-Boc)。

Example 3-113:

Compd A R00365084

According to the similar program described in the example 3-91, just from the product A R00365083 of this example further at THF-MeOH-H ₂Obtain AR00365084 with the LiOH hydrolysis in the O mixture, come synthetic (1S, 4R, 6S; 14S, 18R)-1,3-dihydro-isoindole-2; 5-dicarboxylic acid 2-(14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-yl) ester (compd A R00365084).MS：658(M-Boc)。

Example 3-114:

Compd A R00364989

By the similar fashion described in example 3-57; and with 5-(2-methyl-thiazole-4-yl)-2,2 in 3-dihydro-1H-isoindole step of replacing 5,3-dihydro-1H-isoindole-5-base amine; come synthetic (1S; 4R, 6S, 14S; 18R)-5-(2-methyl-thiazole-4-yl)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00364989). ¹H?NMR(400MHz，CD ₃COCD ₃)δ10.69(bs，1H)8.32(bs，1H)，7.94(d，1H)7.88(d，1H)7.70(d，1H)7.34(dd，1H)6.08-6.16(m，1H)，5.69(q，1H)5.45(bs，1H)5.00(t，1H)4.58-4.81(m，5H)，4.44-4.53(m，1H)，4.12-4.21(m，1H)，3.83-3.91(m，1H)，2.86-2.97(m，1H)，2.57-2.71(m，1H)，2.33-2.54(m，3H)，1.81-1.96(m，2H)，1.75(dd，1H)1.17-1.63(m，20H)，1.06-1.17(m，1H)，0.94-1.06(m，2H)。MS?m/z?711.2(M+1-100)。

Example 3-114a:

According to the experiment of the steps A of example 3-115a, and in step e, utilize thioacetamide, synthesize 5-(2-methyl-thiazole-4-yl)-2,3-dihydro-1H-isoindole to F.

Example 3-115:

Compd A R00365019

By the similar fashion described in the example 3-57; and use 2 in [4-(2,3-dihydro-1H-isoindole-5-yl)-thiazol-2-yl]-sec.-propyl-amine step of replacing 5,3-dihydro-1H-isoindole-5-base amine; come synthetic (1S; 4R, 6S, 14S; 18R)-5-(2-sec.-propyl amino-thiazolyl--4-yl)-1; 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compd A R00365019). ¹H?NMR(400MHz，CD ₃COCD ₃)δ10.69(bs，1H)，8.27-8.36(m，1H)，7.28-7.50(m，2H)7.01-7.20(m，1H)，6.08-6.15(m，1H)，5.70(q，1H)4.45(bs，1H)4.94-5.05(m，1H)，4.68-4.76(m，4H)，4.59-4.64(m，1H)4.45-4.53(m，1H)，4.10-4.20(m，1H)，3.81-3.90(m，1H)3.65-3.76(m，1H)，2.86-2.98(m，1H)，2.63(bs，1H)，2.32-2.54(m，3H)，1.80-1.94(m，2H)，1.70-1.79(m，1H)1.05-1.65(m，19H)0.95-1.05(m，2H)。MS?m/z754.2(M+1-100)。

Example 3-115a:

The synthetic of [4-(2,3-dihydro-1H-isoindole-5-yl)-thiazol-2-yl]-sec.-propyl-amine described in following flow process.

A. under-78 ℃ in the solution of 4ml THF and 1ml ethyl vinyl ether, dropwise add t-BuLi (0.79ml, 1.34mmol).Make the solution temperature to room temperature, and stirred 30 minutes.Dropwise add ZnCl ₂At THF (3.02ml, 1.51mmol) the 0.5M solution in, and stirring reaction 30 minutes at room temperature.Use this mixture without being further purified.

B. at N ₂Down to aryl bromide (0.200g, 0.67mmol) and Pd (PPh ₃) ₄(39mg 0.33mmol) is dissolved in the solution among the THF by intubate and adds crude ethylene base novel substance from steps A.50 ℃ of reacting by heating 36 hours, then by EtOAc via Al ₂O ₃Stopper filters, and the concentrated oil that obtains, and this oil uses without being further purified just.

C. will be dissolved among THF (2ml) and the 1.0N HCl (2ml) from the thick oil of step B and stir one hour.To be reflected among the EtOAc and handle, and separate, organic layer is with saturated sodium bicarbonate and salt water washing, through Na ₂SO ₄Dry and concentrated, obtain orange oil.Utilize 5: 1 hexanes: this oil of EtOAc chromatography purification obtains white solid (95mg, 54%).

D. under-78 ℃ and at N ₂Down, to 1.0M LiHMDS (4.0ml, dropwise add in solution 4.0mmol) TMSCl (3.38ml, 26.6mmol).In this solution, be added on the ketone among the 3ml THF from step C.At-78 ℃ of following stirring reactions 30 minutes and warm to 0 ℃.(1.10g 2.93mmol) and 0 ℃ of following stirring reaction 30 minutes, is concentrated into solid, and handles in EtOAc and water to add PTTB.Organism water and salt water washing are through Na ₂SO ₄Dry and concentrated, and utilize 5: 1 hexanes: this oil of EtOAc purifying obtains yellow solid (0.64g, 71%).

E. under refluxing, heat bromoketone (75mg, 0.22mmol), Na ₂CO ₃(37mg, 0.44mmol) (26mg, 22mmol) slurry in EtOH is 30 minutes with 1-sec.-propyl thiocarbamide.To be reflected among the EtOAc and handle, and separate, organic layer is with saturated sodium bicarbonate and salt water washing, through Na ₂SO ₄Dry and concentrated, obtain yellow oil.Utilize 3: 1 hexanes: this oil of MTBE purifying obtains clarified oil (77mg, 97%).

F. will in 4N HCl/ dioxan (2.0ml), stir one hour from the Boc-amine of step e, and be concentrated into white solid.This solid is handled in 0.1N HCl and washed with DCM.Water layer extracts with 1.0N NaOH alkalization and with DCM, drying, and concentrate, and use without being further purified just.

The preparation of big ring aminoproline intermediate

Example 4-1:

(1S, 4R, 6S, 14S, 18R)-and 18-amino-14-tert-butoxycarbonyl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid, ethyl ester synthetic

A. to (2S, 4R)-and 4-amino-1-[phenmethyl oxygen base carbonyl] tetramethyleneimine-2-methyl carboxylic acids ester hydrochloride (2.00g, 2.34mmol) solution in methylene dichloride (25ml) adds 2-(TMS) ethyl p-nitrophenyl carbonic ether (1.98g, 6.99mmol) and triethylamine (1.81ml, 13.34mmol).To react and stir 3 days, be placed on the silica gel,, obtain water white oil with 40%EtOAc/ hexane eluted product.Described oil is dissolved in follows 10% palladium carbon to stir in the methyl alcohol (20ml) and under the hydrogen air bag.Stir after 4 hours, filtering reaction also concentrates.The gained solid is dissolved in the 1N aqueous hydrochloric acid (75ml), and extracts with methylene dichloride (75ml).By adding sodium hydroxide water layer is alkalized, and (100ml) extracts to use methylene dichloride once more.Merge twice organic extract, concentrate, and utilize 10% ethanol/methylene wash-out,, obtain brown solid (1.29g, 70%) by silica gel chromatography purifying gained resistates.LCMS＝289(H+)。

B. stirred overnight 4 (R)-(2-TMS ethyl carbonylamino)-tetramethyleneimine-2 (S)-carboxylate methyl ester (1.29g, 4.50mmol), 2 (S)-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-olefin(e) acid (1.22g, 4.51mmol), HATU (2.06g, 5.41mmol) and diisopropylethylamine (1.18ml, 6.76mmol) solution in dimethyl formamide (10ml).To react with ethyl acetate (150ml) dilution, (2 * 100ml) washings also concentrate through dried over mgso with the 1N aqueous hydrochloric acid.Obtain oil by silica gel chromatography, (0.28g 6.76mmol) stirs 2 hours together with lithium hydroxide in methyl alcohol (5ml) with this oil.To react with the methylene dichloride dilution, and,, obtain 1.2g (49%) product through dried over mgso and concentrated with the washing of 1N aqueous hydrochloric acid.

C. to 1 (R)-tert-butoxycarbonyl amino-2 (S)-vinyl-cyclopropane carboxylic acid acetoacetic ester (0.70g, add in 2.75mmol) 4N HCl/ dioxan solution (2.87ml, 11.46mmol).Stir after 2 hours, concentration response obtains solid.Add 1-(2 (S)-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-enoyl-)-4 (R)-(2-TMS ethyl carbonylamino)-tetramethyleneimine-2 (S)-carboxylic acid (1.21g to this solid; 2.29mmol), HATU (1.05g; 2.75mmol) and diisopropylethylamine (1.60ml, 9.17mmol) and methylene dichloride (10ml) and at room temperature stir described reaction 18 hours.Reaction is placed on the silica gel, utilize 50% ethyl acetate/hexane eluant solution, obtain being the product (1.27g, 83%) of water white oil.665(H+)。

D. by in wherein blasting N ₂With 1-{[1-(2 (S)-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-enoyl-)-4 (R)-(2-TMS ethyl carbonylamino)-tetramethyleneimine-2 (S)-carbonyl]-amino }-2 (S)-vinyl-cyclopropane-1-(R)-carboxylic acid, ethyl esters (1.27g, the 1.91mmol) solution of (195ml) degassing in methylene dichloride.Add dichloro (adjacent isopropyl phenyl-methylene radical) (tricyclohexyl phosphine) ruthenium (II) (0.057g, 0.096mmol) and 40 ℃ under, will react stirring 16 hours.Concentration response places on the silica gel and utilizes 50% ethyl acetate/hexane wash-out.(1.0M in THF, 2.87ml) handles and is heated to 50 ℃ to gained oil, continues 4 hours with TBAF.Reaction is placed on the silica gel and, obtain brown solid (0.65g, 69%) with 20% ethanol/methylene wash-out. ¹H?NMR(CDCl ₃，400MHz)：δ1.06-1.66(m，17H)，1.85-1.95(m，2H)，2.0-2.1(m，1H)，2.1-2.2(m，1H)，2.2-2.3(m，1H)，2.65-2.75(M，1H)，3.40(m，1H)，3.73-3.83(m，2H)，4.08-4.19(m，2H)，4.56(m，1H)，4.78(d，J＝5.5Hz，1H)，5.20(t，J＝8.1Hz，1H)，5.34(d，J＝8.1Hz，1H)，5.47(dt，J＝4.5，10.8Hz，1H)，7.08(s，1H)。493(H+)。

Preparation with compound of universal architecture V

Example 5-1:

Compd A R00287262

(1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-[(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl)-amino]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00287262) synthetic

With 3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl chloride (0.030g, 0.152mmol), (1S, 4R, 6S, 14S, 18R)-and 18-amino-14-tert-butoxycarbonyl amino-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid, ethyl ester (and 0.025g, 0.050mmol), DIEA (0.027ml, 0.153mmol) and the stirring 18 hours in methylene dichloride (0.3ml) together of the solution of catalytic amount DMAP.Reaction is placed on the silica gel, utilize 40% acetone/hexane wash-out and isolate the solid product that is white in color.Solid is dissolved in the methyl alcohol, with lithium hydroxide (0.011g, 0.254mmol) and 1 processing of dripping.Stir after 5 hours, described reaction is with methylene dichloride (30ml) dilution, and with 1N aqueous hydrochloric acid (30ml), salt water washing, through dried over mgso and concentrated, the solid title compound obtains being white in color.LCMS＝624(MH+)。

Program described in the general formula use-case 5-1, and with 1,3-dihydro-isoindole-2-carbonyl chloride replaces 3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl chloride prepares following compound.LCMS＝610(H+)。

Example 5-2:

Compd A R00298980

According to the program described in the example 5-1, and using 1,3-dihydro-isoindole-2-carbonyl chloride replaces 3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl chloride, prepare (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-[(1,3-dihydro-isoindole-2-carbonyl)-and amino]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00298980).MS?m/e?608.2(M-1)。

Example 5-3:

Compd A R00304160

According to the program described in the example 5-1, and using 3,4-dihydro-2H-quinoline-1-carbonyl chloride replaces 3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl chloride, prepare (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonyl amino-18-[(3,4-dihydro-2H-quinoline-1-carbonyl)-and amino]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304160).MS?m/e?524.3(M ⁺+1-100)。

Preparation with compound of universal architecture VI

Example 6-1:

Compd A R00304010

Same program described in the step 4 of use-case 1-2; just with thio-carbonyldiimidazole substituted carbonyl diimidazole; prepare (1S; 4R, 6S, 14S; 18R)-14-tert-butoxycarbonyl amino-18-[(3; 4-dihydro-1H-isoquinoline 99.9-2-carbon sulfonyl)-and amino]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid (compd A R00304010).LCMS＝640(H+)。MS?m/e?640.1(M ⁺+1)。

Preparation with compound of universal architecture VII

Example 7-1:

Compd A R00287266

According to the same program described in the example 3-1; begin by the prepared acid of program described in the foundation example 5-1; come synthetic (1S; 4R, 6S, 14S; 18R-{4-cyclopropane sulfonyl amino carbonyl-18-[(3; 4-dihydro-1H-isoquinoline 99.9-2-carbonyl)-and amino]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-14-yl-t-butyl carbamate (compd A R00287266).MS?m/e?727.0(M ⁺+1)。

Example 7-2:

Compd A R00304008

According to the same program described in the example 3-1; begin by the prepared acid of program described in the foundation example 5-2; prepare (1S; 4R, 6S, 14S; 18R-{4-cyclopropane sulfonyl amino carbonyl-18-[(1; 3-dihydro-isoindole-2-carbonyl)-and amino]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-14-yl-t-butyl carbamate (compd A R00304008).MS?m/e?613.2(M ⁺+1-100)。

Example 7-3:

Compd A R00304014

According to the program described in the example 2-24; begin by the prepared acyl group sulphonamide of program described in the foundation example 7-4; prepare (1S; 4R, 6S, 14S; 18R)-1; 3-dihydro-isoindole-2-carboxylic acid [14-(3-cyclopentyl-urea groups)-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-yl]-acid amides (compd A R00304014).MS?m/e?724.2(M ⁺+1)。

Example 7-4:

Compd A R00304012

According to the same program described in the example 3-1; begin by the prepared acid of program described in the foundation example 6-1; prepare (1S; 4R, 6S, 14S; 18R)-{ 4-cyclopropane sulfonyl amino carbonyl-18-[(3; 4-dihydro-1H-isoquinoline 99.9-2-carbonyl)-and amino]-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-14-yl-t-butyl carbamate (compd A R00304012).MS?m/e?743.0(M ⁺+1)。

Example 7-5:

AR00424775

By AR00335293 (84mg) is come synthetic (1S in 0.5mL of 4M HCl/Dioxane; 4R; 6S; 14S; 18R)-5-fluoro-1-methoxymethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester hydrochloride (compd A R00424775), and at room temperature stirred 16 hours.Follow concentration response, and in acetonitrile, handle to concentrate once more.Then utilize the dry described hydrochloride of high-vacuum pump to spend the night, the product 80mg of the solid ester that obtains being white in color.+APCI?MSm/z?690.1(M+1)。

Example 7-6:

AR004248`74

By AR00334191 (98mg) is handled come synthetic (1S, 4R, 6S in the 4M of 0.5mL HCl/ dioxan; 14S, 18R)-4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14-amino-4-cyclopropane sulfonyl amino carbonyl-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester hydrochloride (compd A R00424874), and at room temperature stirred 16 hours.Follow concentration response, and in acetonitrile, handle to concentrate once more.Then utilize the dry described hydrochloride of high-vacuum pump to spend the night, solid product (89mg) obtains being white in color.+APCI?MS?m/z?632.1(M+1)。

Example 8

NS3-NS4A proteolytic enzyme is analyzed

Form the NS3 mixture with NS4A-2

Recombination bacillus coli or baculovirus (Baculovirus) total length NS3 are diluted to 3.33 μ M with analysis buffer, and this substance transfer is gone in the eppendorf pipe, and be placed in the interior water-bath of 4 ℃ of refrigerators.Be added on an amount of NS4A-2 that reaches 8.3mM in the analysis buffer, with the volume (conversion factor-3.8mg/272 μ L analysis buffer) that equals NS3 among the step 2.1.1.This substance transfer is gone in the eppendorf pipe, and be placed in the interior water-bath of 4 ℃ of refrigerators.

After the balance to 4 ℃, in the eppendorf pipe, merge isopyknic NS3 and NS4A-2 solution, utilize manual pipettor carefully to mix, and in 4 ℃ of water-baths culturing mixt 15 minutes.Ultimate density in the mixture is 1.67 μ MNS3,4.15mM NS4A-2 (NS4A-2 of 2485 times of molar excess).

4 ℃ after following 15 minutes, shift out NS3/NS4A-2 eppendorf pipe, and in room-temperature water bath, placed 10 minutes.NS3/NS4A-2 is divided into the aliquots containig of proper volume, and is stored in-80 ℃.(during with the intestinal bacteria NS3 of 2nM in analytic liquid operation, be divided into 25 μ L aliquots containigs; During with the BV NS3 of 3nM in analytic liquid operation, be divided into 30 μ L aliquots containigs).

The NS3 restraining effect is analyzed

Step 2.2.5.Sample compound is dissolved in reaches 10mM among the DMSO, then in DMSO, be diluted to 2.5mM (1: 4).Usually, compound is added into analysis plates, obtains analyzing the initial concentration that suppresses 50mM in the curve through dilution with the concentration of 2.5mM.Serial dilution compound in analysis buffer is so that provide the solution that tried of low concentration.

Step 2.2.6.Intestinal bacteria NS3/NS4A-2 is diluted to 4nM NS3 (1.67 μ M liquid storage-18 μ L, 1.67 μ M liquid storages+7497 μ L analysis buffer of 1: 417.5).

BV NS3/NS4A-2 is diluted to 6nM NS3 (1.67 μ M liquid storage-24 μ L, 1.67 μ M liquid storages+6655 μ L analysis buffer of 1: 278.3).

Step 2.2.7.Use manual multichannel pipettor, and, 50 μ L analysis buffer are added into black Costar 96 hole polypropylene store in the A01-H01 hole of plate (storage plate) carefully not in the bubble lead 1-in plate.

Step 2.2.8.Use manual multichannel pipettor, and carefully not in the bubble lead 1-in plate, with 50 μ L being added in the A02-H12 hole of plate among the step 2.2.7 through dilution NS3/NS4A-2 from step 2.2.6.

Step 2.2.9.Use manual multichannel pipettor, and, 25 μ L in the step 2.2.5 Chinese traditional medicine dilution plate mesopore are transferred in the respective aperture of analysis plates among the step 2.2.8 carefully not in the bubble lead 1-in plate.Change the ozzle of multichannel pipettor when shifting every row's compound.

Step 2.2.10.Use manual multichannel pipettor, and carefully not in the bubble lead 1-in plate, by five suctions with distribute the 35 μ L of 75 μ L in each hole and will mix from the hole of analysis plates among the step 2.2.9.Change the ozzle of multichannel pipettor when mixing every round.

Step 2.2.11.Described plate is covered the polystyrene board lid, and at room temperature will cultivate 10 minutes from the plate that contains NS3 proteolytic enzyme and sample compound of step 2.2.10 is pre-.

In the plate of cultivating in advance from step 2.2.11, dilution RETS1 substrate in the 15mL polypropylene centrifuge tube.The RETS1 substrate is diluted to 8 μ M (646 μ M liquid storage-65 μ L, 646 μ M liquid storages+5184 μ L analysis buffer of 1: 80.75).

After the plate of pre-culturing step 2.2.11, use manual multichannel pipettor, with 25 μ L substrates be added into institute on the plate porose in.As the rapid mix aperture inclusion of step 2.2.10, but 65 μ L among the 100 μ L in the mix aperture.

Upward plate is read in Molecular Devices SpectraMax Gemini XS plate reader (plate reader) with dynamic mode.Reader is set: time for reading: 30 minutes; At interval: 36 seconds; Reading times: 51; Excitation wavelength lambda: 335nm; Emission wavelength lambda: 495nm; Threshold value: 475nm; Automix: close; Calibration: once; PMT: height; Reading times/hole: 6; Vmax pts:21 or 28/51, visual response lineal measure and deciding.

Use four parametric line fit equation to determine IC ₅₀, and use following Km value to convert the Ki value to:

Total length intestinal bacteria NS3-2.03 μ M

Total length BV NS3-1.74 μ M

Ki=IC wherein ₅₀/ (1+[S]/Km)

At HCV sub-genome duplication, by selective key thing albumen, (Neomvcin phosphotransferaseII, ELISA NPTII) carries out quantitatively neomycin phosphotransferase II among the GS4.3

HCV sub-genome duplication (1377/NS3-3 ', deposit numbers AJ242652) stably maintain in the HuH-7 liver cancer cell, set up by people such as Lohmann (Science 285:110-113 (1999)).Containing the cell culture of replicon, be appointed as GS4.3, is to derive from cancer research institute (Institute for Cancer Research, Fox Chase CancerCenter, Philadelphia, Christoph doctor Seeger Pennsylvania).

With the GS4.3 cell in 37 ℃, 5%CO ₂Under maintain among the DMEM (Gibco 11965-092), be supplemented with L-glutaminate 200mM (100 times) (Gibco2503 0-081), non-essential amino acid (NEAA) (Biowhittaker 13-114E), hot deactivation (HI) foetal calf serum (FBS) (Hyclone SH3007.03) and 750 μ g/ml Geneticins (geneticin) (G418) (Gibco 10131-035) among the described DMEM.Every 2-3 days cell divided 1: 3 or 4 again.

In analysis preceding 24 hours, collect the GS4.3 cell, counting, and keep substratum (as above) with 100 μ l standards and it is coated in that 96 orifice plates (Costar 3585) are gone up and cultivation under these conditions with 7500 cells/well.For beginning to analyze, shift out substratum, with PBS (Gibco 10010-023) washed cell once, and add 90 μ l and analyze substratum (DMEM, L-glutaminate, NEAA, 10%HI FBS, no G418).Inhibitor is made 10 * liquid storage in analyzing substratum, (from 3 times of dilutions of 10 μ M to 56pM ultimate densities, final DMSO concentration 1%) add 10ul to the double hole, and wobble plate is so that mix, and as above cultivates 72 hours.

Obtain NPRII ELISA test kit (be used for the direct ELISA test macro of compound of neomycin phosphotransferase II, PSP 73000/4800) from AGDIA company.Follow manufacturers instruction, some modifications are wherein arranged.Make 10 * PEB-1 lysis buffer, to comprise 500 μ M PMSF (Sigma P7626, the 50mM liquid storage is in Virahol).Cultivate after 72 hours, with the PBS washed cell once, and in every hole, add the PEB-1 that 150 μ l contain PMSF.Under the room temperature,, then freezing down at-70 ℃ with plate vigorous agitation 15 minutes.Plate is thawed, thoroughly mix lysate, and add in 100 μ l to the NPTII Elisa plates.Obtain typical curve.Make up the lysate of the control wells of the DMSO processing of hanging oneself, use and contain the PEB-1 serial dilution of PMSF, and be applied in the double hole of elisa plate, initial lysate amount is in 150 μ l-2.5 μ l scopes.In addition, double applies 100 μ l damping fluids separately, as the blank group.Plate is sealed and at room temperature stirred gently 2 hours.After ravin is cultivated, plate is washed (5 * 300 μ l) with PBS-T (0.5%Tween-20, PBS-T provides) in the ELISA test kit.For detecting, in PBS-T, make 1 times of diluent of enzyme conjugates diluent MRS-2 (5 *), to specifications to 1: 100 diluent that wherein adds enzyme conjugates A and B.Again with plate sealing, and follow to stir and cultivate: capping, room temperature, 2 hours.Then repeat described washing step, and add the room temperature tmb substrate of 100 μ l.Cultivated back (room temperature, stirring, capping) in about 30 minutes, with 50 μ l 3M sulfuric acid stopped reaction.On Molecular Devices Versamax plate reader, under 450nm, plate is read.

The inhibitor effect is expressed as the percentage ratio of the control signal of handling through DMSO, and uses following 4 parametric equations to calculate and suppress curve: y=A+ ((B-A)/(1+ ((C/x) ^D))), and wherein C is maximum half activity (half-maximal activity) or EC ₅₀

Active example

Wherein:

A represents as shown the IC less than 50 μ M ₅₀Or EC ₅₀

B represents as shown the IC less than 10 μ M ₅₀Or EC ₅₀

C represents as shown the IC less than 1 μ M ₅₀Or EC ₅₀

And D represents as shown the IC less than 0.1 μ M ₅₀Or EC ₅₀

Table 2

Compound	NS3-NS4A IC ₅₀	Replicon EC ₅₀	Compound	NS3-NS4A IC ₅₀	Replicon EC ₅₀
Compound	NS3-NS4A IC ₅₀	Replicon EC ₅₀	Compound	NS3-NS4A IC ₅₀	Replicon EC ₅₀	AR00220042	C	B	AR00301383	B	N/A
AR00220122	A	N/A	AR00301745	C	B	AR00220042	C	B	AR00301383	B	N/A
AR00220122	A	N/A	AR00301745	C	B	AR00226824	B	N/A	AR00301746	D	D
AR00226825	B	N/A	AR00301747	D	D	AR00226824	B	N/A	AR00301746	D	D
AR00226825	B	N/A	AR00301747	D	D	AR00247310	C	N/A	AR00301749	C	B
AR00248687	C	N/A	AR00301751	D	D	AR00247310	C	N/A	AR00301749	C	B
AR00248687	C	N/A	AR00301751	D	D	AR00248688	B	N/A	AR00304000	C	B
AR00248689	C	N/A	AR00304008	D	D	AR00248688	B	N/A	AR00304000	C	B
AR00248689	C	N/A	AR00304008	D	D	AR00254906	D	C	AR00304010	C	B
AR00261407	D	C	AR00304012	D	C	AR00254906	D	C	AR00304010	C	B
AR00261407	D	C	AR00304012	D	C	AR00261408	D	D	AR00304014	D	D
AR00261409	D	B	AR00304062	B	N/A	AR00261408	D	D	AR00304014	D	D
AR00261409	D	B	AR00304062	B	N/A	AR00282131	D	D	AR00304063	C	B
AR00287262	B	N/A	AR00304065	C	B	AR00282131	D	D	AR00304063	C	B
AR00287262	B	N/A	AR00304065	C	B	AR00287266	D	C	AR00304066	C	B
AR00291871	D	C	AR00304067	C	B	AR00287266	D	C	AR00304066	C	B
AR00291871	D	C	AR00304067	C	B	AR00291875	C	B	AR00304072	C	B
AR00294376			AR00304073	C	B	AR00291875	C	B	AR00304072	C	B

?AR00294377	C	B	?AR00304074	C	B
?AR00294377	C	B	?AR00304074	C	B	?AR00294378	C	B	?AR00304075	C	B
?AR00294381	D	D	?AR00304076	D	C	?AR00294378	C	B	?AR00304075	C	B

Compound	NS3-NS4A IC ₅₀	Replicon EC ₅₀	Compound	NS3-NS4A IC ₅₀	Replicon EC ₅₀
Compound	NS3-NS4A IC ₅₀	Replicon EC ₅₀	Compound	NS3-NS4A IC ₅₀	Replicon EC ₅₀	?AR00294382	C	N/A	AR00304077	D	B
?AR00294383	B	N/A	AR00304078	D	C	?AR00294382	C	N/A	AR00304077	D	B
?AR00294383	B	N/A	AR00304078	D	C	?AR00294384	C	B	AR00304079	D	C
?AR00294980	B	N/A	AR00304080	D	D	?AR00294384	C	B	AR00304079	D	C
?AR00294980	B	N/A	AR00304080	D	D	?AR00298989	B	N/A	AR00304081	D	C
?AR00298990	B	N/A	AR00304082	D	D	?AR00298989	B	N/A	AR00304081	D	C
?AR00298990	B	N/A	AR00304082	D	D	?AR00298996	D	D	AR00304103	B	B
?AR00298997	D	D	AR00304125	C	B	?AR00298996	D	D	AR00304103	B	B
?AR00298997	D	D	AR00304125	C	B	?AR00301338	D	B	AR00304126	C	B
?AR00304183	A	N/A	AR00304127	C	B	?AR00301338	D	B	AR00304126	C	B
?AR00304183	A	N/A	AR00304127	C	B	?AR00311814	D	B	AR00304154	B	N/A
?AR00311815	D	C	AR00304158	A	N/A	?AR00311814	D	B	AR00304154	B	N/A
?AR00311815	D	C	AR00304158	A	N/A	?AR00312023	C	N/A	AR00304160	A	N/A
?AR00312024	D	D	AR00304161	D	D	?AR00312023	C	N/A	AR00304160	A	N/A
?AR00312024	D	D	AR00304161	D	D	?AR00312025	D	D	AR00304162	D	D
?AR00312026	D	D	AR00304163	D	D	?AR00312025	D	D	AR00304162	D	D
?AR00312026	D	D	AR00304163	D	D	?AR00314578	C	N/A	AR00320123	C	B
?AR00314635	D	D	AR00320220	D	D	?AR00314578	C	N/A	AR00320123	C	B
?AR00314635	D	D	AR00320220	D	D	?AR00314654	D	D	AR00320221	C	N/A
?AR00314656	D	D	AR00320222	D	B	?AR00314654	D	D	AR00320221	C	N/A
?AR00314656	D	D	AR00320222	D	B	?AR00314685	A	N/A	AR00320403	D	C
?AR00314719	D	D	AR00320445	B	N/A	?AR00314685	A	N/A	AR00320403	D	C
?AR00314719	D	D	AR00320445	B	N/A	?AR00315997	C	B	AR00320446	D	D
?AR00315998	C	B	AR00320447	D	C	?AR00315997	C	B	AR00320446	D	D
?AR00315998	C	B	AR00320447	D	C	?AR00315999	C	B	AR00320448	C	B
?AR00320001	D	D	AR00320449	D	B	?AR00315999	C	B	AR00320448	C	B
?AR00320001	D	D	AR00320449	D	B	?AR00320002	C	B	AR00320450	C	B
?AR00320073	D	D	AR00320506	D	D	?AR00320002	C	B	AR00320450	C	B
?AR00320073	D	D	AR00320506	D	D	?AR00320074	D	B	AR00320547	D	D
?AR00320075	C	B	AR00320548	D	D	?AR00320074	D	B	AR00320547	D	D
?AR00320075	C	B	AR00320548	D	D	?AR00320076	C	B	AR00320549	D	D
?AR00320077	C	B	AR00320556	D	D	?AR00320076	C	B	AR00320549	D	D
?AR00320077	C	B	AR00320556	D	D	?AR00320078	D	B	AR00320557	D	D
?AR00320079	D	D	AR00320574	D	D	?AR00320078	D	B	AR00320557	D	D
?AR00320079	D	D	AR00320574	D	D	?AR00320080	D	C	AR00320575	D	C
?AR00320081	D	D	AR00320576	B	N/A	?AR00320080	D	C	AR00320575	D	C
?AR00320081	D	D	AR00320576	B	N/A	?AR00320082	D	D	AR00320577	C	B
?AR00320119	D	D	AR00320578	D	D	?AR00320082	D	D	AR00320577	C	B
?AR00320119	D	D	AR00320578	D	D	?AR00320120	D	D	AR00320579	D	D
?AR00320121	D	D	?AR00320580	D	D	?AR00320120	D	D	AR00320579	D	D

Compound

?NS3-NS4A

Replicon

Compound

?NS3-NS4A

Replicon

	IC ₅₀	EC ₅₀		IC ₅₀	EC ₅₀
	IC ₅₀	EC ₅₀		IC ₅₀	EC ₅₀	?AR00320122	c	B	?AR00320581	D	D
?AR00324375	c	C	?AR00320582	D	D	?AR00320122	c	B	?AR00320581	D	D
?AR00324375	c	C	?AR00320582	D	D	?AR00334286	D	D	?AR00320774	D	C
?AR00334385	D	D	?AR00333833	D	D	?AR00334286	D	D	?AR00320774	D	C
?AR00334385	D	D	?AR00333833	D	D	?AR00365387	D	D	?AR00334191	D	D
?AR00365425	D	N/A	?AR00340479	D	D	?AR00365387	D	D	?AR00334191	D	D
?AR00365425	D	N/A	?AR00340479	D	D	?AR00365572	D	D	?AR00365388	D	N/A
?AR00333802	D	D	?AR00365426	D	B	?AR00365572	D	D	?AR00365388	D	N/A
?AR00333802	D	D	?AR00365426	D	B	?AR00334188	D	C	?AR00333801	D	D
?AR00334248	D	C	?AR00333803	D	C	?AR00334188	D	C	?AR00333801	D	D
?AR00334248	D	C	?AR00333803	D	C	?AR00334250	D	D	?AR00334247	D	C
?AR00364266	D	C	?AR00334249	D	C	?AR00334250	D	D	?AR00334247	D	C
?AR00364266	D	C	?AR00334249	D	C	?AR00334339	D	D	?AR00334341	D	D
?AR00365438	D	D	?AR00365427	D	D	?AR00334339	D	D	?AR00334341	D	D
?AR00365438	D	D	?AR00365427	D	D	?AR00365349	C	C	?AR00365193	D	D
?AR00340303	D	C	?AR00333842	C	B	?AR00365349	C	C	?AR00365193	D	D
?AR00340303	D	C	?AR00333842	C	B	?AR00340156	D	C	?AR00365381	C	C
?AR00340188	D	C	?AR00340122	D	C	?AR00340156	D	C	?AR00365381	C	C
?AR00340188	D	C	?AR00340122	D	C	?AR00334399	D	D	?AR00340178	D	D
?AR00338070	D	D	?AR00334314	D	D	?AR00334399	D	D	?AR00340178	D	D
?AR00338070	D	D	?AR00334314	D	D	?AR00341649	D	D	?AR00338066	D	D
?AR00333224	B	N/A	?AR00338071	D	D	?AR00341649	D	D	?AR00338066	D	D
?AR00333224	B	N/A	?AR00338071	D	D	?AR00333248	B	N/A	?AR00364936	D	C
?AR00333277	B	N/A	?AR00333225	B	N/A	?AR00333248	B	N/A	?AR00364936	D	C
?AR00333277	B	N/A	?AR00333225	B	N/A	?AR00365083	D	D	?AR00333276	B	N/A
?AR00340494	D	D	?AR00365369	D	C	?AR00365083	D	D	?AR00333276	B	N/A
?AR00340494	D	D	?AR00365369	D	C	?AR00365252	D	C	?AR00333831	D	D
?AR00334220	D	C	?AR00365082	D	C	?AR00365252	D	C	?AR00333831	D	D
?AR00334220	D	C	?AR00365082	D	C	?AR00334225	D	C	?AR00334218	D	D
?AR00340173	D	B	?AR00334222	D	D	?AR00334225	D	C	?AR00334218	D	D
?AR00340173	D	B	?AR00334222	D	D	?AR00333462	D	D	?AR00334226	D	D
?AR00333463	D	D	?AR00340526	D	D	?AR00333462	D	D	?AR00334226	D	D
?AR00333463	D	D	?AR00340526	D	D	?AR00345032	D	D	?AR00345075	D	C
?AR00345090	D	D	?AR00345094	D	D	?AR00345032	D	D	?AR00345075	D	C
?AR00345090	D	D	?AR00345094	D	D	?AR00345095	D	D	?AR00345096	D	D
?AR00364924	D	D	?AR00371946	D	N/A	?AR00345095	D	D	?AR00345096	D	D
?AR00364924	D	D	?AR00371946	D	N/A	?AR00371947	C	N/A	?AR00371948	D	N/A
?AR00340495	D	D	?AR00365084	D	B	?AR00371947	C	N/A	?AR00371948	D	N/A
?AR00340495	D	D	?AR00365084	D	B	?AR00364989	D	D	?AR00365019	D	D
?AR00424775	D	N/A	?AR00424874	D	N/A	?AR00364989	D	D	?AR00365019	D	D

Specificity analyses

When assessing compound in specificity analyses, discoverable type I compound has selectivity, because they do not show remarkable restraining effect in cathepsin B (Cathepsin B), Quimotrase (Chymotrypsin), zymoplasm (Thrombin) or leukocyte elastase (Leukocyte Elastase).

Example 9: the pharmacokinetics analysis of compound

Method

At first synthetic compound and as described in the above example 8 fluorescence NS3/4 proteolytic enzyme analyze and based on the HCV replicon system of cell in its usefulness of test (IC ₅₀).Then in conjunction with live body stranger hepatomicrosome (human liver microsome, HLM) with the liver cell stability study, utilize the drug plasma dynamic metabolism of IV dispensing back in mouse (Rattus sp.) to analyze, come from having less than design metabolic stability compound the compound of the usefulness of 20 nM.Further optimize these iguides' (leads) the rational matter of class medicine, and offer medicine to mouse (Rattus sp.), so that evaluation liver, heart and plasma concentration with oral dosage.

Test in rat after 3mg/kg oral dosage, compound hepatic clearance in time.In liver, presented in back 8 hours than effectively suppressing 50% maximum compound concentration (the replicon EC that suppresses in the replicon analysis for dispensing ₅₀) any compound of concentration of high at least 100 times, use dosage up to the oral BID of 30mg/kg to last seven days and in rat, carry out other toxicology evaluation.

The result

Compd A R294381, AR261408, AR333833 and AR334191 produce the replicon EC of about 2nM ₅₀Value, and in rat, dog and human liver cell culture assays, show in vitro stability, these data will be predicted the clearance rate that how to slow down from liver.In addition, these compounds show the high selectivity with respect to one group of other serine protease, even and also do not have a remarkable restraining effect of pair cell cytochrome p 450 (Cytochrome P450) isomer or hERG channel activity under the highest test concentrations (10 μ M).

For compd A R294381, AR261408, AR333833 and AR334191, their replicon EC separately of the concentration ratio that a 30mg/kg oral dosage in mouse (Rattus sp.) produces back 24 hours of dispensing in liver ₅₀At least 200 times of value height.

Heart that compd A R334191 produces and blood plasma level reach two orders of magnitude than the liver concentration in the same animals is low, and are associated on kinetics with liver concentration.The compd A R334191 of more rational clinically oral dosage (3mg/kg) is at the replicon EC of back 8 hours these compounds of concentration ratio in liver of dispensing ₅₀Be worth big more than 100 times.After the compd A R334191 of the dosage that is exposed to the oral BID of 30mg/kg, in the animal of treatment, do not observing mortality ratio, body weight change or facing the art chemical abnormality.

Conclusion

Effective, small molecules HCV NS3 proteinase inhibitor metabolic stability, can be oral have been developed.Under optimum oral administration concentration (3mg/kg), these compounds show back 8 hours high edema due to dysfunction of the liver that goes out to offer medicine is flat (than replicon EC separately ₅₀Be worth high 100 times).Exposure to blood plasma and heart reaches two orders of magnitude than observed hanging down in the liver, and so low concentration makes any possible general toxicological issues reduce to minimum.

When compd A R334191 in the time of 7 days, does not show toxicity with 30mg/kg BID administration in mouse (Rattus sp.), be provided at least 10 times of security surpluses on the supposition effective dose (3mg/kg), and produce the replicon EC that surpasses this compound ₅₀The liver concentration that is worth 100 times.

The preparation of portion C viral inhibitors

Identical in the employed term in this part and the implication of structure title and the portion C above.Mentioning at optional network specific digit or mark any in this part should be in this part or above understand in used corresponding numbering or the labeling scheme content in the portion C, rather than in this paper other local used possible similar or the numbering that is equal to or labeling scheme content, understand, except as otherwise noted.

Formula XI-XVII compound can synthesize according to method hereinafter described.

Methodology

Prepare NS3 inhibitor as shown in example 1-35 according to chemical reaction illustrated in the flow process 1.Prepare intermediate 1 (R)-tert-butoxycarbonyl amino-2 (S)-vinyl-cyclopropane carboxylic acid acetoacetic ester, 2 (S)-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-olefin(e) acid and big ring intermediate of hydroxyl (step C) with the similar fashion described in the international application case PCT/CA00/00353 No. 00/59929, case WO (open).2 (S)-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-olefin(e) acid also can be buied from RSP Amino Acids.

Example 1: compound 101 synthetic

Flow process 1

Synthesizing of steps A: 2S-(1-ethoxy carbonyl-2-vinyl-cyclopropyl carbamyl)-4R-hydroxyl-tetramethyleneimine-1-carboxylic acid tert-butyl ester

To be equipped with ethyl-(1R, 2S)/(1S, 2R)-1-amino-2-vinyl cyclopropyl carboxylic acid esters (1.0g, 5.2mmol), trans-N-(tert-butoxycarbonyl)-4-hydroxyl-L-proline(Pro) (1.3g, 1.1 add 30mL DMF equivalent) and in the flask of HATU (2.7g, 1.1 equivalents), make solution.Solution is cooled to 0 ℃ in ice-water bath, then follows and stir DMF (15ml) solution that slowly adds DIEA (4.4ml, 4 equivalents).Making reaction be warmed up to room temperature and stir spends the night.

Behind the 16h, react completely by the HPLC monitoring.With EtOAc (100mL) dilution, water (3 * 40mL), saturated sodium bicarbonate (2 * 40mL) and salt solution (2 * 40mL) washings are followed through Na ₂SO ₄Dry and concentrated, obtain dark coppery oil.With crude product purifying (eluent: acetone/hexane 3: 7), obtain being the pure product of wanting (770mg, 32%) of brown spumescence powder on silica gel.

Step B:1R-{[1-(2S-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-enoyl-)-4R-hydroxyl-tetramethyleneimine-2S-carbonyl]-amino }-2S-vinyl-cyclopropane carboxylic acid acetoacetic ester synthetic

Will (2.85g 7.7mmol) be dissolved among the 10mL 4N HCl (dioxan), and keeps 90min in room temperature, to remove the BOC protecting group from two peptide prods of steps A.Then it is concentrated, be dissolved in the acetonitrile, and concentrate twice once more.To this light brown resistates add 2 (S)-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-olefin(e) acid (2.2g, 8.1mmol) and HATU (3.2g, 8.5mmol), then interpolation 80mL DMF under nitrogen.To be reflected on the ice-water bath and cool off 15 minutes, and follow stirring in reaction, dropwise to add DIEA (5.4mL, 5mL DMF solution 30.9mmol) afterwards.Remove ice bath and make it slowly be warming up to room temperature, and will react to stir and spend the night.

Behind the 18h, the TLC demonstration reacts completely.To react with EtOAc (300mL) dilution and water (3 * 150mL), saturated sodium bicarbonate (2 * 150mL), salt solution (150mL) washing, dry (Na ₂SO ₄) and remove and desolvate.On the Biotage40M by flash chromatography on silica gel method purifying (eluent=3% is to 5% MeOH in DCM) crude product, obtain being brown spumescence solid and want product (3.5g, 87%).

Step C:(1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-hydroxyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid, ethyl ester synthetic

Will (2.6g 5.0mmol) be dissolved among the 500mLDriSolve DCE that is in the 1L round-bottomed flask, obtains solution from the product of step B.By sloughing in 1 hour in wherein blasting nitrogen.Then under nitrogen, at room temperature add HoveydaShi catalyzer (0.25 equivalent).Reaction is placed in the pre-heated oil bath (50 ℃) and stirs and spend the night.Behind the 16h, reaction is transformed into Vandyke brown.TLC (DCM/EtOAc 1: 1) demonstration cleaning is converted into has a little low R _fThe new spot of value.Concentration response, and on silica gel purifying (Biotage 40M, eluent=DCM/EtOAc gradient was by 1: 1 to 1: 2), obtain being the product of wanting (0.64g, 52%) of brown spumescence powder. ¹H?NRM(CDCL ₃，400MHz)δ1.21(t，J＝7.0Hz，3H)，1.43(s，9H)，1.20-1.50(m，6H)，1.53-1.68(m，2H)，1.83-1.96(m，2H)，1.98-2.28(m，4H)，2.60(m，1H)，3.13(br?s，1H)，3.68(m，1H)，3.94(m，1H)，4.01-4.19(m，2H)，4.48(m，1H)，4.56(br?s，1H)，4.79(m，1H)，5.26(t，J＝9.4Hz，1H)，5.36(d，J＝7.8Hz，1H)，5.53(m，1H)，7.19(br?s，1H)。MS?m/z?494.0(M ⁺+1)。

Step D:(1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid, ethyl ester synthetic

Will from the big ring product of step C (110mg 0.22mmol) is dissolved among the DCM (2.2mL), follow disposable interpolation CDI (45mg, 0.27mmol).To react at room temperature to stir and spend the night.Behind the 15h, (DCM/MeOH9: 1) monitoring reacts completely by TLC.Dropwise (0.12mL 1.1mmol) adds in the reaction, and spends the night at 40 ℃ of following stirring reactions with isoindoline.Behind the 22h, the TLC demonstration reacts completely.Reaction is cooled to room temperature, with DCM (6mL) dilution, with the 1N aqueous hydrochloric acid (2 * 2mL), saturated sodium bicarbonate (2mL), salt solution (2mL) washing, dry (Na ₂SO ₄), and concentrate.With crude product on silica gel purifying (Biotage 40S, eluent: 2% to 4% MeOH in DCM), the product of (131mg, 90%) of the powder powder that obtains being white in color.

Step e: (1S, 4R, 6S, 14S, 18R)-and 14-tert-butoxycarbonyl amino-18-(1,3-dihydro-isoindole-2-carbonyl oxygen base)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-4-carboxylic acid synthetic

Will (60mg 0.092mmol) be dissolved in 0.9mL (THF/MeOH/H from the macrocyclic ester product of step D ₂O2: 1: 1) in the mixed solvent, then adds LiOH-H ₂O (23mg, 6 equivalents).Mixture at room temperature stirred spend the night.Behind the 18h, TLC (DCM/MeOH 9: 1) shows to have low R _fThe clean new spot of value.Reaction is concentrated to almost dry, and between 1N aqueous hydrochloric acid (15mL) and DCM (20mL), divides molten.(2 * 10mL) extract water layer with DCM.Merge organic layer, through Na ₂SO ₄Dry and concentrate, the product of (50mg, 87%) of the spumescence powder that obtains being white in color. ¹H?NMR(CDCl ₃，500MHz)δ1.21-1.44(m，8H)，1.32(s，9H)，1.54-1.62(m，2H)，1.78-1.88(m，2H)，2.04-2.13(m，1H)，2.16-2.23(m，1H)，2.24-2.36(m，2H)，2.66-2.74(m，1H)，3.87-3.90(m，1H)，4.15(d，J＝11.0Hz，1H)，4.37-4.43(m，1H)，4.61-4.77(m，5H)，5.18(t，J＝10.3Hz，1H)，5.24-5.31(m，1H)，5.40-5.45(m，1H)，5.58-5.66(m，1H)，7.11-7.30(m，4H)。MS?m/z?611.0(M ⁺+1)。

Step F: (1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(N, N-dimethyl methyl acyl group-aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester (compound 101) synthetic

Will from the big naphthenic acid product of step e (40mg 0.066mmol) is dissolved among the DCM of 0.7mL, follow disposable interpolation CDI (13mg, 0.079mmol).Mixture was stirred 2 hours in 50 ℃ of oil baths.TLC (10% methyl alcohol in methylene dichloride) shows that sour initial substance has not had and higher R occurred having _fThe new spot of value.Then in reaction, add N, N-dimethyl methyl acid amides (12mg, 0.098mmol; Available from TCI), then add DBU (15mg, 0.098mmol).Again 50 ℃ of down heating 2 hours, TLC and LCMS all show and react completely and formed product.Concentration response, and directly be loaded on the Biotage 40S silicagel column.By purified by flash chromatography (40% ethyl acetate of eluent=in hexane contains 1% formic acid), the solid that obtains being white in color is wanted product (30mg, 64%) with it.MS?m/z?715.5(APCI-，M-1)。

According to the similar program described in the above example 1, just in step F with other suitable sulfonamide substitutions N, N-dimethyl methyl acid amides and/or with other amine replacement isoindoline prepares the following compound among the example 2-35.Used sulphonamide or buy from commercial source is perhaps by route A described in the following flow process 2 or B preparation.Describe to some extent in the literature with method like the route category-A (for example, Heteroatom Chemistry, 2001,12 (1), 1-5).According to document program (Winum, people such as J-Y, Organic Letters, 2001,3,2241-2243) sulphonamideization (sulfamoylating) the reagent a in the preparation route B.

Route A:

Flow process 2

Synthesizing of N-cyclopropyl sulphonamide

Under 0 ℃, (1mL 11.5mmol) adds anhydrous tertiary butanol (1.1mL, 1 equivalent) in stirred solution in 20mL DriSolve DCM to Sulfuryl chloride isocyanate.Stir after 90 minutes, gained carbamate sulphonamide chlorine solution and the 5mL TEA in 20mL DCM dropwise are added in the solution of cyclopropylamine (0.66g, 1 equivalent) in 25mL DCM and 3mL TEA.During the interpolation temperature of reaction is remained on below 5 ℃.Remove ice bath after the interpolation and at room temperature stirred the gained mixture 3 hours.

TLC (Hex/EA 1: 1) shows to have higher R _fA main spot of value.LCMS shows that product forms.Then with reaction mixture with 100mL DCM dilution and with 0.1N HCl (2 * 200mL) and salt solution (150mL) wash.Organic layer is through Na ₂SO ₄Drying also concentrates, and obtains being the Boc protection sulphonamide 1.2g of light yellow solid. ¹H-NMR shows that it is the product of being wanted that contains small amount of impurities.Crude product from ethyl acetate/hexane recrystallization (room temperature to 0 ℃), is obtained 0.64g canescence crystallization pure products.1H?NMR(CDCl ₃，400MHz)δ0.71-0.77(m，4H)，1.51(s，9H)，2.44(m，1H)，5.58(br?s，1H)，7.42(br?s，1H)。MS?m/z?234.7(APCI-，M-1)。

For removing the Boc protecting group, will be dissolved in DCM: in 1: 1 (volume ratio) mixture of the 10mL of TFA, and at room temperature kept 1 hour from above-mentioned product.Then concentrate by rotary evaporation then by high vacuum.With dense innage vacuum solidification, obtain being the title product of pale solid. ¹H?NMR(CDCl ₃，400MHz)δ0.66-0.74(m，4H)，2.57-2.58(m，1H)，5.29(br?s，2H)，5.42(br?s，1H)。

Synthesizing of pyrrolidinol sulphonamide

For the synthetic described same program of N-cyclopropyl sulphonamide prepares title compound, just use tetramethyleneimine substituted ring propylamine according to above-mentioned.Protect title product for Boc: ¹H NMR (CDCl ₃, 400MHz) δ 1.49 (s, 9H), 1.92-1.95 (m, 4H), 3.48-3.52 (m, 4H), 7.02 (br s, 1H).MS?m/z?249(APCI-，M-1)。

Synthesizing of morpholine alcohol sulphonamide

For the synthetic described same program of N-cyclopropyl sulphonamide prepares title compound, just use morpholine substituted ring propylamine according to above-mentioned.Protect title product for Boc: ¹H NMR (CDCl ₃, 400MHz) δ 1.50 (s, 9H), 3.39 (t, 4H), 3.76 (t, 4H), 7.18 (br s, 1H).MS?m/z?265(APCI-，M-1)。

Synthesizing of thiazol-2-yl SULFAMIDE

For the synthetic described same program of N-cyclopropyl sulphonamide prepares title compound, just use thiazolamine substituted ring propylamine according to above-mentioned.Yet, never isolate Boc protection intermediate, because protecting group can lose during the reaction treatment and after re-crystallization step.(Biotage 40M, the 5%-10%MeOH of eluent=in DCM) isolates title product afterwards at silica gel column chromatography. ¹H?NMR(d ⁶-DMSO，400MHz)δ6.52(br?s，2H)，6.75(d，1H)，7.19(d，1H)，12.1(br?s，1H)。MS?m/z?180(ESI+，MH ⁺)。

Synthesizing of 4-methyl-piperazinyl sulphonamide

Prepare title compound according to the route B in the flow process 2.With 4-methyl-piperazine (0.15g, 1.50mmol) dissolving is among the 3mL DriSolve DCM among the 10mL RBF, then add sulphonamide reagent a (0.45g, 1.50mmol).After stirring about 5 minutes, latter's reagent dissolves gradually, obtains clarifying, almost colourless solution.It is at room temperature stirred spend the night.After 17 hours, TLC shows and to react completely (DCM: MeOH9: 1, contain 1%TEA).Concentration response, and with the thick solid of gained pink fast by Biotage 40S silicagel column (eluent=DCM: MeOH10: 1, contain 1%TEA), the Boc protection title product of the powder that obtains being white in color, productive rate is quantitative basically. ¹H?NMR(CDCl ₃，400MHz)δ1.48(s，9H)，2.33(s，3H)，2.52(t，4H)，3.43(t，4H)。MS?m/z?278(APCI-，M-1)。

Same way as described in then synthesizing by N-cyclopropyl sulphonamide is removed the Boc protecting group, and the gained title product just is directly used in ensuing coupling step without being further purified.

Example 2:

Compound 102

According to the same program described in the example 1; just in step F, use N-cyclopropyl sulfonamide substitutions N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(N-cyclopropyl alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester.MS?m/z?728(APCI-，M-1)。

Example 3:

Compound 103

According to the same program described in the example 1; just in step F, use pyrrolidinol sulfonamide substitutions N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(pyrrolidyl alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester.MS?m/z?742(APCI-，M-1)。

Example 4:

Compound 104

According to the same program described in the example 1; just in step F, use morpholine alcohol sulfonamide substitutions N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(morpholinyl alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester.MS?m/z?758(APCI-，M-1)。

Example 5:

Compound 105

According to the same program described in the example 1; just in step F, replace N with the thiazol-2-yl SULFAMIDE; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(thiazol-2-yl amino-sulfonyl aminocarboxyl)-2; 15-dioxo-3,16 diaza-three ring [14.3.0.0 ^4,6] 19-7 alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.15 (s, 9H), 1.22-1.54 (m, 11H), 1.60 (m, 1H), 1.68-1.88 (m, 2H), 2.35-2.45 (m, 3H), 2.57 (m, 1H), 3.85 (m, 1H), 4.15 (br d, 1H), 4.48 (m, 1H), 4.65 (m, 4H), 4.74 (t, 1H), 4.92 (t, 1H), 5.43-5.52 (m, 2H), 6.92 (d, 1H), 7.20-7.33 (m, 5H), 8.18 (s, 1H).MS?m/z?770(ESI-，M-1)。

Example 6:

Compound 106

According to the same program described in the example 1; just in step D, use 5-fluorine isoindoline to replace isoindoline; come synthetic (1S, 4R, 6S; 14S; 18R)-and 5-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(N, N-dimethyl methyl acyl group-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H?NMR(400MHz，CD ₃OD)δ7.31(q，1H)，7.13(d，1H)，7.03-6.97(m，2H)，6.63(br?s，1H)，5.70(q，1H)，5.40(br?s，1H)，5.07(t，1H)，4.78-4.51(m，7H)，4.10-4.02(m，1H)，3.83(d，1H)，2.84(s，6H)，2.73-2.64(m，1H)，2.55-2.47(m，1H)，2.43-2.29(m，3H)，1.84-1.67(m，4H)，1.64-1.57(m，2H)，1.13(d，9H)，0.94-0.82(m，4H)。MS?m/z?733.4(APCI-，M-1)。

Example 7:

Compound 107

According to the same program described in the example 1; just use 1-piperidines-1-ylmethyl-3 in step D, 4-dihydro-1H-isoquinoline 99.9 replaces isoindoline, comes synthetic (1S; 4R; 6S, 14S, 18R)-1-piperidines-1-ylmethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-2; 15-dioxo-4-(N, N-dimethyl-sulfonyl amino carbonyl)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H?NMR(400MHz，CD ³OD)δ7.32-7.16(m，4H)，5.75-5.64(m，2H)，5.47(br?s，1H)，5.05(t，1H)，4.52-4.45(m，2H)，4.39-4.17(m，3H)，4.12-4.02(m，1H)，3.99-3.88(m，1H)，3.70-3.38(m，6H)，3.14-3.00(m，4H)，2.83(d，6H)，2.59-2.24(m，4H)，2.08-2.01(m，2H)，1.98-1.65(m，10H)，1.63-1.51(m，4H)，1.23(d，9H)，0.92-0.84(m，1H)。MS?m/z?826.6(APCI-，M-1)。

Example 8:

Compound 108

According to the same program described in the example 1; just use 1-piperidines-1-ylmethyl-3 in step D, 4-dihydro-1H-isoquinoline 99.9 replaces isoindoline and use N-cyclopropyl sulfonamide substitutions N, N-dimethyl methyl acid amides in step F; come synthetic (1S; 4R, 6S, 14S; 18R)-1-piperidines-1-ylmethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-2,15-dioxo-4-(N-cyclopropyl-sulfonyl amino carbonyl)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H?NMR(400MHz，CD3OD)δ7.31-7.15(m，4H)，5.75-5.58(m，2H)，5.47(br?s，1H)，5.11(t，1H)，4.62-4.57(m，1H)，4.52-4.45(m，1H)，4.41-4.17(m，3H)，4.15-3.84(m，3H)，3.73-3.34(m，5H)，3.16-2.71(m，5H)，2.70-2.27(m，6H)，2.13-2.67(m，10H)，1.65-1.24(m，15H)，0.73-0.47(m，4H)；MS?m/z?838.4(APCI-，M-1)。

Example 9:

Compound 109

According to the same program described in the example 1; just use 1-piperidines-1-ylmethyl-3 in step D, 4-dihydro-1H-isoquinoline 99.9 replaces isoindoline and use pyrrolidyl sulfonamide substitutions N, N-dimethyl methyl acid amides in step F; come synthetic (1S; 4R, 6S, 14S; 18R)-1-piperidines-1-ylmethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-2,15-dioxo-4-(pyrrolidyl-sulfonyl amino carbonyl)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H?NMR(400MHz，CD ₃OD)δ8.94(d，1H)，7.31-7.16(m，4H)，5.75-5.62(m，2H)，5.48(br?s，1H)，5.08-4.99(m，1H)，4.66-3.84(m，7H)，3.72-3.39(m，7H)，3.28-3.20(m，2H)，3.17-2.25(m，10H)，2.12-1.99(m，2H)，1.98-1.66(m，11H)，1.64-1.22(m，15H)；MS?m/z?852.5(APCI-，M-1)。

Example 10:

Compound 110

According to the same program described in the example 1; just use 1-piperidines-1-ylmethyl-3 in step D, 4-dihydro-1H-isoquinoline 99.9 replaces isoindoline and use morpholinyl sulfonamide substitutions N, N-dimethyl methyl acid amides in step F; come synthetic (1S; 4R, 6S, 14S; 18R)-1-piperidines-1-ylmethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-2,15-dioxo-4-(morpholinyl-sulfonyl amino carbonyl)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H?NMR(400MHz，CD ₃OD)δ7.33-7.14(m，4H)，5.78-5.63(m，2H)，5.47(br?s，1H)，5.11(t，1H)，4.63-3.84(m，7H)，3.74-3.36(m，9H)，3.29-3.19(m，3H)，3.16-2.14(m，11H)，2.13-1.23(m，24H)，0.94-0.81(m，1H)；MS?m/z?868.6(APCI-，M-1)。

Example 11:

Compound 111

According to the same program described in the example 1; just use 1-morpholine-4-ylmethyl-3 in step D, 4-dihydro-1H-isoquinoline 99.9 replaces isoindoline and use pyrrolidyl sulfonamide substitutions N, N-dimethyl methyl acid amides in step F; come synthetic (1S; 4R, 6S, 14S; 18R)-1-morpholine-4-ylmethyl-3; 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid 14-tert-butoxycarbonyl amino-2,15-dioxo-4-(tetramethyleneimine-1-sulfonyl amino carbonyl)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester.MS?m/z?874.3(APCI-，M+18)。

Example 12:

Compound 112

According to the same program described in the example 1; just in step D, use 2-morpholine-4-base-1-phenyl-ethamine to replace isoindoline and in step F, use pyrrolidyl sulfonamide substitutions N; N-dimethyl methyl acid amides; come synthetic (1S, 4R, 6S; 14S; 18R)-and (2-morpholine-4-base-1-phenyl-ethyl)-carboxylamine 14-tert-butoxycarbonyl amino-2,15-dioxo-4-(tetramethyleneimine-1-sulfonyl amino carbonyl)-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester.MS?m/z?828.3(APCI-，M-1)。

Example 13:

Compound 113

According to the same program described in the example 1; just in step D, use 5-chlorine isoindoline to replace isoindoline; come synthetic (1S, 4R, 6S; 14S; 18R)-and 5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(N, N-dimethyl methyl acyl group-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester.MS?m/z?651(APCI+，M-Boc)。

Example 14:

Compound 114

According to the same program described in the example 1; just in step D, use 5-chlorine isoindoline to replace isoindoline and use N-cyclopropyl sulfonamide substitutions N in step F; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(N-cyclopropyl-alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester.MS?m/z?663(APCI+，M-Boc)。

Example 15:

Compound 115

According to the same program described in the example 1; just in step D, use 5-chlorine isoindoline to replace isoindoline and in step F, use pyrrolidyl sulfonamide substitutions N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(pyrrolidyl-alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester.MS?m/z?677(APCI+，M-Boc)。

Example 16:

Compound 116

According to the same program described in the example 1; just in step D, use 5-chlorine isoindoline to replace isoindoline and in step F, use morpholinyl sulfonamide substitutions N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(morpholinyl-alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester.MS?m/z?693(APCI+，M-Boc)。

Example 17:

Compound 117

According to the same program described in the example 1; just in step F, use azetidine-1-sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(azetidine base-alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.21 (s, 9H), 1.28-1.54 (m, 8H), 1.59-1.63 (m, 1H), 1.77-1.89 (m, 3H), 2.38-2.42 (m, 1H), 2.46-2.52 (m, 2H), 3.77 (t, 2H), 3.84-3.94 (m, 3H), 4.14-4.22 (m, 3H), 4.50 (br d, 1H), 4.61-4.72 (m, 5H), 5.12 (t, 1H), 5.44 (br s, 1H), 5.78 (q, 1H), 6.17 (br d, 1H), 7.23-7.36 (m, 4H), 8.38 (s, 1H).MS?m/z?727.4(APCI-，M-1)。

Example 17a:

Prepare title compound according to the route B in the flow process 2, azetidine-1-sulphonamide.With azetidine (0.16g, 2.8mmol) dissolving is among the 5.6mL DriSolve DCM among the 10mL RBF, then add sulphonamide reagent a (0.85g, 2.8mmol).After stirring about 5 minutes, latter's reagent dissolves gradually, obtains clarifying, almost colourless solution.It is at room temperature stirred spend the night.After 17 hours, TLC shows react completely (DCM: MeOH 9: 1).Concentration response, and with gained white solid crude product fast by Biotage 40S silicagel column (eluent=5% is to 10%MeOH/DCM), obtain Boc protection title product, productive rate is quantitative basically.Originally product is dense oil, spends the night progressively to solidify under high vacuum. ¹H?NMR(CDCl ₃，400MHz)δ1.52(s，9H)，2.27(m，2H)，4.15(t，4H)，7.18(br?s，1H)。

Will (0.4g 2mmol) be dissolved in 10mL TFA/DCM (1: the 1 volume ratio) mixture, and at room temperature kept 2 hours from the product of above step.Then remove volatile matter.Gained oily resistates is handled and filtered with ether.The white powder product that filtration obtains just is used for ensuing coupling step without being further purified. ¹H NMR (d ⁶-acetone, 400MHz) δ 2.12-2.19 (m, 2H), 3.77 (t, 4H), 6.05 (br s, 2H).

Example 18:

Compound 118

According to the same program described in the example 1; just in step F, use 4-methylpiperazine-1-sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-methylpiperazine-1-alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.21 (s, 9H), 1.19-1.58 (m, 9H), 1.70-1.73 (m, 1H), 1.85-1.88 (m, 2H), 2.24 (s, 3H), 2.36-2.48 (m, 7H), 2.53 (m, 1H), 3.24-3.29 (m, 4H), 3.84-3.88 (m, 1H), 4.14-4.18 (m, 1H), 4.49 (br d, 1H), 4.60-4.72 (m, 5H), 5.04 (t, 1H), 5.44 (br s, 1H), 5.71 (q, 1H), 6.16 (br d, 1H), 7.23-7.36 (m, 4H), 8.31 (s, 1H).MS?m/z770.5(APCI-，M-1)。

Example 19:

Compound 119

According to the same program described in the example 1; just in step F, use 4-(2-TMS ethoxy carbonyl) piperazine 1-sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-(2-TMS ethoxy carbonyl) piperazine-1-alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 0.06 (s, 9H), 0.94-0.98 (m, 2H), 1.15 (s, 9H), and 1.17-1.50 (m, 8H), 1.50-1.54 (m, 1H), 1.65-1.68 (m, 1H), 1.75-1.82 (m, 2H), 2.30-2.44 (m, 3H), 2.56-2.68 (m, 1H), 3.17-3.26 (m, 4H), 3.44-3.47 (m, 4H), 3.78-3.81 (m, 1H), 4.08-4.14 (m, 3H), 4.44 (br d, 1H), 4.54-4.66 (m, 5H), 4.98 (t, 1H), 5.38 (br s, 1H), 5.56-5.63 (m, 1H), 6.12 (br d, 1H), 7.16-7.30 (m, 4H), 8.26 (s, 1H).MS?m/z?901.3(APCI-，M-1)。

Example 19a:

According to flow process as follows 3 preparation title compounds, 4-(2-TMS ethoxy carbonyl) piperazine-1-sulphonamide.

Flow process 3

Step 1: with piperazine-1-carboxylic acid tert-butyl ester (1.0g, 5.4mmol) dissolving is among the 10mLDriSolve DCM in the 50mL RBF, then add sulphonamide example a (1.6g, 5.4mmol).After stirring about 5 minutes, latter's reagent dissolves gradually, obtains clarifying, almost colourless solution.It is at room temperature stirred spend the night.After 17 hours, TLC shows react completely (DCM: MeOH 20: 1).Concentration response, and gained white solid crude product is passed through Biotage 40S silicagel column fast, and (eluent=2%MeOH/DCM), the spumescence solid Boc that obtains being white in color protects title product. ¹H NMR (d ⁶-acetone, 400MHz) δ 1.45 (s, 9H), 1.46 (s, 9H), 3.30-3.32 (m, 4H), 3.48-3.50 (m, 4H).LCMS?m/z?364.1(APCI-，M-1)。

Step 2: will (0.90g is 2.5mmol) in be dissolved in about 20mL 1: 1 (volume ratio) TFA-DCM mixture and at room temperature kept 2 hours from the product of above step 1.Then it is concentrated.Solid residue is handled in MeCN and concentrated once more, what obtain being meticulous white powder removes to protect product.

Remove to protect interpolation 20mL DriSolve DCM in the product to this, then add 1mL TEA.Follow stirring in gained white suspension thing disposable interpolation Teoc-succinate (0.70g, 2.7mmol).The white suspension thing disappears rapidly, at room temperature stirs colorless cleared solution and spends the night.Also (Biotage 40S, eluent=hexane: ethyl acetate 2: 1), concentration response obtains being white in color solid pure products 0.65g (85%) by the silicon-dioxide chromatography purification then. ¹H NMR (d ⁶-acetone, 400MHz) δ 0.06 (s, 9H), 0.94-0.98 (m, 2H), 3.01 (t, 4H), 3.48 (t, 4H), 4.10-4.14 (m, 2H), 6.03 (br s, 2H).LCMS?m/z?308.2(APCI-，M-1)。

Example 20:

Compound 120

By the protecting group of removing compound 119 synthesize (1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(piperazine-1-alkylsulfonyl-aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester.At first compound 119 (54.8mg, 60.7 μ mol) is dissolved among the 0.5mLDriSolve THF, then adds 1.0M TBAF THF solution (0.2mL, 200 μ mol).To be reflected in 60 ℃ of oil baths and heat 2 hours, and the TLC demonstration reacts completely.By silicon-dioxide chromatography purification reaction (Biotage 12M; Eluent=in DCM 0% to 20%MeOH), the solid compound 120 that obtains being white in color, 42.4mg (92%).MS?m/z?756.4(APCI-，M-1)。

Example 21:

Compound 121

According to the same program described in the example 1; just in step F, use N-cyclopropyl sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(N-cyclopropyl alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H?NMR(500MHz，CD ₃OD)δ8.91(d，1H)，7.32(q，1H)，7.14(d，1H)，7.01(t，1H)，5.63(q，1H)，5.40(br?s，1H)，5.13(t，1H)，4.80-4.68(m，4H)，4.61(q，1H)，4.56-4.49(m，1H)，4.06(t，1H)，3.83(br?s，1H)，3.72(p，1H)，3.22(p，1H)，2.72-2.60(m，1H)，2.57-2.48(m，1H)，2.46-2.31(m，4H)，1.83-1.69(m，4H)，1.66-1.58(m，1H)，1.56-1.19(m，5H)，1.13(d，9H)，0.71-0.51(m，4H)。MS?m/z?745.3(APCI-，M-1)。

Example 22:

Compound 122

According to the same program described in the example 1; just in step F, use sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester.MS?m/z?688.2(APCI-，M-1)。

Example 23:

Compound 123

According to the same program described in the example 1; just in step F, use 1-cyano group cyclopropyl sulfonamide substitutions N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(N-(1-cyano group cyclopropyl) amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.22 (s, 9H), 1.20-1.55 (m, 11H), 1.58-1.61 (m, 1H), 1.66-1.69 (m, 1H), 1.71-1.75 (m, 1H), 1.81-1.90 (m, 2H), 2.42-2.48 (m, 3H), 2.60-2.70 (m, 1H), 3.84-3.88 (m, 1H), 4.16-4.20 (m, 1H), 4.48 (br d, 1H), 4.58-4.71 (m, 5H), 5.07 (t, 1H), 5.44 (br s, 1H), 5.62 (q, 1H), 6.14 (br d, 1H), 7.22-7.36 (m, 4H), 7.88 (br s, 1H), 8.20 (s, 1H).MS?m/z?752.3(APCI-，M-1)。

Example 23a:

According to above-mentioned be synthetic described same program (flow process 2, route A) the preparation title compound 1-cyano group cyclopropyl sulphonamide of N-cyclopropyl sulphonamide, just with the amino cyclopropyl nitrile of 1-hydrochloride substituted ring propylamine. ¹H?NMR(CDCl ₃，400MHz)δ1.41-1.44(m，2H)，1.52-1.55(m，2H)，5.86(br?s，2H)，7.19(br?s，1H)。

Example 24:

Compound 124

According to the same program described in the example 1; just in step F, use cyclopropyl (1-methyl piperidine-4-yl) sulfonamide substitutions N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(cyclopropyl (1-methyl piperidine-4-yl) amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 0.75-0.77 (m, 2H), 0.96-1.01 (m, 2H), 1.21 (s, 9H), and 1.20-1.57 (m, 7H), 1.60-1.66 (m, 1H), 1.71-1.74 (m, 1H), 1.80-1.92 (m, 3H), 1.97-2.06 (m, 1H), 2.38-2.60 (m, 5H), 2.68 (s, 3H), 2.88-3.02 (m, 2H), 3.32-3.41 (m, 2H), 3.90-3.96 (m, 2H), and 4.17-4.23 (m, 2H), 4.41-4.47 (m, 2H), 4.59-4.72 (m, 5H), 5.10 (t, 1H), 5.45 (br s, 1H), 5.63-5.70 (m, 1H), 6.11 (br d, 1H), 6.95 (s, 1H), 7.19-7.35 (m, 4H), 8.42 (s, 1H).MS?m/z?824.4(APCI-，M-1)。

Example 24a:

Prepare title compound cyclopropyl (1-methyl piperidine-4-yl) sulphonamide by the same way as described in example 17a, just replace azetidine with N-cyclopropyl-1-methyl piperidine-4-amine. ¹H?NMR(d ⁶-DMSO，400MHz)δ0.67-0.76(m，4H)，1.93-1.97(m，2H)，2.07-2.18(m，2H)，2.22-2.26(m，1H)，2.75(s，3H)，2.96-3.05(m，2H)，3.45-3.48(m，2H)，3.77-3.83(m，1H)，6.93(br?s，2H)，9.78(br?s，1H)。

Example 25:

Compound 125

According to the same program described in the example 1; just in step F, use 2-cyano ethyl (cyclopropyl) sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(2-cyano ethyl (cyclopropyl) amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 0.74-0.78 (m, 2H), 0.98-1.01 (m, 2H), 1.21 (s, 9H), and 1.20-1.54 (m, 7H), 1.59-1.63 (m, 1H), 1.74-1.77 (m, 1H), 1.82-1.87 (m, 2H), 2.41-2.65 (m, 6H), 2.79-2.83 (m, 2H), 3.49-3.56 (m, 1H), 3.84-3.88 (m, 1H), 3.97-4.04 (m, 1H), 4.14-4.18 (m, 1H), 4.50 (br d, 1H), 4.60-4.72 (m, 5H), 5.05 (t, 1H), 5.45 (br s, 1H), 5.68 (q, 1H), 6.15 (br d, 1H), 7.22-7.36 (m, 4H), 8.33 (s, 1H).MS?m/z781.3(APCI-，M)。

Example 25a:

Prepare title compound 2-cyano ethyl (cyclopropyl) sulphonamide by the same way as described in example 17a, just replace azetidine with 3-(cyclopropyl amino) propionitrile. ¹H?NMR(d ⁶-DMSO，400MHz)δ0.68-0.76(m，4H)，2.36-2.37(m，1H)，2.78(t，2H)，3.35(t，2H)，7.05(br?s，2H)。

Example 26:

Compound 126

According to the same program described in the example 1, just in step F, use N, N-di-isopropyl sulphonamide replaces N; N-dimethyl methyl acid amides; come synthetic (1S, 4R, 6S; 14S; 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(N, N-diisopropylaminoethyl alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.21 (s, 9H), 1.25-1.53 (m, 20H), 1.68-1.71 (m, 1H), 1.81-1.87 (m, 2H), 2.38-2.45 (m, 3H), 2.56-2.68 (m, 1H), 3.84-3.87 (m, 1H), 3.94-4.01 (m, 2H), 4.14-4.18 (m, 1H), 4.47 (br d, 1H), 4.58-4.68 (m, 5H), 5.03 (t, 1H), 5.44 (br s, 1H), 5.62 (q, 1H), 6.11 (br d, 1H), 7.23-7.36 (m, 4H), 8.24 (s, 1H), 10.29 (br s, 1H).MS?m/z?772.3(APCI-，M)。

Example 26a:

Prepare title compound N by the same way as described in example 17a, N-di-isopropyl sulphonamide just replaces azetidine with diisopropylamine. ¹H NMR (d ⁶-acetone, 400MHz) δ 1.23 (d, 12H), 3.70-3.77 (m, 2H), 5.67 (br s, 2H).

Example 27:

Compound 127

According to the same program described in the example 1; just in step F, use phenyl-sulfamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(phenyl amino alkylsulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.20 (s, 9H), 1.20-1.50 (m, 8H), 1.60-1.70 (m, 2H), 1.78-1.86 (m, 1H), 2.30-2.44 (m, 4H), 3.81-3.85 (m, 1H), 4.12-4.17 (m, 1H), 4.45 (br d, 1H), 4.54-4.75 (m, 6H), 5.28 (q, 1H), 5.43 (br s, 1H), 6.11 (br d, 1H), 7.14-7.35 (m, 9H), 8.22 (s, 1H), 8.97 (br s, 1H), 10.80 (br s, 1H).MS?m/z?764.3(APCI-，M)。

Example 27a:

According to above-mentioned be synthetic described same program (flow process 2, route A) the preparation title compound phenyl-sulfamide of N-cyclopropyl sulphonamide, just with aniline substituted ring propylamine. ¹H?NMR(d ⁶-DMSO，400MHz)δ6.95-6.98(m，1H)，7.06(br?s，2H)，7.14-7.16(m，2H)，7.24-7.28(m，2H)，9.46(br?s，1H)。

Example 28:

Compound 128

According to the same program described in the example 1; just in step F, use 4-chloro-phenyl-sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-chloro-phenyl-amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.19 (s, 9H), 1.18-1.51 (m, 8H), 1.61-1.72 (m, 2H), and 1.76-1.87 (m, 1H), 2.32-2.44 (m, 4H), 3.82-3.86 (m, 1H), 4.12-4.16 (m, 1H), 4.45 (brd, 1H), 4.54-4.72 (m, 6H), 5.28 (q, 1H), 5.43 (br s, 1H), 6.10 (br d, 1H), 7.22-7.38 (m, 8H), 8.24 (s, 1H).MS?m/z?798.2(APCI-，M)。

Example 28a:

According to above-mentioned be synthetic described same program (flow process 2, route A) the preparation title compound 4-chloro-phenyl-sulphonamide of N-cyclopropyl sulphonamide, just with 4-chloroaniline substituted ring propylamine. ¹H?NMR(d ⁶-DMSO，400MHz)δ7.09-7.12(m，4H)，7.27(d，2H)，9.59(br?s，1H)。

Example 29:

Compound 129

According to the same program described in the example 1; just in step F, use 4-p-methoxy-phenyl sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-p-methoxy-phenyl amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.20 (s, 9H), 1.18-1.54 (m, 8H), 1.64-1.87 (m, 3H), 2.22-2.46 (m, 4H), 3.80 (s, 3H), 3.77-3.82 (m, 1H), 4.14 (m, 1H), 4.43 (br d, 1H), 4.52-4.70 (m, 5H), 4.88 (t, 1H), 5.40-5.50 (m, 2H), 6.10 (br d, 1H), 6.88-6.90 (d, 2H), 7.18-7.35 (m, 6H), 8.18 (s, 1H).MS?m/z?794.3(APCI-，M)。

Example 29a:

According to above-mentioned be synthetic described same program (flow process 2, route A) the preparation title compound 4-p-methoxy-phenyl sulphonamide of N-cyclopropyl sulphonamide, just with 4-anisidine substituted ring propylamine. ¹H?NMR(d ⁶-DMSO，400MHz)δ3.71(s，3H)，6.85-6.87(m，4H)，7.11(d，2H)，9.01(br?s，1H)。

Compound 130

Example 30:

According to the same program described in the example 1; just in step F, use 4-aminomethyl phenyl sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-aminomethyl phenyl amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.20 (s, 9H), 1.20-1.52 (m, 8H), 1.60-1.74 (m, 2H), 1.76-1.87 (m, 1H), 2.26-2.42 (m, 4H), 2.31 (s, 3H), 3.81-3.84 (m, 1H), 4.14-4.17 (m, 1H), 4.44 (br d, 1H), 4.52-4.79 (m, 6H), 5.32 (q, 1H), 5.42 (br s, 1H), 6.11 (br d, 1H), 7.14-7.35 (m, 8H), 8.20 (s, 1H), 8.79 (br s, 1H), 10.69 (br s, 1H).MS?m/z?778.2(APCI-，M)。

Example 30a:

According to above-mentioned be synthetic described same program (flow process 2, route A) the preparation title compound 4-aminomethyl phenyl sulphonamide of N-cyclopropyl sulphonamide, just with 4-monomethylaniline substituted ring propylamine. ¹H?NMR(d ⁶-DMSO，400MHz)δ2.18(s，3H)，6.91(s，2H)，7.01(s，4H)，9.20(s，1H)。

Example 31:

Compound 131

According to the same program described in the example 1; just in step F, use the 4-cyanophenyl sulfonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-cyano-phenyl amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.20 (s, 9H), 1.18-1.53 (m, 8H), 1.60-1.70 (m, 2H), 1.76-1.87 (m, 1H), 2.32-2.48 (m, 4H), 3.85-3.88 (m, 1H), 4.15-4.17 (m, 1H), 4.46 (br d, 1H), 4.57-4.71 (m, 6H), 5.16 (q, 1H), 5.46 (br s, 1H), 6.10 (br d, 1H), 7.24-7.35 (m, 4H), 7.42 (d, 2H), 7.76 (d, 2H), 8.28 (s, 1H).MS?m/z?788.3(APCI-，M-1)。

Example 31a:

According to above-mentioned be synthetic described same program (flow process 2, route A) the preparation title compound 4-cyanophenyl sulfonamide of N-cyclopropyl sulphonamide, just with 4-aminobenzonitrile substituted ring propylamine. ¹H?NMR(d ⁶-DMSO，400MHz)δ7.22(d，2H)，7.40(br?s，2H)，7.70(d，2H)，10.24(br?s，1H)。

Example 32:

Compound 132

According to the same program described in the example 1; just in step F, use 4-trifluoromethyl sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(4-trifluoromethyl amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.19 (s, 9H), 1.18-1.64 (m, 10H), 1.82 (q, 1H), 2.30-2.46 (m, 4H), 3.84-3.87 (m, 1H), 4.12-4.16 (m, 1H), 4.47 (br d, 1H), 4.57-4.71 (m, 6H), 5.11 (q, 1H), 5.45 (s, 1H), 6.12 (br d, 1H), 7.23-7.35 (m, 4H), 7.45 (d, 2H), 7.69 (d, 2H), 8.30 (s, 1H), 9.53 (br s, 1H), 11.06 (br s, 1H).MS?m/z?832.2(APCI-，M)。

Example 32a:

According to above-mentioned be synthetic described same program (flow process 2, route A) the preparation title compound 4-trifluoromethyl sulphonamide of N-cyclopropyl sulphonamide, just with 4-(trifluoromethyl) aniline substituted ring propylamine. ¹H?NMR(d ⁶-DMSO，400MHz)δ7.26-7.30(m，4H)，7.59(d，2H)，10.05(br?s，1H)。

Example 33:

Compound 133

According to the same program described in the example 1; just in step F, use the cyclobutyl sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(cyclobutyl amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.21 (s, 9H), 1.20-1.70 (m, 11H), 1.80-1.90 (m, 2H), 2.02-2.09 (m, 2H), 2.21-2.30 (m, 2H), 2.41-2.47 (m, 3H), 2.58-2.68 (m, 1H), 3.75-3.87 (m, 2H), 4.15-4.18 (m, 1H), 4.47 (br d, 1H), 4.57-4.72 (m, 5H), 5.11 (t, 1H), 5.44 (s, 1H), 5.63 (q, 1H), 6.14 (br d, 1H), 6.34 (br d, 1H), 7.23-7.36 (m, 4H), 8.18 (s, 1H).MS?m/z741.4(APCI-，M-1)。

Example 33a:

Prepare title compound cyclobutyl sulphonamide by the same way as described in example 17a, just replace azetidine with the ring butylamine. ¹H?NMR(d ⁶-DMSO，400MHz)δ1.20-1.60(m，2H)，1.89-1.94(m，2H)，2.14-2.21(m，2H)，3.67(m，1H)，6.42(br?s，2H)，6.82(br?s，1H)。

Example 34:

Compound 134

According to the same program described in the example 1; just in step F, use the cyclopentyl sulphonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(cyclopentyl amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.21 (s, 9H), 1.20-1.73 (m, 15H), 1.87-1.96 (m, 4H), 2.41-2.49 (m, 3H), 2.56-2.68 (m, 1H), 3.55-3.60 (m, 1H), 3.84-3.87 (m, 1H), 4.15-4.18 (m, 1H), 4.48 (br d, 1H), 4.57-4.72 (m, 5H), 5.08 (t, 1H), 5.44 (s, 1H), 5.63 (q, 1H), 6.15 (br d, 1H), 6.24 (br d, 1H), 7.23-7.35 (m, 4H), 8.25 (s, 1H), 10.25 (br s, 1H).MS?m/z755.4(APCI-，M-1)。

Example 34a:

Prepare title compound cyclopentyl sulphonamide by the same way as described in example 17a, just replace azetidine with cyclopentamine. ¹H?NMR(d ⁶-DMSO，400MHz)δ1.43-1.61(m，6H)，1.80-1.83(m，2H)，3.54(m，1H)，6.42(br?s，3H)。

Example 35:

Compound 135

According to the same program described in the example 1; just in step F, use cyclohexyl sulfonamide to replace N; N-dimethyl methyl acid amides comes synthetic (1S, 4R; 6S; 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonyl amino-4-(cyclohexyl amino-sulfonyl-aminocarboxyl)-2; 15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester. ¹H NMR (400MHz, d ⁶-acetone) δ 1.21 (s, 9H), 1.14-2.0 (m, 21H), 2.41-2.48 (m, 3H), 2.57-2.67 (m, 1H), 3.07-3.16 (m, 1H), 3.84-3.87 (m, 1H), 4.15-4.19 (m, 1H), 4.47 (brd, 1H), 4.57-4.72 (m, 5H), 5.08 (t, 1H), 5.44 (s, 1H), 5.64 (q, 1H), 6.13-6.17 (m, 2H), 7.23-7.36 (m, 4H), 8.23 (s, 1H), 10.30 (br s, 1H).MS?m/z?769.4(APCI-，M-1)。

Example 35a:

Compound 136

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-amino-4-(N, N-dimethyl methyl acyl group-aminocarboxyl)-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-18-base ester hydrochloride (compound 136) synthetic

By being handled in the 4M of 0.5mL HCl/ dioxan, compound 101 (79mg) come synthesising title compound also at room temperature to stir 16 hours.Concentration response and in acetonitrile, handling then so that concentrate once more.Then utilize the dry described hydrochloride of high-vacuum pump to spend the night, solid product (76mg) obtains being white in color.+APCI?MS?m/z?617.1(M+1)。

Example 35b:

Prepare the title compound cyclohexyl sulfonamide by the same way as described in example 17a, just replace azetidine with hexahydroaniline. ¹H?NMR(d ⁶-DMSO，400MHz)δ1.08-1.23(m，5H)，1.50-1.54(m，1H)，1.65-1.68(m，2H)，1.86-1.89(m，2H)，3.02(m，1H)，6.40(br?s，3H)。

Example 36:NS3-NS4 proteolytic enzyme is analyzed

Form the NS3 mixture with NS4A-2

Recombination bacillus coli or baculovirus total length NS3 are diluted to 3.33 μ M with analysis buffer, and this substance transfer is gone in the eppendorf pipe, and be placed in the interior water-bath of 4 ℃ of refrigerators.Be added on an amount of NS4A-2 that reaches 8.3mM in the analysis buffer, with the volume (conversion factor-3.8mg/272 μ L analysis buffer) that equals NS3 among the step 2.1.1.This substance transfer is gone in the eppendorf pipe, and be placed in the interior water-bath of 4 ℃ of refrigerators.

At 4 ℃ after following 15 minutes, shift out NS3/NS4A-2 eppendorf pipe, and be placed in the room-temperature water bath 10 minutes.NS3/NS4A-2 is divided into the aliquots containig of proper volume, and is stored in-80 ℃.(during with the intestinal bacteria NS3 of 2nM in analytic liquid operation, be divided into 25 μ L aliquots containigs; During with the BV NS3 of 3nM in analytic liquid operation, be divided into 30 μ L aliquots containigs).

Example 37:NS3 restraining effect is analyzed

Step 2.2.6.Intestinal bacteria NS3/NS4A-2 is diluted to 4nM NS3 (1.67 μ M liquid storage-18 μ L1.67 μ M liquid storage+7497 μ L analysis buffer of 1: 417.5).BV NS3/NS4A-2 is diluted to 6nM NS3 (1.67 μ M liquid storage-24 μ L, 1.67 μ M liquid storages+6655 μ L analysis buffer of 1: 278.3).

Step 2.2.7.Use manual multichannel pipettor, and, 50 μ L analysis buffer are added into black Costar 96 hole polypropylene store in the A01-H01 hole of plate carefully not in the bubble lead 1-in plate.

After the plate of pre-culturing step 2.2.11, use manual multichannel pipettor, with 25 μ L substrates be added into institute on the plate porose in.The content in the hole of plate as described in mixing rapidly as step 2.2.10, but the 65 μ L of 100 μ L in the mix aperture.

On Molecular Devices SpectraMax Gemini XS plate reader, plate is read with dynamic mode.Reader is set: time for reading: 30 minutes; At interval: 36 seconds; Reading times: 51; Excitation wavelength lambda: 335nm; Emission wavelength lambda: 495nm; Threshold value: 475nm; Automix: close; Calibration: once; PMT: height; Reading times/hole: 6; Vmax pts:21 or 28/51, visual response lineal measure and deciding.

Total length intestinal bacteria NS3-2.03 μ M

Total length BV NS3-1.74 μ M

Ki=IC wherein ₅₀/ (1+[S]/Km)

At HCV sub-genome duplication, by selective key thing albumen, the ELISA of neomycin phosphotransferase II (NPTII) carries out quantitatively among the GS4.3

HCV sub-genome duplication (I377/NS3-3 ', deposit numbers AJ242652) stably maintain in the HuH-7 liver cancer cell, set up by people such as Lohmann (Science 285:110-113 (1999)).Containing the cell culture of replicon, be appointed as GS4.3, is to derive from cancer research institute (Institute for Cancer Research, Fox Chase CancerCenter, Philadelphia, Christoph doctor Seeger Pennsylvania).

With the GS4.3 cell in 37 ℃, 5%CO ₂Under maintain among the DMEM (Gibco 11965-092), be supplemented with among the described DMEM L-glutaminate 200mM (100 times) (Gibco25030-081), non-essential amino acid (NEAA) (Biowhittaker 13-114E), hot deactivation (HI) foetal calf serum (FBS) (Hyclone SH3007.03) and 750 μ g/ml Geneticins (G418) (Gibco 10131-035).Every 2-3 days cell divided 1: 3 or 4 again.In analysis preceding 24 hours, collect the GS4.3 cell, counting, and keep substratum (as above) with 100 μ l standards and with 7500 cells/well it is coated on 96 orifice plates (Costar 3585), and cultivation under these conditions.For beginning to analyze, shift out substratum, with PBS (Gibco 10010-023) washed cell once, and add 90 μ l and analyze substratum (DMEM, L-glutaminate, NEAA, 10%HI FBS, no G418).Inhibitor is made 10 * liquid storage in analyzing substratum, (from 3 times of dilutions of 10 μ M to 56pM ultimate densities, final DMSO concentration 1%) add 10 μ l to the double hole, and wobble plate is so that mix, and as above cultivates 72 hours.

From AGDIA company obtain NPRII ELISA test kit (the direct ELISA test macro of compound that is used for neomycin phosphotransferase II, PSP73000/4800).Follow manufacturers instruction, some modifications are wherein arranged.Make 10 * PEB-1 lysis buffer, to comprise 500 μ M PMSF (Sigma P7626, the 50mM liquid storage is in Virahol).Cultivate after 72 hours, with the PBS washed cell once, and in every hole, add the PEB-1 that 150 μ l contain PMSF., then freezing down under the room temperature at-70 ℃ with plate vigorous agitation 15 minutes.Plate is thawed, thoroughly mix lysate, and add in 100 μ l to the NPTII Elisa plates.Obtain typical curve.Make up the lysate of the control wells of the DMSO processing of hanging oneself, use and contain the PEB-1 serial dilution of PMSF, and be applied in the double hole of elisa plate, initial lysate amount is in 150 μ l-2.5 μ l scopes.In addition, double applies 100 μ l damping fluids separately, as the blank group.Plate is sealed and at room temperature stirred gently 2 hours.After ravin is cultivated, plate is washed (5 * 300 μ l) with PBS-T (0.5%Tween-20, PBS-T provides) in the ELISA test kit.For detecting, in PBS-T, make 1 times of diluent of enzyme conjugates diluent MRS-2 (5 *), to specifications to 1: 100 diluent that wherein adds enzyme conjugates A and B.Again plate is sealed, and follow to stir and cultivate: capping, room temperature, 2 hours.Then repeat described washing step, and add the room temperature tmb substrate of 100 μ l.Cultivated back (room temperature, stirring, capping) in about 30 minutes, with 50 μ l 3M sulfuric acid stopped reaction.On Molecular Devices Versamax plate reader, under 450nm, plate is read.

The inhibitor effect is expressed as the percentage ratio of the control signal of handling through DMSO, and uses following 4 parametric equations to calculate and suppress curve: y=A+ ((B-A)/(1+ ((C/x) ^D))), and wherein C is maximum half activity or EC ₅₀

Active example

Wherein:

A represents the IC less than 1 μ M ₅₀Or EC ₅₀

And B represents the IC less than 0.1 μ M ₅₀Or EC ₅₀

Table 3

Compound	NS3-NS4 IC ₅₀	EC ₅₀
Compound	NS3-NS4 IC ₅₀	EC ₅₀	101	B	B
102	B	B	101	B	B
102	B	B	103	B	B
104	B	B	103	B	B
104	B	B	105	B	N/A
106	B	B	105	B	N/A
106	B	B	107	B	B
108	A	B	107	B	B
108	A	B	109	B	A
110	A	N/A	109	B	A
110	A	N/A	111	B	N/A
112	B	N/A	111	B	N/A
112	B	N/A	113	B	B
114	B	B	113	B	B
114	B	B	115	B	B
116	B	A	115	B	B
116	B	A	117	B	B
118	B	B	117	B	B
118	B	B	119	B	B
120	B	N/A	119	B	B
120	B	N/A	121	B	B
122	B	B	121	B	B
122	B	B	123	B	N/A
124	A	B	123	B	N/A
124	A	B	125	B	B
126	B	B	125	B	B
126	B	B	127	B	B
128	B	B	127	B	B
128	B	B	129	B	B
130	B	B	129	B	B
130	B	B	131	B	B
132	B	B	131	B	B
132	B	B	133	B	B
134	B	B	133	B	B
134	B	B	135	B	B

Example 38: specificity analyses

When assessing compound in specificity analyses, discoverable type I compound has selectivity, because they do not show remarkable restraining effect in cathepsin B, Quimotrase, zymoplasm or leukocyte elastase.

Example 39: the pharmacokinetics analysis of compound

At first synthetic compound and as described in the above example 8 fluorescence NS3/4 proteolytic enzyme analyze and based on the HCV replicon system of cell in its usefulness of test (IC ₅₀).In conjunction with live body stranger hepatomicrosome (HLM) and liver cell stability study, utilize the drug plasma dynamic metabolism of IV dispensing back in mouse (Rattus sp.) to analyze then, come from having less than design metabolic stability compound the compound of the usefulness of 20nM.Further optimize these iguides' (leads) the rational matter of class medicine, and offer medicine to mouse (Rattus sp.), so that evaluation liver, heart and plasma concentration with oral dosage.

Method

The result

Compd A R334187 produces the replicon EC of about 2nM ₅₀Value, and in rat, dog and human liver cell culture assays, show in vitro stability, these data will be predicted the clearance rate that how to slow down from liver.In addition, this compound shows the high selectivity with respect to one group of other serine protease, even and also do not have a remarkable restraining effect of pair cell cytochrome p 450 (Cytochrome P450) isomer or hERG channel activity under the highest test concentrations (10 μ M).

For compd A R334187, the replicon EC of this compound of concentration ratio that a 30mg/kg oral dosage in mouse (Rattus sp.) produced in dispensing in liver in back 24 hours ₅₀At least 200 times of value height.

Heart that compd A R334187 produces and blood plasma level reach two orders of magnitude than the liver concentration in the same animals is low, and are associated on kinetics with liver concentration.The compd A R334187 of more rational clinically oral dosage (3mg/kg) is at the replicon EC of back 8 hours these compounds of concentration ratio in liver of dispensing ₅₀Be worth big more than 100 times.After the compd A R334187 of the dosage that is exposed to the oral BID of 30mg/kg, in the animal of treatment, do not observing mortality ratio, body weight change or facing the art chemical abnormality.

Conclusion

When compd A R334187 in the time of 7 days, does not show toxicity with 30mg/kg BID administration in mouse (Rattus sp.), be provided at least 10 times of security surpluses on the supposition effective dose (3mg/kg), and produce the replicon EC that surpasses this compound ₅₀The liver concentration that is worth 100 times.

The preparation of part D viral inhibitors

Identical among the employed term in this part and the implication of structure title and the part D above.Mentioning at optional network specific digit or mark any in this part should be in this part or above understand in used corresponding numbering or the labeling scheme content in the part D, rather than in this paper other local used possible similar or the numbering that is equal to or labeling scheme content, understand, except as otherwise noted.

Formula XVIII compound can synthesize according to method hereinafter described.

(2S, 4R)-and 4-amino-1-[phenmethyl oxygen base carbonyl] tetramethyleneimine-2-methyl carboxylic acids ester hydrochloride can derive from ArrayBiopharma, and 2 (S)-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-olefin(e) acid and 1 (R)-tert-butoxycarbonyl amino-2 (S)-vinyl-cyclopropane carboxylic acid acetoacetic ester can be prepared according to disclosed program among the international application case PCT/CA00/00353 (No. 00/59929, open case WO).2 (S)-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-olefin(e) acid also can be buied from RSP Amino Acids.

Two big ring intermediate A of main aminoproline and B in the preparation of the NS3 inhibitor shown in the example 1-69, have been used.

1. the preparation of the big ring of oxygen base dried meat oxygen acid acyl group sulphonamide intermediate A

(1S, 4R, 6S, 14S, 18R)-(18-amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-14-yl)-t-butyl carbamate synthetic

Flow process 1

Steps A. to (2S, 4R)-and 4-amino-1-[phenmethyl oxygen base carbonyl] tetramethyleneimine-2-methyl carboxylic acids ester hydrochloride (2.00g, 2.34mmol) solution in methylene dichloride (25ml) adds 2-(TMS) ethyl p-nitrophenyl carbonic ether (1.98g, 6.99mmol) and triethylamine (1.81ml, 13.34mmol).To react and stir 3 days, be placed on the silica gel,, obtain water white oil with 40%EtOAc/ hexane eluted product.Described oil is dissolved in follows 10% palladium carbon to stir in the methyl alcohol (20ml) and under the hydrogen air bag.Stir after 4 hours, filtering reaction also concentrates.The gained solid is dissolved in the 1N aqueous hydrochloric acid (75ml), and extracts with methylene dichloride (75ml).By adding sodium hydroxide water layer is alkalized, and (100ml) extracts to use methylene dichloride once more.Merge twice organic extract, concentrate, and utilize 10% ethanol/methylene wash-out,, obtain brown solid (1.29g, 70%) by silica gel chromatography purifying gained resistates.LCMS＝289(H+)。

Step B. stirred overnight 4 (R)-(2-TMS ethyl carbonylamino)-tetramethyleneimine-2 (S)-carboxylate methyl ester (1.29g, 4.50mmol), 2 (S)-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-olefin(e) acid (1.22g, 4.51mmol), HATU (2.06g, 5.41mmol) and diisopropylethylamine (1.18ml, 6.76mmol) solution in dimethyl formamide (10ml).To react with ethyl acetate (150ml) dilution, (2 * 100ml) washings also concentrate through dried over mgso with the 1N aqueous hydrochloric acid.Obtain oil by silica gel chromatography, (0.28g 6.76mmol) stirs 2 hours together with lithium hydroxide in methyl alcohol (5ml) with this oil.To react with the methylene dichloride dilution, and,, obtain 1.2g (49%) product through dried over mgso and concentrated with the washing of 1N aqueous hydrochloric acid.

Step C. to 1 (R)-tert-butoxycarbonyl amino-2 (S)-vinyl-cyclopropane carboxylic acid acetoacetic ester (0.70g, add in 2.75mmol) 4N HCl/ dioxan solution (2.87ml, 11.46mmol).Stir after 2 hours, concentration response obtains solid.Add 1-(2 (S)-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-enoyl-)-4 (R)-(2-TMS ethyl carbonylamino)-tetramethyleneimine-2 (S)-carboxylic acid (1.21g to this solid; 2.29mmol), HATU (1.05g; 2.75mmol) and diisopropylethylamine (1.60ml, 9.17mmol) and methylene dichloride (10ml) and at room temperature stir described reaction 18 hours.Reaction is placed on the silica gel, utilize 50% ethyl acetate/hexane eluant solution, obtain being the product (1.27g, 83%) of water white oil.665(H+)。

Step D. is by in wherein blasting N ₂With 1-{[1-(2 (S)-tert-butoxycarbonyl amino-ninth of the ten Heavenly Stems-8-enoyl-)-4 (R)-(2-TMS ethyl carbonylamino)-tetramethyleneimine-2 (S)-carbonyl]-amino }-2 (S)-vinyl-cyclopropane-1-(R)-carboxylic acid, ethyl esters (2.57g, the 3.87mmol) solution of (500ml) degassing in methylene dichloride.Add dichloro (adjacent isopropyl phenyl-methylene radical) (tricyclohexyl phosphine) ruthenium (II) (0.116g, 0.193mmol) and 40 ℃ under, will react stirring 16 hours.Concentration response as on the silica gel and utilize 50% ethyl acetate/hexane wash-out, obtains product (2.01g, 3.16mmol, 82%).637.0(H+)。

Step e. to (1S, 4R, 6S, 14S, 18R)-(14-tert-butoxycarbonyl amino-2,15-dioxo-18-(2-TMS-ethoxy carbonyl amino)-3,16-diaza-three ring [14.3.0.0 ^4,6] (1.94g, 3.04mmol) solution in 10: 1 methanol (10ml) adds lithium hydroxide (1.02g 24.37mmol), and at room temperature stirs described reaction and spends the night 19-7-alkene-4-carboxylic acid, ethyl ester.By adding 1N HCl (50ml) stopped reaction, and with dichloromethane extraction (2 * 50ml).Organism after the merging is with salt solution (50ml) washing, through dried over mgso and be concentrated into solid (1.78g, 2.92mmol).This acid and carbonyl dimidazoles (0.711g, 4.39mmol) solution in methylene dichloride under 50 ℃.Behind the 1h, there is initial substance in the HPLC analysis revealed, therefore adds other carbonyl dimidazoles (0.1g).Stirring is after 1 hour down at 50 ℃ again, and HPLC analysis revealed initial substance is used up fully.In this reaction, add the cyclopropane SULPHURYL CHLORIDE (0.46g, 3.80mmol) and DBU (0.57g, solution 3.80mmol), and at 50 ℃ of following stirring reactions.Behind the 1h, judge reaction not exclusively, therefore add the DBU of 0.07g cyclopropyl sulphonamide and 0.1g again by the HPLC monitoring.Behind the restir 30 minutes, judgement reacts completely.Make the reaction cooling, be placed on the silica gel, and obtain white solid with the gradient elution product of 3% methyl alcohol/DCM to 7.5% methyl alcohol/DCM.LCMS?710.5(H-)。

Step F. under 50 ℃, stir 1 together (0.80g, 1.124mmol) and tetrabutyl ammonium fluoride (the 1.0M solution in THF, solution 1h 1.4ml).Make reaction cooling, be placed on the silica gel and, obtain white solid (0.51g) with the gradient elution product of 5% methyl alcohol/DCM to 25% methyl alcohol/DCM.LCMS＝568.0(H+)。

2. the preparation of aminoproline macrocyclic ester intermediate B

Flow process 2

To handle and be heated to 50 ℃ from the compound 1 usefulness TBAF of above flow process 1 (1.0M, in THF, 1.5 equivalents), continue 4 hours.Reaction is placed on the silica gel and, obtain being brown solid B (productive rate 69%) with 20% ethanol/methylene wash-out. ¹H?NMR(CDCl ₃，400MHz)：δ1.06-1.66(m，17H)，1.85-1.95(m，2H)，2.0-2.1(m，1H)，2.1-2.2(m，1H)，2.2-2.3(m，1H)，2.65-2.75(M，1H)，3.40(m，1H)，3.73-3.83(m，2H)，4.08-4.19(m，2H)，4.56(m，1H)，4.78(d，J＝5.5?Hz，1H)，5.20(t，J＝8.1Hz，1H)，5.34(d，J＝8.1Hz，1H)，5.47(dt，J＝4.5，10.8Hz，1H)，7.08(s，1H)。493(H+)。

Utilize above-mentioned intermediate A and B to prepare the acyl group sulphonamide NS3 inhibitor shown in the example 1-69 then via one in the following two lines.Via all the carboxylic acid NS3 inhibitor in the 2 preparation examples of the route in the flow process 3.

Route 1:

Route 2:

Flow process 3

Example 1

(1S, 4R, 6S, 14S, 18R)-(18-[(3-chloro-benzo [b] thiophene-2-carbonyl)-amino]-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-14-yl-t-butyl carbamate synthetic

At room temperature in DCM, stir together (1S, 4R, 6S, 14S, 18R)-(18-amino-4-cyclopropane sulfonyl amino carbonyl-2,15-dioxo-3,16-diaza-three ring [14.3.0.0 ^4,6] 19-7-alkene-14-yl)-t-butyl carbamate (0.254g, 0.44mmol), 3-chloro-benzo [b] thiophene-2-carbonyl chlorine (0.124g, 0.54mmol) and DIEA (0.087g, solution 0.67mmol).After 1 hour, reaction is placed on the silica gel, use the gradient elution product of 1% methyl alcohol/DCM to 5% methyl alcohol/DCM, obtain white solid. ¹H?NMR(C ₆D ₆，400MHz)δ7.66-7.70(m，1H)，7.22-7.24(m，1H)，7.04-7.07(m，2H)，6.97(t，1H)，6.83(bs，1H)，5.61(d，1H)，5.18(t，1H)，5.05(d，1H)，4.48-4.50(b，1H)，4.26(t，1H)，3.8-4.0(m，1H)，3.65-3.74(m，1H)，3.20-3.35(M，1H)，2.78-2.85(M，1H)，2.55-2.65(m，1H)，2.3-2.4(m，1H)，1.95-2.15(m，2H)，1.75-1.85(m，1H)，1.20-1.40(m，16H)，0.95-1.15(m，5H)0.4-0.5(M，1H)，0.25-0.35(M，1H)；LCMS＝662(H ⁺-Boc)。

Example 2-69

Also replace 3-chloro-benzo [b] thiophene-2-carbonyl chlorine according to the synthetic described universal program that is example 1 with suitable chloride of acid and carboxylic acid/HATU; perhaps according to the similar acid amides described in example 1 and A synthetic with acyl group sulphonamide coupling program but the route 2 of employing flow process 3 is finished following example.

Table 4

NS3-NS4A proteolytic enzyme is analyzed

Form the NS3 mixture with NS4A-2

4 ℃ after following 15 minutes, shift out NS3/NS4A-2 eppendorf pipe, and in room-temperature water bath, placed 10 minutes.NS3/NS4A-2 is divided into the aliquots containig of proper volume, and is stored in-80 ℃ and (during with the intestinal bacteria NS3 of 2nM in analytic liquid operation, be divided into 25 μ L aliquots containigs; During with the BV NS3 of 3nM in analytic liquid operation, be divided into 30 μ L aliquots containigs).

The NS3 restraining effect is analyzed

Sample compound is dissolved in reaches 10mM among the DMSO, then in DMSO, be diluted to 2.5mM (1: 4).Usually, compound is added into analysis plates, obtains analyzing the initial concentration that suppresses 50mM in the curve through dilution with the concentration of 2.5mM.Serial dilution compound in analysis buffer is so that provide the solution that tried of low concentration.

Intestinal bacteria NS3/NS4A-2 is diluted to 4nM NS3 (1.67 μ M liquid storage-18 μ L, 1.67 μ M liquid storages+7497 μ L analysis buffer of 1: 417.5).

Use manual multichannel pipettor, and, 50 μ L analysis buffer are added into black Costar 96 hole polypropylene store in the A01-H01 hole of plate carefully not in the bubble lead 1-in plate.

Use manual multichannel pipettor, and carefully not in the bubble lead 1-in plate, with 50 μ L being added in the A02-H12 hole of plate among the step 2.2.7 through dilution NS3/NS4A-2 from step 2.2.6.

Use manual multichannel pipettor, and, 25 μ L in the step 2.2.5 Chinese traditional medicine dilution plate mesopore are transferred in the respective aperture of analysis plates among the step 2.2.8 carefully not in the bubble lead 1-in plate.Change the ozzle of multichannel pipettor when shifting every row's compound.

Use manual multichannel pipettor, and carefully not in the bubble lead 1-in plate, by five suctions with distribute the 35 μ L of 75 μ L in each hole and will mix from the hole of analysis plates among the step 2.2.9.Change the ozzle of multichannel pipettor when mixing every round.

Described plate is covered the polystyrene board lid, and at room temperature will cultivate 10 minutes from the plate that contains NS3 proteolytic enzyme and sample compound of step 2.2.10 is pre-.

In the plate of cultivating in advance from step 2.2.11, dilution RETS1 substrate in the 15mL polypropylene centrifuge tube.

The RETS1 substrate is diluted to 8 μ M (646 μ M liquid storage-65 μ L, 646 μ M liquid storages+5184 μ L analysis buffer of 1: 80.75).

After the pre-plate of cultivating in the described step, use manual multichannel pipettor, with 25 μ L substrates be added into institute on the plate porose in.Plate as described in mixing rapidly as step 2.2.10, the 65 μ L of 100 μ L in the mix aperture.

Total length intestinal bacteria NS3-2.03 μ M

Total length BV NS3-1.74 μ M

Ki=IC wherein ₅₀/ (1+[S]/Km)

Active example

Wherein:

A represents the IC less than 10 μ M ₅₀

B represents the IC less than 1 μ M ₅₀

And C represents the IC less than 0.1 μ M ₅₀

Table 5

Instance number	NS3-NS4 IC ₅₀	Instance number	NS3-NS4 IC ₅₀
Instance number	NS3-NS4 IC ₅₀	Instance number	NS3-NS4 IC ₅₀	1	C	36	C
2	C	37	C	1	C	36	C
2	C	37	C	3	C	38	C
4	C	39	C	3	C	38	C
4	C	39	C	5	C	40	C
6	C	41	C	5	C	40	C
6	C	41	C	7	C	42	C
8	C	43	C	7	C	42	C
8	C	43	C	9	C	44	C
10	C	45	C	9	C	44	C
10	C	45	C	11	C	46	C
12	C	47	C	11	C	46	C
12	C	47	C	13	C	48
14	C	49	C	13	C	48
14	C	49	C	15	C	50	C
16	C	51	C	15	C	50	C
16	C	51	C	17	C	52	C

18	C	53	C
18	C	53	C	19	C	54	C
20	C	55	C	19	C	54	C
20	C	55	C	21	C	56	C
22	C	57	C	21	C	56	C
22	C	57	C	23	C	58	C
24	C	59	A	23	C	58	C
24	C	59	A	25	C	60	A
26	C	61	A	25	C	60	A
26	C	61	A	27	C	62	B
28	C	63	B	27	C	62	B
28	C	63	B	29	C	64	B
30	C	65	B	29	C	64	B
30	C	65	B	31	C	66	B
32	C	67	A	31	C	66	B
32	C	67	A	33	C	68	A
34	C	69	A	33	C	68	A
34	C	69	A	35	C

Synthetic intermediate

Some intermediate that is obtained by synthesis flow is included in the scope of embodiments.The example of useful intermediates is as follows.

A kind of compound with following formula:

Wherein:

Q is the core ring that is selected from and the following:

R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this group replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects;

Y is COOR ⁹, R wherein ⁹Be C _1-6Alkyl;

P=0 or 1;

V is selected from O, S or NH;

Dotted line is represented optional double bond;

R ²¹Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl; Perhaps R ²¹Be C _{6 or 10}Aryl, this aryl replace through maximum 3 following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ²¹Be pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group or sulphur phenoxy group; With

A kind of compound with following formula:

Wherein:

R ⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl or benzyl, described phenyl or benzyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the G that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ⁸Be C _1-6Alkyl, C ^3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, these groups all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this group replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects;

Y is COOR ⁹, R wherein ⁹Be C _1-6Alkyl;

P=0 or 1;

V is selected from OH, SH or NH ₂

Dotted line is represented optional double bond;

Metabolite

Some embodiment is the metabolite of formula I-XIX compound.In some cases, metabolite is a formula I-XIX compound self.The example of useful metabolites is as follows.

Can pass through the metabolite of following steps recognition type I-XIX compound:

1. liver cell is suspended in KHB through replenishing (Krebs-Henseleit Buffer, pH7.3) in, concentration is every milliliter about 2 * 10 ⁶Individual alive liver cell.

2. prepare ITMN-187 and the stock solution (20 μ M) of ITMN-191 in KHB.

3. add the ITMN-187 of 50 μ l or ITMN-191 to 50 μ l hepatocyte suspension in 96 hole polypropylene boards.The substrate ultimate density is 10 μ M (about 7 μ g/mL).

In saturated humidity at 37 ℃, 5%CO ₂Under cultivate described plate 0 or 2 hours.

5. with 100 μ l acetonitrile termination reactions, and under 700rpm oscillating plate 30 seconds.

Immediately in whizzer swivel plate (1,500 * g) 10 minute so that make sex change liver cell precipitation.

7. shift 180 μ l supernatant liquors to another plate.

8. the merging hole utilizes N at 37 ℃ ₂Evaporating solvent restores resistates, and analyzes by LC-MS/MS in volume ratio is water/acetonitrile of 75/25.

Though the present invention is described with reference to its specific embodiment, it will be understood by one of ordinary skill in the art that and under the condition that does not depart from true spirit of the present invention and protection domain, to make various changes and replace with equipollent.In addition, at target of the present invention, spirit and protection domain, can make many modifications so that adapt to special case, material, composition, method, method steps.Expect these revise all belong to this paper within the scope of additional claims.

Claims (according to the modification of the 19th of treaty)

C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects;

Y is COOR ⁹, R wherein ⁹Be C _1-6Alkyl; Perhaps Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-3Alkyl, C _3-7Cycloalkyl or phenyl, described phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-3Alkyl, C _3-7Cycloalkyl or C _1-3Alkoxyl group, perhaps Y is a carboxylic acid;

P=0 or 1;

V and W are selected from O, S or NH independently of one another;

Dotted line is represented optional double bond;

R ²¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl; Perhaps R ²¹Be C _{6 or 10}Aryl, this aryl replace through maximum 3 following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ²¹Be pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group or sulphur phenoxy group; And

R ²²Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl.

201. according to the described compound of claim 174, wherein L is selected from by-OCH ₂-and-NHCH ₂The group of-composition.

202. according to the described compound of claim 174, wherein L be selected from by-CH=CH-and-group that C ≡ C-forms.

203. according to the described compound of claim 174, wherein L is selected from by-SCH ₂-,-SO ₂-and-CH ₂The group that SO-forms.

204. according to the described compound of claim 174, wherein L be selected from by-WC (=V)-NH-and-WC (=V)-group that O-forms, wherein V and W are selected from O, S or NH independently of one another.

205. according to the described compound of claim 182, wherein L is selected from by-OCH ₂-and-NHCH ₂The group of-composition.

206. according to the described compound of claim 182, wherein L be selected from by-CH=CH-and-group that C ≡ C-forms.

207. according to the described compound of claim 182, wherein L is selected from by-SCH ₂-,-SO ₂-and-CH ₂The group that SO-forms.

208. according to the described compound of claim 182, wherein L be selected from by-WC (=V)-NH-and-WC (=V)-group that O-forms, wherein V and W are selected from O, S or NH independently of one another.

209. according to the described compound of claim 189, wherein L is selected from by-OCH ₂-and-NHCH ₂The group of-composition.

210. according to the described compound of claim 189, wherein L be selected from by-CH=CH-and-group that C ≡ C-forms.

211. according to the described compound of claim 189, wherein L is selected from by-SCH ₂-,-SO ₂-and-CH ₂The group that SO-forms.

212. according to the described compound of claim 189, wherein L be selected from by-WC (=V)-NH-and-WC (=V)-group that O-forms, wherein V and W are selected from O, S or NH independently of one another.

Claims

1. compound with formula I:

Wherein:

Q is the core ring that is selected from and the following:

Wherein said core ring can be unsubstituted or replace through following group: H, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, C _1-6Alkyl, be substituted C _1-6Alkyl, C _1-6Alkoxyl group, be substituted C _1-6Alkoxyl group, C _{6 or 10}Aryl, pyridyl (pyridal), pyrimidyl (pyrimidal), thienyl, furyl, thiazolyl, oxazolyl, phenoxy group, sulphur phenoxy group, sulfoamido, urea, thiocarbamide, amide group, ketone group, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxy amino, alkoxyl group heterocyclic radical, alkylamino, alkyl carboxyl, carbonyl, volution cyclopropyl, volution cyclobutyl, volution cyclopentyl or volution cyclohexyl

Perhaps, Q is R ¹-R ², R wherein ¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, described group replace through maximum three following each groups separately according to circumstances: NR ⁶R ⁷, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; And R ²Be H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, described group replaces through maximum three following each groups separately according to circumstances: NR ⁶R ⁷, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁹Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁹For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl, NR ⁶R ⁷, NR ^1aR ^1bOr (CO) OH; Perhaps R ⁹For replacing maximum twice assorted aromatic nucleus through following group according to circumstances: halogen, cyano group, nitro, hydroxyl or C _1-6Alkoxyl group; Perhaps Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

Wherein, R ^1aAnd R ^1bBe H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, C _1-6Alkoxyl group, amide group or phenyl,

Perhaps, R ^1aAnd R ^1bBe H and C independently of one another _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group,

P=0 or 1;

V is selected from O, S or NH;

Dotted line is represented optional double bond;

R ²¹Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl; Perhaps R ²¹Be C _{6 or 10}Aryl, this aryl replace through maximum 3 following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ²¹Be pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group or sulphur phenoxy group; And

R ²²Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl;

Restricted condition is: formula I compound does not comprise the compound with formula II, III or IV:

Wherein:

(aa) R ¹And R ²Be H, halogen, cyano group, nitro, hydroxyl, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group, C _{6 or 10}Aryl, pyridyl, pyrimidyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group, sulphur phenoxy group, S (O) ₂NR ⁶R ⁷, NHC (O) NR ⁶R ⁷, NHC (S) NR ⁶R ⁷, C (O) NR ⁶R ⁷, NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, NHC (O) R ⁸, NHC (O) OR ⁸, SO _mR ⁸, NHS (O) ₂R ⁸, CH _nNR ⁶R ⁷, OCH _nNR ⁶R ⁷Or OCH _nR ⁹(R wherein ⁹Be imidazolyl or pyrazolyl); Described at R ¹And R ²Definition in thienyl, pyrimidyl, furyl, thiazolyl and oxazolyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹And R ²Definition in C _{6 or 10}Aryl, pyridyl, phenoxy group and sulphur phenoxy group replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

(bb) m=0,1 or 2;

(cc) R ⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl or benzyl, described phenyl or benzyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

(dd) R ⁵Be H, C _1-6Alkyl, C (O) NR ⁶R ⁷, C (S) NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, S (O) ₂R ⁸Or (CO) CHR ²¹NH (CO) R ²²

(ee) R ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

(ff) R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ₄The tetrapyran basic ring that the position connects;

(gg) Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁹Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁹For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl, NR ⁶R ⁷Or (CO) OH; Perhaps R ⁹For replacing maximum twice assorted aromatic nucleus through following group according to circumstances: halogen, cyano group, nitro, hydroxyl or C _1-6Alkoxyl group; Perhaps Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

(hh) R ¹⁰And R ¹¹Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C ^{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), described group all replaces one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹⁰And R ¹¹Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹⁰And R ¹¹Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹⁰And R ¹¹Be combined into O;

(ii) p=0 or 1;

(jj) R ¹²And R ¹³Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), described group all replaces one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl: perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C1-6 alkoxyl group that replaces through maximum 5 fluorine according to circumstances; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹²And R ¹³Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹²And R ¹³Independently of one another for according to circumstances through (CH ₂) _nOR ⁸The C that replaces _1-6Alkyl;

(kk) R ²⁰Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), described group all replaces one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

(ll)n＝1-4；

(mm) V is selected from O, S or NH;

(nn) when V is O or S, W is selected from O, NR ¹⁵Or CR ¹⁵When V was NH, W was selected from NR ¹⁵Or CR ¹⁵, R wherein ¹⁵Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl;

(oo) dotted line is represented optional double bond;

(pp) R ²¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl; Perhaps R ²¹Be C _{6 or 10}Aryl, this aryl replace through maximum 3 following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ²¹Be pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group or sulphur phenoxy group; And

(qq) R ²²Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl.

2. compound according to claim 1, wherein said core ring is

3. compound according to claim 1, wherein said core ring is

4. compound according to claim 1, wherein said core ring is

5. compound according to claim 1, it has formula Ia:

6. compound according to claim 1, it has formula Ib:

7. compound according to claim 1, it has formula Ic:

8. compound according to claim 1, it has formula Id:

9. compound according to claim 1, it has formula Ie:

10. compound according to claim 1, it has formula If:

11. compound according to claim 1, it has formula Ig:

12. compound according to claim 1, it has formula Ih:

13. according to the described compound of claim l, it has formula Ii:

14. according to the described compound of claim l, it has formula Ij:

15. compound according to claim 1, it has formula Iz:

16. compound according to claim 1, wherein Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be selected from by C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl and NR ^1aR ^1bThe group that forms, wherein R ^1aAnd R ^1bBe H, C independently of one another _1-6Alkyl or C _3-7Cycloalkyl.

17. compound according to claim 2, wherein Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be selected from by C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl and NR ^1aR ^1bThe group that forms, wherein R ^1aAnd R ^1bBe H, C independently of one another _1-6Alkyl or C _3-7Cycloalkyl.

18. compound according to claim 3, wherein Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be selected from by C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl and NR ^1aR ^1bThe group that forms, wherein R ^1aAnd R ^1bBe H, C independently of one another _1-6Alkyl or C _3-7Cycloalkyl.

19. compound according to claim 4, wherein Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be selected from by C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl and NR ^1aR ^1bThe group that forms, wherein R ^1aAnd R ^1bBe H, C independently of one another _1-6Alkyl or C _3-7Cycloalkyl.

20. compound according to claim 1, wherein the two keys of C13-C14 are cis.

21. compound according to claim 1, wherein the two keys of C13-C14 are trans.

22. a medical composition, it comprises:

A) compound according to claim 1; And

B) pharmaceutically acceptable supporting agent.

23. medical composition according to claim 22, it is not for containing the preparation of any pure and mild any polyvalent alcohol.

24. medical composition according to claim 23, wherein said preparation do not contain any sugar alcohol and any polyoxyethylene glycol (PEG).

25. medical composition according to claim 22, it is not for containing the aqueous formulation of the semipolar vehicle of any reduction aqueous formulation.

26. medical composition according to claim 22, it is a tablet formulation.

27. medical composition according to claim 22, it is the capsule tablet preparation.

28. medical composition according to claim 22, it is a capsule preparations.

29. a method for the treatment of infection with hepatitis C virus in the individuality, described method comprise to the come into operation described compound of claim 1 of significant quantity of described individuality.

30. method according to claim 29 realizes that wherein continuing virus replys.

31. method according to claim 29, wherein said method comprise in addition to the come into operation nucleoside analog of significant quantity of described individuality.

32. method according to claim 31, wherein said nucleoside analog are selected from ribavirin (ribavirin), Levovirin (levovirin), Wella rice fixed (viramidine), L-nucleosides and isatoribine (isatoribine).

33. method according to claim 29, wherein said method comprise in addition to the come into operation NS5B RNA RNA-dependent AG14361 of significant quantity of described individuality.

34. method according to claim 29, wherein said method comprise in addition to the come into operation thymosin-α of significant quantity of described individuality.

35. method according to claim 34, wherein said thymosin-α is to the amount of about 1.6mg twice subcutaneous administration weekly with about 1.0mg.

36. method according to claim 29, wherein said method comprise in addition to the come into operation interferon-(IFN-γ) of significant quantity of described individuality.

37. method according to claim 36, wherein said IFN-γ is with the amount subcutaneous administration of about 10 μ g to about 300 μ g.

38. method according to claim 29, wherein said method comprise in addition to the come into operation interferon-' alpha ' (IFN-α) of significant quantity of described individuality.

39. according to the described method of claim 38, wherein said IFN-α is with the per 8 days compound IFN-α of single Pegylation (30kD, linearity) to per 14 days dosing interval dispensing.

40. according to the described method of claim 38, wherein said IFN-α is the compound IFN-α of single Pegylation (30kD, linearity) with dosing interval dispensing once in per 7 days.

41. according to the described method of claim 38, wherein said IFN-α is the compound IFN-α of INFERGEN.

42. method according to claim 29, described method comprises the reagent that is selected from following group of the significant quantity that comes into operation in addition: 3 '-azidothymidine (3 '-azidothymidine), 2 ', 3 '-the dideoxy inosine (2 ', 3 '-dideoxyinosine), 2 ', 3 '-the dideoxy cytidine(C (2 ', 3 '-dideoxycytidine), 2-, 3-two dehydrogenations-2 ', 3 '-dideoxy thymidine (2-, 3-didehydro-2 ', 3 '-dideoxythymidine), Combivir (combivir), Abacavir (abacavir), adefovir ester (adefovir dipoxil), cidofovir (cidofovir) and inosine monophosphate dehydrogenase (inosine monophosphate dehydrogenase) inhibitor.

43. a method for the treatment of hepatic fibrosis in the individuality, described method comprise to the come into operation described compound of claim 1 of significant quantity of described individuality.

44. according to the described method of claim 43, wherein said method comprises in addition to the come into operation nucleoside analog of significant quantity of described individuality.

45. according to the described method of claim 44, wherein said nucleoside analog is selected from that ribavirin, Levovirin, Wella rice are fixed, L-nucleosides and isatoribine.

46. according to the described method of claim 43, wherein said method comprises in addition to the come into operation NS5B RNA RNA-dependent AG14361 of significant quantity of described individuality.

47. according to the described method of claim 43, wherein said method comprises in addition to the come into operation thymosin-α of significant quantity of described individuality.

48. according to the described method of claim 47, wherein said thymosin-α is to the amount of about 1.6mg twice subcutaneous administration weekly with about 1.0mg.

49. according to the described method of claim 43, wherein said method comprises in addition to the come into operation interferon-(IFN-γ) of significant quantity of described individuality.

50. according to the described method of claim 49, wherein said IFN-γ is with the amount subcutaneous administration of about 10 μ g to about 300 μ g.

51. according to the described method of claim 43, wherein said method comprises in addition to the come into operation interferon-' alpha ' (IFN-α) of significant quantity of described individuality.

52. according to the described method of claim 51, wherein said IFN-α is with the per 8 days compound IFN-α of single Pegylation (30kD, linearity) to per 14 days dosing interval dispensing.

53. according to the described method of claim 51, wherein said IFN-α is the compound IFN-α of single Pegylation (30kD, linearity) with dosing interval dispensing once in per 7 days.

54. according to the described method of claim 51, wherein said IFN-α is the compound IFN-α of INFERGEN.

55. according to the described method of claim 43, described method comprises the reagent that is selected from following group of the significant quantity that comes into operation in addition: 3 '-azidothymidine, 2 ', 3 '-dideoxy inosine, 2 ', 3 '-dideoxy cytidine(C, 2-, 3-two dehydrogenations-2 ', 3 '-dideoxy thymidine, Combivir, Abacavir, adefovir ester, cidofovir and inosine monophosphate dehydrogenase inhibitor.

56. an enhancing has the method for the liver function in the individuality of infection with hepatitis C virus, described method comprises to the come into operation described compound of claim 1 of significant quantity of described individuality.

57. according to the described method of claim 56, wherein said method comprises in addition to the come into operation nucleoside analog of significant quantity of described individuality.

58. according to the described method of claim 57, wherein said nucleoside analog is selected from that ribavirin, Levovirin, Wella rice are fixed, L-nucleosides and isatoribine.

59. according to the described method of claim 56, wherein said method comprises in addition to the come into operation NS5B RNA RNA-dependent AG14361 of significant quantity of described individuality.

60. according to the described method of claim 56, wherein said method comprises in addition to the come into operation thymosin-α of significant quantity of described individuality.

61. according to the described method of claim 60, wherein said thymosin-α is to the amount of about 1.6mg twice subcutaneous administration weekly with about 1.0mg.

62. according to the described method of claim 56, wherein said method comprises in addition to the come into operation interferon-(IFN-γ) of significant quantity of described individuality.

63. according to the described method of claim 62, wherein said IFN-γ is with the amount subcutaneous administration of about 10 μ g to about 300 μ g.

64. according to the described method of claim 56, wherein said method comprises in addition to the come into operation interferon-' alpha ' (IFN-α) of significant quantity of described individuality.

65. according to the described method of claim 64, wherein said IFN-α is with the per 8 days compound IFN-α of single Pegylation (30kD, linearity) to per 14 days dosing interval dispensing.

66. according to the described method of claim 64, wherein said IFN-α is the compound IFN-α of single Pegylation (30kD, linearity) with dosing interval dispensing once in per 7 days.

67. according to the described method of claim 64, wherein said IFN-α is the compound IFN-α of INFERGEN.

68. according to the described method of claim 56, described method comprises the reagent that is selected from following group of the significant quantity that comes into operation in addition: 3 '-azidothymidine, 2 ', 3 '-dideoxy inosine, 2 ', 3 '-dideoxy cytidine(C, 2-, 3-two dehydrogenations-2 ', 3 '-dideoxy thymidine, Combivir, Abacavir, adefovir ester, cidofovir and inosine monophosphate dehydrogenase inhibitor.

69. compound with formula XI:

Wherein:

(a) R ^1aAnd R ^1bBe H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, C _1-6Alkoxyl group, amide group or phenyl,

Perhaps, R ^1aAnd R ^1bBe H and C independently of one another _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

Perhaps, R ^1aAnd R ^1bBe H or heterocycle independently of one another, this heterocycle is 5,6 or 7 yuan of saturated or unsaturated heterocycle shape molecules, and contains one to four heteroatoms that is selected from the group that is made up of nitrogen, oxygen and sulphur,

Wherein, R ^1cBe H, halogen, C _1-6Alkyl, C _3-6Cycloalkyl, C _1-6Alkoxyl group, C _3-6Cycloalkyloxy, NO ₂, N (R ^1d) ₂, NH (CO) R ^1dOr NH (CO) NHR ^1d, each R wherein ^1dBe H, C independently _1-6Alkyl or C _3-6Cycloalkyl;

(b) W is O or NH;

(c) V is selected from O, S or NH;

(d) when V is O or S, W is selected from O, NR ¹⁵Or CR ₁₅When V was NH, W was selected from NR ¹⁵Or CR ¹⁵, R wherein ¹⁵Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl;

(e) Q is the dicyclo secondary amine with following structure:

R wherein ²¹And R ²²Be H, halogen, cyano group, nitro, hydroxyl, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group, C _{6 or 10}Aryl, pyridyl, pyrimidyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group, sulphur phenoxy group, S (O) ₂NR ⁶R ⁷, NHC (O) NR ⁶R ⁷, NHC (S) NR ⁶R ⁷, C (O) NR ⁶R ⁷, NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸, NHC (O) R ⁸, NHC (O) OR ⁸, SO _mR ⁸(m=0,1 or 2) or NHS (O) ₂R ⁸Described at R ²¹And R ²²Definition in thienyl, pyrimidyl, furyl, thiazolyl and oxazolyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ²¹And R ²²Definition in C _{6 or 10}Aryl, pyridyl, phenoxy group and sulphur phenoxy group replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R wherein ¹⁰And R ¹¹Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷Or (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), described group all replaces one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ₁₃Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹⁰And R ¹¹Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹⁰And R ¹¹Be combined into O;

P=0 or 1 wherein;

R wherein ¹²And R ¹³Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), described group all replaces one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in _{C6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹²And R ¹³Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected;

R wherein ²⁰Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷Or (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), wherein said group all replaces one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

N=0-4 wherein;

Perhaps R when W=NH and V=O ²Be R ²AR ^2b, wherein

R ^2aBe C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, described group replace through maximum three following each groups separately according to circumstances: NR ^2cR ^2d, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ^2bBe H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, described group replaces through maximum three following each groups separately according to circumstances: NR ^2cR ^2d, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

(f) R ⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

(g) R ⁵Be H, C _1-6Alkyl, C (O) NR ⁶R ⁷, C (S) NR ⁶R ⁷, C (O) R ⁸, C (O) OR ⁸Or S (O) ₂R ⁸

(h) R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; And

(i) dotted line is represented optional double bond.

70. according to the described compound of claim 69, it has formula XII:

Wherein:

(b) R ²¹And R ²²Be H, halogen, cyano group, hydroxyl, C independently of one another _1-3Alkyl or C _1-3Alkoxyl group;

(c) R ⁵Be H, C (O) NR ⁶R ⁷, C (O) R ⁸Or C (O) OR ⁸

(d) R ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl;

(e) R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or 3-tetrahydrofuran base;

(f) R ¹⁰And R ¹¹Be H, halogen, C independently of one another _1-3Alkyl, perhaps R ¹⁰And R ¹¹Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected;

(g) R ¹²And R ¹³Be H, halogen, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl or the C that replaces through maximum 5 halogen atoms according to circumstances _1-6Alkyl; And

(h) dotted line is represented optional double bond.

71. according to the described compound of claim 69, it has formula XIII:

Wherein:

Perhaps, NR ^1aR ^1bBe three to hexa-atomic alkyl cyclic secondary amine, it contains one to three heteroatoms of incorporating in the ring according to circumstances, and replaces one to three time through following group according to circumstances: halogen, cyano group, nitro, C _1-6Alkoxyl group, amide group or phenyl;

(c) R ⁵Be H, C (O) NR ⁶R ⁷, C (O) R ⁸Or C (O) OR ⁸

(e) R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or 3-tetrahydrofuran base; And

(f) dotted line is represented optional double bond.

72. according to the described compound of claim 69, it has formula XIV:

Wherein:

(b) Q is according to circumstances through maximum three C that following each group replaces ₆Or C ₁₀Aryl: NR ^2cR ^2d, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

(c) R ⁵Be H, C (O) NR ⁶R ⁷, C (O) R ⁸Or C (O) OR ⁸

(f) dotted line is represented optional double bond.

73. according to the described compound of claim 69, it has formula XV:

Wherein:

(a) R ¹And R ²Be H, halogen, cyano group, hydroxyl, C independently of one another _1-3Alkyl or C _1-3Alkoxyl group;

(b) R ⁵Be H, C (O) OR ⁸Or C (O) NHR ⁸

(c) R ⁸Be C _1-6Alkyl, C _5-6Cycloalkyl or 3-tetrahydrofuran base;

(d) R ⁹Be C _1-3Alkyl, C _3-5Cycloalkyl or phenyl, described phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-3Alkyl or C _1-3Alkoxyl group;

(e) R ¹⁰And R ¹¹Be H, C independently of one another _1-3Alkyl or C _4-5Cycloalkyl;

(f) W is selected from O or NH; And

(g) dotted line is represented optional double bond.

74. according to the described compound of claim 69, it has formula XVI:

Wherein:

(a) R ¹And R ²Be H, chlorine, fluorine, cyano group, hydroxyl, C independently of one another _1-3Alkyl or C _1-3Alkoxyl group;

(b) R ⁵Be H, C (O) OR ⁸Or C (O) NHR ⁸

(c) R ⁸Be C _1-6Alkyl or C _5-6Cycloalkyl;

(d) R ⁹Be C _1-3Alkyl, C _3-4Cycloalkyl or phenyl, described phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-3Alkyl, C _1-3Alkoxyl group;

(e) R ¹⁰And R ¹¹Be H, C independently of one another _1-3Alkyl, perhaps R ¹⁰And R ¹¹Form cyclopropyl or cyclobutyl with the carbon that it connected; And

(f) dotted line is represented optional double bond.

75. according to the described compound of claim 69, it has formula XVII:

Wherein:

(b) R ⁵Be H, C (O) OR ⁸Or C (O) NHR ⁸

(c) R ⁸Be C _1-6Alkyl or C _5-6Cycloalkyl;

(d) R ⁹Be C _1-3Alkyl, C _3-4Cycloalkyl or phenyl, described phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-3Alkyl or C _1-3Alkoxyl group; And

(e) dotted line is represented optional double bond.

76. a medical composition, it comprises:

A) according to the described compound of claim 69, and

B) pharmaceutically acceptable supporting agent.

77. according to the described medical composition of claim 76, it is not for containing the preparation of any pure and mild any polyvalent alcohol.

78. according to the described medical composition of claim 77, wherein said preparation does not contain any sugar alcohol and any polyoxyethylene glycol (PEG).

79. according to the described medical composition of claim 76, it is not for containing the aqueous formulation of the semipolar vehicle of any reduction aqueous formulation.

80. according to the described medical composition of claim 76, it is a tablet formulation.

81. according to the described medical composition of claim 76, it is the capsule tablet preparation.

82. according to the described medical composition of claim 76, it is a capsule preparations.

83. a method for the treatment of infection with hepatitis C virus in the individuality, described method comprise to the come into operation described compound of claim 69 of significant quantity of described individuality.

84. 3 described methods realize that wherein continuing virus replys according to Claim 8.

85. 3 described methods according to Claim 8, wherein said method comprise in addition to the come into operation nucleoside analog of significant quantity of described individuality.

86. 5 described methods according to Claim 8, wherein said nucleoside analog are selected from, and ribavirin, Levovirin, Wella rice are fixed, L-nucleosides and isatoribine.

87. 3 described methods according to Claim 8, wherein said method comprise in addition to the come into operation NS5B RNA RNA-dependent AG14361 of significant quantity of described individuality.

88. 3 described methods according to Claim 8, wherein said method comprise in addition to the come into operation thymosin-α of significant quantity of described individuality.

89. 8 described methods according to Claim 8, wherein said thymosin-α is to the amount of about 1.6mg twice subcutaneous administration weekly with about 1.0mg.

90. 3 described methods according to Claim 8, wherein said method comprise in addition to the come into operation interferon-(IFN-γ) of significant quantity of described individuality.

91. according to the described method of claim 90, wherein said IFN-γ is with the amount subcutaneous administration of about 10 μ g to about 300 μ g.

92. 3 described methods according to Claim 8, wherein said method comprise in addition to the come into operation interferon-' alpha ' (IFN-α) of significant quantity of described individuality.

93. according to the described method of claim 92, wherein said IFN-α is with the per 8 days compound IFN-α of single Pegylation (30kD, linearity) to per 14 days dosing interval dispensing.

94. according to the described method of claim 92, wherein said IFN-α is the compound IFN-α of single Pegylation (30kD, linearity) with dosing interval dispensing once in per 7 days.

95. according to the described method of claim 92, wherein said IFN-α is the compound IFN-α of INFERGEN.

96. 3 described methods according to Claim 8, described method comprises the reagent that is selected from following group of the significant quantity that comes into operation in addition: 3 '-azidothymidine, 2 ', 3 '-dideoxy inosine, 2 ', 3 '-dideoxy cytidine(C, 2-, 3-two dehydrogenations-2 ', 3 '-dideoxy thymidine, Combivir, Abacavir, adefovir ester, cidofovir and inosine monophosphate dehydrogenase inhibitor.

97. a method for the treatment of hepatic fibrosis in the individuality, described method comprise to the come into operation described compound of claim 69 of significant quantity of described individuality.

98. according to the described method of claim 97, wherein said method comprises in addition to the come into operation nucleoside analog of significant quantity of described individuality.

99. according to the described method of claim 98, wherein said nucleoside analog is selected from that ribavirin, Levovirin, Wella rice are fixed, L-nucleosides and isatoribine.

100. according to the described method of claim 97, wherein said method comprises in addition to the come into operation NS5B RNA RNA-dependent AG14361 of significant quantity of described individuality.

101. according to the described method of claim 97, wherein said method comprises in addition to the come into operation thymosin-α of significant quantity of described individuality.

102. according to the described method of claim 101, wherein said thymosin-α is to the amount of about 1.6mg twice subcutaneous administration weekly with about 1.0mg.

103. according to the described method of claim 97, wherein said method comprises in addition to the come into operation interferon-(IFN-γ) of significant quantity of described individuality.

104. according to the described method of claim 103, wherein said IFN-γ is with the amount subcutaneous administration of about 10 μ g to about 300 μ g.

105. according to the described method of claim 97, wherein said method comprises in addition to the come into operation interferon-' alpha ' (IFN-α) of significant quantity of described individuality.

106. according to the described method of claim 105, wherein said IFN-α is with the per 8 days compound IFN-α of single Pegylation (30kD, linearity) to per 14 days dosing interval dispensing.

107. according to the described method of claim 105, wherein said IFN-α is the compound IFN-α of single Pegylation (30kD, linearity) with dosing interval dispensing once in per 7 days.

108. according to the described method of claim 105, wherein said IFN-α is the compound IFN-α of INFERGEN.

109. according to the described method of claim 97, described method comprises the reagent that is selected from following group of the significant quantity that comes into operation in addition: 3 '-azidothymidine, 2 ', 3 '-dideoxy inosine, 2 ', 3 '-dideoxy cytidine(C, 2-, 3-two dehydrogenations-2 ', 3 '-dideoxy thymidine, Combivir, Abacavir, adefovir ester, cidofovir and inosine monophosphate dehydrogenase inhibitor.

110. an enhancing has the method for the liver function in the individuality of infection with hepatitis C virus, described method comprises to the come into operation described compound of claim 69 of significant quantity of described individuality.

111. according to the described method of claim 110, wherein said method comprises in addition to the come into operation nucleoside analog of significant quantity of described individuality.

112. according to the described method of claim 111, wherein said nucleoside analog is selected from that ribavirin, Levovirin, Wella rice are fixed, L-nucleosides and isatoribine.

113. according to the described method of claim 110, wherein said method comprises in addition to the come into operation NS5B RNA RNA-dependent AG14361 of significant quantity of described individuality.

114. according to the described method of claim 110, wherein said method comprises in addition to the come into operation thymosin-α of significant quantity of described individuality.

115. according to the described method of claim 114, wherein said thymosin-α is to the amount of about 1.6mg twice subcutaneous administration weekly with about 1.0mg.

116. according to the described method of claim 110, wherein said method comprises in addition to the come into operation interferon-(IFN-γ) of significant quantity of described individuality.

117. according to the described method of claim 116, wherein said IFN-γ is with the amount subcutaneous administration of about 10 μ g to about 300 μ g.

118. according to the described method of claim 110, wherein said method comprises in addition to the come into operation interferon-' alpha ' (IFN-α) of significant quantity of described individuality.

119. according to the described method of claim 118, wherein said IFN-α is with the per 8 days compound IFN-α of single Pegylation (30kD, linearity) to per 14 days dosing interval dispensing.

120. according to the described method of claim 118, wherein said IFN-α is the compound IFN-α of single Pegylation (30kD, linearity) with dosing interval dispensing once in per 7 days.

121. according to the described method of claim 118, wherein said IFN-α is the compound IFN-α of INFERGEN.

122. according to the described method of claim 110, described method comprises the reagent that is selected from following group of the significant quantity that comes into operation in addition: 3 '-azidothymidine, 2 ', 3 '-dideoxy inosine, 2 ', 3 ' dideoxy cytidine(C, 2-, 3-two dehydrogenations-2 ', 3 '-dideoxy thymidine, Combivir, Abacavir, adefovir ester, cidofovir and inosine monophosphate dehydrogenase inhibitor.

123. compound with formula XVIII:

Wherein:

(a) R ¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, described group replace through maximum three following each groups separately according to circumstances: NR ⁵R ⁶, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

(b) R ²Be H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, described group replaces through maximum three following each groups separately according to circumstances: NR ⁵R ⁶, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

(c) R ³Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

(d) R ⁴Be C _1-6Alkyl, C (O) NR ⁵R ⁶, C (S) NR ⁵R ⁶, C (O) R ⁷, C (O) OR ⁷Or S (O) ₂R ⁷

(e) R ⁵And R ⁶Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁵And R ⁶Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

(f) R ⁷Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁷Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

(g) R ⁸Be C _1-3Alkyl, C _3-4Cycloalkyl or phenyl, described phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-3Alkyl or C _1-3Alkoxyl group; And

(h) dotted line is represented optional double bond;

Or its pharmaceutically acceptable salt.

124. according to the described compound of claim 123, wherein

R ¹Be phenyl, benzothiazole, thionaphthene, cumarone or benzoglyoxaline, described group replaces through maximum 1-2 following each group separately according to circumstances: NR ⁵R ⁶, halogen, cyano group, nitro, hydroxyl, C _1-2Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ²Be H, phenyl, pyridine, pyrimidine, thiazole, oxazole, isoxzzole or pyrazoles, described group replaces through maximum 1-2 following each group separately according to circumstances: NR ⁵R ⁶, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ³Be H;

R ⁴Be C _1-6Alkyl, C (O) NR ⁵R ⁶, C (S) NR ⁵R ⁶, C (O) R ⁷, C (O) OR ⁷Or S (O) ₂R ⁷

R ⁵And R ⁶Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁵And R ⁶Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected;

R ⁷Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁷Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ⁸Be C _1-3Alkyl, C _3-4Cycloalkyl or phenyl, described phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-3Alkyl or C _1-3Alkoxyl group; And dotted line is represented optional double bond.

125. according to the described compound of claim 123, wherein

R ¹Be phenyl, benzothiazole or thionaphthene, described group is separately according to circumstances through 1-2 following each group replacement at most: halogen, hydroxyl, C _1-2Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ²Be H or phenyl, described phenyl is according to circumstances through 1-2 following each group replacement at most: halogen, hydroxyl, C _1-3Alkyl, alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-3Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ³Be H;

R ⁴Be C _1-6Alkyl, C (O) NR ⁵R ⁶, C (O) R ⁷Or C (O) OR ⁷

R ⁵Be H, and R ⁶Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

R ⁷Be C _1-6Alkyl or C _3-7Cycloalkyl, described group all replace one to three time through halogen or phenyl according to circumstances; Perhaps R ⁷Be C _{6 or 10}Aryl, this aryl replace through maximum following each group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

126. a medical composition, it comprises:

A) according to the described compound of claim 123, and

B) pharmaceutically acceptable supporting agent.

127. according to the described medical composition of claim 126, it is not for containing the preparation of any pure and mild any polyvalent alcohol.

128. according to the described medical composition of claim 127, wherein said preparation does not contain any sugar alcohol and any polyoxyethylene glycol (PEG).

129. according to the described medical composition of claim 126, it is not for containing the aqueous formulation of the semipolar vehicle of any reduction aqueous formulation.

130. according to the described medical composition of claim 126, it is a tablet formulation.

131. according to the described medical composition of claim 126, it is the capsule tablet preparation.

132. according to the described medical composition of claim 126, it is a capsule preparations.

133. a method for the treatment of infection with hepatitis C virus in the individuality, described method comprise to the come into operation described compound of claim 123 of significant quantity of described individuality.

134., realize that wherein continuing virus replys according to the described method of claim 133.

135. according to the described method of claim 133, wherein said method comprises in addition to the come into operation nucleoside analog of significant quantity of described individuality.

136. according to the described method of claim 135, wherein said nucleoside analog is selected from that ribavirin, Levovirin, Wella rice are fixed, L-nucleosides and isatoribine.

137. according to the described method of claim 133, wherein said method comprises in addition to the come into operation NS5B RNA RNA-dependent AG14361 of significant quantity of described individuality.

138. according to the described method of claim 133, wherein said method comprises in addition to the come into operation thymosin-α of significant quantity of described individuality.

139. according to the described method of claim 138, wherein said thymosin-α is to the amount of about 1.6mg twice subcutaneous administration weekly with about 1.0mg.

140. according to the described method of claim 133, wherein said method comprises in addition to the come into operation interferon-(IFN-γ) of significant quantity of described individuality.

141. according to the described method of claim 140, wherein said IFN-γ is with the amount subcutaneous administration of about 10 μ g to about 300 μ g.

142. according to the described method of claim 133, wherein said method comprises in addition to the come into operation interferon-' alpha ' (IFN-α) of significant quantity of described individuality.

143. according to the described method of claim 142, wherein said IFN-α is with the per 8 days compound IFN-α of single Pegylation (30kD, linearity) to per 14 days dosing interval dispensing.

144. according to the described method of claim 142, wherein said IFN-α is the compound IFN-α of single Pegylation (30kD, linearity) with dosing interval dispensing once in per 7 days.

145. according to the described method of claim 142, wherein said IFN-α is the compound IFN-α of INFERGEN.

146. according to the described method of claim 133, described method comprises the reagent that is selected from following group of the significant quantity that comes into operation in addition: 3 '-azidothymidine, 2 ', 3 '-dideoxy inosine, 2 ', 3 '-dideoxy cytidine(C, 2-, 3-two dehydrogenations-2 ', 3 '-dideoxy thymidine, Combivir, Abacavir, adefovir ester, cidofovir and inosine monophosphate dehydrogenase inhibitor.

147. a method for the treatment of hepatic fibrosis in the individuality, described method comprise to the come into operation described compound of claim 123 of significant quantity of described individuality.

148. according to the described method of claim 147, wherein said method comprises in addition to the come into operation nucleoside analog of significant quantity of described individuality.

149. according to the described method of claim 148, wherein said nucleoside analog is selected from that ribavirin, Levovirin, Wella rice are fixed, L-nucleosides and isatoribine.

150. according to the described method of claim 147, wherein said method comprises in addition to the come into operation NS5B RNA RNA-dependent AG14361 of significant quantity of described individuality.

151. according to the described method of claim 147, wherein said method comprises in addition to the come into operation thymosin-α of significant quantity of described individuality.

152. according to the described method of claim 151, wherein said thymosin-α is to the amount of about 1.6mg twice subcutaneous administration weekly with about 1.0mg.

153. according to the described method of claim 147, wherein said method comprises in addition to the come into operation interferon-(IFN-γ) of significant quantity of described individuality.

154. according to the described method of claim 153, wherein said IFN-γ is with the amount subcutaneous administration of about 10 μ g to about 300 μ g.

155. according to the described method of claim 147, wherein said method comprises in addition to the come into operation interferon-' alpha ' (IFN-α) of significant quantity of described individuality.

156. according to the described method of claim 155, wherein said IFN-α is with the per 8 days compound IFN-α of single Pegylation (30kD, linearity) to per 14 days dosing interval dispensing.

157. according to the described method of claim 155, wherein said IFN-α is the compound IFN-α of single Pegylation (30kD, linearity) with dosing interval dispensing once in per 7 days.

158. according to the described method of claim 155, wherein said IFN-α is the compound IFN-α of INFERGEN.

159. according to the described method of claim 147, described method comprises the reagent that is selected from following group of the significant quantity that comes into operation in addition: 3 '-azidothymidine, 2 ', 3 '-dideoxy inosine, 2 ', 3 '-dideoxy cytidine(C, 2-, 3-two dehydrogenations-2 ', 3 '-dideoxy thymidine, Combivir, Abacavir, adefovir ester, cidofovir and inosine monophosphate dehydrogenase inhibitor.

160. an enhancing has the method for the liver function in the individuality of infection with hepatitis C virus, described method comprises to the come into operation described compound of claim 123 of significant quantity of described individuality.

161. according to the described method of claim 160, wherein said method comprises in addition to the come into operation nucleoside analog of significant quantity of described individuality.

162. according to the described method of claim 161, wherein said nucleoside analog is selected from that ribavirin, Levovirin, Wella rice are fixed, L-nucleosides and isatoribine.

163. according to the described method of claim 160, wherein said method comprises in addition to the come into operation NS5B RNA RNA-dependent AG14361 of significant quantity of described individuality.

164. according to the described method of claim 160, wherein said method comprises in addition to the come into operation thymosin-α of significant quantity of described individuality.

165. according to the described method of claim 164, wherein said thymosin-α is to the amount of about 1.6mg twice subcutaneous administration weekly with about 1.0mg.

166. according to the described method of claim 160, wherein said method comprises in addition to the come into operation interferon-(IFN-γ) of significant quantity of described individuality.

167. according to the described method of claim 166, wherein said IFN-γ is with the amount subcutaneous administration of about 10 μ g to about 300 μ g.

168. according to the described method of claim 160, wherein said method comprises in addition to the come into operation interferon-' alpha ' (IFN-α) of significant quantity of described individuality.

169. according to the described method of claim 168, wherein said IFN-α is with the per 8 days compound IFN-α of single Pegylation (30kD, linearity) to per 14 days dosing interval dispensing.

170. according to the described method of claim 169, wherein said IFN-α is the compound IFN-α of single Pegylation (30kD, linearity) with dosing interval dispensing once in per 7 days.

171. according to the described method of claim 169, wherein said IFN-α is the compound IFN-α of INFERGEN.

172. according to the described method of claim 160, described method comprises the reagent that is selected from following group of the significant quantity that comes into operation in addition: 3 '-azidothymidine, 2 ', 3 '-dideoxy inosine, 2 ', 3 '-dideoxy cytidine(C, 2-, 3-two dehydrogenations-2 ', 3 '-dideoxy thymidine, Combivir, Abacavir, adefovir ester, cidofovir and inosine monophosphate dehydrogenase inhibitor.

173. compound with following formula:

Wherein:

(a) Z sets the group that is connected and is connected with NS3 proteolytic enzyme Gly137 nitrogen-atoms hydrogen bond with NS3 proteolytic enzyme His57 imidazoles part hydrogen bond for;

(b) P ₁' for setting the group that forms with at least one NS3 proteolytic enzyme S1 ' bag (pocket) apolar interaction partly for, described part is selected from the group that is made up of Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42 and Phe43;

(c) linking group formed for the atom that selects the group that free carbon, oxygen, nitrogen, hydrogen and sulphur forms by 1 to 5 of L;

(d) P2 is selected from the group that is made up of following each group: the aryl that is unsubstituted, the aryl that is substituted, the heteroaryl that is unsubstituted, the heteroaryl that is substituted, the heterocyclic radical that is unsubstituted and the heterocyclic radical that is substituted; To form and at least one NS3 proteolytic enzyme S2 bag apolar interaction partly, described part is selected from the group that is made up of His57, Arg155, Va178, Asp79, Gln80 and Asp81 to P2 by the L location;

(e) dotted line is represented optional double bond;

(f) R ⁵Be selected from NR by H, C (O) ⁶R ⁷And C (O) OR ⁸The group that forms;

(g) R ⁶And R ⁷Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl or phenyl, described phenyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁶And R ⁷Form indoline base, pyrrolidyl, piperidyl, piperazinyl or morpholinyl with the nitrogen that it connected; And

(h) R ⁸Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ⁸Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ⁸For according to circumstances through the C of maximum 5 fluorine-based replacements _1-6Alkyl; Perhaps R ⁸Be C via the tetrahydrofuran (THF) ring ₃Or C ₄The tetrahydrofuran (THF) ring that the position connects; Perhaps R ⁸Be C via the tetrapyran basic ring ⁴The tetrapyran basic ring that the position connects;

Restricted condition is: described compound does not comprise the compound with formula II, III or IV:

Wherein:

(bb) m=0,1 or 2;

(hh) R ¹⁰And R ¹¹Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), described group all replaces one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹⁰And R ¹¹Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹⁰And R ¹¹Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹⁰And R ¹¹Be combined into O;

(ii) p=0 or 1;

(jj) R ¹²And R ¹³Be H, C independently of one another _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl), described group all replaces one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Perhaps R ¹²And R ¹³Form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon that it connected; Perhaps R ¹²And R ¹³Independently of one another for according to circumstances through (CH ₂) _nOR ⁸The C that replaces _1-6Alkyl;

(kk) R ²⁰Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _{6 or 10}Aryl, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or (CH ₂) _nNR ⁶R ⁷, (CH ₂) _nC (O) OR ¹⁴(R wherein ¹⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl), wherein said group all replaces one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group or phenyl; Perhaps R ¹⁴Be C _{6 or 10}Aryl, this aryl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; Described at R ¹²And R ¹³Definition in C _{6 or 10}Aryl replaces through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

(ll)n＝1-4；

(mm) V is selected from O, S or NH;

(oo) dotted line is represented optional double bond;

174. according to the described compound of claim 173, wherein L is made up of 2 to 5 atoms.

175. according to the described compound of claim 173, wherein L comprise-W-C (=V)-group, wherein V and W are selected from O, S or NH independently of one another.

176. according to the described compound of claim 173, wherein L is selected from the group that is made up of ester, acid amides, carbamate, monothioester and thioamides.

177. according to the described compound of claim 173, wherein P2 is interacted partly to form hydrogen bonding with at least one the NS3 proteolytic enzyme S2 bag that is selected from the group that is made up of His57, Arg155, Va178, Asp79, Gln80 and Asp81 by the L location in addition.

178. according to the described compound of claim 173, wherein the two keys of C13-C14 are cis.

179. according to the described compound of claim 173, wherein the two keys of C13-C14 are trans.

180. according to the described compound of claim 173, wherein P2 is

181. according to the described compound of claim 173, it has following formula:

182. according to the described compound of claim 181, wherein L is made up of 2 to 5 atoms.

183. according to the described compound of claim 181, wherein, L comprises-W-C (=V)-and group, wherein V and W are selected from O, S or NH independently of one another.

184. according to the described compound of claim 181, wherein L is selected from the group that is made up of ester, acid amides, carbamate, monothioester and thioamides.

185. according to the described compound of claim 181, wherein P2 is interacted partly to form hydrogen bonding with at least one the NS3 proteolytic enzyme S2 bag that is selected from the group that is made up of His57, Arg155, Va178, Asp79, Gln80 and Asp81 by the L location in addition.

186. according to the described compound of claim 181, wherein the two keys of C13-C14 are cis.

187. according to the described compound of claim 181, wherein the two keys of C13-C14 are trans.

188. according to the described compound of claim 173, it has following formula:

189. according to the described compound of claim 188, wherein L is made up of 2 to 5 atoms.

190. according to the described compound of claim 188, wherein, L comprises-W-C (=V)-and group, wherein V and W are selected from O, S or NH independently of one another.

191. according to the described compound of claim 188, wherein L is selected from the group that is made up of ester, acid amides, carbamate, monothioester and thioamides.

192. according to the described compound of claim 188, wherein P2 is interacted partly to form hydrogen bonding with at least one the NS3 proteolytic enzyme S2 bag that is selected from the group that is made up of His57, Arg155, Va178, Asp79, Gln80 and Asp81 by the L location in addition.

193. according to the described compound of claim 188, wherein the two keys of C13-C14 are cis.

194. according to the described compound of claim 188, wherein the two keys of C13-C14 are trans.

195. compound with following formula:

Wherein:

Q is the core ring that is selected from and the following:

Perhaps, Q is R ¹-R ², R wherein ¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, described group replace through maximum three following each groups separately according to circumstances: NR ⁶R ⁷, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group; And R ²Be H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, furans, thiophene, thiazole, oxazole, imidazoles, isoxzzole, pyrazoles, isothiazole, naphthyl, quinoline, isoquinoline 99.9, quinoxaline, benzothiazole, thionaphthene, cumarone, indoles or benzoglyoxaline, described group replaces through maximum three following each groups separately according to circumstances: NR ⁶R ⁷, halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group;

Y is COOR ⁹, R wherein ⁹Be C _1-6Alkyl;

P=0 or 1;

V is selected from O, S or NH;

Dotted line is represented optional double bond;

R ²²Be C _1-6Alkyl, C _3-7Cycloalkyl or C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances: halogen, cyano group, nitro, hydroxyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl.

196. according to the described compound of claim 195, it has following formula:

197. compound with following formula:

Wherein:

R ⁴Be H, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, phenyl or benzyl, described phenyl or benzyl replace through maximum three following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group:

Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-3Alkyl, C _3-7Cycloalkyl or phenyl, described phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-3Alkyl, C _3-7Cycloalkyl or C _1-3Alkoxyl group, perhaps Y is a carboxylic acid;

P=0 or 1;

V is selected from OH, SH or NH ₂

Dotted line is represented optional double bond;

R ²¹Be C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, described group all replace one to three time through following group according to circumstances; Halogen, cyano group, nitro, hydroxyl, C _1-6Alkoxyl group, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl, or phenyl; Perhaps R ₂₁Be C _{6 or 10}Aryl, this aryl replace through maximum 3 following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _3-7Cycloalkyl, C _4-10Alkyl-cycloalkyl, C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl-C _1-6Alkyl, the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkyl or the C that replaces through maximum 5 fluorine according to circumstances _1-6Alkoxyl group: perhaps R ²¹Be pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy group or sulphur phenoxy group; And

198. according to the described compound of claim 197, it has following formula:

199. according to the described compound of claim 198, wherein Y is formula-C (O) NHS (O) ₂R ⁹Sulfimide, R wherein ⁹Be C _1-3Alkyl, C _3-7Cycloalkyl or phenyl, described phenyl replace through maximum two following each groups according to circumstances: halogen, cyano group, nitro, hydroxyl, C _1-3Alkyl, C _3-7Cycloalkyl or C _1-3Alkoxyl group, and wherein V is selected from OH and NH ₂

200. compound with following formula:

Wherein:

Q is the core ring that is selected from and the following:

P=0 or 1;

V and W are selected from O, S or NH independently of one another;

Dotted line is represented optional double bond;